Memorias Curso Actualización en Oncología Médica y Quirúrgica Parte 2

AMMVEPE 1968 - 2015

MEMORIAS DE LAS PONENCIAS EN EL CURSO DE ACTUALIZACIÓN EN ONCOLOGÍA MÉDICA Y QUIRÚRGICA MÉXICO, D. F. AGOSTO 26, 27 y 28 DE 2015

Asociación Mexicana de Médicos Veterinarios Especialistas en Pequeñas Especies, S. C. www.ammvepe.com.mx

PONENCIAS DEL CURSO DE ACTUALIZACIÓN EN ONCOLOGÍA MÉDICA Y QUIRÚRGICA

AMMVEPE

Agosto 26, 27 y 28 de 2015

ABORDAJE DEL PACIENTE CON CARCINOMA DE CÉLULAS ESCAMOSAS MVZ MMVZ Angelina Gutiérrez Barroso

ACTUALIZACIONES EN EL TRATAMIENTO DE MASTOCITOMA CANINO MVZ MMVZ Angelina Gutiérrez Barroso

CONSIDERACIONES EN EL PACIENTE ONCOLÓGICO MVZ MMVZ Angelina Gutiérrez Barroso

DIAGNOSIS AND PROGNOSIS OF CANINE OSTEOSARCOMA DVM, MS Bernard Séguin

FELINE AND CANINE THYROID TUMORS DVM, MS Bernard Séguin

INDICATIONS AND OUTCOME FOR PULMONARY METASTASECTOMY DVM, MS Bernard Séguin

LINFOMA CANINO Y FELINO: TOMA DE DECISIONES MVZ MMVZ Angelina Gutiérrez Barroso

LYMPHOLOGY AND SENTINEL LYMPH NODE MAPPING DVM, DACVS-SA Deanna R. Worley

MELANOMA MVZ MMVZ Angelina Gutiérrez Barroso

ORAL AND INTESTINAL TUMORS IN DOGS AND CATS DVM, DACVS-SA Deanna R. Worley

ORBITECTOMIES DVM, DACVS-SA Deanna R. Worley

PERIANAL TUMORS DVM, DACVS-SA Deanna R. Worley

QUIMIOTERAPIA EN TUMORES MAMARIOS: CUÁNDO Y CUÁL? MVZ MMVZ Angelina Gutiérrez Barroso

QUIMIOTERAPIA PALIATIVA Y METRONÓMICA EN PERROS Y GATOS: USOS Y ABUSOS MVZ MMVZ Angelina Gutíerrez Barroso

RESPIRATOY NEOPLASIA DVM, DACVS-SA Deanna R. Worley

SOFT TISSUE SARCOMAS & HEMANGIOSARCOMAS DVM, DACVS-SA Deanna R. Worley

SURGEON’S APPROACH TO ADRENAL TUMORS DVM, MS Bernard Séguin

SURGEON’S APPROACH TO PRIMARY HYPERPARATHYROIDISM DVM, MS Bernard Séguin

SURGICAL ONCOLOGY CASE ROUNDS DVM, DACVS-SA Deanna R. Worley

THORACIC AND CARDIOVASCULAR SURGERY: ONCOLOGY DVM, DACVS-SA Deanna R. Worley

TIPS AND TRICKS TO PERFORMING A BIOPSY DVM, MS Bernard Séguin

TIPS AND TRICKS TO REMOVING A TUMOR DVM, MS Bernard Séguin

TREATING APPENDICULAR OSTEOSARCOMA IN DOGS DVM, MS Bernard Séguin

Oral and Intestinal Tumors in Dogs and Cats Deanna Worley, DVM, Diplomate ACVS ACVS Founding Fellow, Surgical Oncology Associate Professor, Surgical Oncology Colorado State University dworley@colostate.edu

Overview • Diagnostic work-up for oral masses – Emphasis on practice tips and avoiding common pitfalls

• Specific tumor types and therapeutic approaches for canine tumors – Prognosis

• Specific tumor types and surgical approaches for feline tumors – Prognosis

• Intestinal tumors: types, diagnosis and therapy

Objectives • List the most common oral and intestinal tumors seen in dogs and cats • List differentials for oral and intestinal tumors in dogs and cats • Design a diagnostic plan for an oral or intestinal tumor • Construct a therapeutic plan for a patient with an oral or intestinal tumor • Describe the different biologic behaviors of oral and intestinal tumors in dogs and cats

Oral Tumors Diagnostic challenge: • difficult for owner to see (esp. cats) • commonly misdiagnosed as dental disease • may mimic inflammatory/infectious conditions • “tip of the iceberg”

Oral Tumors Clinical Signs • mass in mouth • halitosis!

• dysphagia • bloody discharge • loose teeth • drooling* • poor grooming* * esp. cats

Oral Tumors Diagnostic Work-Up • What is it?

– FNA- difficult to obtain accurate diagnosis due to background of infection, inflammation – Biopsy- incisional best!

• doesn’t require general anesthesia in most cases

Fine Needle Aspirate

Where should you go for your biopsy?

- On the cheek over the swelling - Intranasal - Lift the lip and go through the lip - Lift the lip and go through the maxilla

Biopsy Important Points!!

• incisional biopsy works best • DON’T go through the lip or cheek!!

• Always biopsy an oral mass from the oral cavity • record exactly where the lesion is

Oral Tumors Diagnostic Work-Up • Where is it?

– Thoracic radiographs – Lymph nodes-aspirate if enlarged – Abdominal ultrasound

3 Views

Oral Tumors Diagnostic Work-Up • How bad is it?

– “tip of the iceberg”?

– skull radiographs – CT/MRI

Oral Tumors

Oral Tumors

Dogs

• Fibrosarcoma • Melanoma • Squamous Cell Carcinoma Also – Osteosarcoma – – – – –

Cats

• Squamous Cell Carcinoma • Fibrosarcoma

Mast Cell Tumor Plasmacytoma Tonsillar Lymphoma Multilobular ostechondrosarcoma Epulides • Acanthomatous ameloblastoma

Oral Tumors- Canine Fibrosarcoma • 10-20% of oral cancer • large breed dogs (Golden Retriever) • young dogs common

• located on palate, maxilla, mandible • slow to metastasize • bone is commonly involved

If it touches bone, bone has to go!

Oral Tumors- Canine Fibrosarcoma • treatment is complete surgical resection – maxillectomy, mandibulectomy – Radiation alternative

• fair to good prognosis • 9.5-24 month median survival • cure possible

• will recur if incomplete excision

Dogs recover very quickly after aggressive maxillectomy or mandibulectomy

What are potential resulting side effects from resection of a mandibular segment?

-

Mandibular drift?

Tongue hanging from side?

Head tilt?

Saliva induced dermatitis?

Dysphagia?

What changes result following a maxillectomy should you counsel an owner preoperatively?

-

Desensate maxillary lip Bloody nasal discharge Epiphora Oronasal fistula Dysphagia

Histologically Low Grade, Biologically High Grade Fibrosarcoma • “Hi Lo” FSA • Retriever breeds overrepresented • Most common on face→facical deformity, bone destruction – firm mass, smooth, non-ulcerated

Histologically Low Grade, Biologically High Grade Fibrosarcomas • previously diagnosed as fibroma, fibrous tissue, scar tissue, inflammation on histology • Very benign on histology – fibroma, reactive fibroplasia, etc.

• Very invasive • Low metastatic rate, high local recurrence

Oral Tumors-Canine Melanoma • 30-40% of oral tumors • older dogs most common • small breeds > large • begins in mucosa/gingiva – anywhere in mouth or on lip margin will behave aggressively – invasive to bone

Oral Tumors-Canine Melanoma • metastasis to lymph node common • metastasis to lung common • 2/3rds pigmented, often ulcerated • bone involvement common

Melanoma Treatment • treat by complete excision – Maxillectomy/ mandibulectomy – regional draining lymph nodes (sentinel LNs)

Melanoma Adjuvant therapy • Radiation therapy if incomplete margins – microscopic disease responds

• Radiation therapy of gross tumor with chemo sensitization – Large fractions required – Median survival 363 days

• Chemotherapy if margins are complete?

• Immunotherapy/vaccines – Oncept® – Others

Melanoma • prognosis poor-fair – 25% alive at 1 year published – survival > 1 year common if no mets at diagnosis

• death due to – metastasis if completely excised – local recurrence if margins incomplete

Oral Tumors-Canine Squamous Cell Carcinoma • 20-30% oral tumors • larger breed dogs> smaller breeds • rostral mandible, tonsil, tongue • red, cauliflower, raised, ulcerated

Oral Tumors-Canine Squamous Cell Carcinoma • rostral = better prognosis • respond well to complete excision (rostral) – cure is possible – responsive to radiation if margins dirty – Radiation alternative to excision

• prognosis poorer if – caudally located – tonsil – lymph node positive or lung mets

Oral Tumors-Canine Squamous Cell Carcinoma • tonsillar form very aggressive • bilateral tonsillectomy • radiation therapy reported to help control disease • <10% alive at 1 year

Oral Tumors-Canine Squamous Cell Carcinoma • tongue form – rostral has better prognosis – if completely excised >50% alive at 1 year

• can be confused with granular cell myoblastoma – good prognosis

Oral Tumors-Canine Squamous Cell Carcinoma • Adjuvant Therapy – Piroxicam 0.3mg/kg PO daily – Cisplatin or carboplatin – Radiation therapy

Oral Tumors-Canine Squamous Cell Carcinoma • partial glossectomy – >50%-100% of moveable tongue in dogs • Short term enteral feeding tube • Nutrition, hydration, hypersalivation, thermoregulation

• prognosis with tongue SCC varies with grade and location of tumor – caudal tongue worse – high grade worse

Oral Tumors-Canine Epulides • Fibrous epulis- benign • Ossifying epulis- benign • Acanthomatous ameloblastoma- invasive!

– Acanthomatous epulis – must remove bone – 90% cure with clean margins – do not metastasize

Oral Tumors-Canine • Radiation therapy very effective for residual microscopic disease, select macroscopic disease • Surgical “debulking” where residual gross disease remains does not improve prognosis • radiation therapy will palliate bone pain in animals with non-resectable tumors • Stereotactic radiation therapy select macroscopic disease

Feline Oral Tumors

Oral Tumors-Feline • Most common: – squamous cell carcinoma (70%) – fibrosarcoma (20%)

• others – nasopharyngeal polyps - benign – eosinophilic granuloma - benign

Oral Tumors-Feline Squamous Cell Carcinoma • involve maxilla, mandible, under tongue • extensive invasion of bone common • lymph node or lung mets uncommon

Oral Tumors-Feline Squamous Cell Carcinoma • response to surgery poor • response to radiation poor • <10% alive at 1 year for sub lingual SCC • other sites- prognosis variable

Feline Maxillectomy/Mandibulectomy Requires more aggressive postoperative care â&#x20AC;˘ G-tube â&#x20AC;˘ grooming

Oral Tumors-Feline Fibrosarcoma • occur on gingiva, lip or cheek • firm, raised mass +/ulcerated • occasionally metastasize • bone involvement common • fair response to surgery

Oral Tumors-Summary • commonly misdiagnosed as dental disease • bone involvement common • biopsy necessary- don’t just extract teeth and assume dental disease in an older animal!

• incisional biopsy best at first – don’t go through the skin or lips!!!

• record exactly where lesion is

Intestinal Tumors

You are performing an abdominal exploratory in a 7 YO mixed breed dog having intermittent vomiting, weight loss, and a small palpable mass. At surgery you find a focal circumferential jejunal lesion with omental adhesions, diffuse mesenteric nodules, and a liver nodule. What action do you take?

A. Biopsy all masses and recover B. Resect intestinal mass, biopsy other lesions, and recover C. Call owner, recommend euthanasia on the table; itâ&#x20AC;&#x2122;s poor prognosis

Common Intestinal Tumors • Small Intestine and stomach: – Lymphoma #1, adenocarcinoma #2 in cats – Adenocarcinoma #1, lymphoma #2 in dogs • Large Intestine – Colo-rectal adenocarcinoma – Rectum more frequently affected than colon • http://www.youtube.com/watch?v=_N0w2rORwSc

• Ileum – Leiomyosarcoma – GIST • CD117 (c-KIT)

– Carcinoid

Others: • Mast cell tumor • Extramedullary plasmacytoma • Fibrosarcoma

Gastric Lymphoma

Intestinal Lymphoma

Intestinal Adenocarcinoma

Gastric Adenocarcinoma

Rectal Adenocarcinoma

Leiomyosarcoma

Diagnosis • Wt loss, vomiting, melena or tenesmus common clinical signs • Abdominal mass noted on palpation or mass noted on rectal • CBC may show anemia • Serum chemistry may show hypoproteinemia, high ALP, high BUN (why?), electrolyte disturbances

Imaging and other diagnostics • Abdominal rads-may identify obstructive pattern or mass effect • Abdominal ultrasound- more sensitive can evaluate lymph nodes within abd cavity, guide FNA • Exploratory laparotomy

Treatment • Solitary masses or obstructive tumors require surgery – Resection and anastomosis, gastric resection, rectal pull through, etc.

– Palliation • Stenting, rerouting, bypass

• Diffuse lymphoma treated with chemotherapy

• What rule of thumb surgical margins should be obtained (orad and aborad) when resecting an obstructive intestinal mass?

• • • •

A. 1 cm B. 3 cm C. 5 cm D. 10 cm

Prognosis Positive factors – solitary mass – complete margins – response to chemo in cats with lymphoma – Pendunculated vs annular colorectal adenocarcinoma

Negative Factors – Metastasis to lymph node, lung, peritoneum

Prognosis • No large studies on survival time – Dogs with non-lymphoma small intestinal masses with no mets- 15 months – Cats with intestinal lymphoma- small intestine does better than large intestine – Dogs receiving palliative Sx for malignant obstruction with metastasis, MST 1 month

Orbitectomies Deanna Worley, DVM Diplomate ACVS, Small Animal Surgery ACVS Founding Fellow, Surgical Oncology Associate Professor, Surgical Oncology dworley@colostate.edu

Orbitectomy • Superior = Caudomedial orbit • Inferior = Rostrolateral orbit • Partial versus Complete – Without or with enucleation

• Orbit boundaries – Open orbit dogs, cat – Maxilla, frontal, zygoma, palatine, lacrimal, sphenoid bones – Soft tissues and endorbita

• • • • • • •

Temporalis,masseter mm=caudal Open jaw, pressure on orbital soft tissues via vertical ramus Extraocular mm Incomplete bony floor, pterygoid m & zygomatic s.g. dog, infraorbital salivary gland cat Trespassers: maxillary a, orbital vv, orbital plexus, maxillary branch trigeminal n, pterygopalantine ganglion & nn Nearby roots of carnassial and molars Angularis oculi v, nictitans & gland

Complete orbitectomy • Enucleation if tumor involved or in close proximity with: – Eye – Neurovascular supply – Significant % eyelid

Neoplastic DDx • • • • •

OSA FSA STS HSA MLO

• • • •

CSA SCC Osteomas Melanomas

Case Presentation 1 • Complete superior orbitectomy with partial inferior orbitectomy • 10 YO FS mix • STS via Bx

â&#x20AC;¢ 1-2 cm margins

â&#x20AC;¢ Zygomatic arch

â&#x20AC;¢ Frontal Sinus

â&#x20AC;¢ Open Sinus, healing

Case Presentation 2 • Caudal maxillectomy with inferior orbitectomy • 7 YO MI Vizsla • OSA, recurrent • Masseter fibrosis

• Blood products • Temporary tarsorrhapy

Case Presentation 3 â&#x20AC;˘ Complete inferior orbitectomy with caudal maxillectomy

Case Presentation 4 • Partial inferior orbitectomy – Zygomatic arch resection – STS

Case Presentation 5 â&#x20AC;˘ Exenteration with partial orbitectomy â&#x20AC;˘ Anaplastic carcinoma

Case Presentation 6 • Inferior orbitectomy with caudal maxillectomy • Subsequent superior partial orbitectomy • 8 YO MC Maine Coon • Osteoma/angioendotheliomatosis = HSA? • Eye Function – Temporal tarrsorrhapy – Corneal ulceration

Perianal Tumors Deanna Worley, DVM Diplomate ACVS, Small Animal Surgery ACVS Founding Fellow, Surgical Oncology Associate Professor, Surgical Oncology dworley@colostate.edu

Overview • Discuss the common perianal tumor types • Utilize a case based –approach to illustrate appropriate case work up and treatment • Discuss prognosis • Overview of common paraneoplastic syndromes associated with perianal masses

Objectives • List the most common perianal tumors • Design a diagnostic plan for a perianal tumor in a small animal patient • Construct a therapeutic plan for the common perineal tumors • Describe the different biologic behaviors of a perineal tumor • List known prognostic factors associated with perianal tumors

Tumors Near the Anus Common Types of Tumors: • • • • • • • •

Perianal adenoma* Perianal adenocarcinoma* Apocrine gland adenocarcinoma* Mast cell tumors Lymphoma SCC Lieomyoma/Leiomyosarcoma Melanoma

Diagnostic Approach Whenever there is a suspicious mass ask yourself : 1) What is it?

2) Where is it?

3) How bad is it?

Diagnostic Approach Every patient should receive a rectal exam What is it?

• Fine needle aspiratecytology • Biopsy

Fine Needle Aspirate

Fine Needle Aspirate

Fine Needle Aspirate

Fine Needle Aspirate

Cytology Algorithm Inflammatory or Neoplastic ?

1.

2.

Cytology Algorithm • If Neoplastic – – Benign vs. Malignant?

– If Malignant – A. Round cell B. Epithelial cell C. Mesenchymal cell origin

Diagnostic Approach Where is it?

• Staging: – Thoracic radiographs – Attempt palpation of sublumbar lymph nodes – Abdominal ultrasound

Diagnostic Approach How bad is it?

• Histologic type • Histologic grade • Local extent of disease • Other proven prognostic factors unique to tumor type – size, paraneoplastic syndrome, clinical signs, etc.

Patient “A” : 10 yr intact male Pug

Patient “A”: 10 yr intact male Pug • What is it?

– FNA

• Where is it?

– thoracic radiographs – rectal palpation

• How bad is it?

– palpation of mass and surrounding tissue

Patient â&#x20AC;&#x153;Aâ&#x20AC;?: 10 yr intact male Pug Results: What kind of predominate cells are these?

- Round cell - Mesenchymal - Epithelial - Inflammatory

Patient “A”: 10 yr intact male pug • Thoracic radiographs- WNL • Rectal palpation- no palpable sublumbar node enlargement • Palpation of massfreely moveable

Patient â&#x20AC;&#x153;Aâ&#x20AC;?: 10 yr intact male Pug Most Likely Diagnosis?

Perianal Adenoma

Perianal Adenoma • most common perianal tumor in intact male dog – aka hepatoid gland tumors, circumanal gland tumors • androgen dependent – often have concurrent testicular tumor (interstitial cell tumor) – What about a spayed female having perianal adenoma?

Perianal Adenoma Typical Behavior and Appearance: • slow-growing • non-painful • freely moveable • may occur on tail head, prepuce or scrotum • +/- ulcerated • diffuse form

Perianal Adenoma Treatment: • conservative resection + castration • castration alone for diffuse form • castration + cryosurgery for small lesions Always submit for histopathology!!

Perineal Adenoma Prognosis • Good • >90% cure with castration and removal • always submit for histopathology • recurrences may be adenocarcinoma

Patient “B”: 9yr male castrated mixed breed

Patient “B”: 9yr male castrated mixed breed • What is it?

– FNA or biopsy

• Where is it?

– thoracic radiographs – rectal palpation – abdominal ultrasound

• How bad is it?

– palpation of mass and surrounding tissue

Patient â&#x20AC;&#x153;Bâ&#x20AC;?: 9yr male castrated mixed breed Results: What kind of predominate cells are these?

- Round cell - Mesenchymal - Epithelial - Inflammatory

Patient “B”: 9yr male castrated mixed breed

• Thoracic radiographsWNL • Rectal palpation- no palpable sublumbar node enlargement • Palpation of mass- fixed, invasive into deeper tissue

Patient â&#x20AC;&#x153;Bâ&#x20AC;?: 9yr male castrated mixed breed Most Likely Diagnosis?

Perineal Adenocarcinoma

Patient “B”: 9yr male castrated mixed breed Most Likely Diagnosis?

Perineal Adenocarcinoma • fixed, invasive into underlying tissue • occurred in a castrated dog Next Step BIOPSY

Perineal Adenocarcinoma Typical Behavior and Appearance: • can look similar to perineal adenoma – cytology may not differentiate between perineal adenoma and adenocarcinoma

• usually more rapidly growing, invasive and may be painful • occur in intact males, castrated males or females (non-androgen dependent) • metastasize to sublumbar lymph nodes

Perineal Adenocarcinoma Diagnostic work-up – caudal abdominal radiographs or ultrasound – rectal exam – chest radiographs for metastasis – +/- advanced imaging (CT, MRI) to assess degree of invasiveness

Perineal Adenocarcinoma Treatment • aggressive surgical removal with margins if possible – radiation therapy may be required if margins are incomplete • do not respond to castration

Perineal Adenocarcinoma Prognosis • >15% will have lymph node metastasis • local recurrence common with conservative sx • prognosis variable – <5 cm diameter and no metastasis, 2 year survival – worse with metastasis to lymph nodes or lungs, 2 month survival

• surgery or surgery + XRT provides excellent local control

Surgery of Perianal Tumors Surgical Techniques: â&#x20AC;˘ up to 50% of the anal sphincter can be removed with good function â&#x20AC;˘ Sliding advancement flap useful to prevent stricture

Patient “C”: 7yr FS Keeshound • Large subcutaneous mass in perineal region • Straining to defecate • Weight loss • PU/PD • Lethargic

Patient “C”: 7yr FS Keeshond • What is it?

• Where is it?

• How bad is it?

Patient “C”: 7yr FS Keeshond • What type of predominate cells are these?

-

Round cells Mesenchymal Epithelial Inflammatory

Patient “C”: 7yr FS Keeshond Results • FNA- Carcinoma cells • Thoracic rads- WNL • Abdominal ultrasound- multiple enlarged sublumbar LNs- FNA • Rectal- soft ball-sized mass, right side, firmly attached • Chem- Calcium 16 mg/dl, BUN 45 mg/dl, Creat 2.5 mg/dl, albumin 3.5 mg/dl • U/A- SG 1.008

Patient “C”: 7yr FS Keeshond These are aspirates of what organ?

Patient “C”: 7yr FS Keeshond Most Likely Diagnosis?

Anal Sac Adenocarcinoma

Patient “C”: 7yr FS Keeshond Most Likely Diagnosis?

Anal Sac Adenocarcinoma • large, invasive subcutaneous mass • hypercalcemia- paraneoplastic syndrome • female Next step?

Aggressive fluid diuresis

Anal Sac Adenocarcinoma Hypercalcemia of Malignancy • common paraneoplastic syndrome25-80% • tumor secretion of parathyriod hormone-related petpide (PTH-rp) • causes PU/PD, lethargy, renal failure • consider all possible diagnoses if found incidentally

Hypercalcemia • calcium is bound to serum albumin, active portion is the ionized fraction – must correct value or run ionized Ca++

Simple way to correct serum Ca++ • normal albumin = 3.5 mg/dl • take the difference between your patient’s serum albumin and 3.5 • add or subtract this difference from the patient’s serum calcium value • *Measuring for ionized Ca++ is best

Anal Sac Adenocarcinoma Treatment-Hypercalcemia of Malignancy • correct for serum albumin levels to see if corrected value is still elevated • 0.9% NaCl diuresis- promotes Ca++ excretion by increasing GFR, calciuresis, natruresis • furosemide (Lasix®)- must be fully hydrated • recheck ionized calcium or serum chemistry until normal • if refractory, consider corticosteroids ONLY if lymphoma has been ruled out!

• What is another drug choice? =Bisphosphonates

Anal Sac Adenocarcinoma Typical Behavior and Appearance: • a.k.a apocrine gland carcinoma • highly invasive and metastasize readily to sublumbar LNs or further • classic signalment is FS but also occurs in males with similar frequency • hypercalcemia reported in 25-50% • subcutaneous, centered at 4:00 or 8:00 • may be very small and still cause hypercalcemia and LN metastasis

Anal Sac Adenocarcinoma Diagnostic Work-Up • FNA • rectal exam with palpation of mass and sublumbar lymph nodes • CBC, Chem, U/A, ionized calcium • abdominal ultrasound • thoracic radiographs • CT/MRI to assess extent of disease and resectability

Anal Sac Adenocarcinoma Treatment: â&#x20AC;˘ resolve hypercalcemia prior to anesthesia or surgery â&#x20AC;˘ surgical excision of primary mass along with enlarged sublumbar lymph nodes

Anal Sac Adenocarcinoma Treatment: • wide margins rarely obtainable • RT is useful to prevent local recurrence and treat sublumbar lymph node bed – side effects include colitis, proctitis, moist desquamation of perineal skin – short term, self-limiting

• mitoxantrone • doxorubicin • carboplatin

Anal Sac Adenocarcinoma Prognosis: • guarded to poor if no adjuvant therapy used • 1-2 years if complete resection or adjuvant radiation therapy • reports suggest chemotherapy may improve survival, metastectomy for locoregional metastasis • negative prognostic predictors

– hypercalcemia, large size, failure of hypercalcemia to resolve after surgery or treatment, renal compromise

â&#x20AC;¢ Questions?

Mystery Case #1 Patient “D” • 11 yr FS German shepherd

Mystery Case # 2 Patient “E” • 12 yr old MC terrier mix • recently neutered

Patient “E”: 12yr MC terrier mix

Patient “F”: 14 yr MI standard poodle

Patient “F”: 14 yr MI standard poodle

Patient “F”: 14 yr M/I standard poodle

Patient “G”: 11 yr FS Newfoundland

Patient “G”: 11 yr F/S Newfoundland

Tips and tricks to removing a tumor Bernard SĂŠguin, DVM, MS dip ACVS, Founding Fellow, Surgical Oncology

“Cut big, cut wide, cut deep, live forever” - SJ Withrow

The surgery for excision • There can be 3 therapeutic goals when excising a mass – Curative – Palliative – Cytoreductive

• The tumor type, size , and location, the stage of the patient, and the goals of the owners will determine the goal of the surgery – This will dictate the “dose” of the surgery

“Doses” of surgery • 4 “doses” – Intracapsular – Marginal – Wide – Radical

Doses of surgery

Doses of surgery • Do not over-treat • Do not under-treat – The dose is appropriate for the patient • The dose is proportional to the goals of the surgery – Curative – Palliative – cytoreductive

“dose” of the surgery • Dictated by the goal of the surgery – The tumor type – Stage of the patient – size , and location of the tumor – goals of the owners

Goals and doses of surgery • Benign tumors → marginal • Malignant tumors – Distant metastasis → palliative → marginal, intracapsular – No distant metastasis → curative → wide/radical

• Relatively large malignant tumor on extremity, owner refuses amputation, possibility of adjuvant therapy → cytoreductive → marginal

The successful surgery • The success of a surgery is not limited to the operation itself – Steps before the surgery: biopsy, imaging, staging – Steps after the surgery: • Postoperative care • Submitting the sample

Approaching the oncologic patient • Know who the enemy is • Stage the patient • Overall health status T: tumor type L: location C: condition of patient

Planning the treatment regimen • Involve the owners • Minimize morbidity • Maximize quality of life

The surgery for excision • There can be 3 goals when excising a mass – Curative – Palliative – Cytoreductive

Surgery for a cure â&#x20AC;˘ Refers to the procedure where the goal is to remove the entire tumor locally; also referred to as the definitive surgery

Cancer is a contaminant that can seed and spread

â&#x20AC;&#x153;A chance to cut is a chance to cureâ&#x20AC;?

â&#x20AC;&#x153;The first surgery is the best chance for a cureâ&#x20AC;?

Anatomy of a tumor

Concept of surgical margins

Surgical margins â&#x20AC;&#x201C; wide excision

Quantity versus quality

Imaging the tumor â&#x20AC;˘ Sometimes, it is the tip of the iceberg

Principles for curative- intent surgery -

• Never puncture or rupture the tumor.

Therefore manipulate and handle the tumor with great care • Ligate the vascular supply before transecting (artery or vein first?)

• Remove previous drainage and biopsy tract • Use sharp dissection • Use monofilament suture material -

Principles for curative- intent surgery • Isolate (pack off) the tumor from the rest of the surgical wound • Irrigate as needed with sterile saline • Avoid touching ulcerated areas of the tumor with gloves or instruments • Remove tumor with adequate margins (lateral and deep)

Principles for curative- intent surgery â&#x20AC;˘ Use separate instruments, gloves, and drapes for closure and reconstruction and also when removing another mass

Principles for the curative-intent surgery â&#x20AC;˘ Adhesions should be removed en bloc with the tumor â&#x20AC;˘ Avoid placing surgical drains or if a drain is necessary, place it such that it will not compromise a second surgery or radiation therapy

Principles for curative- intent surgery • Lavage the wound bed or body cavity (??)

• Identify the surgical wound with hemoclips • “If it is worth removing, it is worth submitting” – mark the margins

Marking the margins

Marking the margins

Marking the margins

The “second” surgery • First surgery had incomplete surgical margins (“dirty” margins) • Usually for microscopic disease • Even when only one site was “dirty”, the entire previous incision with additional normal tissue must be excised • Also remove any draining sites if present

Primary re-excision for incompletely excised soft tissue sarcomas • Local recurrence in 15% dogs • Liposarcomas and fibrosarcomas more likely to recur • Presence of residual tumor in scar not predictive of local recurrence – Residual tumor in 22% of scars Bacon et al, JAVMA 2007

Cytoreductive surgery • Planned incomplete excision of a tumor • Indicated when complete excision carries unacceptable consequences (e.g. amputation) • Goal is to is to “downstage” the disease, i.e. decrease tumor burden and therefore enhance the response to an adjuvant therapy (e.g. radiation therapy)

Cytoreductive surgery â&#x20AC;˘ Usually, need to downstage disease to microscopic level to be of any benefit â&#x20AC;˘ Unproven role in certain instances

Cytoreductive surgery • If adjuvant therapy is radiation – Need to “mark” the surgical bed so can identify it later to plan radiation treatment field appropriately (usually use hemoclips) – Surgical incision must be in the best orientation and plane to facilitate radiation therapy planning

Surgical excision

Palliative surgery • Goal is to improve quality of life without trying to prolong survival • Consider very carefully inflicted morbidity vs anticipated gain in relief of pain/improved function – which of the two is the worse evil • Amputation without chemotherapy for osteosarcoma in dogs is a classic example

ď&#x192;&#x2DC; La neoplasia con mayor prevalencia en perras enteras (40%) ď&#x192;&#x2DC; Hasta el 50% de las neoplasias mamarias en perras son de comportamiento maligno

 La incidencia incrementa con la edad

 Mayor presentación entre 10 y 12 años  Rara en menores de 4 años  Se reduce de forma drástica con la esterilización en perras jóvenes

El desarrollo de neoplasias malignas es dependiente de estímulo hormonal  Riesgo antes del 1er estro: 0.5%  Riesgo antes del 2º estro : 8%  Riesgo antes del 3er estro: 26% **No se observa diferencia con OVH después del 3er estro para malignas pero si en las benignas Schneider et al. 1969



Tumores benignos presentan receptores estrógeno y progesterona



Tumores malignos en baja frecuencia



Raro en metástasis

Tumor mamario

 Presencia de 3 o más estros

 Cronicidad de una neoplasia benigna  Administración de estrógenos/progestágenos  Edad avanzada  Obesidad (pubertad)

 Apoya teoría de evolución de tumores benignos a malignos (análisis clínico/histopatológico)  Mayor porcentaje de neoplasias malignas en perras de edad avanzada VS perras jóvenes

TUMORES BENIGNOS  Pequeños  Bien delimitados  Firmes

 Mayoría de tumores de 1 cm o menores fueron benignos (96 de 97 tumores)  Mayoría tumores de 1 a 2 cm benignos (50 de 54)

TUMORES MALIGNOS    

Crecimiento rápido Pobre delimitación Extensión hacia piel y tejido adyacente Ulceración e inflamación

CARCINOMA INFLAMATORIO      

Rápido crecimiento Afecta varias glándulas e involucra piel Firmeza y calor a la palpación Edema de miembros cercanos al tumor Eritema Dolor

      

Tamaño del tumor Involucro de LN Metástasis a distancia Grado histológico Infiltración vascular o linfática Grado de invasión Receptores hormonales

 Hemograma  Bioquímica completa

ď&#x192;ź CitologĂ­a * Poco sensible benigno vs maligno

Ayuda

a orientar el diagnóstico de otras neoplasias (mastocitoma, sarcomas)

De valor para carcinoma inflamatorio

Metástasis a linfonodos

Diagnóstico definitivo

Información

importante

quimioterapia

Factor pronóstico

para

decidir

GRADO 0 Células tumorales limitadas en tejido ductal I Células tumorales invadiendo tejido estromal II Invasión linfática/vascular, metástasis a linfonodos regionales III Metástasis a distancia

Gilbertson, A et al. 1983

GRADO I II III

Bien diferenciado Moderadamente diferenciado Pobremente diferenciado

(Elston and Ellis, 1991; Sloane et al., 1999)

CirugĂ­a

Excepto

Nodulectomía

 Masas pequeñas  Superficiales  Implica remover márgenes de 1 cm

Mastectomía simple  Tumores localizados mayores a 1 cm  Invasión a piel y fascia abdominal  Márgenes de 1 a 2 cm

Mastectomía regional  Glándulas 1,2,3 ó 3,4,5  Masas más grandes o múltiples  Linfonodos inguinal y axilar

Mastectomía radical  Enfermedad extensa  Masas más grandes o múltiples  Mejor tolerada bilateral en 2 pasos

Objetivos:  Retardar el tiempo de aparición y/o evitar de metástasis (adyuvante)  Reducción de crecimiento neoplásico local (paliativo, ej: carcinoma inflamatorio)  Pacientes (paliativo)

con

metástasis

pulmonar

Criterios para administrar quimioterapia:  Grado histológico (> 20 mitosis/10 HPF ó 2-3 mitosis/HPF)  Permeación vascular/linfática

 Tipo histológico (carcinomas sólidos, anaplásicos, carcinosarcomas, sarcomas)

 Características clínicas tamaño, tumor fijo, crecimiento)

(infiltración ulceración,

piel, tasa

• • • • •

16 pacientes 8 pacientes en cada grupo (sin/con quimioterapia) Todas en estadío III Grado de invasión I y II Carcinomas simples y carcinosarcomas

â&#x20AC;˘ Protocolo quimioterapia 5- fluorouracilo 150 mg/m2 y ciclofosfamida 100 mg/m2 una vez por semana x 4

Promedio sobrevida 24 meses

Promedio sobrevida 6 meses

• • • • • • •

31 pacientes 19 cirugía monoterapia 6 quimioterapia con doxorubicina 6 quimioterapia con docetaxel Estadios I, II, III, IV Estadios histológicos II y III Pacientes con metástasis

• Sobrevida promedio 370 días • Sobrevida sin quimioterapia 390 días • Sobrevida con quimioterapia 231 días • Resultados inconclusos

• • • • • •

19 pacientes 9 cirugía monoterapia 10 cirugía + gemcitabine Grado de invasión II y III Estadío IV y V 10 pacientes con metástasis a distancia en total

• Sobrevida con cirugía monoterapia 178 días • Sobrevida cirugía + gemcitabine 203 días • Sin diferencias significativas entre grupos

Se utilizan con mayor frecuencia la doxorrubicina, 5fluorouracilo y ciclofosfamida.

â&#x20AC;˘ 5- fluorouracilo 150 mg/m2 y ciclofosfamida 100 mg/m2 mismo dĂ­a, una vez por semana

Protocolo AC • Doxorrubicina 30 mg/m2 EV día 1 (1 mg/kg en perros menores de 15 kg) • Ciclofosfamida 200 mg/m2 IV día 10

• El ciclo es repetido cada 21 días

Protocolo FAC • Doxorubicina: 30 mg/m2 (1 mg/kg en perros de menos de 15 kg) IV día 1 • Ciclofosfamida: 100-200 mg/m2 IV día 1

• 5-Fluoruracilo: 150 mg/m2 IV días 8 y 15

ď&#x192;ź Doxorubicina 30 mg/m2 cada 3 semanas Se puede continuar con AINE de mantenimiento y quimioterapia metronĂłmica

• 3er neoplasia más común en gatas

• 17 % de las neoplasias en la especie • 85 al 93 % de los tumores mamarios en felinos son malignos

 Influencia de hormonas sexuales

 Esterilización en gatas antes del 1er estro reduce el riesgo 91%  Antes del 1er año en un 86%

 Fuerte asociación entre el uso de drogas que contienen progestinas sintéticas o estrógenos

o Masas de rĂĄpido crecimiento

o FijaciĂłn a piel circundante y pared abdominal o MĂşltiples y ulceradas

Hiperplasia fibroepitelial

o MetĂĄstasis comĂşn

- Disnea - Derrame pleural

 Tamaño del tumor*  Grado histológico**  Extensión de la cirugía

 Tamaño del tumor*/ Tiempo sobrevida - Mayores de 3 cm/ 4 a 6 meses - Menores de 3 cm/ +/- 2 años

Grado histológico**  Sobrevida grado I, 36 meses  Sobrevida grado III, 6 meses  Metástasis a linfonodo 9 meses  Estadísticamente significativo

 Citología

 Histopatología

Objetivos:  Retardar el tiempo de aparición de metástasis pulmonar (después de QX)

Objetivos:  Paliativo metástasis pulmonar

 No resecables  50 % de respuesta

Pacientes con cirugía radical unilateral:

• Sobrevida con cirugía 414 días • Sobrevida con cirugía + quimioterapia 1998 días

Pacientes con cirugía + quimioterapia doxorubicina:

• Sobrevida pacientes estadio III, 416 días • Comparado con histórico de 120- 180 días

• Sin grupo control***

Se utilizan con mayor frecuencia la doxorrubicina, y ciclofosfamida.

5-fluorouracilo

ï&#x192;¼ Doxorubicina 1 mg/kg IV cada 3 semanas

Protocolo AC • Doxorrubicina 1 mg/kg EV día 1 • Ciclofosfamida 200 mg/m2 IV día 10 • El ciclo es repetido cada 21 días

 Existen tendencias en diversos estudios que sugieren el beneficio de la quimioterapia adyuvante en perras y gatas  Son necesarios estudios prospectivos y homogéneos que evalúen el beneficio directo de la quimioterapia en tumores mamarios

 A pesar de la poca evidencia sigue siendo el estándar la administración de quimioterapia adyuvante en tumores mamarios de perras y gatas  Para la adecuada selección de pacientes, es importante considerar factores de riesgo y características clínicas/histopatológicas de los tumores

“QUIMIOTERAPIA PALIATIVA Y METRONÓMICA EN PERROS Y GATOS: USOS Y ABUSOS”

MVZ MMVZ Angelina Gutiérrez Barroso Oncología médica veterinaria

HERRAMIENTAS EN EL TRATAMIENTO DE CÁNCER

CIRUGIA

QUIMIOTERAPIA

RADIOTERAPIA

TERAPIAS BLANCO

TRATAMIENTO TUMORES SÃ&#x201C;LIDOS

CIRUGIA

TRATAMIENTO TUMORES SÃ&#x201C;LIDOS

RADIOTERAPIA

TRATAMIENTO TUMORES SÃ&#x201C;LIDOS

QUIMIOTERAPIA?

ENFERMEDAD METASTÁSICA

???

BASES QUIMIOTERAPIA/CÁNCER

Objetivo: células en proceso de división Mecanismo: interferencia ciclo celular

DEFINICIÓN QUIMIOTERAPIA CONVENCIONAL

Administración de fármacos a dosis máximas para eliminar el mayor número posible de células tumorales

DEFINICIร N QUIMIOTERAPIA CONVENCIONAL

Tratamientos asociados a toxicidad y periodos de descanso para permitir la recuperaciรณn de los tejidos sanos con alta tasa de proliferaciรณn celular

OBJETIVO: METÁSTASIS

TIPOS DE QUIMIOTERAPIA      

Adyuvante Neoadyuvante Terapia de inducción Terapia de mantenimiento Terapia de consolidación Terapia de rescate

OTRAS OPCIONES TERAPÉUTICAS

QUIMIOTERAPIA PALIATIVA

QUIMIOTERAPIA

METRONÓMICA

TERAPIAS ANTIANGIOGÉNICAS

QUIMIOTERAPIA PALIATIVA Su objetivo es disminuir los signos clĂ­nicos en los pacientes cuyo tumor no es resecable o cuando la enfermedad esta diseminada y asociada con dolor o alteraciones funcionales

USOS QUIMIOTERAPIA PALIATIVA Mastocitoma

USOS QUIMIOTERAPIA PALIATIVA Carcinoma tiroideo

USOS QUIMIOTERAPIA PALIATIVA Adenocarcinoma de glรกndulas anales

http://alexandretarrago.blogspot.mx/

USOS QUIMIOTERAPIA PALIATIVA Carcinomas mamarios

Tumores quimioresistentes

Osteosarcoma

Melanoma (oral o metastรกsico)

Sarcomas/Carcinomas escamosos

DEFINICIÓN QUIMIOTERAPIA METRONÓMICA

• Administración continua sin pausas por un largo periodo de tiempo y dosis muy inferiores a las utilizadas convencionalmente • Menor toxicidad • Casos refractarios a regímenes quimioterapéuticos convencionales

DEFINICIÓN QUIMIOTERAPIA METRONÓMICA • Diana terapéutica: la vasculatura o angiogénesis tumoral VS directamente a las células neoplásicas

ANGIOGÃ&#x2030;NESIS

FUNCIÓN QUIMIOTERAPIA METRONÓMICA

• Puede estar relacionada con el restablecimiento de la respuesta inmune antitumoral que a menudo se encuentra disminuida en animales con cáncer

BENEFICIOS QUIMIOTERAPIA METRONÓMICA MV

• Bajo costo • Monitorización poco frecuente • Baja prevalencia de efectos adversos

USOS QUIMIOTERAPIA METRONร MICA

Enfermedad metastรกsica localizada

Enfermedad metastรกsica localizada: Carcinosarcoma mamario

DespuĂŠs de 3 meses con quimioterapia metronĂłmica

Melanoma digital

Inmediato después de cirugía

DespuĂŠs de 4 meses con quimioterapia metronĂłmica

USOS QUIMIOTERAPIA METRONÓMICA

Mantenimiento después de cirugía paliativa/incompleta

USOS QUIMIOTERAPIA METRONÃ&#x201C;MICA

85 perros en el estudio 30 con tratamiento de ciclofosfamida + piroxicam 55 control

USOS QUIMIOTERAPIA METRONĂ&#x201C;MICA

Intervalo libre de enfermedad prolongado en los pacientes que recibieron el tratamiento

EstadĂ­sticamente significativo Cada 48 horas menor toxicidad

Enfermedad metastรกsica generalizada

Tumores sรณlidos: sarcomas, osteosarcoma, melanoma oral

TRABAJOS RECIENTES 2013

EVALUACIÓN DE CÉLULAS T REGS CD4+CD25+FOXP3 ANTES Y DESPUÉS DE UN MES CON CLORAMBUCILO METRONÓMICO EN PERROS CON SARCOMAS DE TEJIDO BLANDO • 7 pacientes con sarcomas de tejido blando y resección incompleta grado 1 y 2 • Disminuyó de forma significativa los porcentajes de T regs después de 30 días de medicación (no así los CD8)

TERAPIA ANTIANGIOGÉNICA

Los receptores tirosin cinasa juegan un papel importante en la formación de vasos sanguíneos Sobreexpresados en diversos tipos de tumores malignos

TERAPIA ANTIANGIOGร NICA

Receptores importantes - R- Factor de crecimiento endotelial vascular - R- Factor de crecimiento derivado de plaquetas

- R- Factor de crecimiento fibroblรกstico

INHIBIDORES DE R- TIROSIN CINASA

Evitan la auto-fosforilación de los receptores, inhibiendo la vía de señalización intracelular para su expresión

PALLADIA

Bloquea: c-kit, VEGFR y PDGFR

MASIVET Bloquea: c-kit, PDGFR y FGFR

MECANISMO DE ACCIÃ&#x201C;N

MECANISMO DE ACCIÃ&#x201C;N

USOS PALLADIA

USOS PALLADIA

Inhibidor c-kit

MASTOCITOMA

USOS PALLADIA

Inhibidor VEGFR y PDGFR HEMANGIOSARCOMA

USOS PALLADIA

Inhibidor VEGFR y PDGFR METÁSTASIS

USOS PALLADIA

METÁSTASIS:

 Osteosarcoma  Carcinoma tiroideo  Adenocarcinoma de glándulas anales

 Mantenimiento después de cirugías con bordes limpios  Tumores sólidos resistentes  Neoadyuvante***

PROTOCOLOS DE ADMINISTRACIร N

Combinaciรณn de dos o tres fรกrmacos - AINE - Alquilante - IRTK

PROTOCOLOS DE ADMINISTRACIÓN

 Ciclofosfamida 10 a 15 mg/m2 PO : Martes, Jueves y Sábado  AINE (dosis recomendada)

PROTOCOLOS DE ADMINISTRACIÓN

 Clorambucilo 4 a 5 mg/m2 PO : Martes, Jueves y Sábado  AINE (dosis recomendada)

PROTOCOLOS DE ADMINISTRACIÓN

 Lomustina 2.84 mg/m2  AINE (dosis recomendada)

PROTOCOLOS DE ADMINISTRACIÓN

 Toceranib (Palladia) 2.5 a 2.75 mg/kg PO: Lunes, Miércoles y Viernes  AINE (dosis recomendada)

PROTOCOLOS DE ADMINISTRACIÓN

 Toceranib (Palladia) 2.5 a 2.75 mg/kg PO : Lunes, Miércoles y Viernes

 Clorambucilo 4 a 5 mg/m2 PO : Martes, Jueves y Sábado  AINE (dosis recomendada)

 La quimioterapia metronómica y antiangiogénica ha demostrado ser una opción prometedora en el tratamiento de pacientes veterinarios con cáncer  Parte del éxito del tratamiento estará en la adecuada selección de los pacientes  La indicación principal es enfermedad resecable, metastásica o con fines paliativos

no

 Dentro de los beneficios están la baja toxicidad, bajo costo y poco monitoreo médico requerido

 Limitantes importantes en ciertos tipo de tumores con enfermedad local extensa

Respiratory Neoplasia Deanna Worley, DVM, Diplomate ACVS-SA ACVS Founding Fellow, Surgical Oncology Associate Professor, Surgical Oncology Colorado State University dworley@colostate.edu

Goals • Identify the clinical signs associated with nasal and lung tumors • List differential diagnoses for nasal discharge • List important diagnostic tests for nasal and lung tumors • Appropriately stage nasal and lung tumors • Describe available treatment options

Respiratory Neoplasia • Nasal Tumors • Mediastinal Masses • Lung Tumors

Canine Nasal Tumors • Incidence – 1% of all canine neoplasia • Predispositions• • • •

Medium to large breeds 10 years of age Dolichocephalic breeds Environmental exposures • Pollution • Smoke

Feline Nasal Tumors • Nasal Planum most common • Nasosinal much less common than the dog • Mean age 10 years

History / Clinical signs • Nasal planum:

– Crusting, erythema, superficial erosions, ulcers – Progress to deep erosions and ulcers

• Nasosinal:

– Epistaxis, mucopurulent discharge • Unilateral → Bilateral

– Facial deformity – Dyspnea, sneezing – Chronic duration • 2-3 months

• What are differential diagnoses for a suspected nasal tumor

…..in a dog …..in a cat?

Differential Diagnoses • Degenerative, Developmental: • nasopharyngeal polyps (cat)

• Anomalous, (Autoimmune): • Metabolic: • hypertension

• Nutritional, Neoplastic: • Inflammatory (Infectious, Noninfectious), Immune-mediated, Iatrogenic, Idiopathic: • foreign body

• w/ 2˚infection

• rhinitis - bacterial, fungal, parasitic • tooth root abscess • lymphoplasmacytic/eosinophilic rhinitis

• Trauma, Toxicity, (Tumor) • Vascular • coagulopathy

Diagnostic Work Up • PE

• BMBT • BP

• Blood work

• CBC w/ platelets • ACT or PT/PTT

• • • • •

3v TXR **CT/ MRI Rhinoscopy Bx Regional LN FNA, esp. if enlarged • 10% positive

Air flow

**Open mouth DV most useful view What are the radiographic findings?

CT Scan • Superior imaging value • Findings: • • • •

Destruction of the ethmoid bones Destruction of bones surrounding the nasal cavity Abnormal soft tissue in the retrobulbar space Hyperostosis of the lateral maxilla

Biopsy • Rhinoscopy

• Small samples

• Curette • Laryngeal cup forceps/uterine biopsy forceps • Core • Rhinotomy • Bloody!

• Hydropulsion

• 60 ml or bulb syringe with saline • May yield larger pieces

Measure first!

Histopathology • Carcinoma (roughly 2/3)

– Adenocarcinoma, squamous cell carcinoma, solid carcinoma

• Sarcoma

– Chondrosarcoma, fibrosarcoma, osteosarcoma

• Miscellaneous histologies – Hemangiosarcoma – Mast cell tumors

• Cats:

– Carcinomas predominate – Lymphoma more common in cats than dogs • Usually FeLV-

Biologic Behavior • Very locally aggressive • Slow to metastasize

• Low incidence at time of presentation • Up to 50% at time of necropsy • Lymph nodes, lungs • Metastasis rarely the cause of death

Treatment • Palliative treatment only • Median 95 days in 139 carcinoma patients • Rassnick et al JAVMA 2006

• Surgery alone- similar to no tx • Rhinotomy • Lack of clean margins • Median survival 3-6 months • Chemotherapy • Not curative when used alone • Cisplatin median survival up to 5 months • Hahn et al JAVMA 1992

• Alternating doxorubicin/carboplatin and piroxicam • 75% clinical response with several documented CR • Langova et al Australian Vet J 2004

Treatment: Radiation • Treatment of choice for nasal tumors** • Advantages • Treat the entire tumor

• Disadvantages • Cost • Availability • Side effects (acute and late) • Mucositis, skin changes, dry eye, cataracts

• Improving with newer planning and treatment technologies

Radiation • Cats with solitary LSA - Long-term (> 2 years) control is common!

• Most will experience significant improvement in clinical signs • Palliative (e.g. once-weekly) RT improves clinical signs in approximately 90%, median survival time = 7-8 months

Radiation Side Effects • Acute effects (100% of patients) Rapidly dividing cells – Oral mucositis – Rhinitis – Moist desquamation – Keratoconjunctivitis, blepharitis

• Late effects (5% of patients, cataracts 100%) Slowly dividing cells – Cataracts, corneal changes – Bone necrosis, oral nasal fistulas, skin fibrosis

Side effects

Side effects

Side effects • Supportive care – Acute effects usually occur toward the end of therapy – Nutritional support- Severe mucositis • Feeding tubes if needed

– Analgesics – Antibiotics – Ocular support • Artificial tears, cyclosporine

– Prevent Self Trauma!!!!

• E collar, tape hobbles, sedation

Radiation Advances • Newer modalities developed to maintain or increase dose to tumor but spare normal tissues better!

• 3D CRT • IMRT

3D Conformal Treatment Planning • Assign dose to tumor based on normal tissue tolerance in the area • Advanced imaging (CT or MRI) • Requires exact positioning daily • Bite blocks, vacuum beds

• Multiple beams combined with dose modifying wedges and blocks or multi-leaf collimators

3D CRT 2 beams large dose to skin (red)

Intensity Modulated Radiation Therapy (IMRT) • Greater sculpting of dose using leaves that are moved during each treatment beam allowing the beam intensity to vary within each portal • More beams used (up to 12) • Inverse treatment planning • “sculpt out” the normal tissues

• Similar fractionation schedule

• More dose to tumor, theoretically better control with less side effect

IMRT 12 beams minimal dose to skin

3D CRT

IMRT

IMRT • IMRT – Better normal tissue sparing – Acute side effects are less – Specialized equipment – Greater efficacy?

• Stereotactic Radiosurgery (SRT) – Increased dose per fraction – 3-5 fractions – Probable efficacy as IMRT

Combination Therapy • Surgery plus radiation

– Unknown benefit if done prior to radiation – Improved survival in small group of dogs that had surgery after radiation • Median survival 47 months (Adams et al JAVMA 2005)

• Radiation plus chemotherapy

– Longer survival 19 months vs 14 months

• Other treatments

– Piroxicam – Carotid artery ligation – Interventional Radiology (IR) selective embolization

Outcome / Prognosis- Canine Summary • No treatment/palliative care – 3-6 months

• Radiation – Median survival 12-19 months

• Die of local disease vs. metastasis – Sarcomas do better – Smaller is better

Feline nasal tumors • Treatment • Radiation • Chemotherapy if LSA

• Outcome • local disease • systemic if LSA (~10% of cases)

• Prognosis

• LSA ~ 1.5 to 2 years • Carcinomas- 1 year

• 10 year old, SF, DSH • 9 month history, crust/scab on nose • Transient response to antibiotics, steroids

Work up • Cytology • Bx • LN • 3v TXR

Squamous Cell Carcinoma

Treatment • Surgery • Cryotherapy • Small, superficial lesions

• Radiation • Photodynamic therapy • Chemotherapy • intralesional • retinoids

1 Year post surgery

Prognosis • Good • local recurrence

• Margins • radiation

• Other sites • 2nd primaries

Respiratory Neoplasia • Nasal Tumors • Mediastinal Masses • Lung Tumors

History/Clinical Signs Respiratory Signs • Pre-caval syndrome • PU/PD (hypercalcemia) • “Noncompressible thorax” in cats • Regurgitation/ weakness •

What causes precaval syndrome?

Compression of the esophagus Compression of the carotids Compression of the lymphatic vessels Compression of the cranial vena cava

Differential Diagnoses • Lymphoma • Thymoma • Thyroid (ectopic) • Chemodectoma • Histiocytic sarcoma • Others (rare)

10 YO FS Border Collie Search and rescue Ground Zero Iraq Katrina Assymptomatic, incidental finding

Diagnosis • US-guided FNA / Trucut • Flow cytometry for LSA vs. thymoma (CD4+CD8+) • Pre-operative CT (thyroid, thymoma, chemodectoma)

(FNA of the border collie = Lymphoid tissue)

Treatment • LSA: Chemotherapy • Thyroid / Thymoma: Surgery • Chemodectoma : ?

The same border collie….

Respiratory Neoplasia • Nasal Tumors • Mediastinal Masses • Lung Tumors

Background • Metastasis more common than primary • Almost all malignant (carcinoma) • Higher incidence in urban environment?

• Passive smoke?

History/Clinical Signs • Cough / Hemoptysis • Dyspnea • Lethargy • Weight loss • Lameness (mechanism????)

• Incidental finding (25%) • Cats - Digit mass → primary lung tumor

Staging • Thoracic Radiographs

• Solitary lung mass • Often caudodorsal lung fields • Evaluate lymph nodes • Pleural effusion

Differential Diagnoses • • • • • • • • •

Primary lung tumor (carcinoma) Metastasis Malignant histiocytosis Granuloma Fungal (travel history?)

Pulmonary infiltrates with eosinophils (parasitic) Pulmonary lymphomatoid granulomatosis Esophageal?

Hernia?

Staging â&#x20AC;˘ CT scan

â&#x20AC;&#x201C;Allows much more sensitive evaluation of thorax for lymphadenopathy, other pulmonary lesions (intra-lung metastasis)

CT Scan for Lymphadenopathy â&#x20AC;¢ 83% sensitivity, 100% specificity

Paoloni MC et al, JAVMA 228: 1718, 2006

Cytology / Histopathology • Fine-needle aspirate or tru-cut biopsy • Usually done under ultrasound, occasionally CT, guidance • Low risk of complications • Not wrong to bypass if lesion is solitary and “classic” in appearance

Treatment • Lung lobectomy is the treatment of choice – Evaluate all lung fields for evidence of metastasis – Evaluate and biopsy hilar lymph nodes – What about thoracoscopic lobectomy?

• Less invasive, shorter recovery time • Can’t biopsy lymph nodes • Limited to smaller peripheral lesions

– Stereotactic radiation therapy?

Prognosis Factor

__

Clinical Signs:

YES NO Lymph Node: + Histo Grade: Low Med/Hi

Median Survival Time 240 d 545 d 26 d 452 d 495 d 44 d

Adjuvant Therapy?

• Platinum drugs • Navelbine (vinorelbine) • Aerosol-delivered chemotherapy (investigational)

Soft Tissue Sarcomas & Hemangiosarcomas Deanna Worley, DVM Diplomate ACVS, Small Animal Surgery ACVS Founding Fellow, Surgical Oncology Associate Professor, Surgical Oncology dworley@colostate.edu

Lecture Objectives:

• Understand the nomenclature and biologic behavior for the soft tissue sarcomas (STS) • Know how to properly biopsy and stage a suspected STS • Know current treatment options and associated prognosis for STS • Understand the presentation, behavior, and treatment options for Hi-Lo FSA • Understand the etiology and significance of vaccineassociated sarcomas in cats • Understand the behavior and prognosis of HSA and know current treatment options

Tissue of Origin Nomenclature

Primary Sites

Nervous tissue

*Peripheral nerve sheath tumor

extremity

Skeletal ms

Rhabdomyosarcoma Rhabdomyoma

tongue, bladder, heart

Smooth ms

**Leiomyosarcoma Leiomyoma

GI, spleen, liver, vulva, SQ tissues

Fibrous tissue

Fibrosarcoma **Malignant fibrous histiocytoma

Extremity,oral (FSA) spleen, SQ (MFH)

Adipose tissue

Lipoma Liposarcoma

extremity, bone, cavitary

Myxomatous tissue

Myxosarcoma Myxoma

Extremity joints

*Also includes hemangiopericytoma, schwannoma, neuroFSA,

**Higher metastatic potential than other STS when visceral

Soft tissue sarcoma

Fibrosarcoma PNST* Liposarcoma Myxosarcoma Malignant mesenchyoma

Other soft tissue sarcoma

Leiomyosarcoma Rhabdomyosarcoma Synovial cell sarcoma Lymphangiosarcoma

Non-soft tissue sarcoma

Histiocytic sarcoma Anaplastic sarcoma of young dogs Hemangiosarcoma Osteosarcoma Chondrosarcoma Melanoma Lymphosarcoma (lymphoma)

Have higher metastatic rate and different biologic behavior!!

STS grading system Score

Differentiation

Mitosis

Necrosis

1

Resembles normal adult mesenchymal tissue

0-9

None

2

Specific histologic subtype

10-19

<50% necrosis

3

Undifferentiated

>20

>50% necrosis

• Grade 1: cumulative score ≤4 • Grade 2: cumulative score of 5-6 • Grade 3: cumulative score ≥7

(mitotic figures/ 10 HPF)

Biologic behavior • Any anatomic location • Soft to firm, variable consistency, typically non-painful • Locally invasive and infiltrative • Recurrence common after conservative excision – Pseudocapsule = compressed tumor cells + reactive tissue

• Resected tumor margins predict local recurrence Ehrhart JAAHA 2005

Biologic behavior • Histopathologic grade predictive of metastasis – Grades 1&2 low to moderate metastatic rate (<20%) – ~40 – 50 % of grade 3 tumors will ultimately met – Hematogenous spread (usually to lungs) – Regional LN mets uncommon • Exception synovial cell sarcoma

• Poor response to chemo and RT when gross tumor (>5cm) is present • Visceral sarcomas typically more aggressive – Leiomyosarcoma – especially liver • Exception intestinal leiomyosarcoma – Pleiomorphic liposarcoma

Clinical Presentation • Cutaneous or SQ mass – Usually non-painful – Variable consistency – Often normal haired skin overlying – Variable growth rate – Can occur anywhere

Diagnosis and Staging: • Fine needle aspirate of tumor – Often exfoliate poorly or bloody – May hit necrotic or inflamed area – May need larger gauge needle with 6 or 12 cc syringe attached

Diagnosis and Staging: • Incisional – Punch – Tru-cut (needle core) – Wedge

• Excisional – May be inappropriate for a mass not amenable to wide resection

Additional staging diagnostics: • Thoracic radiographs – 3 views • FNA regional lymph node

The metastatic rate is low but is not zero!

CT or MRI often provide essential presurgical information • Indicated for: – Large tumors – Head and neck tumors – Intra-cavitary tumors

Aggressive surgery is the mainstay of treatment • 3 cm margins laterally, at least one fascial plane beneath, include Bx tract • Identify margins for histopathology – Ink – Suture

• < 1 to 3-mm margins = incomplete excision!

• Consider radical procedures in advance if necessary – mandibulectomy, maxillectomy – amputation – body wall resection

Treatment and Prognosis • Interpreting the pathology report – Histotype – Histologic grade (ask!)

• “high grade,” anaplastic, undifferentiated tumors have a higher metastatic rate (40-50%)

– Margins

• Margins must be interepreted taking into account tumor biology and aggressiveness of surgery!

What if surgical margins are incomplete?

• Determine if second surgery reasonable – Avoid multiple marginal excisions – The best chance to cure is with the first surgery!

• Radiation therapy • Chemotherapy?

• Limb distal to elbow and stifle joints – Exception?

• Bacon JAVMA 2007

End of Tx

1 month Post Tx

Radiation therapy is an effective adjunct to surgery • Much more effective in the context of microscopic disease • Aggressive, high-dose protocol necessary – 85% 3-year local control after incomplete excision (Except oral cavity) – 50% 1-year control rate if treating gross disease

Forrest, et al. JVIM, 2000

Higher doses of irradiation result in higher control rates Percent Tumor Control vs.

Radiotherapy Dose for Incompletely Resected Soft-Tissue Sarcomas

Current CSU radiation therapy protocol:

100

Curative intent: 80

• M-F x 4.5 weeks • Usually 3Gy x 18 = 54Gy total – Limb 30 Gy circumfential, then sparing strip for collateral circulation

60 40 20 0

45 Gy

50Gy

52 Gy

Total Radiation Dose

63 Gy

Radiation Therapy

1 week post Tx End of Tx • • • •

Cost = $5500 – 7000 for full course Mild to severe acute local reaction Multiple general anesthesias Hospitalization time

2 months Post Tx

Indications for chemotherapy: • High-grade (grade III), anaplastic, undifferentiated sarcomas • higher metastatic rate (40-50%) • Certain histotypes – Histocytic, lipoSA? • Young dogs?

• Most visceral sarcomas – Exception - GI leiomyosarcoma • r/o GIST w/ special stains for c-Kit • Aggressive local therapy declined or not possible

Chemotherapy for canine STS: • Doxorubicin (Adriamycin) – single agent – 30 mg/m2 IV q 3 weeks • A/C ?

– doxorubicin 30 mg/m2 iv q 3 weeks – cyclophosphamide 100-200 mg/m2 iv or po q 3 weeks • V/A/C ?

– Doxorubicin 30 mg/m2 IV day 1 – Cyclophosphamide 100-200 mg/m2 day 1 or PO days 2-5 – Vincristine 0.7-0.75 mg/m2 IV days 8 and 15 – Repeat every 21 days In adjuvant setting, consider 4-5 cycles

Other Chemotherapy for canine STS: • CCNU (Lomustine) for histiocytic sarcomas • Skorupski JVIM 2007

• 70 mg/m2 PO q 3-4 weeks • 50% response rate (mostly PR) • Median response duration = 90 days

• Metronomics or continuous, low dose chemotherapy • Goal is not eliminating the disease, but to arrest growth and spread • Cyclophosphamide (Cytoxan) + Non Steroidal Anti Inflammatory • Cytoxan has antiangiogenic properties at low doses • 15 mg/m2 daily – Burton JVIM 2011 – Treg depletion, inhibit tumor angiogenesis

• Chemo worth considering as adjuvant Tx following surgery, but no stats

Prognosis STS • Size: <5cm • Histologic grade: low or intermediate • Fixation: freely moveable vs. fixed • Metastasis: none • Completeness of surgical margins: clean

Biopsy of FSA in oral cavity can be very misleading on histopathology • Histologically low-grade, biologically high-grade – “High-low” or “HiLo” FSA

• Hard palate, maxilla • GRs and Labs over-represented • previously diagnosed as fibroma, fibrous tissue, scar tissue, inflammation on histology • Very benign on histology fibroma, reactive fibroplasia, etc.

• Very locally invasive • Metastasis to lungs, regional nodes in ~30% dogs • HIGH local recurrence

Feline injection site sarcomas (ISSs =VACs) • Incidence ~ 12 in 10,000 vaccines – 1000 – 2000 cats in US/yr – 1/3000 to 1/10,000 vaccines • <3mo to >3yr onset • Genetic predisposition????

• Chronic inflammation a factor Multi-step carcinogenesis – Genetic factors – PDGF, p53, FGF, TGF-α – Granulomatous inflammation • Vaccines • Long-acting drugs • Microchips??

Feline injection site sarcomas (ISSs =VACs) • Histologically and biologically aggressive • Many vaccine types/brands implicated • Variable metastatic rate (5-25%) depending on study • Shift: lateral abdominal wall sites, interscapular space, pelvis • Ferrets, dogs affected too

Rabies vaccine associated with highest incidence of VAS??

120

100

80

•No correlation between live, killed, or brand of vaccine

60

40

+/- higher incidence in adjuvanted vaccines – role of aluminum is still unknown

20

0 Rabies

FVRCP

FeLV

Combination

•Incidence of VAS low in countries that do not vaccinate for FeLV or rabies Macy and Hendrick, Vet Clinics, 1996

Aggressive surgical resection is superior to conservative resection for tumor control

• DFI = 325 days with aggressive surgery vs.

• DFI = 79 days with marginal resection • DFI = 274 days if sx at referral instituion vs.

• DFI = 66 days at RDVM

Hershey, et al. JAVMA 2000.

Aggressive surgical resection is superior to conservative resection for tumor control • Radical excision w/o adjuvant treatment for VACs – 5 cm margins laterally, at least 2 fascial planes below – Include Bx tract

– Overall MST 901 days – MST w/ and w/o local recurrence • 499 and 1,461 days – MST w/ and w/o metastasis • 388 and 1,528 days

Phelps JAVMA 2011

Adjunctive therapy is always indicated if tumor resection is incomplete Radiation therapy

Chemotherapy

• Pre-operative (DFI 398 d, MST 600d) vs.

• Post-operative +/- chemo (DFI 661d)?

• ~15 – 45% of tumors will return despite both sx +/- RT

• ~ 10 – 25% metastatic rate • Minimal impact on survival when given with sx + RT • Adjuvant doxorubicin – DFI = 390 days vs. 90 days with sx alone • Gross disease – Carboplatin (40-50% response rate), DOX or A/C (40-60% response rate), Doxil (45% response rate), Vin (case reports), CCNU (case reports)

– Cronin Vet Rad Ultrasound 1998; Bregazzi JAVMA 2001

• Kisseberth Proc VCS 1996; Poirier JVIM 2002; Cronin Proc VCS 1998; Hahn JAVMA 1990; Saba JCO 2011

– Recurrent tumors may have higher metastatic rate

• 8/9 cats with metastasis had recurrent tumors!

• So get aggressive early, don’t wait for recurrence!

• Hershey JAVMA 2000

Hemangiosarcomas • Visceral – Spleen, right atrial appendage, liver – Pericardium, lung, kidneys, oral cavity, muscle, bone, genitourinary tract, peritoneum, retroperitoneum

• Cutaneous

Hemangiosarcomas—visceral • • • • • •

middle aged, older dogs more common GSD, GR, Labs overrepresented Feline (equal distribution cutaneous, visceral) Splenic most common Double two thirds rule Non traumatic hemoabdomen – 46% cats neoplasia, 60% HAS • Culp JAVMA 2010

– 63% dogs HSA, 63% discharged • Aronsohn JAAHA 2009

– 70% dogs w/ splenic mass = HSA; 63% discharged • Pintar JAAHA 2003

Hemangiosarcomas—visceral • Solitary, multifocal, disseminated • Poorly circumscribed, nonencapsulated, adherent, extremely friable • Hematogenous spread, abdominal implantation • Aggressive biologic behavior, rapid metastasis

Hemangiosarcomas—visceral – CBC, chem • schistocytes, acanthocytes

– Coag • 50% criteria for DIC

– TXR – +/-echo • mass absence or presence not specific

– abd U/S • contrast harmonic u/s – liver metastasis = 100% sensitivity / specificity for persistent hypoechoic liver nodules post contrast

– +/- AXR – Centesis • serosanguinous, typically non clotting

– FNA low yield – no needle core Bx for visceral HAS • hemorrhage, seeding

– blood type/cross match – plasma cardiac troponic I?

Hemangiosarcomas—visceral • Stages –I • T0 or T1 (< 5cm), N0, Mo

– II • T1 or T2 (>5cm or ruptured), N0 or N1 (regional LN +), M0

– III • T2 or T3 (invading adjacent structures), N0, N1 or N2 (distant LN +), M1 (distant mets)

Hemangiosarcoma—visceral • Surgery – Splenectomy • Arrhythmias – 1◦ cardiac HSA • Similar Px to other 1◦ HSA visceral sites • Pericardectomy palliative – MST 1-2 mo w/o adjuvant Tx – Lingual MST 553 d – Burton VCO 2012

 Feline

– Splenectomy MST 197 d, 50% HSA

Hemangiosarcomas—visceral • Adjuvant Chemotherapy—DOX-based protocols Px MST 5-6 mo – Single agent – Dox/cyclophosphamide, Dox/cyclophosphamide/vincristine – Metronomic – Dox w/ allogenic tumor lysate vaccine – Dox/dacarbazine/vincristine (DAV) ~4 mo • Unresectable HSA, stage II and III Px MST 9mo – Dox/cyclophosphamide/L-MTP-PE • Not commercially available Future role tyrosine kinase inhibitors?

Hemangiosarcomas—cutaneous • Cutaneous – Stage I • Dermis – light-haired, low pigment, ventral abd/preputial—solar cause?

– Stage II • Extends to subcutaneous tissue – Stage III • Extends to muscle – Feline • Older cats, solitary lesions, low pigment skin, head, ventral abd, inguinal SQ

Hemangiosaromas—cutaneous  Staging  Includes TXR, Abd U/S, CBC, Chem  Treatment  Wide local excision similar to STS  Non metastatic stages II and III  WLE  Adjuvant chemotherapy  DOX-based protocols similar to visceral HSA  DOX-based protocols 38% response rate (Wiley VCO 2010)  Radiation therapy  Incomplete resections  Solitary dermal HSA  Feline nonvisceral HSA

Hemangiosarcomas—cutaneous • Stage I vs. Stages II, III – I ~80% complete resection, 30%met rate---distant dermis, MST 780 d – II, III ~20% complete resection (larger, less circumscribed), 60% met rate to lungs, LN, distant dermis, MST 172-307 d

• Stage II vs. Stage III – Stage II MST 1189 d • younger dogs better Px and dogs w/o RT – Stage III MST 272 d

• Stages II and III – OST 172 d, 25% alive at 1 yr, no survival between stages – local tumor control, tumor diameter ≤ 4 cm, presence of metastasis at Dx, presence of gross disease all significantly associated w/ OST

Hemangiosarcomas—cutaneous • Feline cutaneous HSAs – local tumor control poor with Sx • local recurrence 50%-80% at median 420 d PO – mets less common than dog – MST >1460 d with Sx vs 60 d w/o Tx

â&#x20AC;˘ dworley@colostate.edu