Romjoh 6 (1) 2015

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T H I S J O U R N A L I S I N T E R D I S C I P L I N A R Y A N D I S D E D I C A T E D T O A L L S P E C I A L I S T S I N T H E M E D I C A L F I E L D R E L A T E D T O O N C O LO GY A N D H E M A T O LO GY

O n c o l o g y & H e m at o l o g y

R o m a n i a n

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Volume III I Issue 1 I 2015

BDI Indexed:

IBI Factor: 2,66

GIF Factor 2013 - 0,452 GIF Factor 2014 - 0,595

(doxorubicinã lipozomalã)

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O n c o l o g y & H e m at o l o g y Issue 1 I Volume 3 I April 2015 PUBLISHED UNDER THE AUSPICES OF

BDI INDEXED: IBI Factor: 2,66

GIF Factor 2013 - 0,452 GIF Factor 2014 - 0,595

Editor-in-Chief & Managing Editor

Şef Lucrări Dr. Lucia Stănculeanu (Universitatea de Medicină şi Farmacie “Carol Davila”, Bucureşti, România)

Editor-in-Chief Assistants

Dr. Raluca Bunghez, Institutul Oncologic “Prof. Dr. Al. Trestioreanu”, Bucureşti Dr. Bogdan Georgescu, Institutul Oncologic “Prof. Dr. Al. Trestioreanu”, Bucureşti

Senior Editors Medical Oncology Prof. Dr. Florin Bădulescu (Universitatea de Medicină şi Farmacie Craiova, Craiova, România) Şef Lucrări Dr. Simona Mihuţiu (Universitatea de Medicină şi Farmacie Oradea, Oradea, România) Hematology Prof. Dr. Anca Roxana Lupu (Universitatea de Medicină şi Farmacie “Carol Davila”, Bucureşti, România) Paediatric & Oncology Conf. Dr. Monica Dragomir (Universitatea of Medicină şi Farmacie “Carol Davila”, Bucureşti, România) Radiology & Oncology Dr. Ciprian Enachescu (Centre Hospitalier Lyon Sud, Lyon, France) Gynecology & Oncology Conf. Dr. Alexandru Filipescu (Universitatea of Medicină şi Farmacie “Carol Davila”, Bucureşti, România) Dermatology & Oncology Asist. Univ. Dr. Victor Gabriel Clătici (Universitatea of Medicină şi Farmacie “Carol Davila”, Bucureşti, România) ENT & Oncology Prof. Dr. Romeo Călăraşu (Institutul de Fonoaudiologie şi Chirurgie Funcţională ORL “Prof. Dr. D. Hociotă”, Bucureşti, România) Stomatology & Oncology Prof. Dr. Marian Vladimir Constantinescu (Universitatea Titu Maiorescu, Bucureşti, România) Prevention & Screening Asist. Univ. Mircea O. D. Lupusoru (University of Medicine and Pharmacy “Carol Davila”; Director Medical - Spitalul de Psihiatrie Titan “Dr. C-tin Gorgos”)

Romanian Editorial Board

International Editorial Board

Prof. Dr. Oltean Galafteon (Universitatea of Medicină şi Farmacie Târgu Mureș, Târgu Mureș, România) Prof. Dr. Ljubomir Petrov (Universitatea of Medicină şi Farmacie „Iuliu Haţieganu”, Cluj-Napoca, România) Prof. Dr. Ioniță Hortensia (Universitatea of Medicină şi Farmacie “Victor Babeș” , Timișoara, România) Prof. Dr. Cătălina Poiană (Universitatea of Medicină şi Farmacie “Carol Davila”, Bucureşti, România) Conf. Dr. Coriu Daniel (Universitatea of Medicină şi Farmacie “Carol Davila”, Bucureşti, România) Conf. Dr. Adriana Coliță (Universitatea of Medicină şi Farmacie “Carol Davila”, Bucureşti, România) Conf. Dr. Anca Coliţă (Universitatea of Medicină şi Farmacie “Carol Davila”, Bucureşti, România) Conf. Dr. Horia Bumbea (Universitatea of Medicină şi Farmacie “Carol Davila”, București, România) Conf. Dr. Elena Copaciu (Universitatea of Medicină şi Farmacie “Carol Davila”, București, România) Conf. Dr. Gabriel Kacso, (Universitatea of Medicină şi Farmacie „Iuliu Haţieganu”, Cluj-Napoca, România) Șef Lucrări Dr. Laura Mazilu (Facultatea de Medicină, Universitatea Ovidius, Constanţa, România) Șef Lucrări Dr. Coliță Andrei (Universitatea of Medicină şi Farmacie “Carol Davila”, Bucureşti, România) Şef Lucrări Dr. Cristian Silviu Voinea (Universitatea of Medicină şi Farmacie “Carol Davila”, Bucureşti, România) Şef Lucrări Dr. Diana Paun (Universitatea of Medicină şi Farmacie “Carol Davila”, Bucureşti, România) Asist. Univ. Gabriela Elena Lupusoru (University of Medicine and Pharmacy “Carol Davila”) Asist. Univ. Dr. Nicolae Bacalbaşa (University of Medicine and Pharmacy “Carol Davila”) Asist. Univ. Dr. Carsote Mara (Universitatea of Medicină şi Farmacie “Carol Davila”, Bucureşti, România) Asist. univ. dr. Adina Alexandru (Universitatea de Medicina si Farmacie “Carol Davila”, Bucuresti, România) Asist. Univ. Dr. Trandafir Maria Silvia (Universitatea of Medicină şi Farmacie “Carol Davila”, Bucureşti, România) Asist. Univ. Dr. Ioana Soare (Universitatea Titu Maiorescu, Facultatea de Medicină, București, România) Dr. Adrian Udrea (Medisprof, Cluj-Napoca, România) Dr. Eugenia Carmen Lisencu – Institutul Oncologic “Prof.dr. Ion Chiricuţă”, Cluj-Napoca, România Dr. Radu Niculescu (Institutul Clinic Fundeni, Bucureşti, România) Dr. Ana Maria Boeru (Asociaţia Free of Pain, Bucureşti, România) Dr. Virgil Dincă (Asociația Română pentru Studiul Durerii, Bucureşti, România)

Prof. Dr. med. Anca-L. Grosu (Klinik für Strahlenheilkunde, Universität Freiburg, Freiburg, Germany) Prof. Dr. Shibo Li (University of Oklahoma Health Sciences Center, Oklahoma City, USA) Prof. Dr. Mariusz Z. Ratajczak (University of Louisville, Louisville, USA) Prof. Dr. Arnold Ganser (Hannover Medical School, Hanover, Germany) Prof. Dr. Saverio Bettuzzi (University of Parma Via Volturno, Parma, Italy) Prof. Dr. Lodovico Balducci (Moffitt Cancer Center, Tampa, USA) Prof. Dr. Leonard Wartofsky (Georgetown University School of Medicine, Washington, USA) Prof. Dr. Robert Amato (Memorial Hermann Cancer Center, Texas, USA) Prof Dr. Kevin R. Loughlin (Harvard University, Cambridge, USA) Prof. Dr. Maureen Markman (Drexel University College of Medicine, Philadelphia, USA) Prof. Dr. Stephen P. Hunger (University of Colorado School of Medicine, Colorado, USA) Prof. Dr. M.W.M. van den Brekel (Academic Medical Center Amsterdam, Amsterdam, Netherlands) Prof. Dr. M Sitki Copur (University of Nebraska Medical Center, Nebraska, USA) Prof. Dr. Derek Raghavan (UNC School of Medicine, Levine Cancer Institute, Charlotte, NC, USA) Prof. Dr. Richard J. Ablin (University of Arizona, Arizona, USA) Prof. Dr. Florian Strasser (Cantonal Hospital St. Gallen, Switzerland) Prof. Dr. Michel Rigaud (Scientific advisor - IRST, Meldola, Italy) Associate Prof. Dr. Mishu Popa McKiver (Massachusetts General Hospital, Massachusetts, USA) Assistant Prof. Dr. Alina Mihai (Univ Pittsburgh School Medicine, Pittsburgh, USA) Assistant Prof. Dr. Doru Paul (Hofstra North Shore-LIJ School of Medicine, New York, USA) Assistant Prof. Dr. Bruno Vincenzi (University Campus Bio-Medico, Rome, Italy Assistant Prof. Dr. Elizabeta C. Popa (Weill Cornell Medical College, NY, USA) Assistant Prof. Dr. Gabriela Oprea (Emory University, Atlanta, USA) Dr. Wainer Zoli (Director of the Bioscience Laboratory, IRST, Meldola, Italy) Dr. Javier Martín Broto (Son Espases Hospital, Palma de Mallorca Spain) Dr. David Gómez Almaguer (Universidad Autónoma de Nuevo León, Monterrey, México) Dr. Sankalp Yadav (General Duty Medical Officer-II, Chest Clinic Moti Nagar, North Delhi Municipal Corporation, New Delhi, India)

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EDITORIAL

Abordare multidisciplinară în afecţiunile oncologice – un “musthave” pentru managementul pacienţilor oncologici Stanculeanu D.L.

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ORIGINAL ARTICLE

Novelties in Her2 New Positive Breast Cancer Therapy/ Does 2014 Changes Therapeutic Approach In Her 2Newpositive, Estrogen Receptorspositive Breast Cancer?

Stanculeanu D.L., Zob D.

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INTERNATIONAL ARTICLE Oligometastasis: New Paradigm in Practical Oncology.

General Aspects (part I) Enachescu C., Caraivan I., Tita A.

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REVIEWS

Borderline Ovarian Tumors – Literature Review Bacalbasa N., Popoici D., Balescu I.

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The Role Of Pancreatic Cysts Fluid Analysis In Determining Malignant Lesions – Literature Review Bacalbasa N., Gireada A., Balescu I.

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Ovarian tumor revealed by polyserositis with massive pericardial effusion – an atypical Meigs syndrome Boiangiu A., Vladu C., Clim N., Filipescu A.

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Giant ovarian mucinous cyst adenoma at 70 years old – case report Boiangiu A., Vladu C., Clim N., Andrei F., Filipescu A.

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CAIET DE ABSTRACTE Health Meeting: “Actualităţi în oncologie Abordare multidisciplinară în afecţiunile oncologice”

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Editorial

Abordare multidisciplinară în afecţiunile oncologice – un “must-have” pentru managementul pacienţilor oncologici Şef lucr. Dr. Dana Stănculeanu, Redactor-şef Romanian Journal of Oncology & Hematology

Disciplina oncologică cuprinde mai multe ramuri distincte strâns corelate între ele: oncologia medicală (gestionează tratamentul sistemic al cancerului), radioterapia (tratamentul folosind radiaţii ionizante) şi chirurgia oncologică. În cele mai multe cazuri, evoluţia afecţiunilor neoplazice este silenţioasă, existând simptome doar atunci când masa tumorală este extinsă, creând astfel dereglări în funcţionalitatea organelor sau sistemelor în care apare.

Tratamentul cancerelor presupune o abordare extinsă, multidisciplinară, cuprinzând echipe de medici specialişti (în funcţie de localizarea acestora în organism), oncologi, radioterapeuţi, chirurgi, fiecare având un rol bine stabilit în funcţie de tipul cancerului, stadiu şi afecţiunile asociate ale pacientului. Tratamentele adiacente necesare în managementul afecţiunilor neoplazice au drept obiectiv asigurarea confortului pacientului, ameliorarea anumitor simptome sau a unor reacţii adverse cauzate de tratamentele specifice. Printre acestea se numără tratamentul durerii, al infecţiilor din cursul chimioterapiei, controlul simptomelor cauzate de tumorile cerebrale, tratamentul tulburărilor organelor afectate de evoluţia cancerului etc.

Astfel, managementului pacienţilor oncologici trebuie orientat către dezvoltarea de teste diagnostice care să depisteze cancerul în formele cele mai precoce, de tehnici superioare de radioterapie, noi tehnici chirurgicale şi molecule antitumorale.

Pornind de la nevoia specialiştilor de a colabora în echipe multidisciplinare în managementul pacienţilor cu leziuni neoplazice, pe 15 mai 2015, la Hotel Novotel, Bucureşti, personalităţi şi cadre medicale specializate din domeniul oncologiei, ginecologiei, neonatologiei, pediatriei, hematologiei, urologiei, radioterapiei se vor reuni în cadrul Celei de-a III-a Ediţie a manifestării ştiinţifice Health Meeting, cu tema “Abordare multidisciplinară în afecţiunile oncologice”, organizată de Media Systems Communication şi Societatea Română de Ultrasonografie în Obstetrică şi Ginecologie, pentru a dezbate teme precum “Particularităţile de screening şi conduita în cancerul de col uterin la adolescente”, „Tehnici moderne în chirurgia oncologică a sânului”, “Tumorile trofoblastice agresive: diagnostic, conduită”, “Actualităţi în tratamentul cancerului ovarian”, “Recidiva în cancerul mamar: Semnificaţie prognostică şi implicaţii terapeutice”, “Diagnosticul perinatal al neuroblastomului”, “Hemopatiile maligne şi sarcina - de la diagnostic la tratament”, “Particularităţi ale bolilor maligne la adolescent şi adultul tânăr”, “Indicaţiile şi rezultatele transplantului medular în pediatrie”, „Haplotransplantul de celule stem hematopoietice – o alternativă a transplantului alogeneic de la donator neînrudit”, „Posibilităţi şi limite ale radioterapiei externe în cancerele urologice”, “Evidenţe şi recomandări în cancerul de prostată. De la teorie la practică. Caz clinic”, “Mamografia tridimensională, tomosinteza, în diagnosticul şi depistarea cancerului de sân”.

Mai multe detalii despre eveniment, puteţi afla de pe site-ul http://healthmeeting.msc-ro.com/.

Drumul Odăi, Nr. 42, Otopeni, Ilfov Drumul Odăi, Nr. 42, Otopeni, Ilfov Telefon: 021.9368 • 0737.877.889 Telefon: 021.9368 • 0737.877.889 E-mail: office@amethyst-radiotherapy.ro E-mail: office@amethyst-radiotherapy.ro

TOMOSINTEZA - O PROMISIUNE PENTRU VIITOR Timp de decenii, medicii au căutat o tehnologie care să îi ajute în depistarea celor mai mici indicii de cancer sau în eliminarea rezultatelor de tip fals pozitiv şi a reduce numărul femeilor care sunt rechemate pentru efectuarea unei mamografii de diagnostic.

Tomosinteza sânului este o tehnologie nouă în lupta împotriva cancerului de sân care permite medicilor să examineze ţesutul sânului strat cu strat. În timpul examinarii 3D - tomosinteză braţul de raze X se deplasează într-o uşoară curbă peste sân, făcând multiple fotografii ale sânului în doar câteva secunde. Se foloseşte un nivel foarte redus de radiaţii pentru ca expunerea să fie similara cu cea a unei mamografii tradiţionale. După aceea, computerul creează o imagine tridimensională a ţesutului mamar în straturi de 1 milimetru.

Intr- o imagine 2D suprapunerea de tesut poate ascunde structuri si poate duce la erori de diagnostic. Mamografia 3D elimina efectul suprapunerii de tesut.

Acum radiologul poate vizualiza în detaliu ţesutul mamar într-un mod care până acum nu era posibil. În loc să vizualizeze toate complexităţile ţesutului mamar pe o imagine în plan, acum medicul poate analiza ţesutul milimetru cu milimetru.

Cele mai mici detalii sunt mai clar vizibile, nemaifiind ascunse de ţesuturi.

Sistemul de mamografie digitala cu tomosinteza SELENIA DIMENSION 3D de la HOLOGIC a fost disponibil in Europa inca din 2008 de cand a obtinut marca CE. In februarie 2011 SELENIA DIMENSION a fost primul sistem cu tomosinteza care a obtinut aprobarea FDA. Primul sistem cu tomosinteza din tara a fost instalat in septembrie 2012 la Institutul Oncologic Cluj.

Pana acum, in Romania, au fost instalate 5 sisteme de mamografie digitala cu tomosinteza model SELENIA DIMENSION.

Original article

Novelties in Her2 New Positive Breast Cancer Therapy/ Does 2014 Changes Therapeutic Approach In Her 2Newpositive, Estrogen Receptorspositive Breast Cancer?

NOVELTIES IN HER2 NEW POSITIVE BREAST CANCER THERAPY/ DOES 2014 CHANGES THERAPEUTIC APPROACH IN HER 2NEWPOSITIVE, ESTROGEN RECEPTORSPOSITIVE BREAST CANCER? Şef Lucrări Dr. Lucia Stănculeanu1,2 , Dr. Daniela Zob2 1. Universitatea de Medicină şi Farmacie “Carol Davila”, Bucureşti, România 2. Institutul Oncologic “Prof. Dr. Alexandru Trestioreanu” Bucuresti Corresponding author: Dr. Dana Lucia Stanculeanu Email: dlstanculeanu@gmail.com

Open Access Article

Abstract Keywords: breast cancer, novelties, treatment

Received: April 2015 Reviewed: April 2015 Accepted: April 2015 Cite this article: Stanculeanu D.L., Zob D. Novelties in Her2 New Positive Breast Cancer Therapy/ Does 2014 Changes Therapeutic Approach In Her 2Newpositive, Estrogen Receptorspositive Breast Cancer? Rom J Oncol Hematol. 2015; 6(1):14-17

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Breast cancer remains the main cause of morbidity through cancer within the global female population.2014 was marked by the publication of the results of some major studies: CLEOPATRA , EMILIA, ALTTO, which have provoked changes in the guidelines for metastatic HER2+ disease or by the results of SOFT& TEXT studies in positive hormonal receptors breast cancer and POEMS in negative receptors breast cancer, that have determined the shading of the therapeutic attitude. Clinical studies SOFT (Suppression of Ovarian Function Trial ) and TEXT (Tamoxifen and Exemestan Trial) proved that the perspective of the management for EBC ( early breast cancer) ER (estrogen receptors ) positive patients can be changed from the ovarian suppression point of view.

POEMS (Phase III trial of LHRH analog during chemotherapy to reduce ovarian failure in HRnegative EBC:An international intergroup trial of SWOG, IBCSG, ECOG, and CALGB (alliance) showed that LHRH analogue (Goserelin) administered along with chemotherapy, on young patients with negative hormonal receptors prevent the ovarian disfunction and decreases the infertility risk. Two randomized phase III clinical studies looked for verifying this concept through the dual blockade of the HER2new receptor by associating two molecules: Trastuzumab and Lapatinib. Reductively this studies, 2014 ASCO guide put :in the I-st line of treatment on HER2+patients no matter the hormonal receptors status - the treatment with taxans/Trastuzumab/Pertuzumab, in the II- nd line of treatment TDM1, in the III-rd line of

treatment Lapatinib/Capecitabin; Trastuzumab/ Lapatinib; Trastuzumab/chemotherapy; TDM1 if it didn’t get any before and Pertuzumab if it didn’t get any before.

Breast cancer remains the main cause of morbidity through cancer within the global female population. For the HER2+ breast cancer (BC), 2014 was marked by the publication of the results of some major studies: CLEOPATRA, EMILIA, ALTTO, which have provoked changes in the guidelines for metastatic HER2+ disease or by the results of SOFT & TEXT studies in positive hormonal receptors BC and POEMS in negative receptors BC, that have determined the shading of the therapeutic attitude for specific categories of patients.

An other major element comprised the change in the assessment of the clinical studies

Stanculeanu D.L., Zob D.

results, so that the Overall Survival (OS) would represent the quintessenceof the assessment of the clinical trials results in establishing the therapeutic decision.

The 3 major congresses, ASCO, ESMO and SABCS brought major changes in the management of BC treatment.: Hormonal treatment in patients with EBC and positive receptors A major change in the therapeutic attitude and decision addresses the adjuvant hormonal treatment of the ER positive patients. These represent about 75% from the all BC patients.

Two clinical studies SOFT (Suppression of Ovarian Function Trial ) and TEXT (Tamoxifen and Exemestan Trial) though apparently with negative results proved that the perspective of the management for EBC ER positive patients can be changed from the ovarian suppression point of view. Paradoxically, even though from DFS (Disease Free Survival) perspective 2 studies from 2004 and 2014 showed negative results of the LHRH analogue addition to Tamoxifen (Cuzick J et al Lancet 2004; 369-1711 siTevaarwerk A J et al JCO 2014; 32:3948-3958), two other studies show that the addiction of amenorrhea at the Tamoxifen treatment increases the survival and DFS for the same category of women (IBCSG 13-93 , JCO 2006;24:1332-1341, si Swain SM et al., N. Engl. J. Med 2010;363:2268-2270).

The two studies presented at ASCO 2014 by Olivia Pagani, try to solve the ovarian suppression antinomyand to answer to the question if the adjuvant aromatase inhibitors treatment in women at premenopause (specifically Exemestanum) and ovarian suppression improve DFS ( disease free survival ) compared to Tamoxifen and ovarian suppression. The both are phase III multicentric clinical studies that aim to show which is the optimum endocrine adjuvant treatment for the women at premenopause. The two studies randomized 5738 premenopause operated patients at a ≤12 weeks interval from the surgical intervention, only that in Text study the ovarian inhibition was done using Triptorelin every 28 days for 6 months and then optionally bilateral oophorectomyor irradiation, or if the patients had also adjuvant chemotherapy then the ovarian function wasn’t documented at his closurecompared to the patients in SOFT whose ovarian suppression method was at investigator’s choice and the treatment has been done at ≤ 8 months from the chemotherapy with documentation of the ovarian function.

In both studies the recurrence was due to the secondary determinations (soft tissue, bones or internal organs). The mean follow-up period was of 5,7 years. The Kaplan - Meyer curves showed an improvement in an absolute value of 3.8% for

ovarian suppression with Exemestan compared to Tamoxifen and of 2% for DFS. For the first two years there weren’t any differences between the two groups. The differences show up in time so that in the first 5 years the most aggressive tumors begin to proliferate, which would explain the benefit of aromatase inhibitors in the very aggressive tumors no matter the menopausal status. Forest plot analysis shows a minimum benefit for the patients that were chemotherapy treated in TEXT study. Although the difference in absolute value is small (5.2% improvement in TEXT vs 3.7% in SOFT ), the data must be cautiously interpreted due to the fact that in Soft the hormonal treatment is delayed because of the protocol. If from the low risk patients that didn’t required adjuvant chemotherapy perspective there weren’t significant differences from local, distant recurrence or survival point of view, these differences exist for those following adjuvant chemotherapy. Accordingly with the age groups, the patients with the highest recurrence risk that were part of the group below the 35 years of age received chemotherapy in 95 % showed significant differences. Within this subgroup DFS at 5 years was of 67.7% for those treated with Tamoxifen, 78.9% for those treated with Tamoxifen and ovarian suppression and 83.4% for those treated with Exemestan and ovarian suppression. So, if one patient out of three had recurrence in the Tamoxifen group, for the Exemestan group only one out of six showed recurrence.

Related to the layering of the patients in risk groupsit’s important to advise the patient concerning the ovarian suppression possibility but also on the adverse reactions.

An other subgroup was that of the patients age over 40 (1084 patients) who after chemotherapy remained in premenopause. Within this group DFS at 5 years was of 78% for Tamoxifen, 82.5% for Tamoxifen an ovarian suppression and of 85.7% for Exemestan and ovarian suppression, that meant a decrease in the relative risk of the evolution renewal of 22% for Tamoxifen with ovarian suppression vsTamoxifen alone and 35% for Exemestan and ovarian suppression vsTamoxifen alone. Bycontrast was the subgroup of women of median age over 46 that recieved chemotherapy, were at perimenopause and for whom the ovarian suppression brought no benefit and where Tamoxifen alone can be considered sufficient. TEXT study confirms date from SOFT study, The combined analysis of the two studies proved the increase in adverse reactions due to ovarian inhibition and the endocrine treatment as a consequence of the induced menopause (hot flashes, sweating, sexual problems realted to the decrease of April 2015

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Original article

Novelties in Her2 New Positive Breast Cancer Therapy/ Does 2014 Changes Therapeutic Approach In Her 2Newpositive, Estrogen Receptorspositive Breast Cancer?

libido and vaginal dryness or amplifying of the depressive condition). If the ESMO presentation advised for caution and to wait for the final results of the SOFT study,respectively for the Tamoxifen treated subgroup SABCS confirmed through the final results that Tamoxifen with ovarian suppression is more effective than Tamoxifen alone and Exemestan with ovarian suppression is more effective than Tamoxifen and ovarian suppression. With these results transmitted at the end of 2014 there can discussed a new therapeutic standard for women below 35 years and with high reccurence risk for whom the ovarian suppression and the intake of Exemestan increase DFS, but with toxicities that must be known.

Conclusively these results create a dilemma: on one hand changing the clinical approach with the well known risk of adverse reactions or on the other hand waiting for a 10 year long period of following that confirms these results.

An other study that caught attention is POEMS (S-0230) (Phase III trial of LHRH analog during chemotherapy to reduce ovarian failure in HRnegative EBC: An international intergroup trial of SWOG, IBCSG, ECOG, and CALGB (alliance). that showed that LHRH analogue (Goserelin) administered along with chemotherapy, on young patients with negative hormonal receptors prevent the ovarian disfunction and decreases the infertility risk. The prospective analysis using Kaplan Meyer curves proves that the association on adjuvant/ neoadjuvant treatment of the LHRH analogue increases PFS and OS. The only criticism brought on the study is the small number of patients.

Novelties in HER2+ breast cancer treatment HER2 positive breast cancers represent only 20% -25% from the whole breast cancer patients.

HER2new positive breast cancer treatment brought up into discussion the role of the neoadjuvant treatment in complete pathological response and the transposition of this concept into OS increase. Two randomized phase III clinical studies looked for verifying this concept through the dual blockade of the HER2new receptor by associating two molecules: Trastuzumab, a humanisedmonoclonal antibody and a small molecule , tyrosine kinase inhibitor, Lapatinib.

NEOALTTO clinical study in HER2+ locoregional advanced disease neoadjuvanttreatment and ALTTO study in the adjuvant treatment of the same patient category.

If in the neoadjuvant treatment Trastuzumab­ Lapatinib association proves its therapeutic efficacy by increasing the percentage of patients with complete pathological response (pCR), and also of the 3 years event free survival (EFS) and

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overall survival (OS) for a 3 year period, the ALTTO study doesn’t reach its primary endpoint, DFS and OS for a 4 year time follow-up in neither of its arms. The explanation is probably because of the too short follow-up interval and of the small number of recorded events. So, the NEOALTTO investigators report that the dual blockade TrastuzumabLapatinib Paclitaxel produces more pRC compared to the association Trastuzumab Paclitaxel. Though the EFS and OS wasn’t very different in the three patients groups (3 year OS 93% for Lapatinib, 90% for Trastuzumab and 95% for the combination), still this effect was consistent in the pRC and ER negative patients subgroup.

In ALTTO study after a 4.5 year follow-up the total number of events in the study arm was more reduced compared to the one planned (555 vs 850) and the dual combination toxicity was far bigger compared to the other arms.Conclusively there still aren’t any proofs that usage of the Lapatinib - Trastuzumab combination would shift pCR effect in an event free survival benefit or overall survival though the two studies have different populations on one hand and different results on the other hand.

Concerning the HER2 positive metastatic disease treatment two molecules changed the guidelines: Pertuzumab and TrastuzumabEtamsine.

The CLEOPATRA study presented by Sandra Swain at ESMO 2014 shows for the first time for a mean follow-up of 50 months a significant difference in OS of 15.7 months for the patients treated with TrastuzumabPertuzumab , a never met survival in metastatic disease. The patients treated in the first line with the association TrastuzumabPertuzumabDocetaxel had a survival of 56. 5 moths compared to those treated with DocetaxelTrastuzumab of 40.8 months. So, these patients present a decline of the death risk of 32%, for a statistic significant p (p=0.0002). CLEOPATRA study brings proofs regarding the efficacy on the patients that were previously treated with Trastuzumab within the adjuvant treatment but doesn’t bring data about the patients that showed relapse of the evolution on an interval of less than a year. Another question launched by this study is if Docetaxel is the only effective partner of the combination or if the treatment is effective also after disease progression.

The second molecule that produced changes in HER2 metastatic disease guideline is Trastuzumabemtasine (Kadcyla), an antibody conjugated with a drug that releases DM1 right in the HER2 overexpressed cell. Two studies EMILIA and THERESA presented response rates (RR), DFS and OS significant in favor or TDM1 treatment. EMILIA study, a phase III study, that compares the TDM1 molecule with the association LapatinibCapecitabin at patients treated

Stanculeanu D.L., Zob D.

adjuvantly with taxans and Trastuzumab or for the locally advanced or metastatic disease on the documented progression of the disease during the treatment or after treatment for the advanced or metastatic disease or at less than 6 months since the end of Trastuzumab treatment. Main endpoint progression free survival (PFS) defined by the Independent Committee, overall survival (OS) and the treatment safety. The decline of the secondary adverse reactions of all degrees and of these of 3/4 degree for TDM1 administration, the PFS increase from 6.4 to 9.6 months, increase of the response length (DOR) from 6.5 to 12.6 months and of the overall response rate (ORR) from 30.8% to 43.6% confers the treatment the license as a second line therapy. This treatment can be this way an option for the patients progressing under a year from the adjuvant Trastuzumab therapy. THERESA study represents the second study in which the TDM1 treatment proves its efficacy in the third line of treatment on the metastatic disease patients that progressed after two lines of treatment with Trastuzumab, Lapatinib and a taxan, having as main objective progression free survival (PFS) defined by an investigator, overall survival (OS) and secondary objectives overall response rate (ORR) defined by the investigator and treatment safety. The study compares the TDM treatment with physician’s choice treatment till the disease progression.

According to the study PFS doubled for TDM1 reaching a median of 6.2 months compared to 3.3 months for the physician’s choice treatment and the first interim analysis on OS published in Lancet this year was of 14.9 months for the comparator arm and couldn’t be assessed for TDM1 because there weren’t noticed only 21% of the planned events.

Reductively this studies, 2014 ASCO guide put in the Ist line of treatment on HER2+patients no matter the hormonal receptors status - the treatment with taxans/Trastuzumab/Pertuzumab in the IInd line of treatment TDM1 in the IIIrd line of treatment Lapatinib/Capecitabin; Trastuzumab/ Lapatinib; Trastuzumab/chemotherapy; TDM1 if it didn’t get any before and Pertuzumab if it didn’t get any before.

Other molecules with a potential effect in treating HER2new metastatic breast cancer: Neratinib (HKI 272), oral irreversible tyrosine kinase inhibitor, Ramucirumaban antibody that acts on the receptor 2 of VEGF that inhibits angiogenesis or new chemotherapics such as Eribulin.

An old, but recently assessed,element is the immunologic treatment and the new studies showed the role of the stromal lymphocytic infiltrate on patients with HER2 positive breast cancer and the probability that roughly 10% of those who showed stromal lymphocytic infiltrate wouldn’t benefit from the advantage of Trastuzumab treatment.

Conclusively: - SOFT and Text studies change the therapeutic perspective on the hormonal treatment of the under 35 years of age patients’ subgroup.

- Changing the management of HER2 positive patients adjuvant treatment.

- Defining new therapeutic standards for HER2 new metastatic breast cancer that modified all the guidelines.

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References 1. Piccart-Gebhart M, Holmes AP, Baselga J, et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). Presented at: 2014 ASCO Annual Meeting Press Briefing; June 1, 2014; Chicago, IL. Abstract LBA4.

2. Piccart-Gebhart M, Holmes AP, de Azambuja E, et al. The association between event-free survival and pathological complete response to neoadjuvantlapatinib, trastuzumab, or their combination in HER2-positive breast cancer.Survival follow-up analysis of the NeoALTTO study. Presented at: the 36th Annual San Antonio Breast Cancer Symposium; December 1014, 2013; San Antonio, TX. Abstract S1-01.

3. ALTTO: Optimizing Targeted Therapy for HER2 Breast Cancer. National Cancer Institute website. http://www.cancer.gov/clinicaltrials/noteworthy-trials/altto.

Updated June 1, 2014. Accessed June 1, 2014.

Trial overview. ALTTO trial website.http://alttotrials.com/hcp.php. Accessed June 1, 2014.

4. Lapatinib clinical trial update [press release]. London, UK: GlaxoSmithKline. September 9, 2011. http://us.gsk.com/html/media-news/ pressreleases/2011/2011-pressrelease-614856.htm. Accessed June 1, 2014. http://www.onclive.com/conference-coverage/asco-2014/Negative-ALTTOResults-Reverberate-for-Lapatinib-Novel-Clinical-Trials#sthash.Pl8CJBYE.dpuf

5. Pagani O, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. NEJM early online. June 1, 2014. ASCO late breaking abstract #1. TEXT: Clinicaltrials.govNCT00066703. SOFT: Clinicaltrials.govNCT00066690.

6. Adjuvant Ovarian Suppression in Premenopausal Breast Cancer Prudence A. Francis, M.D., Meredith M. Regan, Sc.D., Gini F. Fleming, M.D., IstvánLáng, M.D., Eva Ciruelos, M.D., MeritxellBellet, M.D., Hervé R. Bonnefoi, M.D., Miguel A. Climent, M.D., Gian Antonio Da Prada, M.D., Harold J. Burstein, M.D., Ph.D., Silvana Martino, D.O., Nancy E. Davidson, M.D., Charles E. Geyer,Jr., M.D., Barbara A. Walley, M.D., Robert Coleman, M.B., B.S., M.D., Pierre Kerbrat, M.D., Stefan Buchholz, M.D., James N. Ingle, M.D., Eric P. Winer, M.D., Manuela RabaglioPoretti, M.D., Rudolf Maibach, Ph.D., Barbara Ruepp, Pharm.D., Anita Giobbie-Hurder, M.S., Karen N. Price, B.S., Marco Colleoni, M.D., Giuseppe Viale, M.D., Alan S. Coates, M.D., AronGoldhirsch, M.D., and Richard D. Gelber, Ph.D. for the SOFT Investigators and the International Breast Cancer Study Group N Engl J Med 2015; 372:436-446January 29, 2015DOI: 10.1056/ NEJMoa1412379 7. NCCN Clinical practice Guidelines 2015 8. ASCO Guidelines 9. ESMO GUIDELINES Breast Cancer

April 2015

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International article

Oligometastasis: New Paradigm in Practical Oncology. General Aspects (part I)

OLIGOMETASTASIS: NEW PARADIGM IN PRACTICAL ONCOLOGY. GENERAL ASPECTS (PART I) Ciprian Enachescu*, Ionela Caraivan*, Alina Tita** * Centre Hospitalier Lyon Sud, 165, Chemin du Grand Revoyet, 69495 Pierre-Benite cedex, FRANCE ** Carol Davila University of Medicine and Pharmacy, Bucharest, Romania, medical student

Open Access Article

Abstract Keywords: oligometastasis, metastatic cascade, cancer progression, local therapies

The metastasis is the last stage of cancer progression , defined by limited therapeutic resources and therefore poor prognostic. In the last decade, the Oligometastasis, a subgroup of few and slowly progressive metastasis that can be successfully controlled by local therapies, has been identified. The Oligometastases origins can be possibly explained by clonal origin theory, based on the tumor heterogeneity or by the sequential development theory, based on progressive evolution of cellular genetic alterations, based on progressive accumulation of genetic anomalies in the tumor cells. The metastatic cascade include the intravasation, the access of tumor cells into the vasculature, the intravascular passage and, for the surviving tumoral cells, the extravasation phase and colonisation of the host tissue. Metastasis process in organs and tissues is not random, but is determined by the relationship between the primary tumor and host tissue (‘seed and soil’ and ‘anatomical/ mechanical’ teories). The distinction between Oligo- and Poly-metastatic state can be done on microRNA analysis, an up-regulated micro-RNAs defining a slow progressive tumore, corresponding to the oligometastatic phenotype. The surgery (metastasectomy), radiofrequence and stereotactic radiotherapy are therapeutic options for the local control of oligometastasis.

Rezumat Cuvinte-cheie:

Received: March 2015 Reviewed: April 2015 Accepted: April 2015

Cite this article: Enachescu C., Caraivan I., Tita A. Oligometastasis: New Paradigm in Practical Oncology.

General Aspects (part I) Rom J Oncol Hematol.

2015; 6(1):18-24

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oligometastaze, cascada metastazării, progresia cancerului, tratament local

Apariţia metastazelor reprezintă ultimul stadiu în progresia cancerului, situaţie în care resursele terapeutice sunt limitate şi prin urmare prognosticul este rezervat. În ultimul deceniu s-a identificat un subgrup de metastaze, numite oligometastaze, leziuni limitate ca număr şi cu progresie lentă, ce pot fi controlate prin tratament local eficace.

Originea oligometastazelor poate fi explicată eventual prin teoria originii clonale, bazată pe heterogenitatea tumorii primitive sau prin teoria dezvoltării secvenţiale, care pune accentul pe acumularea progresivă a anomaliilor genetice la nivelul celulelor tumorale. Etapele metastazării sunt intravazarea, adică accesul celulelor tumorale în reţeaua vasculară, pasajul intra-vascular şi, pentru celulele tumorale care supravieţuiesc, extravazarea şi colonizarea testului gazdă. Metastazarea nu se face la întâmplare, ci este rezultatul interacţiunii dintre tumora primară şi ţesutul gazdă (teoriile ‘sămânţa-sol’ şi ’anatomic-mecanică’).

Distincţia între oligo- şi polimetastaze se poate face prin analiza microARN-ului, supraexprimarea acestuia fiind în favoarea unei tumori lent evolutive ce corespunde cu fenotipul de oligometastază. Chirurgia (metastazectomia), tratamentul prin radio-frecvenţa şi radioterapia stereotactică sunt opţiunile terapeutice în tratamentul oligometastazelor.

Enachescu C., Caraivan I., Tita A.

Figure 1. Metastatic Propensity. The cell-of origins Model.

(adapted from Wan. Tumor metastasis: moving new biological insights into the clinic.

Nature Medecine 19, 1450–1464 (2013) , with permission) Described in 1995 by Hellman and Weichselbaum, the Oligometastasis state is considered an intermediate state between localized disease and widespread metastases, defined by a limited number of metastatic tumours involving a single or few organs. The Oligometastases have specific biological properties that make them potentially amenable to locoregional antitumor therapy, so that local control of all metastatic lesions leads to a longterm patient survival. (1)

The Oligometastasis origin theories There are two disparate approaches underlying the apparition and behaviour of oligometastases: the clonal origin theory and the sequential development theory.

The clonal origin theory (clonal selection hypothesis) is based on tumour heterogeneity, which refers to the presence in the same tumour, of distinct geographic regions containing different cell clones, clones which express distinct cellular behaviour (including the metastatic potential). From this perspective the oligometastases originate from cancer clones with ‘de novo’ limited proliferation and metastatic potential. The sequential development theory regards the metastatic process as a continuous progression from oligoto polymetastatic disease, process in which

mutations and chromosomal rearrangements accumulate gradually. From this point of view, the oligometastases represent only a transient stage of general metastatic progression and the tumour’s heterogeneity can be explained by the metastatic cascades itself. (2)

The Metastatic Process A) The Metastatic potential of the primary tumour Metastatic Propensity represents the potential of primary tumour clonogens to generate metastases, parameter described by different cellular models. The cell-of-origins model presumes that the same oncogenic alterations, when occurring in different cells (different cell types or different cellular differentiation stages of the same cell type) produce different effects and may lead to distinct metastatic behaviours.

Regarding the oncogenic driver-mutation model, the same cell hit by different oncogenic driver mutations can give rise to tumours with distinct metastatic potential, dissemination patterns or both. (3) If a primary tumour can successfully shed its first metastatic clonogen, when it contained 109 clonogens (1 ml tumour volume, 30 doubling), its metastatic propensity would be 10−9 (i.e. 1 in a billion). In fact, for a 1 ml tumour volume, the real number of tumour clonogens is less than 109 due to other components, such as stroma, April 2015

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International article

Oligometastasis: New Paradigm in Practical Oncology. General Aspects (part I)

Figure 2. Metastatic Propensity. The Oncogenic-driver mutation Model.

(adapted from Wan. Tumor metastasis: moving new biological insights into the clinic.

Nature Medecine 19, 1450–1464 (2013), with permission) blood, differentiated nonclonogenic cells or macrophages, which furthermore contribute to the tumour volume. A high propensity increases the absolute likelihood that a tumour will produce metastases despite its modest size and inversely, a tumour with a low propensity for metastasis will be large before shedding its first metastasis. (4) B) Dissemination of tumour cells and their implantation at distant sites is a complex multistep process. The first step is the intravasation, which implies the access of tumour cells into the vasculature of lymphatic and blood systems.

In order to be able to migrate, the tumour cells undergo a reversible process called Epithelial– Mesenchymal Transition or EMT, that enables carcinomatous to lose their epithelial properties, such as cell polarity and cell-to-cell adhesion, in order to gain mesenchymal characteristics, enhancing migration and invasion. (5) Upon arrival into the vessel, all tumour cells leave the cell cycle and no longer proliferate . Moreover, tumour cells can undergo apoptosis and die, which means that less than 0.02% of circulating tumour cells can survive long enough to form metastases , according to animal modelling. (6) After the intravascular passage, the circulating

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tumour cells extravasate, leave the bloodstream and seed into the parenchyma of the host organ. Tumour cell extravasation may occur across intercellular junctions between adjacent endothelial cells (paracellular route) or by direct penetration through the body of a single endothelial cell (transcellular route). (7) After the extravasation phase, the tumour cell returns to an epithelial identity via Mesenchymal–Epithelial Transition (MET), a reverse transformation process, that allows the cancer cell to regain its ability to proliferate. (8) The metastatic process in organs and tissues is not arbitrary (it is not due to chance related events) and it is in fact determined by the relationship between the primary tumour and host tissue. Two hypotheses can explain the specificity of metastatic dissemination: The ‘seed and soil’ theory presumes that metastases result only when the appropriate ‘seed’ (tumour cell) is implanted in its suitable ‘soil’, represented by the microenvironment of target organs or even selected regions within this organs (tumour cells preferentially adhere to the microvasculature).

The anatomical/mechanical theory speculates that the patterns of tumour metastasis were

Enachescu C., Caraivan I., Tita A.

Figure 3. Metastatic Process (adapted from Chambers AF1, Groom AC, MacDonald IC.

Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer.

2002 Aug;2(8):563-72. , with permission) determined by the anatomical proprieties of vascular and lymphatic drainage. This theory is argued by the evidence that the first organ encountered is the principal site of tumour cell arrest, and therefore it will possess the highest number of metastases.

An example is the liver as a common site of haematogenous metastases caused by tumours arising in the gastrointestinal tract due to the unique venous drainage that takes place through the portal venous system. It is accepted that neither the “seed and soil” , nor the anatomical-mechanical hypothesis need to be mutually exclusive. (9) C) The proliferation and invasion of a new site The metastatic proliferation in a new site depends on the rate of growth of metastatic clonogenic cells. In the first phase (early phase) after the seeding, the clonogenic cells grow fast with only a brief deceleration, at the time of initiation of neovascularization. In the second phase (late phase), the micro-metastases continue to growth exponentially. but the growth rate decreases as the metastases enlarge (the Gompertzian growth model). (4)

METASTATIC SPECIFIC SITES. FEATURES AND SPECIFICITIES. Bone Metastases There are two types of bone marrow tissue, red marrow containing hematopoietic stem cells (HSC) and yellow marrow, mainly consisting of fat cells. (10) The pathophysiology of bone metastases is complex and involves both site-

specific molecular interactions and anatomical/ mechanical mechanisms (e.g., Batson venous plexus, especially for prostate cancer).

The first step in the metastatic cascade is the attraction of tumour cells to the bone by the action of different cytokines, Osteopontin (a protein implicated in bone remodelling), Osteonectin (a protein that induces the matrix metalloproteinase production and activity, an important step in bone invasion by cancer cells) and Stromal-Derived Factor-1 (SDF1 or CXCL12, a strong chemotactic cytokine recruiting endothelial progenitor cells, and playing an important role in neoangiogenesis and cancer cell attraction). After the colonization, tumour cells interact with bone microenvironment resulting in production of angiogenic (VEGF) and bone-resorbing factors (RANKL) (11) Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL), member of the tumour necrotic factor ligand superfamily, is essential for the formation, activation and function of osteoclasts. In metastatic states, RANKL activates osteoclast-mediated bone resorption with a consequent release of matrix growth factors, than can further induce the growth of tumour cells and contribute to metastatic progression, establishing a positive feedback mechanism (‘vicious circle’) (12)

Lung Metastases The principal characteristic of the lungs is their dense vascular surface and the extremely small diameter of lung capillaries which explains why the pulmonary or bronchial arteries represent April 2015

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International article the main metastatic routes (anatomical/ mechanical mechanism). The ratio between the diameter of lung capillaries (4 μm) and tumor cells (20 μm) explains why the adhesion molecules may not play an important role for tumour cell arrest in this organ.

Moreover, the chronic tissular stress may have a profound impact on the metastatic process, as the increased levels of catecholamines are responsible for an increase of the tumour’s vascular surface area. (13) Metastatic lesions start at the level of small pulmonary arterioles and from there they must breach the tight endothelial junctions lining the intima of lung blood vessels and the transverse basement membrane. The ‘seed and soil’ mechanism also contributes to secondary lung tumours formation and progression, as some tumours transmit prometastatic signals to the lung, signals that prepare the metastatic soil for the influx of tumour cells. (14) Two factors are principally involved: Vascular endothelial growth factor (VEGF) and Matrix metalloproteinases (MMP) system. Vascular endothelial growth factor A (VEGF-1) , a member of the platelet-derived growth factor (PDGF) family , is an important angiogenic cytokine with critical roles in normal vasculogenesis (the formation of the circulatory system during embryonic development or after injury) and nomal or pathological angiogenesis (the growth of blood vessels from pre-existing vasculature). The VEGF-1 factor triggers cellular response by binding to a tyrosine kinase receptor (the VEGFRs) on the cell surface, causing the receptor’s dimerisation and activation. (15) The activation of VEGF-1 induces not only endothelial proliferation and permeabilization, but also an increase in the expression of the matrix metalloproteinase in distal endothelial cells and macrophages. (16, 17) Matrix metalloproteinases (MMPs) are zincdependent endopeptidases, enzymes that degrade all types of extracellular matrix proteins and that also play a critical role in tissue remodelling during the development of pathological processes, including inflammation, tissue repair, tumour invasion and metastasis (18).

Liver Metastases The liver parenchyma is also one of the most densely vascularized tissues with a unique vascular supply via both the systemic circulation and the portal vein. Moreover the sinusoids capillaries are highly permeable and do not represent a major barrier to extravasations.

Gastrointestinal malignancies such as colorectal carcinomas have a tendency to metastasize to the liver, likely due to the nature of the portal circulation (anatomical/mechanical mechanism).

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Oligometastasis: New Paradigm in Practical Oncology. General Aspects (part I)

Regarding the relationship between tumour cells and hepatic microenvironment (‘seed and soil’ theory), many aspects are to be discussed.

The attachment of circulating cancer cells to the vascular endothelium, a mandatory step in the metastatic process, is possible due to organspecific receptors on the luminal surface of the endothelium which are specifically recognized by tumour cell ligands.

Such a receptor is E-selectin (endothelialleukocyte adhesion molecule 1, ELAM-1), a cytokine-inducible endothelial cell adhesion receptor that mediates the adhesion of tumour cells to endothelial cells. (19) The fate of tumour cells who have reached the hepatic parenchyma depends not only on the presence of growth factors locally but also on the host’s immune response. An important role in the development of tumour cells is played by the Transforming Growth Factor α (TGF α), a protein member of the Epidermal Growth Factor (EGF) family, which activates a signalling pathway through the Epidermal Growth Factor Receptor (EGFR), leading to cell proliferation. (20) Regarding the immune response, the Kuppfer cells (resident macrophages within the hepatic sinusoids) play a bimodal role in metastasis development, as their activation determines the production of growth factors and chemotactic cytokines capable of facilitating both anti- and pro-tumour effects. Kuppfer cells are the major source of VEGF expression in the liver tumour’s microenvironment and play an important role in regulating cancer progression through stimulating tumour angiogenesis and tumour cell invasion. Experimental studies on mice show that early Kuppfer cells depletion before tumour induction causes an increased liver tumour burden, but late Kuppfer cells depletion has the opposite effect, producing significantly decreased liver tumours. (21)

Brain Metastases An important particularity of the brain is its protection by the Blood Brain Barrier (BBB), the tightest endothelial barrier in the organism, barrier that forms an obstacle for the traffic of solutes (limits and regulates molecular exchange) and cells.(22) Transport across the brain endothelium is strictly limited through a four-fold defence line : the paracellular barrier (represented by interendothelial junctions), the transcellular barrier (endocytosis and transcytosis), the enzymatic barrier and the efflux transporters. This mechanical resistance along with the absence of lymphatic drainage should theoretically protect the brain parenchyma against tumour cells colonisation. Nevertheless, this barrier can be overcome by the invading

Enachescu C., Caraivan I., Tita A.

tumour cells, the transendothelial migration being possible by two routes: the paracellular pathway (through the interendothelial junctions) and the transcellular one (through single endothelial cells) .(23) Moreover , such as all other host tissues, the vasculature itself plays a “soil” role for metastatic success, the vascular basement membrane being an active substrate for tumour cells growth. (24) Once the metastatic cells have crossed the BBB they encounter and interact with astrocytes, which (injury-reacting astrocytes) produce different cytokines , such as Nerve Growth Factor (NGF, role in the growth, maintenance, and survival of nerve cells), which selectively supports the growth of metastatic cells and Heparanase (a proteolytic enzyme that acts both at the cell-surface and within the extracellular matrix) , both of them being able to modulate cell invasion. (25)

Oligometastases versus Polymetastases The distinction between the Oligo- and the Poly-metastatic state is essential for prognostic evaluation and for choosing an appropriate therapeutic strategy (local-curative versus systemic-palliative treatments).

Clinical differential diagnostic, even if there is a long latent interval between the primary tumour control and the metastasis occurrence (Timeto-Progression) favouring oligometastases, is difficult if not impossible. (26) A molecular tool to differentiate oligo- from poly-metastatic lesions is the microRNA expression.

The microRNAs (micro Ribonucleic Acid) are small (about 22 nucleotides) non-encoding RNA molecules that can regulate gene expression by binding to messenger ARN (mRNAs) and inducing translation repression or RNA degradation. (27) Consequently MicroRNAs are critical regulators of self-renewal and differentiation in normal embryonic and adult tissue stem cells and are involved in a wide variety of biological processes including cell proliferation, cell death and energetic metabolism, but also in cancer development and progression. (28) The upregulated microRNAs have been characterized as tumour suppressors that may repress oncogenic genes/pathways and that may limit metastatic spread. (29) Moreover, the micro-RNA expression’s signature correlates with metastasis progression, regardless of the primary tumour’s histology. The metastatic patients are defined as slow progressors, corresponding to the oligometastatic phenotype, if the micro-RNAs are up-regulated, respectively rapid progressors,

according to the polymetastatic phenotype, if the micro-RNAs are down-regulated (30) .

Oligometastasis :clinical classification Depending on the time of their occurrence and diagnosis, the oligometastases can be classified in three distinct cohorts : - “synchronous” oligometastases, that are present at the time of diagnosis, before any treatment (primary tumour not treated and hence, not controlled); - “metachronous” oligometastases, that represent a recurrence after an effective curative local or regional treatment (primary tumor treated and controlled).

- “induced” oligometastases, that occur after a cytoreductive treatment (primary tumor treated but not controlled) (31) Another classification is the Niibe-OnishiChang classification, that defines the metastasis as it follows: Oligo-metastasis if the primary tumour is not controlled (corresponds to synchronous and induced metastases) and Oligo-recurrences for the controlled primary tumour cases (corresponds to metachronous metastases). These different groups probably have different prognoses and therapeutic approaches.

The prognostic factors are the number of metastasis, the primary tumour control and the site of metastasis. From this point of view, 1 to 2 brain or adrenal metastasis of Non-Small Cell Lung Cancer and 1-2 lung or liver metastasis of colorectal cancer are favourable situations.

On the other hand, the metastatic pancreatic cancer, sarcoma and melanoma represent a group of poor prognosis, despite having 5 or less metastatic sites. (32)

Oligometastasis treatment principles For metastatic stage IV cancer, the standard treatment is still represented by systemic therapy, including cytotoxic chemotherapy, hormonal manipulation and targeted molecules; the local treatments like radiotherapy or surgery are considered palliative approaches. On the contrary, for the oligometastatic condition the main therapeutic role belong to the local treatments (surgery, radiotherapy and radiofrequency) , that are expected to control the local progression and to improve the overall survival rate. Metastasectomies was proposed for liver, lung and adrenal metastases, the surgical resection of all tumour sites being considered the only curative therapy enabling long-term survival. The Radiofrequency Ablation (RFA) delivers a high temperature directly into the tumour tissue producing cellular destruction and coagulative necrosis. This technique is April 2015

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International article used to control liver and lung metastasis. The Stereotactic Radiotherapy is a technique that allows a large radiation dose to be delivered with high precision in few fractions to small and well defined target volumes.

The brain metastases are treated by Stereotactic Radiosurgery (SRS) in a single fraction, while extra-cerebral metastases (lung, liver, adrenal and bone) are treated most often

Titlul articolului

by fractionated Stereotactic body radiation therapy (SBRT). (33)

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21. Wen SW, Ager EI, Christophi C. Bimodal role of Kupffer cells during colorectal cancer liver metastasis. Cancer Biol Ther. 2013 Jul;14(7):606-13 22. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7:41–53 23. Wilhelm I, Molnár J, Fazakas C, Haskó J, Krizbai IA. Role of the bloodbrain barrier in the formation of brain metastases . Int J Mol Sci. 2013 Jan 11;14(1):1383-41 24. Lorger M, Felding-Habermann B. Capturing changes in the brain microenvironment during initial steps of breast cancer brain metastasis. Am J Pathol 2010;176:2958-71.

25. Marchetti D, Li J, Shen R. Astrocytes contribute to the brain-metastatic specificity of melanoma cells by producing heparanase. Cancer Res. 2000 Sep 1;60(17):4767-70.

26. Tree AC, Khoo VS, Eeles RA, Ahmed M, Dearnaley DPet al. Stereotactic body radiotherapy for oligometastases. Lancet Oncol (2013) 14:e28–e37.

27. Ambros V, Bartel B, Bartel DP, Burge CB, Carrington JC, Chen X, Dreyfuss G, Eddy SR, et al . A uniform system for microRNA annotation. RNA. 2003 Mar;9(3):277-9.

28. Hwang HW, Mendell JT: MicroRNAs in cell proliferation, cell death, and tumorig-enesis. Br J Cancer 2006, 94:776-780.

29. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, et al MicroRNA expression profiles classify human cancers. Nature (2005) 435:834–838 30. Uppal A, Ferguson MK, Posner MC, Hellman S, Khodarev NN, Weichselbaum RR. Towards a molecular basis of oligometastatic disease: potential role of micro-RNAs. Clin Exp Metastasis. 2014 Aug;31(6):735-48.

31. Daniel R. Gomez, Yuzuru Niibe, and Joe Y. Chang, “Oligometastatic Disease at Presentation or Recurrence for Nonsmall Cell Lung Cancer. Pulm Med , 2012, 2012 : 396592.

32. Niibe Y, Chang JY, Onishi H, Salama J, Hiraki T, Yamashita H. Oligometastases/ Oligo-recurrence of lung cancer. Pulm Med. 2013;2013:438236.

33. Timmerman RD, Bizekis CS, Pass HI, Fong Y, Dupuy DE, Dawson LA, Lu D. Local surgical, ablative, and radiation treatment of metastases. CA Cancer J Clin.

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Reviews

Borderline Ovarian Tumors – Literature Review

BORDERLINE OVARIAN TUMORS – LITERATURE REVIEW Nicolae Bacalbasa1, Diana Popoici2, Irina Balescu3 1. “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 2. Emergency University Hospital, Bucharest, Romania 3. “Ponderas” Hospital, Bucharest, Romania Corresponding author: Nicolae Bacalbașa Adress: Dimitrie Racoviță Street, no. 2, Bucharest, Romania E-mail: nicolae_bacalbasa@yahoo.ro Phone no: +40723540426

Open Access Article

Abstract Keywords: borderline ovarian tumors, serous, mucinous, conservative treatment

Borderline ovarian tumors are rare entities accounting for less than 10% of all ovarian neoplasms. The most frequently seen histopathological subtypes are serous and mucinous tumors.

Usually they are asymptomatic lesions; however sometimes atypical manifestations such as diffuse abdominal pain or constipation might be seen. When it comes to the most appropriate treatment, a conservative approach seems to be the best option due to the low risk of developing local or distant recurrences.

Rezumat Cuvinte-cheie:

Received: December 2014 Reviewed: February 2015 Accepted: March 2015

Cite this article: Bacalbasa N., Popoici D., Balescu I. Borderline Ovarian Tumors – Literature Review.

Rom J Oncol Hematol.

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tumori ovariene borderline, seros, mucinos, tratament conservator

Tumorile ovariene borderline sunt entități rare ce reprezintă aproximativ 10% din toate neoplasmele ovariene. Cele mai fercvente subtipuri histologice sunt cele seroase și mucinoase. De obicei aceste leziuni sunt asimptomatice; uneori pacienții pot prezenta manifestări atipice cum ar fi durerea abdominală difuză sau constipația. In ceea ce privește cea mai potirivită strategie terapeutică, o abordare conservativa pare să fie cea mai buna optiune datorită riscului mic de a dezvolta recurență locală sau la distanță.

Introduction Also known as tumors of low malignant potential (LMP) or atypical proliferative ovarian tumors (APOT), borderline ovarian lesions are one of the most controversial topics regarding ovarian carcinomas.

Borderline ovarian tumors (BOT) are considered to be noninvasive lesions with a superior prognosis when compared to ovarian carcinomas. (1)

Between 20% and 40% of BOT are associated with extraovarian tumors deposits or implants.

The presence of stromal invasion or the noninvasive nature of these tumor deposits is a very important histological parameter in order to determine the tumor behavior.

Some borderline tumors have a minor form of invasion designated as microinvasion. The presence of microinvasion has been introduced

Bacalbasa N., Popoici D., Balescu I.

in the past few decades. The size of microinvasion is calculated by using three different scales.

Bell and Scully (1) reported that tumor invasion should not exceed 3 mm in diameter while later, a 10 mm2 area was suggested by other authors (2,3) ; nowadays a 5 mm linear invasion was also suggested and is recommended as a cut-off value for all forms of BOT. It is probably the most common dimension(4,5) used in the present to calculate microinvasion. The 3 mm linear dimension and the 10 mm2 area are arbitrary numbers and have not been scientifically validated.

Bot Staging According to the latest studies, BOT are classified in four stages: Stage I: tumor growth is limited to the ovaries, Stage II: tumor growth is limited to one or both ovaries, Stage III: Tumor involving one or both ovaries with peritoneal metastasis outside the pelvis and/or positive retroperitoneal or inguinal lymph nodes. Superficial liver metastasis equals stage III Stage IV: tumor growth involving one or both ovaries with distant metastases. If pleural effusion is present there must be positive cytology to allot a case to stage IV. Tumor spread inside the liver equals stage IV(6).

Clinical Most tumors are asymptomatic; however when they become clinical symtomatic, the most frequently seen symptoms include abdominal pain, discomfort, fullness and pressure (44%), increased abdominal growth without any abdominal mass (39%), symptomatic pelvic mass, gastrointestinal symptoms including abdominal cramps and changes in bowel habits (5%), gynecological or urinary symptoms (7,8,9,10).

The use of oral contraceptives and increased parity has a protective effect (excluding mucinous tumors) (11); interanexial hysterectomy and tubal ligation appear to have a protective effect (12,13), while early menarche, obesity, late menopause, and estrogen replacement therapy are among the most encountered risk factors (14).

Serous Bot Serous BOT account for 56% of all borderline tumors (15). At the moment of diagnostic the patients have an average age of 46 years. Serous BOT occur in slightly older women when compared to cystadenomas, but in younger women than ovarian invasive carcinomas. Serous BOT are bilateral in 25–37% of the cases (16,17). In a more recent studies, bilateralism was reported as 55% (18).

The tumors are round, ovoid or irregular in shape with the size ranging from 1 to 35

cm in diameter, they are reddish, pink or yellowish blue, occasionally exhibiting brown discoloration secondary to intraluminal or intramural hemorrhage. Their external surface may be smooth with indurate areas which are occasionally associated with dystrophic calcification. Blood vessels in the cyst wall can be very prominent; on palpation it can be fluctuant or somewhat firm. On sectioning the tumor, it can be unilocular or multilocular, and may show secondary or “daughter” cysts of varying size and shape (19). Small or exuberant papillary structures can be seen on the external surface of the cyst wall, identical to those present in the cyst lumen.

Frequently the fallopian tube is attached to the cyst wall, and could be quite elongated; sometimes it is embedded in the cyst wall. Fibrous adhesions are often seen.

The tumor contents can be a clear straw-colored fluid, hemorrhagic or quite frequently thick and mucinous. The mucinous content does not necessarily indicate that the tumor is of mucinous type. The cyst inner lining exhibits arborizing or papillary structures; they are generally yellowbrown or tan in color; they are soft and fragile and are covered by serous, brown or mucinous fluid.

The ovary can be difficult to identify, especially when the tumor is very large, it may be reduced just to a thickened part of the cyst wall.

Histologic characteristic The most important histological characteristics include the presence of epithelial hyperplasia with hierarchical branching pattern papillae, epithelial stratification and tufting, nuclear enlargement with mild to moderate atypia, absence of microinvasion (3 mm linear size or 10 mm2 (WHO) or 5 mm in the newly proposed classification), noninvasive peritoneal implants and the absence of destructive invasion.

In practice it has been noted that microinvasion is found more often during pregnancy; the frequency has been as high as 80% (20).

Five different types of microinvasion have been described, but the only type that has an aggressive behavior is the micropapillar one (20).

It is reported that peritoneal implants, exophytic growth, and bilaterality are more commonly present in cases presenting microinvasions (21). As it can be expected, the presence of intratumoral vascular space invasion is associated with an increased risk for lymph node involvement and disseminated disease in other organs.

In a certain case, all the implants can be noninvasive, all invasive, or a mixture of the two (22,23,24,25,26,27) . Noninvasive implants account for 83–96% of all peritoneal implants.

Based on molecular biology and genetics, in association with clinical and morphological April 2015

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Borderline Ovarian Tumors – Literature Review

evidence (14), high-grade serous carcinoma and low-grade serous carcinoma are not related, in other words, high-grade serous carcinoma does not represent a more advanced form of lowgrade serous carcinoma.

Present knowledge suggests that ovarian tumors can be divided in two major groups.

The first group, or type I tumors, is composed of neoplasms that in general are limited to the ovary at the time of diagnosis, are genetically stable, develop slowly in a stepwise fashion and behave in a less aggressive form. Type I tumors are usually found as large stage I neoplasms. Low-grade serous ovarian carcinoma, a type I tumor, is less responsive to conventional chemotherapy when compared to high-grade ovarian carcinoma (28).

Patients with type I tumors are younger than patients with type II tumors; type II tumors develop relatively fast.

Serous BOT or APSOTs, low-grade serous carcinoma, mucinous carcinoma, low-grade endometrioid carcinoma, clear cell, and transitional cell carcinoma or Brenner carcinomas are all type I tumors.

Type II tumors, contrary to type I tumors, encounter a rapid growth, are very aggressive and are considered as high-grade from the beginning.

Most type II tumors (75%) are high-grade serous neoplasms. This group also includes malignant mixed mesodermal tumors or carcinosarcoma (a rare tumor which is more often diagnosed nowadays due to an improved sampling associated with an improved microscopic recognition of small areas of the sarcomatous component) and undifferentiated carcinomas.

Recent data suggest that many of these tumors arise from pre-existing fimbriae of fallopian tubes intraepithelial carcinomas. Type II neoplasms are characterized by TP53 mutations and they lack mutations of KRAS, BRAF, or ERBB2. High-grade serous carcinomas seem to arise especially from type II pathway and only very rare by pathway I (29).

A recent study suggests the possibility that low-grade serous carcinoma originates from the implantation of exfoliated epithelial cells from the fimbriated end of the fallopian tube onto the ovarian surface, or from fimbriated end of the fallopian tube cells; it is thought that these cells will fall into the defects created on the surface epithelium by ovulation or other disruptions such as inflammatory processes with subsequent acquisition of KRAS or BRAF, or perhaps other mutations in the transplanted epithelium, resulting in the transformation to serous borderline tumors (30).

Peritoneal or Extraovarian Serous Bot Peritoneal BOT are usually associated with widespread involvement of peritoneal and omental

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surfaces but with minimal or no ovarian presence of atypical epithelium. The ovaries are of normal in size and may show very small or even absent serosal lesions. This form of presentation could simulate a diffuse malignant mesothelioma or peritoneal carcinomatosis of other origin. The most important symptoms are infertility and abdominal pain. Rarely these tumors are suspected on a Pap smear, due to the presence of papillary clusters or psammoma bodies on the cytology specimen. Inspection of the abdominal and pelvic cavities might reveal fibrous adhesion associated with fine granularity or large nodules. Most of the lesions are less than 0.6 cm in diameter. The peritoneal surface appears congested, while ascites might be also seen (31,32).

Mucinous Bot Nowadays it is known that the survival rate of patients with enteric or intestinal mucinous BOTs is 99–100% in cases with ovary confined tumors (33); this data is in complete contrast to a survival rate of only 40–50% encountered in advanced stage tumors. Mucinous ovarian tumors which encounter ruptures at the time of surgery are not associated with the development of pseudomyxoma peritonei (34). They are very benign neoplasms that probably never spread beyond the ovary.

Grossly they are characterized by masses that are most often unilateral. Their size widely varies but tumors larger than 12 cm, weighting more kilograms are often seen.

Intestinal or Enteric Mucinous Bot Enteric mucinous BOT are characterized by a mean age of 35 years at the moment of diagnosis; only in few cases a germ-cell origin can be incriminated, most cases being supposed to be metastatic lesions. Patients diagnosed with stage I enteric mucinous BOT report an excellent prognostic with an overall survival of up to 99% while patients diagnosed in an advanced stage of the disease report a poor outcome (with a reported survival rate of 40-45%) (35).

Endocervical-like mucinous BOT or APE-LMTs Endocervical like mucinous BOT represent almost 10-15% of all mucinous BOT (33) which are often associated with endomteriosis (in up to 35% of cases) (36); usually they are small size, bilateral tumors with both serous and mucinous components. Histopathological studies revealed the presence of edematous bulbous papillae associated with PMN (37); occasionally squamous or endometrial cell component might be seen.

Patients diagnosed with this histopathological subtype report an excellent prognosis even in those cases with microinvasion or intraepithelial carcinoma (36).

Bacalbasa N., Popoici D., Balescu I.

Pseudomyxoma Peritonei Pseudomyxoma peritonei (PMP) is consider to be a condition in which mucinous or gelatinous material is present in abdomino-pelvic cavity; this mucus might be sometimes adherent to abdominal organs.

Appendicular tumors often coexist. The mucus material sometimes infiltrates the stroma of intraabdominal organs. In the case of the ovay is known as pseudomyxoma ovary (38).

Endometrioid Bot Endometroid BOT are very rare tumors, similar to endometrial atypical simple or complex hyperplasia or well-differentiated adenocarcinoma (39); 43% are associated with squamous metaplasia, while 7% with microinvasion. Up to 63% of them are associated with endometriosis (40). They have a biologically benign behavior.

Transitional Cell (Brenner) Bot These tumors are unilateral in more than 90% of cases and represents 3–5% of all Brenner tumors (41,42) . Up to 25–30% of cases are associated with endometriosis. Brenner BOT associate no risk of recurrence or metastatic disease. Brenner tumors epithelium resembles to urothelium; p63 nuclear immunoreactivity expression might be also seen (43,44).

Treatment In cases diagnosed in early stages, when the contro-lateral ovary is normal and the patient desires to preserve fertility, total hysterectomy with bilateral adnexectomy is not needed. Results published in 2015 from a nationwide Danish register-based case-control

study between 1982 and 2011 indicate that tubal ligation is an effective method in reducing the risk of epithelial ovarian cancer, especially endometrioid cancer. If the tumor is unilateral and adjacent to normal tissue, unilateral cystectomy can be performed; however, inspection of the capsule for signs of rupture should be performed before resection. If no normal adjacent tissue is present, oophorectomy or salpingo-oophorectomy should be performed. If the contralateral ovary is normal in appearance, a biopsy should not be performed on the adjacent ovary due to the risk of ovarian failure (if fertility is an issue).

Various chemotherapy regimens have been used, but evidence is insufficient to determine exactly which therapy is indicated for each BOT (45).

Conclusions BOT account for a small percentage (approximately 10%) of epithelial ovarian cancers. The most often seen histopathological subtypes are serous or mucinous cell tumors. They have large diameters at the moment of diagnosis, but they rarely metastasize.

Many patients with borderline tumors are young and wish to preserve their fertility. Often, their treatment has been more aggressive than it is necessary, based on their behavior, which is usually benign, because borderline tumors are regarded as a subset of carcinomas.

This work is licensed under a Creative Commons Attribution 4 .0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/4.0/

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8. Munnell, E.W. and H.C. Taylor, Jr., Ovarian carcinoma; a review of 200 primary and 51 secondary cases. Am J Obstet Gynecol, 1949. 58(5): p. 94359, illust.

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23,257 women with ovarian cancer and 87,303controls. Lancet. 2008 Jan 26;371(9609):303-14.

12. Riman, T., et al., Risk factors for epithelial borderline ovarian tumors: results of a Swedish case-control study. Gynecol Oncol, 2001. 83(3): p. 57585.

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17. Michael, H., L.M. Roth, and P.K. Kotylo, Recent developments in the pathology of ovarian epithelial tumors of low malignant potential and related neoplasms. Pathol Annu, 1993. 28 Pt 2: p. 1-22.

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19. Colgan, T.J. and H.J. Norris, Ovarian epithelial tumors of low malignant potential: a review. Int J Gynecol Pathol, 1983. 1(4): p. 36782.

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2006 Oct;30(10):1209-21.

21. Seidman JD, Surface epithelial tumors of the ovary. In Kurman RJ (ed) Blaustein’s pathology of the female genital tract, New York, Springer-Verlar 2002. 2002: p. 791.

22. Bell, D.A., M.A. Weinstock, and R.E. Scully, Peritoneal implants of ovarian serous borderline tumors. Histologic features and prognosis. Cancer, 1988.

62(10): p. 2212-22.

23. Gershenson, D.M., et al., Serous borderline tumors of the ovary with noninvasive peritoneal implants. Cancer, 1998. 83(10): p. 2157-63.

24. Michael, H. and L.M. Roth, Invasive and noninvasive implants in ovarian serous tumors of low malignant potential. Cancer, 1986. 57(6): p. 1240-7.

25. Russell, P., Borderline epithelial tumours of the ovary: a conceptual dilemma. Clin Obstet Gynaecol, 1984. 11(1): p. 259-77.

26. McCaughey, W.T., et al., Peritoneal epithelial lesions associated with proliferative serous tumours of ovary. Histopathology, 1984. 8(2): p. 195208.

27. Gershenson, D.M., et al., Ovarian serous borderline tumors with invasive peritoneal implants. Cancer, 1998. 82(6): p. 1096-103.

28. Schmeler KM, Gershenson DM: Low-grade serous ovarian cancer: a unique disease. Curr Oncol Rep. 2008 Nov;10(6):519-23.

29. Vang R, Shih IeM, Kurman RJ: Ovarian low-grade and high-grade serous carcinoma: pathogenesis,clinicopathologic and molecular biologic features, and diagnostic problems. Adv Anat Pathol. 2009 Sep;16(5):26782.

30. Li J, Abushahin N, Pang S et al: Tubal origin of ‘ovarian’ low-grade serous carcinoma. Mod Pathol. 2011 Nov;24(11):1488-99. doi: 10.1038/ modpathol.2011.106. Epub 2011 31. McCaughey, W.T., et al., Peritoneal epithelial lesions associated with proliferative serous tumours of ovary. Histopathology, 1984. 8(2): p. 195208.

32. Burmeister, R.E., R.E. Fechner, and R.R. Franklin, Endosalpingiosis of the peritoneum. Obstet Gynecol, 1969. 34(3): p. 310-8.

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35. Seidman, J.D., R.J. Kurman, and B.M. Ronnett, Primary and metastatic mucinous adenocarcinomas in the ovaries: incidence in routine practice with a new approach to improve intraoperative diagnosis. Am J Surg Pathol, 2003. 27(7): p. 985-93.

36. Khunamornpong, S., P. Russell, and J.C. Dalrymple, Proliferating (LMP) mucinous tumors of the ovaries with microinvasion: morphologic assessment of 13 cases. Int J Gynecol Pathol, 1999. 18(3): p. 238-46.

37. Nomura, K. and S. Aizawa, Clinicopathologic and mucin histochemical analyses of 90 cases of ovarian mucinous borderline tumors of intestinal and mullerian types. Pathol Int, 1996. 46(8): p. 575-80.

38. Szych, C., et al., Molecular genetic evidence supporting the clonality and appendiceal origin of Pseudomyxoma peritonei in women. Am J Pathol, 1999. 154(6): p. 1849-55.

39. Roth, L.M., R.E. Emerson, and T.M. Ulbright, Ovarian endometrioid tumors of low malignant potential: a clinicopathologic study of 30 cases with comparison to well-differentiated endometrioid adenocarcinoma. Am J Surg Pathol, 2003. 27(9): p. 1253-9.

40. Snyder, R.R., H.J. Norris, and F. Tavassoli, Endometrioid proliferative and low malignant potential tumors of the ovary. A clinicopathologic study of 46 cases. Am J Surg Pathol, 1988. 12(9): p. 661-71.

41. Hallgrimsson, J. and R.E. Scully, Borderline and malignant Brenner tumours of the ovary. A report of 15 cases. Acta Pathol Microbiol Scand Suppl, 1972. 233: p. 56-66.

42. Miles, P.A. and H.J. Norris, Proliferative and malignant brenner tumors of the ovary. Cancer, 1972. 30(1): p. 174-86.

43. Soslow, R.A., et al., Transitional cell neoplasms of the ovary and urinary bladder: a comparative immunohistochemical analysis. Int J Gynecol Pathol, 1996. 15(3): p. 257-65.

44. Ordonez, N.G., Transitional cell carcinomas of the ovary and bladder are immunophenotypically different. Histopathology, 2000. 36(5): p. 433-8.

45. Madsen C, Baandrup L, Dehlendorff C, Kjaer SK. Tubal ligation and salpingectomy and the risk of epithelial ovarian cancer and borderline ovarian tumors: a nationwide case-control study. Acta Obstet Gynecol Scand. Jan 2015;94(1):86-94. [Medline].

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Titlul articolului

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The Role Of Pancreatic Cysts Fluid Analysis In Determining Malignant Lesions – Literature Review

THE ROLE OF PANCREATIC CYSTS FLUID ANALYSIS IN DETERMINING MALIGNANT LESIONS – LITERATURE REVIEW Nicolae Bacalbasa1, Alexandra Gireada2, Irina Balescu3 1. “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 2. “Carol Davila” Central Military Emergency Hospital, Bucharest, Romania 3. “Ponderas” Hospital, Bucharest, Romania Corresponding author: Bacalbasa Nicolae Adress: Dimitrie Racoviță Street, no. 2, Bucharest, Romania E-mail: nicolae_bacalbasa@yahoo.ro Phone no: +40723540426

Open Access Article

Abstract Keywords: pancreatic cyst, CA 19-9, CEA

Under the generic name of pancreatic cyst various lesions are included. In order to decide whether surgery is needed for their treatment the clinician should have the possibility to establish the nature of the lesions and to distinguish between benign and malignant cysts. Although classically has been considered that imagistic studies should provide a differential diagnosis of the lesions, recent studies have demonstrated that the analysis of the cystic liquid might offer a more specific preoperative diagnosis.

Introduction:

Received: December 2014 Reviewed: February 2015 Accepted: March 2015 Cite this article: Bacalbasa N., Gireada A., Balescu I. The Role Of Pancreatic Cysts Fluid Analysis In Determining Malignant Lesions – Literature Review.

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2015; 6(1):34-37

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The most commonly seen cystic pancreatic lesions are pseudocyst (75-80%) followed by common cystic pancreatic neoplasms: mucinous cystic neoplasm (10-45%), serous cystic neoplasm (32-39%), IPMN (Intraductal Papillary Mucinous Neoplasm) (21-33%), rare cystic pancreatic neoplasms: solid pseudopapillary tumor (<10%), acinar cell cystadenocarcinoma, lymphangioma, hemangioma, paraganglioma, solid pancreatic lesions with cystic degeneration: pancreatic adenocarcinoma (<1%), cystic islet cell tumor (insulinoma, glucagonoma, gastrinoma) (<10%), metastasis, cystic teratoma, sarcoma, hydatid cyst, lymphatic cyst and true epithelial cysts: von Hippel-Lindau disease, autosomal-dominant polycystic kidney disease (1) Pancreatic cysts might also be classified in three distinct categories: pseudocysts, retention (simple) cysts and cystic neoplasms (serous,

mucinous, IPMNs and papillary cystic neoplasms), the last one being the largest category. (2)

Histological classification: Histologically, the cystic tumors can be divided in two categories: nonmucinous (pseudocyst and serous cystadenoma), with no potential of malignancy, and mucinous (mucinous cystic neoplasm - MCN and intraductal papillary mucinous neoplasm - IPMN). MCN are considered premalignant lesions and the indication for surgery depends on the age and clinical status, while IPMN lesions are always malignant.(3)

Laboratory analysis of the cystic fluids The laboratory serum markers that can be elevated in the cystic lesions of the pancreas are amylase and lipase (increased in cases diagnosed with pseudocysts or IPMN), CA19-9 and CEA

Bacalbasa N., Gireada A., Balescu I.

(modestly elevated in patients with malignant lesions such as MCNs and IPMNs and markedly elevated in patients with adenocarcinoma due to the obstruction of the main pancreatic duct and formation of cyst).

Through the endoscopic ultrasoundguided fine needle aspiration the cyst fluid can be aspirated and some parameters can be analyzed. These parameters are cytology, viscosity, extracellular mucin, tumor markers like CEA, CA19-9, CA15-3, CA72-4, enzymes such as amylase and lipase and DNA analysis. The results can be used for risk stratification, in association with imagistic methods. Using the tumor markers a differentiation between benign and malignant lesions or mucinous and non mucinous lesions can be made.

In this way, investigation of the cyst fluid parameters has lead to a higher accuracy of the diagnosis.

When studying the cyst viscosity, mucinous adenomas and adenocarcinomas have a higher viscosity than pseudocysts and serous cystadenoma.

In order to distinguish between benign and malignant lesions, tumor markers such as CEA might be used.

In a study performed by M.S. Bhutani et al , CEA levels were determined in order to establish a differential diagnoses. In mucinous cystadenoma they found a value of 878 ng/ ml, while in mucinous cystadenocarcinoma a value of 27581 ng/ml was encountered. Lower concentrations were obtained in pseudocyst (189 ng/ml) and serous cystadenoma (121 ng/ml). For the accuracy of the diagnosis of mucinous cysts they found a CEA value of ≥ 480 ng/ml and a viscosity >1,6. Other studies have found another way of establishing this diagnosis, by measuring the CEA concentration, identifying the presence of extracellular mucin and examining cellularity (2).

In the study performed by Frossard et al, concentrations of CEA > 400 ng/ml differentiated with a sensitivity and specificity of 57% and 100% between mucinous tumors and cystadenocarcinomas, on one side, and pseudocysts, on the other side. At a cut-off of 4 ng/ml, CEA provided a positive diagnosis of serous cystadenomas with a sensitivity of 100% and a specificity of 93% (4) In the study of Waaij et al the benign character of pancreatic cysts was predicted by CEA < 5 ng/ ml and CA19-9 < 37 U/ml with a sensitivity of 50% and a specificity of 95%. Malignant (mucinous cystadenocarcinoma) or premalignant (mucinous cystadenoma) were predicted by CEA > 800 ng/ ml with a sensitivity of 48% and a specificity of 98%. This study proposed that the combination

of CEA, amylase concentration and cytologic examination can be used for the differentiation of malignant versus benign cysts (5).

In a large multicenter study, it was found that at a cut-off of 192 ng/ml for CEA was able to distinguish between mucinous and nonmucinous cysts with an accuracy of 79%, which was higher than that of cytology or other combination of tests (2).

A study which included 442 patients with pancreatic cysts analyzed subsequently different tumor markers concentrations. A CEA cut-off of 30 ng/ml diagnosed mucinous cysts with a sensitivity of 79%, a specificity of 73% and a positive predictive value of 84%. Patients with CEA values < 30 ng/ml were divided in two groups.

Those with amylase concentrations >8500 U/l were pseudocysts in 91% of cases, while those with amylase < 350 U/l represented 85% of cases diagnosed with serous cystadenomas.

For patients with CEA >30 ng/ml, CA19-9 led to the formation of another two groups. Those with CA19-9 < 8000 U/ml represented 71% of patients with IPMN. (2) Hammel et al found that CEA levels < 5ng/ ml diagnosed serous cystadenomas with a sensitivity of 100% and a specificity of 86%. (6) In a study performed by R.Talar-Wojnarowska et al in 2012, for malignant cysts, concentrations of 238±12,5 ng/ml for CEA and 222±31,5 for CA19,9 were obtained, significantly higher than the results obtained for benign lesions (34,5±3,7 ng/ml for CEA and 18,5±1,9 ng/ml for CA19-9). At a cut-off of 45ng/ml for CEA, the sensitivity and specificity of diagnosis were 91,8% and 63,9%. For a cut-off of 37 U/ml, the sensitivity and specificity of CA19-9 were 81,3% and 69,4% (7).

An analysis performed by Brugge et al in a large group of patients demonstrated that CEA is the most useful tumor marker for the detection of malignant pancreatic lesions; the same study demonstrated that the accuracy of the method was not improved by the additional use of CA199, CA72-4, CA125 or CA15-3, or by the additional use of cyst morphology or cytology.(8) A number of studies have shown that CEA and amylase can’t distinguish between different types of malignant lesions.(6) A study performed by Frossard et al demonstrated that for a cut-off of 50000 U/ ml CA19-9 has a sensitivity and a specificity of 15% and 81% respectively in order to diagnose mucinous cysts and a sensitivity and specificity of 86% and 85% respectively when it comes to the diagnosis of cystadenocarcinoma.(4) In the study performed by Hammel et al CA 19-9 > 50000 U/ml diagnosed mucinous tumors with a sensitivity of 75% and a specificity of 90%.(6) In the study of R. Talar-Wojnarowska et al, lower April 2015

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The Role Of Pancreatic Cysts Fluid Analysis In Determining Malignant Lesions – Literature Review

The use of biochemical parameters measured

from cystic fluid can be synthesized as follows:

SCA

MCN

MCAC

PseudocystPP

CEA

Low

High

High

Low

CA 125

Variable

Variable

High

Low

CACA 19-9

Variable

Variable- high

Variable-high

Variable

Amylase

Low-high

Low-high

Low-high

High

Lipase

Low

Low

Low

High

SCA: Serous cystadenoma; MCN: Mucinous cystic neoplasm; MCAC: Mucinous cystadenocarcinomas(4)

levels of CA19-9 in the cyst fluid (less than 37 U/ ml) were associated with benign lesions. (7) In a study performed by Snozek et al CA 19-9 determined in cyst fluid could differentiate mucinous cystadenomas and IPMN (p=0,003). The study raised the question about the possibility of existence of a tumor marker capable to distinguish between various mucinous types. (9) In the same study performed by Frossard et al a correlation was established between high levels of CA72-4 and the presence of mucinous cystic tumors (P<0,005). The sensibility and specificity of the tumor marker in the diagnosis of mucinous or malignant cysts was 80%, respectively 95%. (4) In a later performed study, for a cut-off value of CA 72-4 of 40 U/ml, the sensibility and specificity for the differential diagnosis of mucinous cystadenomas or cystadenocarcinomas from pseudocysts and serous cystadenomas were 63% and 98%.(2) Sperti et al found that high concentrations of CA 72-4 in pancreatic cyst fluid are associated with mucinous tumors (P<0,005) and that CA724 can detect mucinous or malignant cysts with a sensitivity of 80% and a specificity of 95%. The results were that high serum CA19-9 values, positive cytology or high CA 72-4 in the cyst fluid are an indication for surgical resection of the pancreatic cysts. (10)

Serum amylase and lipase In patients with pancreatic pseudocysts, amylase and lipase concentrations are elevated most of the time, but normal values might be encountered too (1,2).

Serum bilirubin The presence of high bilirubin levels in patients with pseudocysts may indicate the presence of gallstones, extrinsic compression of biliary tract or alcoholism. (1,2)

36

Serum liver chemistry markers When they are elevated, they can lead to the possibility of biliary pancreatitis with the subsequent development of a pseudo-cyst. (1,2) Amylase levels can be determined in the fluid of pancreatic cysts. Concentrations higher than 5000 U/ml can diagnose pseudocysts with a sensitivity and specificity of 94% and 74%. (4) A study performed by R.Talar-Wojnarowska et al in 2012 obtained higher concentrations of amylase levels in benign pancreatic cysts (27825,7±91,9 U/l) than in malignant cysts (8359,2±32,7 U/l). Of all lesions, pseudocysts had the highest concentration (41778±131,5 U/l). The amylase concentration did not have the accuracy of CEA and CA19-9 in the diagnosis of malignant lesions. (7) Snozek et al found, in 91% of pseudocysts, concentrations of CEA of less than 30 ng/ml and concentrations of amylase higher than 8500 U/l (8).

Attasaranya et al found that for a cut-off of 5000 U/l, amylase has a sensitivity of 100% and a specificity of 63,6% in the diagnosis of pseudocysts. This is related to the fact that high amylase fluid levels can be also found in MCN and IPMN (11).

One small study investigated a tumor marker named Plectin-1 (Plec-1), which is associated with pancreatic cancer. The study used the results from seven patients, four of them having malignant cysts and three of them having benign cysts. Only the four patients with malignant cysts had high concentrations of Plec-1. (3) A problem that is possible to appear in the detection of tumor markers from pancreatic cysts by some laboratory methods (Roche E170 immunoassays) is the marked nonlinearity upon dilution. A few explanations can lead to this phenomenon. a) A possible explanation is that there are differences in the antigen and its immunoreactivity in the cyst fluid compared

Bacalbasa N., Gireada A., Balescu I.

to serum. CA19-9 was first detected in gastrointestinal tumor cells, where it has the structure of a ganglioside. In the serum it is associated with a mucin, but its biochemical characters in the cyst fluid are unknown.

CEA can be found in many molecular forms, depending on the type of glycosylation. b) Another explanation can be given by the fluid viscosity and the presence of a cellular debris that can be invisible, but these properties have not been revealed and associated with nonlinearity. c) A high-dose hook effect can produce abnormal CA19-9 results upon sample dilution.

It is advisable that the measurements of CA 19-9 and CEA from pancreatic cysts be done cautiously. Serial dilutions can be one of the

quality-assessment measures necessary in this case.(7)

Conclusions Association of laboratory analysis of pancreatic cyst fluids is a safe method which seems to improve the preoperative diagnosis and to better guide the clinician to establish which is the most appropriate therapeutical option in patients diagnosed with pancreatic cysts.

This work is licensed under a Creative Commons Attribution 4 .0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/4.0/

References 1) Lewandrowski, KB, Southern, J F, Pins, M R, Compton, C C, Warshaw, A L Cyst fluid analysis in the differential diagnosis of pancreatic cysts. A comparison of pseudocysts, serous cystadenomas, mucinous cystic neoplasms, and mucinous cystadenocarcinoma, Ann Surg. 1993 Jan; 217(1): 41–47.

2) Bhutani, M., Gupta, V., Guha, S., Gheonea, DI, Săftoiu, A., Pancreatic Cyst Fluid Analysis – A Review, J Gastrointestin Liver Dis June 2011 Vol. 20 No 2, 175-180 3) Park,W., Screening for pancreatic cancer: what can cyst fluid analysis tell us?, F1000 Medicine Reports 2011, 3:3 (doi:10.3410/M3-3) 4) Frossard JL, Amouyal P, Amouyal G, et al. Performance of endosonographyguided fine needle aspiration and biopsy in the diagnosis of pancreatic cystic lesions. Am J Gastroenterol 2003; 98: 1516–1524 5) van der Waaij LA, van Dullemen HM, Porte RJ. Cyst fluid analysis in the differential diagnosis of pancreatic cystic lesions: a pooled analysis. Gastrointest Endosc 2005; 62: 383-389.

6) Hammel P, Voitot H, Vilgrain V, Lévy P, Ruszniewski P, Bernades P. Diagnostic value of CA 72-4 and carcinoembryonic antigen determination in the fluid of

pancreatic cystic lesions. Eur J Gastroenterol Hepatol 1998; 10: 345-348.

7) TalarWojnarovska, R., Pazurek, M., Durko, L., Degowska, M., Rydewska, G., Smigielsk, J., Janiak, A.,, Olakowski, A., Lampe, P.,, Grezelak, P., Stefanczyk, L., MaleckaPana, E. Pancreatic cyst fluid analysis for differential diagnosis between benign and malignant lesions, Oncology Letters 5: 613-616, 2013 8) Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study.

Gastroenterology 2004; 126: 1330-1336.

9) Snozek CL, Mascarenhas RC, O’Kane DJ. Use of cyst fluid CEA, CA19-9, and amylase for evaluation of pancreatic lesions. Clin Biochem 2009; 42: 1585-1588.

10) Sperti C, Pasquali C, Guolo P, Polverosi R, Liessi G, Pedrazzoli S. Serum tumor markers and cyst fluid analysis are useful for the diagnosis of pancreatic cystic tumors. Cancer 1996; 78: 237-243.

11) Attasaranya, S., Pais, S., LeBlanc, J., McHenry, L., Sherman, S., DeWitt, J.,Endoscopic Ultrasound-Guided Fine Needle Aspiration and Cyst Fluid Analysis for Pancreatic Cysts, JOP. J Pancreas (Online) 2007; 8(5):553-563.

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Ovarian tumor revealed by polyserositis with massive pericardial effusion – an atypical Meigs syndrome

OVARIAN TUMOR REVEALED BY POLYSEROSITIS WITH MASSIVE PERICARDIAL EFFUSION – AN ATYPICAL MEIGS SYNDROME Andreea Boiangiu1, Cristina Vladu1, Nicoleta Clim1, Alexandru Filipescu1,2 1. Department Of Obstetrics and Gynecology – University Hospital ELIAS, Bucharest 2. University Of Medicine and Pharmacy “Carol Davila”, Bucharest Corresponding author: Andreea Boiangiu andreeaboiangiu@gmail.com

Open Access Article

Abstract Keywords: ovarian tumor; pericardial effusion; ascitis; pleural effusion

Meigs syndrome consists of a triad that includes benign ovarian tumor with ascites and pleural effusion, that resolves after resection of the tumor. It is a diagnosis of exclusion and it can be certified only after ovarian carcinoma is ruled out. The treatment of choice is surgery and it has a very good prognosis. It is mandatory to exclude an ovarian tumor in any woman with unexplained pleural or pericardial effusion. We report a rare case of atypical Meygs syndrome revealed by massive pericardial effusion.

Introduction Meigs syndrome consists of a triad that includes benign ovarian tumor with ascites and pleural effusion, that resolves after resection of the tumor.

Because ovarian cancer has the highest mortality rates of all gynaecologic malignancies, this triad should be considered a malignant process until proven otherwise. We report a rare case of atypical Meygs syndrome revealed by massive pericardial effusion. A few cases of ovarian tumors associated with ascitis, pleural and pericardial effusion are reported in the literature and are referred also as an atypical Meigs syndrome.

Received: April 2015 Reviewed: April 2015 Accepted: April 2015

Case report

Cite this article: Boiangiu A., Vladu C., Clim N., Filipescu A. Ovarian tumor revealed by polyserositis with massive pericardial effusion – an atypical Meigs syndrome. Rom J Oncol Hematol. 2015; 6(1):38-41

A 46 year old woman was admitted to our emergency room with increasing breathlessness and pleuritic chest pain, after an episode of faintness at work. On examination she was hypotensive, tachycardic and tachypneic. Bilateral jugular distension was detected. She had equidistant heart sounds and evidence of bilateral pleural effusion.

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On the electrocardiogram there were: sinus tachycardia, widespread concave ST and PR depression (I, II, III, aVF, V4-6) and reciprocal ST depression and PR elevation in V1 and aVR. (Fig. 1).

Cardiomegaly and bilateral pleural effusions were seen on chest radiography and an echocardiogram showed pericardial thickening with a 3 cm global pericardial effusion and evidence of cardiac tamponade (Fig. 2).

Due to the patient’s clinical instability, drainage of the pericardial effusion was mandatory and also an aspiration of the pleural effusion with drainange of 500 cc of amber-coloured fluid. Cytology of the pericardial and pleural liquid showed no evidence of malignancy, only non-specific inflamatory changes.

After the patient was hemodynamically stable a thoracoabdominal CT was performed. The CT examination showed: a low pleural effusion, ascitis and a right ovarian mass with nonhomogeneous izoechogenity and the suspicion of a malignant ovarian process was raised. (Fig. 3).

Boiangiu A., Vladu C., Clim N., Filipescu A.

Figure 1. Sinus tachycardia, widespread concave ST and PR depression (I, II, III, aVF, V4-6)

and reciprocal ST depression and PR elevation in V1 and aVR

Figure 2.

Echocardiogram showing large pericardial effusion At this moment a gynaecological opinion was sought and a laparotomy was recommended. The patient underwent total abdominal hysterectomy and bilateral salphingo-oophorectomy (Fig.4) .

Frozen section pathology and paraffin histopathological examination confirmed that the patient had a benign ovarian tumor: an association of serous papillary cyst adenoma and mature ovarian teratoma (Fig.5).

After the surgical treatement, the pleural and pericardial effusions, as well as the ascitis resolved completelyâ&#x20AC;&#x201D;as it was confirmed by a repeated echocardiography and a CT of chest and abdomen at 1 week post surgery. The patient was also referred to the department of autoimmune diseases in order to investigate the origin of the polyserostis, knowing that lupus can be a condition with similar symptomatology and that it was reported

as a possible associated condition in Meigs syndrome.

At follow-up the patient remains free of pericardial, pleural and ascitic fluid on clinical examination. Four weeks after discharge the chest X-ray, echocardiography, ECG and abdominal ultrasound were of entirely normal appearance.

Disscusion In 1937, Meigs et al1 described what was later known as Meigsâ&#x20AC;&#x2122;syndromeâ&#x20AC;&#x201D;a rare triad of ovarian fibroma/thecoma, ascites, and hydrothorax, in which the cure was achieved by completely removing the benign tumor. 1 In 1954 Meigs, by now chief of gynaecology at the Massachusetts General Hospital, proposed that his syndrome should be confined to benign solid ovarian tumours in association with ascites and pleural effusion and that April 2015

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Reviews

Ovarian tumor revealed by polyserositis with massive pericardial effusion – an atypical Meigs syndrome

Figure 3.

Contrast-enhanced CT scan shows a right nonhomegenous ovarian tumor with fat and calcifications

Figure 4.

Intraoperative aspect of the right ovarian tumor – sugesting a dermoid cyst

it was cured without recurrence, when the tumour was removed.2 This syndrome occurs in only 1–2% of ovarian “fibromas”; histologically, the tumour may be a fibroma, thecoma, cystadenoma or granulosa cell tumour.

Since the original description by Meigs, ascites and hydrothorax have been reported in other gynaecological conditions, including fibroids, degenerative ovarian changes, mature cystic teratomas and ovarian hyperstimulation syndrome; such variants have been termed pseudo-Meigs’ syndrome.3 However, Meigs syndrome is a diagnosis of exclusion, only after ovarian carcinoma is ruled out4.

The treatment of choice is exploratory laparotomy

40

with unilateral salpingo-oophorectomy in women of reproductive age and total hysterectomy is preferred in postmenopausal women. Ascites and hydrothorax resolve within a few weeks after surgery, without any recurrence.5 Pseudo-pseudo Meigs syndrome includes patients with systemic lupus erythematosus and enlarged ovaries.6 Ascitic fluid and pleural fluid are mostly transudative effusions and are negative for malignant cells, but in some cases they can also be exudative. The origin of the fluid accumulations is unknown; inflammatory cytokines and hormonal or tumoral stimulation are possible etiologies.7 A possible pathogenesis of the formation of the pleural and peritoneal effusions in the case of ovarian tumors can be explained

Boiangiu A., Vladu C., Clim N., Filipescu A.

Figure 5. a) ovarian mature teratoma showing adipose, connective, muscular, epidermal tissue

b) serous papillary ovarian cyst adenoma - unilocular cysts that contain clear, straw-colored fluid, lined by simple epithelium with cilia . HE staining x 10 X by the filtration of interstitial liquid to the peritoneum through the ovarian tumor capsule.

This liquid can also diffuse to the pleural space through the diaphragmatic lymphatic vessels in the Bochdalek’s foramen or through diaphragmatic defects.8 The most significant differential diagnosis includes malignant ovarian tumor, which is more prevalent in comparison to Meigs’ syndrome and which generates ascites with high protein content.

But pleural effusion tends to be less common in the case of the malignancy. Other differential diagnosis include cancers of the colon and the lung, tuberculosis, nephrotic syndrome, congestive heart failure and cirrhosis.

Dyspnea, jugular distension and hypotension suggest the presence of pericardial effusion and cardiac tamponade is an acute presentation. The diagnosis is confirmed by echocardiography and the pericardial drainage is indicated. An abdominal CT scan can confirm the presence of an ovarian tumor. Any woman presenting with pericardial or pleural effusion should be investigated for ovarian tumors.9,10,11

Conclusions The triad of ascites, hydrothorax and a benign ovarian tumor defines a rare clinical en-

tity termed Meigs syndrome. Subsequently a new variant appeared, known as Meigs-like syndrome, which associates pericardial effusion with the original definition of Meigs syndrome. 12 Because of the rarity of the syndrome and its low place in the differential diagnosis, there is usually an attempt to treat the ascites and pleural effusion by aspiration.

Also due to the possible association with an autoimmune disease, autoimmunity testing should be performed.

It is mandatory to exclude an ovarian tumor in any woman with unexplained pericardial effusion.9,10 Although Meigs syndrome mimics a malignant condition, it is a benign disease and it has a very good prognosis, if it’s properly managed. Life expectancy after surgical removal of the tumor mirrors that of the general population. 11 This work is licensed under a Creative Commons Attribution 4 .0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/4.0/

References 1. Meigs JV, Cass JW. Fibroma of the ovary with ascites and hydrothorax: 2. Meigs JV. Fibroma of the ovary with ascites and hydrothorax—Meigs’ syndrome. Am J Obstet Gynecol 1954;67:962–87 3. O’Flanagan SJ, Tighe BF, Egan TJ, Delaney PV. Meigs’ syndrome and pseudo Meigs’ syndrome. J R Soc Med 1987;80:252–3 4. Riker D, Goba D. Ovarian mass, pleural effusion, and ascites: revisiting meigs syndrome. J Bronchology Interv Pulmonol. Jan 2013;20(1):48-51. [Medline].

5. Bretelle F, Portier MP, Boubli L, Houvenaeghel G. Recurrence of DemonsMeigs syndrome. A case report. Ann Chir 2000; 125 (3): 269-277 6. Schmitt R, Weichert W, Schneider W, Luft FC, Kettritz R. Pseudo-pseudo Meigs’ syndrome. Lancet. Nov 5 2005;366(9497):1672. [Medline].

7. Abramov Y, Anteby SO, Fasouliotis SJ, et al. The role of inflammatory cytokines in Meigs’ syndrome. Obstet Gynecol. 2002;99:917---91.

8. Sahn SA. The pleura. Is Rev Respir Dis 1988; 138: 184-234.

9. María Elena Arnáiz-Garcíaa, José María González-Santosa, Javier LópezRodrigueza, María José Dalmau-Sorlia,María Encarnación Bueno-Codonera, Javier Arnáiz: Meigs-like syndrome presenting as cardiac tamponade Rev Port Cardiol. 2013;32(6):547---548 10. Sohail Qaisar, Faizel Osman ,Michael Pitt Resolution of pericardial effusion after removal of ovarian fibroma—a Meigs’-like syndrome - J R Soc Med 2005;98:313–314 11. Mohammed N Al-Khafaji, Salim Ahmed - Meig’s syndrome with massive pericardial effusion, bilateral pleural effusion and ascites - Br J Cardiol 2005;12:394–5 12. Qaisar S, Osman F, Pitt M. Resolution of pericardial effusion after removal of ovarian fibroma --- a Meigs’-like syndrome. J R Soc Med. 2005;98:313---4.

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Giant ovarian mucinous cyst adenoma at 70 years old – case report

GIANT OVARIAN MUCINOUS CYST ADENOMA AT 70 YEARS OLD – CASE REPORT Andreea Boiangiu1, Cristina Vladu1, Nicoleta Clim1, Florin Andrei2, Alexandru Filipescu1,3 1. Department Of Obstetrics and Gynecology – University Hospital ELIAS, Bucharest 2. Department Of Histopathology - University Hospital ELIAS, Bucharest 3. University Of Medicine and Pharmacy “Carol Davila”, Bucharest Corresponding author: Andreea Boiangiu andreeaboiangiu@gmail.com

Open Access Article

Abstract Keywords: postmenopausal; ovarian cancer; giant cyst adenoma

Of all the gynecologic cancers, ovarian malignancies represent the greatest clinical challenge. Ovarian epithelial tumors comprise about half of all ovarian tumors, accounting for about 40% of benign tumors and 86% of malignant tumors. Regarding the evolution, ovarian tumors often are clinically silent, so they can considerable grow in size.

We present the case of a 70 years old postmenopausal woman, who arrived to the emergency department for dyspnea, palpitations, fatigue and walking deficiencies and she was suspected of ovarian cancer, but finally was diagnosed with a giant ovarian mucinous cyst adenoma. The case that we are presenting, is one of the largest ovarian mucinous cyst adenoma in literature and the largest cyst reported in our clinic.

Introduction:

Received: April 2015 Reviewed: April 2015 Accepted: April 2015 Cite this article: Boiangiu A., Vladu C., Clim N., Andrei F., Filipescu A. Giant ovarian mucinous cyst adenoma at 70 years old – case report. Rom J Oncol Hematol. 2015; 6(1):42-47

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Of all the gynecologic cancers, ovarian malignancies represent the greatest clinical challenge. Epithelial cancers are the most common ovarian malignancies and because they are usually asymptomatic until they have metastasized, patients have advanced stages of the disease at diagnosis in more than two thirds of the cases.

A woman’s risk at birth of having ovarian cancer sometime in her life is 1% to 1.5%, and that of dying from ovarian cancer almost 0.5% (1) .

Ovarian tumors are divided by the origin of the cells in three main groups: epithelial, stromal and germ cell. Ovarian epithelial tumors comprise about half of all ovarian tumors, accounting for about 40% of benign tumors and 86% of malignant tumors (2).

Classified by histopathology ovarian benign tumors can be: serous cyst adenomas, mucinous cyst adenomas, dermoid cyst, Brennen tumor,

disgerminomas, tumors with granulose cells, tumors with techal cells, androblastomas and ginandroblastomas. Regarding evolution ovarian tumors are often mute clinical so they can grow considerable in size. Sometimes they can be complicated by torsion, hemorrhage, rupture and 1-3% of them can transform into malignancies (3).

Case report: We present the case of a 70 years old postmenopausal women, who presented at the emergency department for dyspnea, palpitations, fatigue and walking deficiencies. At admission her abdomen was so distended that she looked like a 9-month pregnant women. (Fig 1 a,b).

Her medical history was normal, with no other pathology intricate, none other illness or surgery in her medical history. She noticed a gradually increasing of her abdomen in the last 2 years. In

Boiangiu A., Vladu C., Clim N., Andrei F., Filipescu A.

Figure 1 a,b.

Distended abdomen â&#x20AC;&#x201C; front and lateral view

Figure 2.

A large tense mass lying between symphysis and the diaphragmatic cupolas

the last 6 months she also felt abdominal diffuse pain and tension, and her abdomen has doubled in size. Due to the huge mass that she was carrying day by day, she developed difficulties at walking, fainting attacks, palpitations and extreme fatigue. Her intestinal transit was normal and had no bladder problems. She is a 7G 5P and attained menopause at 49 years old. In her family there are no malignancy histories.

On general clinical examination we observed an undernourished thin build woman with extreme thin limbs and a batrachians abdomen.

She weighed 67 kg. She was pale, normotensive but tachycardic. The abdomen was grossly distended with engorged veins present â&#x20AC;&#x201C; like a collateral circulation, at palpation a painless huge mass extended from the pubic symphysis to the

xiphoid process was revealed and fluid thrill was present. Bowell sound were heard in the flanks.

Vaginal examination showed voluminous cystorectocele, cicatricial cervix and both fornices full. Preoperative exams were normal, but with growth of the tumoral marker CA 125=67 mU/ ml (<35 mU/ml).

At the abdominal ultrasonography a giant mixed cystic- solid mass was occupying the whole abdomen and compression of the other abdominal organs was seen. The origin of this mass was still uncertain. Nor the uterus or the ovaries were identified. A CT exam was requested at that moment.

The CT exam revealed a large mass lying between the pubic symphysis and the xiphoid process with a probably origin on the right ovary.

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Giant ovarian mucinous cyst adenoma at 70 years old â&#x20AC;&#x201C; case report

Figure 3.

Clamping the vascular pedicles of the right ovarian mass

The next step was planning an exploratory laparotomy. The abdomen was opened initially with a vertical midline incision from the pubic symphysis and subxyphoidian and then it was extended to the xyphoid process due to the large mass. As we revealed earlier, in the abdominal cavity we observed a large tense and highly vascularized mass lying between symphysis and the diaphragmatic cupolas â&#x20AC;&#x201C; apparently attached to the right ovary. The right fallopian tube was also adherent to the tumor; the left ovary and fallopian tube were visible at that moment. In the abdominal cavity was no free liquid. (Fig. 2) We decided to excise the tumour mass intact. So we identified the vascular pedicles and clamped them. (Fig.3) After that thoroughly adhesolysis was made. After clamping, the sectioning and ligaturing the vascular pedicles was practiced and we excised a tumoral mass measuring 320/310/200 mm, with very ferm consistence, partially round shaped and with irregular surface.(Fig. 4) After excising the tumor in the

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left abdominal flank, we identified the left ovary which was attached to a 170/150/100 cm mass with the same appearance with the previous mass. We clamped, sectioned and ligatured the vascular pedicles from this tumor to and excise it.(Fig. 5) The first mass weight 22 kg and the second mass 5 kg. Both tumors were sent to the histopathology department for examination. At that moment frozen sections confirmed a benign tumor so that we continued with total abdominal hysterectomy. The uterus and the left fallopian tube seemed normal, as the rest of the abdominal organs. Postsurgery period was uneventful; the status of the patient was good, with a fast recovery. In the third day postsurgery she was discharged.

Histopathology conclusions Macroscopic examination revealed a 320/ 310/ 200 mm tumor, with smooth surface, thin and smooth walls (1-2mm) with serocitrin liquid inside and a polycystic mass with hemorrhage and congestion areas

Boiangiu A., Vladu C., Clim N., Andrei F., Filipescu A.

Figure 4.

The large tumor after excision measuring 320/310/200 mm

Figure 5.

The second tumor before clamping her vascular pedicle

of 70/40mm, a 170/150/100 mm cyst with thin walls and opalescent content, 95/35/55 mm uterus with normal appearance.(Fig. 6, 7) Histopathologicaly exam showed a cyst with thin fibromuscular walls lined with mucinous epithelium, without nuclear and cellular atypia â&#x20AC;&#x201C; suggestive aspect for mucinous ovarian cystadenoma.

Correlating clinical findings with paraclinical and histopathology results, we resume the diagnostic: giant ovarian mucinous cystadenomas presented in a 70 years old postmenopausal woman.

Discussions Such large ovarian cysts are a rare pathology, the most remarkable descriptions are those of Spohn, who in 1922 reported one that weighed 148.6 kg (328 lb), and of Symmonds, who in 1963 reported encountering one that weighed 79.4 kg (175 lb). Such descriptions were among the curiosities reported in the 19th and early 20th centuries. They have become rarer as imaging modalities improveand diagnoses are made earlier (4,5,6,7) .

Ovarian epithelial tumors comprise about half of all ovarian tumors, accounting for about 40% April 2015

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Giant ovarian mucinous cyst adenoma at 70 years old â&#x20AC;&#x201C; case report

Figure 6.

Thin and smooth walled tumor with serocitrin content

Figure 7.

Polycystic mass (70/40 mm) with hemorrhage and congestion areas

of benign tumors and 86% of malignant tumors.

These tumors are common representing about 25% of all benign ovarian neoplasms and 58% of all ovarian serous tumors. The serous tumors are bilateral in about 10% of cases of all serous tumors, about 70% are benign, 5-10% have borderline malignant potential and 20-25% are malignant, depending largely on the patientâ&#x20AC;&#x2122;s age.

They tend to be multilocular, but unilocular serous cyst adenomas are not uncommon. They

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present grossly as large as 35 cmin diameter, spherical or ovoidmasses (4,5).

Conclusions The peak incidence of invasive epithelial ovarian cancer is at 56 to 60 years of age. About 30% of ovarian neoplasms in postmenopausal women are malignant, whereas only about 7% of ovarian epithelial tumors in premenopausal patients are frankly malignant (1).

Boiangiu A., Vladu C., Clim N., Andrei F., Filipescu A.

Tabel 1 . Comparative giant ovarian cyst – a review of specialty literature 1. Spohn

148.6 kg

1922

2. Symmonds

79.4 kg

1963

3. P. Morrison, G. Morgan

113 kg

1987

4. Miguel Zamora-Garza, Joel Rizo, Alberto Dominguez

70 kg

1990

5. Ajit Sebastian, Anitha Thomas*, Annie Regi

30 kg

2012

6. A. Boiangiu, C. Vladu, N. Clim, F. Andrei, A. Filipescu

27 kg

2013

7. Vellanki Venkata Sujatha, Sunkavalli Chinna Babu

23 kg

2009

8. SH Pandya, R Divekar, L Tuteja

22,5 kg

1992

9. Mülayim B, Gürakan H, Dagli V, Mülayim S, Aydin O, Akkaya H:

9,5 kg

2006

Nowadays giant cyst adenomas became a rare pathology due to the regular medical check-ups and routine ultrasonographyes.

Nevertheless there are still some patients with low medical knowledge and addressability, so we can still find cases with such big tumors developing in time and being neglected. While making a time analysis, we found a few cases with giant ovarian cases as we illustrate them in Table 1. The case that we presented is one of the largest ovarian cystadenoma in literature and the largest cyst reported in our

clinic. It is a pathology with deep emotional impact, but with a good postsurgery recovery. The 6 months and 1 year clinical evaluation showed a total recovered patient with a good quality of life after surgery.

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References 1. Berek Jonathan S. - Section VIII - Gynecologic Oncology > 35 - Ovarian and Fallopian Tube Cancer in 2. Mülayim B, Gürakan H, Dagli V, Mülayim S, Aydin O, Akkaya H: Unaware of a giant serous cyst adenoma: a case report. Arch Gynaecol Obstet 2006, 273:381-383.

3. Vladareanu R. –chapters 61- Ovarian benign tumors, 62- Ovarian malign tumors in Obstetrics and Clinical Ginecology for residents and students – ed. Univ. “Carol Davila”, Bucharest, 2006

4 Sujatha Vellanki V. , Babu Sunkavalli C. - Giant ovarian serous cystadenoma in a postmenopausal woman:a case report- Cases Journal 2009, 2: 7875 doi: 10.4076/1757-1626-2-7875 5. Menahem S, Shvartzman P: Giant ovarian cyst mimicking ascites. J FamPract 1994, 39:479-481.

6. Young TH, Lee HS: Images in clinical medicine. Giant Ovarian Cyst N Engl J Med 2008, 358:e22.

April 2015

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International articles

48

Titlul articolului

Nume autori

ACTUALITĂŢI ÎN ONCOLOGIE:

ABORDARE MULTIDISCIPLINARĂ ÎN AFECŢIUNILE ONCOLOGICE 15 MAI 2015 HOTEL NOVOTEL, BUCUREȘTI

CAIET DE ABSTRACTE April 2015

49

SPEAKERI Prof. Dr. Alexandru Blidaru, UMF Carol Davila, București Prof. Dr. Radu Vlădăreanu, UMF Carol Davila, București Conf. Dr. Alexandru Filipescu, UMF Carol Davila, București Conf. Dr. Monica Dragomir, UMF Carol Davila, București Conf. Dr. Carmen Orban, UMF Carol Davila, București Conf. Dr. Anca Coliţă, UMF Carol Davila, București Conf. Dr. Gabriel Kacso, UMF Iuliu Haţieganu, Cluj-Napoca Sef. Lucr. Dr. Dana Stănculeanu, UMF Carol Davila, București Sef. Lucr. Dr. Simona Vlădăreanu, UMF Carol Davila, București Sef. Lucr. Dr. Silviu Voinea, UMF Carol Davila, București Asist. Univ. Dr. Nicoleta Berbec, UMF Carol Davila, București Dr. Ciprian Enăchescu, Centre Hospitalier Lyon Sud, Pierre Benite, France Dr. Eugenia Carmen Lisencu – Institutul Oncologic Cluj-Napoca

PARTENERI GOLD

PARTENERI SILVER

PARTENERI

50

www.healthmeeting.msc-ro.com

ACTUALITĂŢI ÎN ONCOLOGIE: ABORDARE MULTIDISCIPLINARĂ ÎN AFECŢIUNILE ONCOLOGICE

CERVICAL CANCER IN ADOLESCENCE: SCREENING AND THERAPEUTIC CONDUCT PARTICULARITIES Alexandru Filipescu1,2 Andreea Boiangiu1, Nicoleta Clim1 1. Department Of Obstetrics and Gynecology – University Hospital ELIAS, Bucharest; 2. University Of Medicine and Pharmacy “Carol Davila”, Bucharest Corresponding author: Andreea Boiangiu, andreeaboiangiu@gmail.com

Open Access Article

Abstract Keywords: adolescent; cervical cancer; screening; HPV; therapeutic conduct

The introduction of cervical cancer screening through Pap exams in adult patients resulted in an increase in early detection of this disease, thus improving the associated morbidity. The decreased age of the onset of sexual life combined with the risk of sexually transmitted infections, increased incidence of HPV infection at an early age have outlined a new health problem. The incidence of cervical cancer in adolescents (14 to 19 years) worldwide, although small <1%, is one of the reasons why the methods of screening, prevention and therapeutic conduct addressed to this age category are in permanent changing and improving.Latest screening recommendations suggest an adapting screening by age with cytology and high-risk HPV infection detection, followed by an appropriate follow-up. When the cytological examination of a teenage girl is modified, it is important to know which is the correct therapeutic attitude so as to minimize potential adverse effects and to focus on the future patient’s fertility. The oncology protocol addressed to an adolescent woman with cervical cancer is adapted depending on the disease stage, putting in balance the potential risks, complications, long term prognosis, with the most important indicator: survival rate followed by the idea of preserving ​​ fertility.

Rezumat Cuvinte-cheie: adolescentă; cancer de col uterin; screening; HPV; conduită terapeutică

Introducerea screening-ului cancerului de col uterin prin examen PAP la pacientele adulte a dus la o creştere a ratei de detecşie precoce a acestei patologii, îmbunătăţind astfel morbiditatea asociată. Scăderea vârstei de debut a vieţii sexuale împreună cu riscul de infecţii cu transmitere sexuală, creşterea incidenţei infecţiei HPV la vârste tinere au conturat o nouă problemă de sănătate. Incidenţa cancerului de col la adolescente (14-19 ani) la nivel mondial, deşi mică <1%, este un motiv pentru care metodele de screening, prevenţie şi conduită terapeutică adresate acestei categorii de vârstă sunt în permanentă schimbare şi îmbunătăţire. Ultimele recomandări presupun adaptarea screening-ului pe grupe de vârstă prin citologie şi detecţia infecţiilor HPV cu risc înalt urmate de follow up adecvat. Atunci când examenul citologic al unei adolescente este modificat, este important de ştiut care este atitudinea terapeutică sau de follow up corectă astfel încât să se minimalizeze potenţialele efecte negative punând pe primul plan viitoarea fertilitate a pacientei. Protocolul oncologic adresat adolescentei cu cancer de col uterin se adaptează în funcţie de stadiul bolii, punându-se în balanţă posibilele riscuri, complicaţii, prognosticul pe termen lung, pe primul loc fiind rata de supravieţuire, urmată de ideea conservării fertilităţii.

April 2015

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51

Caiet de abstracte

ACTUALITĂŢI ÎN ONCOLOGIE: ABORDARE MULTIDISCIPLINARĂ ÎN AFECŢIUNILE ONCOLOGICE

TUMORI TROFOBLASTICE AGRESIVE: DIAGNOSTIC ŞI CONDUITĂ Prof. Dr. Radu Vlădăreanu1, Asist. Univ. Dr. Vlad Zamfirescu2, Dr. Andrei Trăistaru3, Dr. Alina Marin4, Şef Lucr. Dr. Simona Vlădăreanu5 1. U.M.F. „Carol Davila” Bucureşti, Spitalul Universitar de Urgenţă Elias; 2. Medic Specialist Obstetrică-Ginecologie; 3. Medic Rezident Obstetrică-Ginecologie; 4. Medic Rezident Obstetrică-Ginecologie; 5. U.M.F. „Carol Davila” Bucureşti, Spitalul Universitar de Urgenţă Elias Bucureşti - Şef Secţie Neonatologie

Open Access Article

Rezumat Cuvinte-cheie: neoplazie trofoblastică gestaţională, sarcină molară, β-hCG

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Neoplazia trofoblastică gestaţională (NTG) include entităţi patologice care se dezvoltă sincron sau secundar atât unei sarcini molare, dar şi unei sarcini normale. Majoritatea NTG sunt diagnosticate pe baza dozării β-hCG, punân­du-se astfel în evidenţă persistenţa ţesutului trofoblastic. Stabilirea tipului optim de tratament necesită o evaluare completă a gradul de extensie al bolii.

Stadializarea anatomică a NTG, respectiv stratificarea riscului este determinată de sistemul elaborat de FIGO, respectiv de scorul prognostic elaborat de OMS. Lucrarea prezintă pricipalele metode de diagnostic ale NTG, punându-se accent pe urmărirea în dinamică a nivelurilor serice ale β-hCG, pe importanţa probelor imagistice în identificarea gradului de invazie locală şi a celor mai frecvente situsuri metastatice şi, nu în ultimul rând, pe componenta histologică a diagnosticului.

Principiile de conduită, urmărire şi terapie sunt detailate diferenţiat, în funcţie de scorul prognostic determinat printr-o interpretare corectă a parametrilor privind criteriile de stadializare. Pentru rezultate cât mai eficiente, este necesară solidarizarea chimioterapiei cu tratamentul chirurgical, precum şi monitorizarea post-terapeutică minuţioasă a nivelurilor serice ale β-hCG.

DIAGNOSTICUL PERINATAL AL NEUROBLASTOMULUI CONGENITAL Şef Lucr. dr. Simona Vlădăreanu1, Prof. dr. Radu Vlădăreanu1, Asist. univ. dr. Simona Popescu1, Dr. Bobe Mădălin Nicolae2, Gheorghe Andrei Preda2 1.UMF “Carol Davila” Bucureşti; 2. rezident neonatologie, SUU Elias

Rezumat Cuvinte-cheie: neuroblastom, congenital, neonatal, diagnostic perinatal, ecografie

52

Open Access Article

Tumorile congenitale sunt rare. Neuroblastomul este una dintre cele mai frecvente tumori maligne ale nou-născutului şi sugarului, cu localizare extracraniană. Tumora îşi are originea la nivelul celulelor crestei neurale, prezente de-a lungul întregului lanţ ganglionar simpatic sau al glandei suprarenale. Manifestările clinice ale neuroblastomului congenital sunt foarte variate, în funcţie de localizare, de vârsta la care se pune diagnosticul, de stadiul tumorii, dar şi de profilul citogenetic al acesteia. Prognosticul variază de la excelent, în formele cu regresie spontană până la extrem de sever, cu evoluţie rapid progresivă şi decesul pacientului. Aproape 1/5 din neuroblastoame sunt diagnosticate fie antenatal (neuroblastoamul fetal), fie în primele 3 luni de viaţă (neuroblastomul neonatal ). În ultimii 20 ani ecografia antenatală de rutină a crescut semnificativ rata diagnosticării neuroblastomului congenial, cu precădere în trimestrul al treilea. Metastazele in utero pot fi prezente, totuşi localizările multiple sunt rare.

ACTUALITĂŢI ÎN ONCOLOGIE: ABORDARE MULTIDISCIPLINARĂ ÎN AFECŢIUNILE ONCOLOGICE

CANCERUL OVARIAN – ACTUALITĂŢI ÎN TRATAMENTUL STANDARD ÎN 2015 Şef. Lucr. Dr. Dana Stănculeanu UMF “Carol Davila” Bucureşti

Abstract Keywords: ovarian cancer, chemotherapy, mutation

Open Access Article

Ovarian cancer is the 4th most common cause of cancer death among women. In over 60% of all cases, the disease is being diagnosed in late stages III and IV, with a survival rate of 70% at 1 year and 40% at 5 years.

One of the risk factors for 15 -20% of all the cases is familial transmission, the majority being linked with the BRCA 1 and 2 mutations, both germline and somatic. In fact ovarian cancer is not just one disease, but a group of diseases that can be classified according to tumorigenesis in “low grade” and “high grade” ovarian cancer, which is primarily due to ovarian cancer cell genomic instability. Ovarian cancers with BRCA mutation 1 and 2 are associated with high grade ovarian tumors (HGSOCs).

Advanced ovarian cancer is a chronic disease with multiple recurrences and it’s treatment is multidisciplinary (high-specialized in oncology gynecologist surgeon, medical oncologist, pathologist and radiologist).

The contribution of the oncology gynecologist surgeon is crucial in achieving surgical cytoreduction of the tumor volume and an absent tumor residue (R0) is a key element in a relapse-free survival.

The association paclitaxel- carboplatin based chemotherapy still represents the “standard of care” in the treatement of this disease.

Another challenge is the intraperitoneal chemotherapy which can be effective in a well selected group of patients. In the last two years, the medical therapeutic arsenal has two new molecules, Bevacizumab and PARP inhibitors (poly ADP -riboz – polymerase) Olaparib. Bevacizumab is the first molecule with an antiangiogenic role registered in adjuvant treatment and in maintenance treatment (GOG 0218 trial and ICON 7) and also in platinum-sensitive recurrent tumors (OCEAN) or platinum- resistant (AURELIA). To be noted that the results of treatment with Bevacizumab are significant in terms of progression-free survival (PFS), but not in terms of overall survival (OS). The most plausible explanation of this paradox is the possibility of encountering the “cross-over” phenomenon early in the studies on one hand, and on the other hand the studies need a larger number of patients who should participate, so that the study can be statistically significant in terms of an early cross over. The second molecule, Olaparib fulfills the criteria of a personalized treatment that targets the BRCA 1 and 2 mutation, somatic or germline, or BRCA deficiency-ness.

Targeting BRCA 1/2, its determination should be done in all patients with “high grade” ovarian cancer, with familial or ethnic transmission. PARP inhibitors work by the concept of synthetic lethality where PARP or BRCA deficiency alone has no impact on cell viability, but the presence of both deficiencies cause a lethal death. Olaparib is the first FDA approved PARP inhibitor, in advanced ovarian cancer in monotherapy, after three lines of treatment, while in Europe EMA approved its use in maintenance monotherapy, in patients with relapsed platinum-sensitive, somatic or germline BRCA mutation in serous, epithelial ovarian “high grade” tumor, peritoneal or fallopian primitive tumor, with complete or partial response to platinum-based chemotherapy. Other target molecules are in Phase II / III studies, focusing on suppressor genes such as p53 gene, or amplifying the immune mechanisms such as Nivolumab.

April 2015

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53

Caiet de abstracte

ACTUALITĂŢI ÎN ONCOLOGIE: ABORDARE MULTIDISCIPLINARĂ ÎN AFECŢIUNILE ONCOLOGICE

Rezumat Cuvinte-cheie: cancer ovarian, chimioterapie, mutaţie

54

Cancerul ovarian reprezintă a 4-a cauză de deces prin cancer la femei. Boala este diagnosticată în peste 60% din cazuri în stadii avansate de boală, III şi IV, cu o supravieţuire la 1 an de 70% şi la 5 ani de numai 40%. Unul dintre factorii de risc pentru 15-20% dintre cazuri este reprezentat de transmiterea familială, majoritatea cazurilor fiind legate de mutaţiile BRCA 1 şi 2, atât germinale, cât şi somatice. În fapt, cancerul ovarian nu este doar o singură boală, ci un grup de boli care în funcţie de tumorigeneză pot fi catalogate în cancere ovariene “low grade“ şi “high grade”, aceasta fiind datorată în primul rând instabilităţii genomice a celulelor tumorale ovariene. Cancerele ovariene cu mutaţie BRCA 1 şi 2 sunt asociate cu tumori ovariene cu grad înalt (HGSOCs).

Cancerul ovarian avansat reprezintă o boală cronică, cu multiple recidive, al cărei tratament este multidisciplinar (chirurg ginecolog supraspecializat în oncologie, oncolog medical, anatomopatolog şi radiolog). Aportul chirurgului este crucial în realizarea citoreducţiei volumului tumoral, iar absenţa restului tumoral (R0) reprezintă un element cheie în supravieţuirea fără recidivă.

Chimioterapia bazată pe asocierea paclitaxel-carboplatin reprezintă şi a reprezentat până nu de mult “standard of care“ în tratamentul bolii. O altă provocare o reprezintă chimioterapia intraperitoneală care poate fi eficientă la un grup bine selectat de pacienţi. În ultimii doi ani au intrat în arsenalul terapeutic medical două molecule noi, Bevacizumab-ul şi inhibitorii de PARP (poli ADP-riboz-polimerază)Olaparib. Tratamentul cu Bevacizumab, prima moleculă înregistrată cu rol antiangiogenic neselectiv este indicat în tratamentul adjuvant şi de mentenanţă (trialurile GOG 0218 şi ICON 7), dar şi în tumorile recidivate sensibile la platină (OCEAN) sau rezistente la platină (AURELIA). De menţionat că rezultatele obţinute de tratamentul cu Bevacizumab sunt semnificative din punct de vedere al supravieţuirii fără semn de progresie (PFS-ului), dar nu şi din punct de vedere al supravieţuirii generale (OS-ului). Explicaţia posibilă a acestui paradox s-ar datora probabil fenomenului de “cross-over” realizat timpuriu în aceste studii pe de o parte, iar pe de altă parte necesităţii unui număr foarte mare de pacienţi care ar trebui să participe la studii pentru ca acestea să fie semnificative statistic, în condiţiile de cross-over timpuriu. Cea de a doua moleculă Olaparib îndeplineşte condiţia unui tratament personalizat care are ca ţintă mutaţia BRCA 1 şi 2 somatică sau germinală, sau deficienţa BRCA-ness. Ţinta fiind BRCA 1/2, determinarea acesteia trebuie realizată la toţi pacienţii cu cancere ovariene “high grade“, cu transmitere familială sau etnică. Inhibitorii de PARP acţionează prin conceptul de letalitate sintetică, unde deficienţa, fie de PARP, fie de BRCA singură nu are impact pe viabilitatea celulei, dar pierderea ambelor determină un efect letal. Olaparib este primul inhibitor de PARP aprobat de FDA în indicaţia cancer ovarian avansat, în monoterapie, după trei linii de tratament, în timp ce în Europa EMA a aprobat utilizarea acestuia în monoterapie, în mentenanţă la pacienţii cu recidivă, sensibili la platină, cu mutaţie BRCA somatică sau germinala, cu tumoră ovariană seroasă, epitelială, “high grade”, de trompa sau peritoneala primitive, aflată în răspuns complet sau parţial la tratamentul pe bază cu platină.

Alte molecule care ţintesc alte căi, aflate în studii de faza II/III se adresează fie unor gene supresoare cum este p53, fie amplificării mecanismelor imune, precum Nivolumab.

ACTUALITĂŢI ÎN ONCOLOGIE: ABORDARE MULTIDISCIPLINARĂ ÎN AFECŢIUNILE ONCOLOGICE

RECIDIVA ÎN CANCERUL MAMAR Şef de lucrări Dr. Voinea Silviu, As. Univ. Dr. Şandru Angela U.M.F. „Carol Davila”, București, I.O.B. „Prof. Dr. Al. Trestioreanu”

Open Access Article

Abstract Keywords: breast cancer, local recurrence, regional recurrence, distant recurrence (metastasis)

Cancer recurrence represents the return of cancer after giving curative care to the patient and after a variable period of time during which the patient had no signs of the disease. Breast cancer recurrence (local, regional and distant) is an unfortune event with great implications for the patient as well as for the physician. Local recurrence of breast cancer can appear after mastectomy or after conservative surgery and it is not yet clear if it represents a marker for the appearance of the potential future metastasis.

The treatment of local recurrence is sometimes dificult to acheave and imposes the definition of new standart of care regarding their treatment.

Regional recurrence of breast cancer (axillary, supraclavicular and internal mammary lymph nodes) represents a therapeutical challenge with different controversial aspects. The presence of distant metastazis usually is a contraindication for surgery, but we can still consider it in the cases of unique metastasis found in parenchimatous organs. Their appearnce should be symptomatic and the goal of surgery is paleativ and to improve patient’s quality of life. One of the most important factor for the treatment of breast cancer recurrence is a multidisciplinary approach (multimodal treatment) which leads to a crucial collaboration between physicians of various specialities (surgeon, plastic surgeon, oncologist, radiotherapist, radiologist, anatomopathologist, etc.). There is an imperous need for large, multicentric studies in order to better define the determinant factors that lead to the appearace of breast cancer recurrences and to better identify the subgroup of patients for which the recurrence represents a marker for the appearance of metastasis.

Rezumat Cuvinte-cheie: cancerul mamar, recidivă locală, recidivă regională, recidivă la distanță (metastaze)

Recidiva reprezintă reapariția cancerului după efectuarea tratamentului cu intenție curativă, după o perioadă variabilă de timp fără semne de boală.

Recidiva în cancerul mamar (locală, regională sau la distanță) este un eveniment neplăcut cu implicații atât pentru pacient, cât și pentru medicul curant. Recidiva locală în cancerul mamar, poate apărea după mastectomie sau tratament chirurgical conservator și nu se știe dacă reprezintă un marker pentru dezvoltarea ulterioară a metastazelor. Tratamentul recidivei locale este uneori dificil de efectuat și se impune definirea unor noi standarde de tratament al recidivelor. Recidiva regională în cancerul mamar (limfonoduli axilari, supraclaviculari sau mamari interni ipsilaterali), reprezintă o provocare din punct de vedere terapeutic cu multe aspecte controversate. Prezența metastazelor la distanță de obicei contraindică chirurgia, dar se poate discuta de intervenție chirurgicală pentru metastazele izolate situate în organele parenchimatoase care sunt simptomatice, scopul fiind paleativ, de îmbunătățire a calității vieții. Este foarte importantă abordarea multidisciplinară (tratament multimodal) și ca atare este foarte importantă echipa terapeutică implicată (chirurg oncolog, chirurg plastician, oncolog medical, radioterapeut, imagist, anatomopatolog etc.). Sunt necesare studii retrospective lărgite, multicentrice, pentru definirea mai precisă a facto­rilor determinanți pentru apariția recidivelor și pentru identificarea subgrupu­lui de pacienți pentru care recidiva reprezintă un marker de apariție a metastazelor.

April 2015

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55

Caiet de abstracte

ACTUALITĂŢI ÎN ONCOLOGIE: ABORDARE MULTIDISCIPLINARĂ ÎN AFECŢIUNILE ONCOLOGICE

“HEMOPATIILE MALIGNE ŞI SARCINĂ DE LA DIAGNOSTIC LA TRATAMENT” Şef Lucr. Dr. Nicoleta Berbec1, Şef Lucr. Dr. Silvana Angelescu2, Şef Lucr. Dr. Anca Simionescu3 1.UMF “Carol Davila”, Spitalul Clinic Colţea – Bucureşti; 2. UMF “Carol Davila”, Spitalul Clinic Colţea – Bucureşti; 3. UMF “Carol Davila”, Spitalul Clinic Filantropia Bucureşti

Open Access Article

Abstract Pregnancy complicated by cancer is rare, but as childbearing among older women increases, so will the incidence of cancer during pregnancy.

The hematological malignancies represent 25% of cancer complicating pregnancy. The most frequent hematological malignancies during pregnancy are lymphoma (incidence 1:6,000 births) and acute leukemia (incidence 1:75,000-100,000 births). Chronic myeloproliferative neoplasms, multiple myeloma, chronic lymphoid leukemia and myelodysplastic syndromes are reported less frequently in pregnancy, these malignancies were considered of the elderly.

A multidisciplinary team of health care professionals is essential for counseling and deciding optimal treatment.

Keywords: hematological malignancies, pregnancy, optimal treatment

Rezumat Cuvinte-cheie: hemopatii maligne, sarcină, terapie optimă

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56

Afecţiunile maligne reprezintă 25% din cancerele ce pot complica o sarcină. Dintre acestea limfoamele şi leucemiile acute au cea mai mare incidenţă, 1 la 6.000, respectiv 1 la 75.000-100.000 de naşteri, neoplasmele mieloproliferative cronice, mielomul multiplu, leucemia limfatică cronică şi sindroamele mielodisplazice fiind raportate mai rar în sarcină, clasic fiind considerate ca afecţiuni maligne ale vârstnicului. Limfoamele maligne sunt neoplazii ale ţesutului limfoid, limfomul non-Hodgkin (LNH) reprezentând cea mai frecventă neoplazie hematologică (4% din totalitatea cancerelor nou diagnosticate), fiind de 5 ori mai frecvent decât limfomul Hodgkin (LH). Prezentarea clinică este similară: adenopatii localizate sau generalizate, periferice sau profunde (mediastinale sau abdominale), cu determinări extraganglionare (amigdală, cavum, ficat, splină, tract digestiv, piele, os, sistem nervos central etc.), semne generale (febră, transpiraţii profuze şi pierderea în greutate semnificativă - care va trece neobservată în sarcină). Determinările profunde subdiafragmatice sunt uneori greu de încadrat la femeia însărcinată.

Examentul anatomo-patologic (histopatologie şi imunohistochimie) al ţesutului tumoral (ganglion, ficat, tegument, pulmon, splină etc.) precizează tipul de limfom.

ACTUALITĂŢI ÎN ONCOLOGIE: ABORDARE MULTIDISCIPLINARĂ ÎN AFECŢIUNILE ONCOLOGICE

Rezumat - Continuare Cuvinte-cheie: hemopatii maligne, sarcină, terapie optimă

Se recomandă o stadializare limitată şi bazată pe anamneză, examen clinic, testele sangvine, biopsia osteo-medulară şi radiografia pulmonară cu protecţie abdominală, ecografia abdominală. Tomografia computerizată şi PET-CT-ul sunt contraindicate la pacientele gravide cu LNH. Tratamentul limfoamelor maligne diagnosticate în sarcină depinde de vârstă gestaţională, tipul histologic, stadiul şi factorii prognostici.

Leucemiile acute sunt afecţiuni maligne, clonale, ce se caracterizează prin proliferarea neoplazică a precursorilor imaturi ai hematopoiezei, în special la nivelul măduvei osoase.

Leucemia acută mieloblastică (LAM) are o incidenţă mai mare în sarcină (60-84%) comparativ cu leucemia acută limfoblastică (LAL) şi, de asemenea, majoritatea cazurilor de LA au fost diagnosticate în al doilea sau al treilea trimestru de sarcină. Clinic: debut brutal cu alterarea stării generale, semne ale insuficienţei medulare sau posibilelor determinări extramedulare. Diagnosticul LA apărute în sarcină se bazează pe examenul morfologic al sângelui periferic şi măduvei osoase şi examenul histopatologic al măduvei osoase (biopsia osteo-medulară fiind fără riscuri majore pentru mamă şi făt), imunofenotipare, examen citogenetic şi teste moleculare.

Indiferent de tipul sau subtipul LA ce apare într-o sarcină în evoluţie, tratamentul se iniţiază rapid, indiferent de vârsta gestaţională, rezultatele fiind mai bune când intervenţia terapeutică este precoce. Neoplasmele mieloproliferative cronice (MPN) reprezintă un grup heterogen de afecţiuni caracterizate prin dereglare la nivelul celulei stem multipotente.

Diagnosticul acestora la femeia gravidă comportă etapele standard de diagnostic.

Nu a fost stabilit un standard al tratamentului pentru MPN la femeia însărcinată, atitudinea terapeutică bazându-se pe datele publicate în literatură, cazuri clinice sau serii mici de paciente. Apariţia unei malignităţi hematologice în sarcină ridică probleme de diagnostic şi stadializare a afecţiunii, dar adevărata provocare este reprezentată de alegerea terapiei optime cu rezultate bune, dar cu efecte adverse minime asupra mamei şi fătului. Managementul corect al acestor cazuri este realizat prin colaborarea interdisciplinară (hematolog sau oncolog, obstetrician, neonatolog) şi nu trebuie neglijate aspectele legale, etice şi religioase, extrem de importante uneori în abordarea cazului.

April 2015

57

Caiet de abstracte

ACTUALITĂŢI ÎN ONCOLOGIE: ABORDARE MULTIDISCIPLINARĂ ÎN AFECŢIUNILE ONCOLOGICE

RADIOTERAPIA CANCERULUI DE PROSTATĂ: DE LA EVIDENŢELE MEDICALE LA PRACTICA CLINICĂ - PREZENTARE DE CAZ

Dr. Ciprian Enăchescu Centre Hospitalier Lyon Sud, 165, Chemin du Grand Revoyet, 69495 Pierre-Benite cedex

Abstract Keywords: prostate cancer, radiotherapy, irradiation

Open Access Article

Patient aged 61 years , diagnosed with localised prostate cancer, TNM stage T1cNoMo and classified D’Amico intermediate risk , defined by clinical stage T1c, Gleason Score 7 (3+4) and PSA value 8 ng/mL. The therapeutic choice was immediate curative treatment by radical prostatectomy. Despite the absence of clinical evidence regarding the superiority of surgery against radiotherapy, the reasons for prostatectomy choice were the life expectancy (more than 15 years) and the results of retrospectives studies that shows a long term overall survival benefit in favour of surgery. Cancer postoperative classification is pT3 a (capsular perforation) and the resection was ‘non in sano’ (R1 resection). Adjuvant or salvage radiotherapy are the 2 validated option, no randomised clinical trial proving a overall survival benefit in favour of immediate postoperative radiotherapy. Because the post-operative PSA was undetectable, the medical decision was regular PSA monitoring. Two years post surgery the PSA is more than 0.2 ng/ml, the cut-off level for biochemical recurrence definition. The standard treatment proposed was a combination of short term chemical castration (LH-RH analogues) and external beam radiotherapy, 46 Gy in 23 fraction to the pelvic lymph nodes and 66 Gy in 33 fractions to the prostate loge. The PSA nadir is obtained 6 months after radiotherapy at 0.01 ng/ml. One years post salvage radiotherapy the PSA value increase and the CholinPET examination show an left primitive iliac lymphadenopathy, witch was irradiated by stereotactic radiotherapy technique with a 36 Gy total dose in 6 fractions. Seven month post irradiation the PSA level decrease at 0.43 ng/ml (against 4.22 ng/ml preradiotherapy) and at 19 month it became undetectable.

Rezumat Cuvinte-cheie: cancer de prostată, radioterapie, iradiere This work is licensed under a Creative Commons Attribution 4.0 Unported License.

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Pacient în vârstă de 61 de ani diagnosticat cu cancer de prostată localizat, stadializat conform sistemuluui TMN T1c No Mo şi clasificat după sistemul D’ Amico în cancer cu risc intermediar de progresie definit printr-un stadiul clinic T1c, un Scor Gleason = 7 (3+4) şi un PSA = 8 ng/mL. Indicaţia este de tratament cu intenţie curativă imediat prin prostatectomia radicală. Deşi nu există dovezi privind superioritatea chirurgiei faţă de radioterapie, s-a ales prostactectomia întrucât speranţa de viaţă a pacientului depăşeşte 15 ani, iar rezultatele studiilor retrospective arată un beneficiu de supravieţuire prin chirurgie. Post-operator pacientul este clasificat pT3a (efracţie capsulară) cu Scor Gleason 8 (4+4), iar chirurgia este în margine invadată (chirurgie R1). Cele 2 opţiuni, radioterapia adjuvantă versus radioterapie la recidiva biologică (PSA) pot fi în mod egal propuse pacientului, întrucât nu există evidenţe de beneficiu de supravieţuire dovedit pentru tratamentul imediat. Întrucât nivelul PSA este nedetectabil în post-operator, s-a decis monitorizarea PSA-ului. La 2 ani post-operator PSA-ul depăşeşte limita de 0,2 ng/mL, definită ca nivel al recidivei biologice. Se propune ca tratament radioterapia asociată cu castrarea chimică prin analogi de LH-RH pentru 6 luni. Iradierea distribuie 46 Gy în 23 şedinţe la nivelul ganglionilor pelvici şi 66 Gy în 33 şedinţe la nivelul lojei de prostatectomie. Nadirul PSA se obţine 6 luni după terminarea iradierii la valoarea de 0,01 ng/ml. Un an post-radioterapie se constată creşterea PSA-lui şi examenul PET-choline pune în evidenţă o hiperfixare moderată la nivelul unei adenopatii iliace comune stângi care este iradiată în tehnică stereotactică cu doza de 36 Gy în 6 şedinţe, doza calculată în periferia volumului tumoral. La 7 luni după iradiere PSA-ul scade de la 4,22 ng/ml la 0,43 ng/ml pentru ca la 19 luni să devină indozabil.

ACTUALITĂŢI ÎN ONCOLOGIE: ABORDARE MULTIDISCIPLINARĂ ÎN AFECŢIUNILE ONCOLOGICE

PARTICULARITĂŢI ALE BOLILOR MALIGNE LA ADOLESCENT ŞI ADULTUL TÂNĂR Conf. dr. Monica Dragomir UMF “Carol Davila” Bucureşti, Institutul Oncologic “Prof. Dr. Al. Trestioreanu”, Bucureşti

Abstract Keywords: adolescents, young adults, cancer, survival, treatment

Open Access Article

Adolescents and young adults aged 15 to 39 are much more likely to be diagnosed with cancer than children under the age of 15. The most common types of cancer seen in adolescents and young adults are lymphoma, leukemia, germ cell tumors (including testicular cancer), melanoma, central nervous system tumors, sarcomas, and breast, cervical, liver, thyroid, and colorectal cancers.

Despite unique tumor epidemiology, a higher incidence and modest survival improvement compared to pediatric patients, adolescents and young adults have not been considered as a separate, “special” group of patients in the frame of medical oncology and pediatrics. In an effort to emphasize this need, we review the particular characteristics of diagnosed tumors, etiologic associations, nosologic classification, management, outcome and late effects. Adolescents and young adults are in need of specialized care for intensive treatment of curable malignancies, skilled nursing care, interaction with peers, family and physicians as well as continuous psychosocial support. Enrolment in clinical research trials and close follow up via the development of a cooperative infrastructure are imperative for the optimization of management and avoidance of late effects.

Similar to pediatric oncology, intensification of treatment, support and research multidisciplinary efforts in order to better fulfill the demands of this patients group is needed. Adolescent and young adults between the ages of 15 and 39 are a distinct patient population within oncology. Pediatric and adult oncology research and clinical agendas are not designed to focus on the unique biological, clinical, psychosocial, and survivorship issues of this age group

Rezumat Cuvinte-cheie: adolescent, adult tânăr, cancer, supravieţuire, tratament

Adolescenţii şi adultii tineri cu vârste cuprinse între 15 şi 29 de ani au o probabilitate de a fi diagnosticaţi cu cancer mai mare decât copiii cu vâste sub 15 ani. Cele mai frecvente tipuri de cancere la adolescent şi adultul tânăr sunt: limfoamele, leucemiile tumorile cu celule germinale (inclusiv tumorile testiculare), melanomul, tumorile sistemului nervos central, sarcoamele, cancerele mamare, de col uterin, tiroidiene şi colorectale. În ciuda epidemiologiei particulare, incidenţei mai mari şi a ratei de supravieţuire mai modeste decât în malignităţile copiilor, adolescenţii si adulţii tineri nu au fost consideraţi o categorie “specială” nici în cadrul oncologiei medicale nici al pediatrei. În încercarea de a evidenţia nevoile specifice de asistenţă medicală, sunt trecute în revistă caracteristicile tumorale, etiologia, clasificarea nosologică, particularităţi legate de tratament, evoluţie şi efectele secundare tardive care deosebesc această categorie de pacienţi oncologici, atât de copii, cât şi de adulţi. Adolescenţii si adulţii tineri necesită asistenţă special calificată şi tratament intensiv pentru malignităţile curabile, asistenţa particularizată de nursing, suport familial, medical şi psiho-social continuu. Înrolarea în trialuri clinice şi supravegherea îndelungată necesită dezvoltarea unor infrastructuri care să optimizeze tratamentul şi să minimizeze efectele secundare tardive. Ca şi în oncologia pediatrică, sunt necesare intensificarea tratamentului, suportul şi cercetarea multidisciplinară pentru îndeplinirea dezideratelor pe care le impune această categorie de pacienţi.

Adolescenţii şi adulţii tineri, cu vârste între 15 şi 29 de ani sunt un grup particular de pacienţi oncologici. Oncologia pediatrică şi oncologia adultului nu au încă pregătite programe de cercetare şi asistenţă medicală centrate pe aspectele biologice, clinice, psiho-sociale şi de supravieţuire ale acestui grup particular de pacienţi oncologici.

April 2015

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59

Caiet de abstracte

ACTUALITĂŢI ÎN ONCOLOGIE: ABORDARE MULTIDISCIPLINARĂ ÎN AFECŢIUNILE ONCOLOGICE

INDICAŢIILE ŞI REZULTATELE TRANSPLANTULUI DE CELULE STEM ÎN PRACTICA PEDIATRICĂ Conf. Dr. Anca Coliţă, Prof. dr. Constantin Arion Universitatea de Medicină şi Farmacie “Carol Davila”, Bucureşti, Institutul Clinic Fundeni, Bucureşti

Open Access Article

Abstract Keywords: stem cell transplantation, indications, children

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Stem cell transplantation (SCT) is a potential curative procedure for some malignant and non-malignant diseases in children. SCT is categorized by the source of the stem cells, with its role in pediatric diseases dependent in part on the indication for which it is being used. The spectrum and biological characteristics of hematological malignancies are significantly different between children and adults. Autologous transplant treats cancer by exposing patients to mega-dose (myeloablative) therapy with the intent of overcoming chemotherapy resistance in tumor cells, followed by infusion of the patient’s previously stored hematopoietic stem cells. Current pediatric indications for autologous transplant include patients with certain lymphomas, neuroblastoma, high risk Ewing sarcoma, germinal cell tumors. Allogeneic SCT uses stem cells from a donor who is either matched or unmatched on human leukocyte antigen (HLA) and either related or unrelated. Allogeneic transplant approaches to cancer treatment also may involve high-dose therapy, but because of immunologic differences between the donor and recipient, an additional graft-versus-tumor (GVT) or graft-versus-leukemia (GVL) treatment effect can occur. Current indication for allogeneic transplant include high risk acute myeloblastic leukemia (AML), relapsed AML, very high risk acute lymphoblastic leukemia (ALL), high risk relapsed ALL, myelodisplastic syndromes(MDS), juvenile myelomonocytic leukemia (JMML), chronic myeloproliferative disorders, severe aplastic anemia (SAA), inherited bone marrow failure syndromes (IBMFS), hemoglobinopathies, primary immunodeficiency diseases, inborn errors of metabolism.

In Fundeni Clinical Institute, between 2002-2015 we have been performed 83 transplant procedures for children with different malignant or non-malignant diseases. The age range was from 10 months to 18 years. Allogeneic SCT has been performed in 27 cases for the following indications: AML -8, ALL-5, JMML-4, SAA-5, IBMFS-4, hemoglobinopathies -1. The donors were siblings in 21/27 cases and unrelated in 6/27 cases. Autologous SCT has been performed in 56 patients: Hodgkin lymphoma-27, non-Hodgkin lymphoma-4, neuroblastoma – 12 cases (13 procedures), Ewing sarcoma- 5 cases (6 procedures), germinal cell tumors 3 cases (5 procedures), AML-1. The overall survival was 44,6% for autologous SCT, where the main cause of unfavorable outcome was relapse, and 55,5% for allogeneic SCT where the unfavorable outcome was associated especially with graft versus host disease and severe viral infections.

Advances in supportive care and management of graft-versus-host disease have resulted in improvements in outcomes of related and unrelated donor SCT, creating controversies as to which strategy might be the optimal therapy for individual patients.

ACTUALITĂŢI ÎN ONCOLOGIE: ABORDARE MULTIDISCIPLINARĂ ÎN AFECŢIUNILE ONCOLOGICE

Rezumat Cuvinte-cheie: transplant celule stem hematopoietice, indicaţii, copii

Transplantul de celule stem hematopietice (TCSH) este o procedură potenţial curativă pentru unele afecţiuni maligne şi non-maligne ale copilului. Procedură de transplant este deosebită în funcţie de sursă de celule stem şi de indicaţia terapeutică. Tipul şi caracteristicile biologice ale afecţiunilor care au indicaţie de transplant sunt diferite la copil faţă de adult.

Principiul autotransplantului constă în utilizarea unor megadoze de chimioterapie în speranţa depăşirii chimiorezistenţei, urmat de reinfuzia celulelor stem proprii ale pacientului care au fost anterior recoltate şi stocate. Indicaţiile curente de autotransplant în practica pediatrică sunt reprezentate de unele limfoame (Hodgkin şi nonHodgkin), neuroblastom, formele cu risc crescut de sarcom Ewing şi tumorile germinale. Transplantul alogeneic utilizează celule stem care pot fi complet compatibile sau parţial compatibile HLA de la donator familiali sau neînrudiţi. Principiul allotransplantului constă în utilizarea atât a efectului ablativ al chimioterapiei, dar în mod special al efectului immunologic determinat de diferenţele dintre donor şi receptor, fenomen denumit grefă contra leucemie sau mai general grefă contra tumoră. Efectul de grefă contra tumoră este însă asociat cu efectul de grefă contra gazdă, care continuă să reprezinte complicaţia cea mai severă a tranplantului alogeneic. Indicaţiile allotransplantului în practica pediatrică sunt reprezentate de leucemia acută mieloblastică (LAM) risc rescut, LAM la recădere, forme cu risc foarte crescut de leucemie acută limfoblastică (LAL), unele forme de LAL la recădere, sindroamele mielodisplazice (SMD), leukemia mielomonocitară cronică juvenilă (LMMCJ), bolile mieloproliferative cronice, anemiile aplastice severe (AAS), sindroamele de insuficienţă medulară congenitală (SIMC), hemoglobinopatiile, imunodeficienţele primare, erorile înnăscute de metabolism. În Institutul Clinic Fundeni, în perioada 2002-2015, au fost efectuate 83 de proceduri de transplant la copii cu vârste între 10 luni şi 18 ani.

S-au efectuat 27 de allogrefe pentru următoarele indicaţii: LAM-8, LAL5, LMMVJ-4, AAS-5, SIMC-4, hemoglobinopatii -1. În 21/27 de cazuri s-au folosit donori familiali şi în 6/27 de cazuri donator din registru.

S-au efectuat 56 de procedură de autotransplant: limfom Hodgkin -27, limfom non-Hodgkin 4, neuroblastom 13, sarcom Ewing 6, tumora cu celule germinale -5, LAM -1. Unii pacienţi au efectuat dublă autogrefă.

Supravieţuirea generală a fost de 44,6% în cazul autotrasnplantului, la care principala cauză de deces a reprezentat-o recăderea bolii şi de 55,5% în cazul allotransplantului, unde principalele cauze de deces au fost reacţia de grefă contra gazdă (RGCG) sau infecţiile virale secundare imunodepresiei severe pentru tratarea RGCG. Creşterea performanţelor tratamentului suportiv şi a managementului reacţiei de grefă contra gazdă ameliorează rezultatele transplantului de la donatori înrudiţi şi neînrudiţi şi determină apariţia controverselor legate de terapia optimală pentru aceşti pacienţi.

April 2015

61

Caiet de abstracte

ACTUALITĂŢI ÎN ONCOLOGIE: ABORDARE MULTIDISCIPLINARĂ ÎN AFECŢIUNILE ONCOLOGICE

HAPLOIDENTICAL STEM CELL TRANSPLANTATION – AN ALTERNATIVE TO UNRELATED HEMATOPOIETIC STEM CELL TRANSPLANT Conf. Dr. Carmen Orban, Dr. Alina Tănase, Conf. Dr. Anca Coliţă Fundeni Clinical Institute Center for Bone Marrow Transplantation

Open Access Article

Abstract Keywords: hematopoietic stem cell transplantation, malignant, donor

Hematopoietic stem cell transplantation (SCT) is an established treatment for many malignant and non-malignant haematological disorders, more than 30.000 SCT are currently performed each year in the Western world. Two-thirds of patients who require allogeneic hematopoietic stem cell transplantation (SCT) do not have a human leukocyte antigen (HLA)-matched related donor available. A matched unrelated donor can be identified in only 50% to 60% of these cases.

Haploidentical donors – parents, children, and half of siblings – are alternative stem cell sources for such patients without matched donors. Transplant outcomes using haploidentical donors with post_Cyclophosphamide have improved past several years and are comparable with outcomes of matched unrelated donors. These encouraging early results could extend this form of transplantation worldwide.

In the current papers, we present the case of 33 year-old young woman that has underwent a haploSCT after she relapsed from several chemotherapy regiments, as well as after an autologous stem cell transplantation. This success represent a premiere in Romanian clinical hematology, being the first case of a haploSCT in Romania.

Rezumat Cuvinte-cheie: This work is licensed under a Creative Commons Attribution 4.0 Unported License.

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62

transplantul de celule stem hematopoietice, malign, donator

Transplantul de celule stem hematopoietice (HSCT) reprezintă o metodă standard de tratament pentru diferite afecţiuni maligne şi non-maligne, efectuându-se peste 30.000 de HSCT în fiecare an în Europa de Vest. Două treimi din pacienţii care necesită un HSCT nu au un donator HLA compatibil disponibil, un donator voluntar, neînrudit, identificându-se în 50-60% din cazuri. Donatorii haploidentici - părinţi, copii şi fraţi 50% compatibili – sunt alternative de donator pentru aceşti pacienţi la care nu se găseşte un donator. Rezultatele haplotransplatului folosind Ciclofosfamida post-transplant s-au îmbunătăţit în ultimii ani şi sunt comparabile cu cele ale transplantului de la donator neînrudit. Aceste rezultate încurajatoare au determinat ca această procedură să se extindă în întreaga lume. În această lucrare, prezentăm cazul unei paciente de 33 de ani, care a efectuat haplotransplant după ce a recăzut după mai multe regimuri de chimioterapie, inclusiv după autotransplant de celule stem hematopoietice. Această procedură de haplotransplant efectuată cu succes, reprezintă o premieră pentru hematologia clinică în România.

ACTUALITĂŢI ÎN ONCOLOGIE: ABORDARE MULTIDISCIPLINARĂ ÎN AFECŢIUNILE ONCOLOGICE

POSIBILITĂŢI ŞI LIMITE ALE RADIOTERAPIEI EXTERNE ÎN CANCERELE UROLOGICE Gabriel Kacsó 1,2,3, Renata Zahu2, Catalin Iacob2, Noemi Schultes2, Andrea Eva2, Dan Dordai2 1.UMF „Iuliu Hatieganu”, Cluj-Napoca; 2. RTC Amethyst Cluj; 3. Institutul Oncologic „Prof. Dr. Ion Chiricuta”

Open Access Article

Abstract Keywords: external beam radiotherapy, urooncology

External beam radiotherapy (EBRT) is widely used as curative treatment for urologic cancers, except testicular disgerminomas.

X-Photons are generally used, whereas proton therapy has gain scarce acceptance outside US. Intensity modulated radiotherapy (IMRT), weather “step and shoot” or rotational (VMAT, Rapid Arc or Tomotherapy) is considered standard of care for prostate and penile cancers, as the acute and late toxicity are significantly reduced. The mild toxicity of IMRT and encouraging results of retrospective and prospective but non-randomized studies have identified possible new EBRT IMRT indications such as selected oligo-metastatic prostate cancers. Due to the low alfa/beta ratio of prostate cancer (around 3 or even lower), hypofractionation is appealing and can be a good alternative for overwhelmed RT facilities (like in Romania), particularly as a simultaneously integrated boost trough IMRT techniques. Moderate hypo-fractionated regimens (2.5-3Gy/fr) have been proven equally effective as standard fractionation schemes in prostate or bladder cancer. Stereotactic radiotherapy with 5-6 Gy/ fr , 6 to 7 fractions are suitable for low/intermediate risk prostate cancer or inoperable early stages kidney cancers, addressing the under-used RT issue for senior adults, accounting for > 25 % of Western Europe and US uro-oncology patients. In this respect, reduced margins from CTV to PTV for minimizing the toxicity are of crucial importance. Tracking the target by fiducial markers or transponders injected in the target, as well as breathe control technique allow for very precise RT delivery in prostate, bladder or kidney cancer. Cone-beam computed tomography or even MV/ kVportal imaging is accurate enough for testis or penile lymph nodes irradiation. Although dose escalade has been proven to improve local, distant control and biochemical free survival in prostate cancer, to date there is no evidence 1 level for better overall survival of doses above 76 Gy in standard fractionation. This is partly due to the median age around 70 years of the EBRT cohorts but also to the lack of RT volume standardization, particular the lymph nodes. Same reasons apply for bladder cancer. EBRT increases the risk of other cancer in the pelvic area by roughly a factor 2, at a median onset time of 6 years after RT delivery. Longer follow-up in this respect is needed for IMRT techniques. This fact shadowed the EBRT use in seminoma, increasing the active surveillance policy in stage I or the chemotherapy use in all stages.

April 2015

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63

International articles

ACTUALITĂŢI ÎN ONCOLOGIE: ABORDARE MULTIDISCIPLINARĂ ÎN AFECŢIUNILE ONCOLOGICE

Rezumat Cuvinte-cheie: radioterapie externă, cancere urologice

64

Radioterapia externă (RTE) este utilizată pe scară largă ca tratament curativ în cancerele urologice, mai puţin în disgerminoamele testiculare. Fotonii-X deţin monopolul întrucât protonii sau alte particule nu au convins că își justifică costul suplimentar.

Radioterapia cu modularea intensităţii (IMRT), fie ca tehnică „step & shoot” , fie rotaţională (VMAT, Rapid Arc sau Tomoterapie) este considerată standard terapeutic pentru cancerul de prostată sau penian deoarece toxicitatea acută şi tardivă radioindusă este semnificativ mai mică. Profilul de toxicitate favorabil al IMRT a permis extinderea indicaţiilor RTE cu doze în intenţie curativă şi la stadii considerate paliative, precum cancerele de prostată oligometastatice.

Radiobiologic, raportul alfa/beta scăzut al cancerului prostatic (în jur de 3 sau chiar mai mic) face hipofracţionarea atractivă, în particular ca „boost” simultan integrat al tehnicii IMRT, mai ales în centre supraaglomerate ca cele din România. Scheme moderate de hipofracţionare sunt izoeficace cu cele cu fracţionare standard în adenoacarcinomul de prostată (70Gy/28fr, 60Gy/20 fr) sau în carcinoamele tranziţionale de vezică urinară (55Gy/20fr).

Hipofracţionarea intensă, sub forma RT stereotactice (cu 5-6 Gy/fr x 6-7 fracţiuni) sunt alternative viabile pentru cancerele inoperabile de prostată cu risc scăzut/ intermediar sau pentru cele renale, în particular la pacienţi vârstnici, adesea sub-trataţi (aceştia reprezintă actual un sfert din pacienţii uro-oncologici din Europa Occidentală sau Statele Unite). Pentru minimizarea iatrogenităţii este necesar ca marginile de expansiune CTV spre PTV să fie cât mai mici (în jur de 5 mm), ceea ce obligă la tehnici de reducere a mobilităţii interne a ţintei (controlul respiraţiei şi sincronizarea ei cu iradierea, pentru cancerul renal), respectiv de detectare precisă a ţintei înainte de fiecare sedinţă de iradiere, prin marcaje intratumorale cu repere metalice (Aur) sau emiţătoare de unde detectabile (transponderi) - pentru cancerele de vezică sau prostată. Verificarea computertomografică (Cone beam CT) sau imageria portală cu sursa de RTE este suficientă pentru iradierea ganglionară în cancerele peniene sau testiculare. În cancerul de prostată, escaladarea dozei RTE peste 76Gy în fracţionare standard a ameliorat controlul local şi supravieţuirea fără recidivă biochimică, a scăzut rata metastazelor la distanţă dar nu există (încă) nivel de evidenţă de nivel 1 în favoarea îmbunătăţirii supravieţuirii globale. Posibile explicaţii sunt vârsta medie înaintată (în jur de 70 ani pentru trialurile randomizate), precum şi absenţa standardizării. volumelor iradiate, în particular ganglionar, cel puţin pentru cancerele de vezică urinară sau de prostată.

RTE creşte de circa 2x riscul unui al doilea cancer pelvin, cu interval mediu de apariţie de circa 6 ani. Pentru IMRT este necesară o urmărire mai lungă. Pe acest considerent, RTE este actual tot mai rar utilizată în seminoamele testiculare.

ACTUALITĂŢI ÎN ONCOLOGIE: ABORDARE MULTIDISCIPLINARĂ ÎN AFECŢIUNILE ONCOLOGICE

DIGITAL BREAST TOMOSYNTHESIS IN BREAST CANCER SCREENING AND DIAGNOSIS Carmen Lisencu The Oncology Institute “Ion Chiricuta”, Cluj-Napoca

Abstract Keywords: breast cancer, diagnosis, screening, digital mammography, tomosynthesis.

Open Access Article

Breast cancer remains one of the main causes of death by cancer for women. Mammographic screening has led to an important decrease of mortality produced by breast cancer, but it cannot identify all cancer forms in an incipient stage. The use of full-field digital mammography has been proven to bring about significant improvements in the radiologists’ performance when it comes to the interpretation of examinations obtained particularly on women with dense breast tissue. In conventional mammographic views, the presence of overlapping dense fibroglandular breast tissue substantially reduces the conspicuity of some breast lesions. This thing limits the sensitivity of mammography and, thus, it may lead to a percentage of lost cancers. On the other hand, due to this overlapping, a significant number of women will undertake further investigations because of misleading images. Improvements in digital imaging generally, and full-field digital mammography particularly, has allowed the development of digital breast tomosynthesis imaging systems designed for 3D -breast examinations. Digital breast tomosynthesis represents a great achievement in screening and diagnostic procedures, because it enables 3D reconstruction. This ability facilitates cross-sectional visualization of breast tissue and it reduces the difficulty caused by the superposition of overlapping tissue in the interpretation of projected mammograms. In breast imaging, the potential benefits include the increasing of sensitivity of mammography in women with dense breast tissue, less frequent recall rates in screening mammography, improving the diagnosis of benign findings, and, consequently, reducing the number of biopsies with negative findings, also assessing therapeutic efficiency.

The purpose of this paper is to sum up several studies regarding the advantages and limitations of digital tomosynthesis, and to show a personal experience in the use of this method at The Oncology Institute “Ion Chiricuta”, Cluj-Napoca .

Rezumat Cuvinte-cheie: cancer de san, diagnostic,screening, mamografie digitala, tomosinteza

Cancerul de sân rămâne una din cauzele principale de deces prin cancer la sexul feminin. Mamografia de screening a dus la scăderea importantă a mortalităţii prin cancer de sân dar nu identifică toate cancerele în stadiu incipient. Utilizarea mamografiei digitale a dus la îmbunătăţirea semnificativă a performanţelor în cea ce priveşte interpretarea imaginilor mamografice mai ales în cazul femeilor cu densitate crescută a parenchimului mamar. În mamografia bidimensională convenţională, suprapunerile de ţesut fibroglandular pot reduce semnificativ vizibilitatea anumitor formaţiuni existente, ceea ce duce la scăderea sensibilităţii mamografiei şi, prin urmare, la un procentaj de cancere pierdute. Pe de altă parte, datorită acestor suprapuneri, un număr de femei fără cancer vor fi supuse unor testări suplimentare datorate unor imagini false. Achiziţiile în imagistica digitală în general, în mamografia digitală în particular, au permis dezvoltarea sistemelor de tomosinteză destinate examinării tridimensionale a sânului. Tomosinteza reprezintă o examinare mamografică de interes crescut, atât în ceea ce priveşte sceeningul, cât şi diagnosticul cancerului de sân. Această capacitate de vizualizare secţională a parenchimului mamar reducând dificultăţile de interpretare a imaginilor mamografice datorate suprapunerilor de ţesut fibroglandular. În imagistica sânului, beneficiul potenţial este reprezentat de creşterea sensibilităţii mamografiei la femeile cu san dens, reducerea rechemărilor inutile în screeningul mamografic, îmbunătăţirea diagnosticului leziunilor benigne şi prin urmare reducerea biopsiilor inutile. Totodată promite o mai bună posibilitate de evaluare a terapiilor administrate. Scopul lucrării de faţă e acela de a face o sumarizare a catorva studii privitoare la avantajele şi limitele tomosintezei şi de a vă prezenta experienţa personală în utilizarea acestei metode în Institutul Oncologic Cluj-Napoca.

April 2015

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