SOFT TISSUE PATHOLOGY

FRCPath Course Manchester Soft Tissue Slide Seminar DR P Shenjere Consultant Histopathologist The Christie NHS Foundation Trust

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Case 1 • 15M; Lesion LT cheek

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SMA The Christie NHS Foundation Trust

DIAGNOSIS

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Case 10 • 19M; Neck mass

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DIAGNOSIS

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Nodular Fasciitis (NF): • • • • •

Common in young adults(20 to 40yrs) Most lesions grow rapidly and then stabilize Sites – usually upper extremity, trunk, head and neck Size – usually 2-3cm, almost never more than 5cm Anatomically – subcutaneous, fascial or intramuscular and rarely dermal

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Nodular Fasciitis (NF):

• Circumscribed or infiltrative, unencapsulated • Plump spindle cells which lack nuclear pleomorphism • Markedly cellular, but focally shows loose, myxoid, torn, feathery character. Formation of microcysts in some cases

• Spindle cells form S- or C- shaped fascicles • Mitotic figures may be numerous but no atypical forms seen • Extravasated RBC, mononuclear inflammatory cells and osteoclast-like GC – commonly seen

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NF (cont……): • Immuno-stains for SMA, MSA and calponin strongly positive; negative for desmin, CK, S100 protein, CD34 and h-Caldesmon.

CD68 stains the osteoclast-like GC as well as some spindle cells • EM – myofibroblasts and fibroblasts • Variants: Intravascular, cranial and ossifying fasciitis

intradermal NF

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D/D of Nodular Fasciitis (NF) • • • • • • • •

Leiomyosarcoma Low grade myofibrosarcoma Low grade fibromyxoid sarcoma Low grade myxofibrosarcoma Myxoid DFSP Fibromatosis Benign fibrous histiocytoma Myxoma The Christie NHS Foundation Trust

• t(17;22(p13;q12.3) -cryptic • USP6-MYH9

• (ABC)

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Reactive/”transient neoplasia” • NF • Proliferative fasciitis • Proliferative myositis • Ischaemic fasciitis With heterotopic ossification • Fasciitis ossificans • fibro-osseous pseudotumour • Myositis ossificans • Heterotopic mesenteric ossification The Christie NHS Foundation Trust

Case 7 • 28F; vocal cord lesion

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ALK 1 The Christie NHS Foundation Trust

SMA The Christie NHS Foundation Trust

DIAGNOSIS

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Diagnosis • Inflammatory Myofibroblastic Tumour

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Inflammatory myofibroblastic tumour(IMT) • Mostly affect children and young adults • Common sites – lung, mesentery and omentum. Other sites – soft tissue, viscera, oral cavity and URT, GIT, GUT, breast and CNS • Systemic symptoms, anaemia, fever, polyclonal hypergammaglobulinaemia and raised ESR in some cases (probably related to IL-6 production) • Solitary or multinodular/multifocal

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Inflammatory myofibroblastic tumour • Size varies from 1 to 20cm • macro: firm and fleshy; may contain gelatinous areas with foci of hmg • Composed of a mixture of myofibroblasts, fibroblasts and mostly mononuclear inflammatory cells(B & T lymphocytes and polyclonal plasma cells). Compact fascicular or storiform growth pattern in cellular areas • Lymphoid follicles with germinal centres in some lesions • Large numbers of blood vessels mimicking granulation tissue may be seen • Variable myxoid and collagenized areas

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IMT • Ganglion-like myofibroblasts may be seen • Calcification and metaplastic bone rarely seen • Three patterns have been described, the first mimicking NF, the second LGMFS or LMS, and the third fibromatosis • Frankly malignant transformation in rare cases

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IMT • • • •

80-90% SMA +ve Desmin and calponin focally +ve in 60-70% 1/3 +ve for CK ALK +ve in 36-50%; positivity reliably predicts the presence of ALK gene rearrangement (Alk gene rearrangement can be detected by FISH) • 10% show ROS-1 rearrangement & are positive for ROS1 IHC • Rare cases show RET or PDGFB gene rearrangements

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• ETV6-NTRK3 Is expressed in a subset of ALK— ve IMTs Am J Surg Pathol 2016;40:1051–1061

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ALK Dual Colour Break Apart Probe; Abnormal Result

Key; Red/Green Fusion Signal = Normal ALK gene.

Red (3’) & Green (5’) signals flank the ALK breakpoint cluster region.

The separate red and green signals indicate a Rearrangement of ALK

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IMT

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IMT

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IMT

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D/D of IMT • • • • • • • • •

NF Fibromatosis LGMFS Leiomyosarcoma SFT GIST FDRCT Retroperitoneal fibrosis Sarcomatoid carcinoma (in CK positive cases)

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Case 23 • 27F; Abdominal wall mass

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SMA

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ß-CATENIN The Christie NHS Foundation Trust

DIAGNOSIS • Fibromatosis

D/D • • • • • • • •

NF Desmoplastic fibroblastoma Perineurioma SFT LGMFS LGFMS LG-MPNST FS The Christie NHS Foundation Trust

Case 20 • 59M; vocal cord lesion

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AE1/3 The Christie NHS Foundation Trust

34BE12 The Christie NHS Foundation Trust

p63 The Christie NHS Foundation Trust

SMA The Christie NHS Foundation Trust

DIAGNOSIS

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Spindle Cell Carcinoma • Also called sarcomatoid carcinoma • M>F • Associated with drinking, smoking and previous radiotherapy treatment • Usually situated in the glottic region

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Macroscopy & Histology • Polypoid lesion • Usually ulcerated • Biphasic – sarcomatoid/spindle cell component & squamous cell component • Sarcomatoid component consist of spindle cells arranged in different patterns such as fascicles, myxoid, storiform etc • Foci of chondrosarcomatous/rhabdomyosarcomatous differentiation may be present • Neoplastic squamous component present in upto 81% - Either as an in-situ or invasive component

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IHC • CK +ve – broad spectrum ck e.g MNF116 & AE1/3, HMW CKs • p63 • Mesenchymal markers +ve in the sarcomatoid component

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Differential Diagnosis • Benign spindle cell lesions• Nodular fasciitis, ossifying & non ossifying fibro-osseous lesions, vocal cord nodule with stromal atypia, laryngeal contact ulcer/ granulation tissue, • SarcomasMPNST, synovial sarcoma,leiomyosarcoma, IMT, SFT, KS, etc • Spindle cell melanoma • Spindle cell myoepithelioma

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Case 4 • 62F; Perineal tumour

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CD34

BCL2 The Christie NHS Foundation Trust

DIAGNOSIS

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Solitary Fibrous Tumour • • • • • •

CD34 (95%) CD99 BCL2 EMA (33%) SMA (33%) Some cases may show focal S100, CK or desmin positivity

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SFT • NAB2-STAT6 gene fusion • inv(12)(q13q13) •

NAB2 exon 4 – STAT6 exon3 & NAB2 exon 6 – STAT6 exon 17 most common fusion variants

• Other fusion gene reported: STAT6- TRAPPC5 • Overexpression of STAT6

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Solitary Fibrous Tumour • • • • • •

CD34 (95%) CD99 BCL2 EMA (33%) STAT6 SMA (33%) Some cases may show focal S100, CK or desmin positivity • STAT6

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Malignant Solitary Fibrous Tumour Features associated with malignancy • >4 mitoses/10HPF • High cellularity • Pleomorphism • necrosis

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“Dedifferentiated” SFT

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SFT Differential diagnosis • Sarcomatoid mesothelioma • Sarcomatoid carcinoma • Synovial sarcoma • Dedifferentiated LPS • Low grade fibromyxoid sarcoma • Cellular schwannoma • MPNST The Christie NHS Foundation Trust

Case 8 • 29F; Thigh mass

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DIAGNOSIS

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Monophasic Synovial Sarcoma

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IHC • Most cases show positivity for CK and EMA • EMA expressed more often and more widely • EMA consistently +ve in epithelial elements of biphasic SS • Other markers- TLE1 (85-97%), CD99 • Focal positivity for S100 in ≈40% • CD34 positivity – very rare

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Synovial Sarcoma • SS18 (18q11.2) • SSX (Xp11.21-23) types 1, 2, 4 (of 5)

• SS18/SSX fusion genes 60% SSX1, 40% SSX2,<1% SSX4 •

Rare variants e.g. t(X;20)(p11.23;q13.33) (SS18L1-SSX)

•

(SS18L1-SSX)

•Ladanyi 2002; Allander 2002; Guillou 2004; Baird 2005; Storlazzi 2007; Amary 2007; Nakayama 2007

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Fusion proteins • SS18 protein - transcriptional coactivator • SSX protein

- transcriptional corepressors

• Fusion protein - functions of both targets include: IGF2, CD44, EGR1, JUNB, WNT

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D/D • • • • •

Fibrosarcoma Leiomyosarcoma Clear cell sarcoma Fibromatosis carcinoma

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Biphasic SS

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Poorly Differentiated SS

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Hemangiopericytic Growth Pattern Stout & Murray: “Hemangiopericytoma: a vascular tumor featuring Zimmerman’s pericytes” Annals of Surgery, 1942.

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Tumours with Haemangiopericytic Pattern • • • • • •

SFT Myofibroma Synovial sarcoma Mesenchymal chondrosarcoma Some MPNST ESS

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Case 27 • 35M; Shoulder lesion

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IHC • Diffusely positive for CD34

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DIAGNOSIS • DFSP

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Dermatofibrosarcoma Protuberans (DFSP) • • • • •

Dermal and subcutaneous tumour Atrophic epidermis Cytologically bland and uniform Prominent storiform pattern Lace-like or honeycomb pattern of infiltration of subcutaneous fat • Infiltrates along septa of adipose tissue • Rarely has giant cell fibroblastoma component

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IHC • Diffusely positive for CD34 • Rare examples –ve for CD34 • SMA+/Other superficial spindle cell tumours +ve for CD34: 1.

2.

3.

4.

5.

6.

Myxoinflammatory fibroblastic sarcoma Cellular angiofibroma Superficial acral fibromyxoma Spindle cell lipoma SFT Mammary type myofibroblastoma The Christie NHS Foundation Trust

Morphological Variants • Pigmented (Bednar tumour) • Myxoid • Granular cell and atrophic variants also described

Myxoid DFSP

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Occasionally contain myoid whorls/bodies

CD34

SMA The Christie NHS Foundation Trust

DFSP with Fibrosarcomatous Transformation

• DFSP rarely undergoes fibrosarcomatous change (<5%) • Occur de novo or in recurrences • Gradual or abrupt • Cellular with associated nuclear atypia, increased mitoses • Cells arranged in fascicles producing a herringbone pattern • 10-15% metastasise The Christie NHS Foundation Trust

DFSP Molecular Pathology • t(17;22)(q22;q13) - most common • Supernumerary ring chromosomes containing material from 17q22 and 22q13 → fusion of COL1a1 and PDGFβ Fusion protein processed into functional PDGF-β

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When is FISH Required?

• Not in classical cases • Useful in unusual histologic patterns & in cases with fibrosarcomatous transformation & metastases • Small punch biopsies

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Tumours with a storiform growth pattern • Other fibrohistiocytic tumours (BFH, PDS/pleomorphic undifferentiated sarcoma) • Perineurioma • Occasional cases of MPNST • Occasional cases of spindle cell carcinoma • Some cases of SFT • Nodular Fasciitis

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Low grade fibromyxoid sarcoma(LGFMS) Originally described by Harry Evans in 1987 (n=2) • Both originally diagnosed as benign • Both locally recurred and eventually metastasized • One patient died from disease Follow-up study by Evans in 1993 (n=10) • 10 new cases • 8/10 diagnosed retrospectively after recurrence / metastasis • 7/10 recurred • 5/10 metastasized (some late) • 4/10 died of disease

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LGFMS

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LGFMS

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Low-grade Fibromyxoid Sarcoma

Giant collagenous rosettes in some cases

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LGFMS – IHC & Molecular Pathology • • • • • • •

Vimentin + EMA -/+ (30%) SMA +/S100 -/+ CD34 – rarely focally +ve Desmin – neg.

MUC4 +ve - most useful marker

•

LGFMS/SEF

•

EWSR1-CREB3L1 rearrangements harbored by a smaller number of LGFMS

t(7;16)(q33;p11); t(11;16)(p13;p11) FUS-CREB3L1; FUS-CREB3L2

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•MUC4

•EMA

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LGFMS – D/D • • • • • •

Neurofibroma Perineurioma Nodular fasciitis Fibromatosis LG MFS Myxofibrosarcoma

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Case 6 • 52F; Thigh lesion

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CD34 CD34

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DIAGNOSIS • Benign Fibrous Histiocytoma

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Benign Fibrous Histiocytoma • PRKCB-PDPN t(1;16)(p36;p11) • PRKCD-LAMTOR1 t(3;12)(p21;q13) • PRKCD-RDH5 t(3;12)(p21;q13)

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Case 11 • 33F; Middle finger lesion

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DIAGNOSIS

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Atypical Fibrous Histiocytoma • Extremities of young patients, non sun damaged skin • Low power view resembles ordinary BFH • High power view reveals foci of severe cytological atypia, high mitotic count, necrosis • Characterised by frequent local recurrence, rare mets • Rx- complete excision and follow up

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D/D • • • • • •

BFH AFX Spindle cell Ca Leiomyosarcoma Melanoma Spindle cell Sarcoma NOS (MFH)

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Variants of FH • • • •

Cellular Aneurysmal Atypical Deep

• • • • • • • • •

Epithelioid fibrous histiocytoma Clear Cell Granular cell Keloidal Lipidized Atrophic Myxoid Palisading Myofibroblastic

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Case 19 • 70M; Forehead lesion

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DIAGNOSIS

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Diagnosis • Spindle cell sarcoma NOS • Not AFX because of subcutaneous extension, and necrosis

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Case 25 • 80M; Scalp lesion

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IHC • +ve for CK14, CK5, p63 • No mucin on PAS

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DIAGNOSIS • Spindle cell carcinoma/sarcomatoid carcinoma

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Case 22 • 69M; Forehead lesion

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CD34

CD31 Fli-1

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DIAGNOSIS

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Angiosarcoma (AS) • Conventional (idiopathic) • Lymphoedema assoc.

• Post radiation

Conventional AS • • • •

Elderly pts Sun-damaged skin Head & neck M>F

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Epithelioid AS

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Epithelioid AS

CD31

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Clear Cell/Signet Ring Cell AS

Am. J. Dermatopathol.2013; 35; 671–675 Histopathology 2015, 66, 856–863

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Clear Cell/Signet Ring Cell AS

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Other Morphological Variants of Epithelioid AS • Foamy cell • Granular cell

Dermatopathol. 2014; 36; 669–672 J. Cutan. Pathol. 2010; 37; 901–906 J. Cutan. Pathol. 2012; 39; 476–478, 475

Histopathology 2015, 66, 856–863

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AS • Can be mostly epithelioid/spindled • Vasoformation can be inconspicuous, usually seen at the periphery • Can be easily mistaken for other tumours if index of suspicion low!

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AS IHC • Use more than one endothelial marker • CD34, CD31, Podoplanin, Fli-1, FVIIIRA

• CD31 – not entirely specific, also expressed by histiocytes • CD34 – less sensitive than CD31 & not specific • Fli-1 – poor specificity; expressed by carcinomas, AFX/PDS, MM The Christie NHS Foundation Trust

ERG • • • •

ERG = ETS-related gene ETS family of transcription factor Expressed in normal endothelial cells Expressed by haemangiomas, lymphangiomas, almost all angiosarcomas, EHE and PMHE • Also +ve in AML, subset of EWS + some prostatic adenocarcinoma

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ERG

CD31

ERG The Christie NHS Foundation Trust

D/D of cutaneous Spindle Cell Tumour with cellular pleomorphism • • • • • •

Atypical Fibroxanthoma (AFX) Spindle Cell Carcinoma Melanoma Leiomyosarcoma Angiosarcoma Atypical Fibrous Histiocytoma

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IHC in D/D of Pleomorphic Cutaneous Spindle Cell Tumours Tumour

AE1/3 or MNF116

34BE12

CK5

p63

SMA

Desmin

S100

CD31

SpCC

+

+

+

+

+/-

-

-

-

AFX

-

-

-

-

-

-

-

-/+

AS

-/+

-

-

-

+

-

-

+

LMS

-/+

-

-

-

+

+

-

-

MM

-/+

-

-

-

+/-

-

+

-

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Case 12 • 61M; Groin mass

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SMA The Christie NHS Foundation Trust

DIAGNOSIS

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Intravascular Leiomyosarcoma • Most commonly involve IVC/PA D/D • Intimal sarcoma

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Case 17 • 31F; Bladder tumour

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SMA

Desmin

h-caldesmon The Christie NHS Foundation Trust

DIAGNOSIS • Leiomyosarcoma • Pt Rxd for retinoblastoma in childhood Ref: Soft tissue, pelvic, and urinary bladder leiomyosarcoma as second neoplasm following hereditary retinoblastoma.

Venkatraman L, Goepel JR, Steele K, Dobbs SP, Lyness RW, McCluggage WG. J Clin Pathol. 2003 Mar;56(3):233-6.

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Case 16 • 68F; Lt buttock lesion

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S100 The Christie NHS Foundation Trust

DIAGNOSIS • Schwannoma

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Cystic change The Christie NHS Foundation Trust

Plexiform Schwannoma The Christie NHS Foundation Trust

Case 21 • 76M; Lt knee lesion

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IHC • Dot-like paranuclear positivity for CK20 and cam 5.2 • Positive for Chr, Synapt and NF • -ve for TTF-1

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DIAGNOSIS • Merkel cell Carcinoma

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D/D • PNET, lymphoma, small cell melanoma, metastatic small cell carcinoma, rhabdomyosarcoma and other SRBCTs

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PAS+/-DIASTASE

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CD99 Synaptophysin S100

MNF116 Chrom A CD45 Tdt

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DESMIN The Christie NHS Foundation Trust

Myo-D1

Myogenin

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CD56 The Christie NHS Foundation Trust

Diagnosis • Rhabdomyosarcoma (solid variant of alveolar subtype)

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Case 24 • 85F; Breast mass

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DIAGNOSIS • Sarcomatoid carcinoma

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Case 26 • 34F; Thigh mass • (Microscope)

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DIAGNOSIS • • • • •

EMC Pos for S100+/-, (EMA, Chr, Synap) 75% have EWSR – t(9;22), variant translocations seen in others D/D: MFS, Myxoid Liposarc, Myoepithelial tumour, carcinoma

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EMC • • • • •

M=F Extremities Slow growing Multinodular Most low grade

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Case 13 • 79M; Perineal lesion

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DIAGNOSIS

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Cellular Angiofibroma

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Soft Tissue Tumours of the Genital Tract • • • •

AA Smooth muscle tumours Fibroepithelial polyp (cellular) Angiomyofibroblastoma

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Case 2 • 40M; Thigh lesion

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DIAGNOSIS

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Cellular Myxoma • • • •

Involves deep soft tissues May have intramuscular component >20% cellular areas Cytologically bland

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D/D • • • • • •

Aggressive angiomyxoma Myxoid NF LGFS Myxoid liposarc Low grade myxofibrosarcoma Intramuscular myxoma

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Case 5 • 61M; Mass adherent to stomach

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DOG 1.1 The Christie NHS Foundation Trust

Case 15 • 20F; Gastric Mass

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IHC • Positive for CD34, CD117, DOG1.1, SMA and hcaldesmon

• DOG1 The Christie NHS Foundation Trust

DIAGNOSIS • GIST

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Case 29 • 29F; Parotid mass

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DIAGNOSIS • Spindle cell lipoma

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Case 9 • 64F; Shoulder mass

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DIAGNOSIS

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Spindle Cell Lipoma (SCL) (1)

• Usually involve head, neck and shoulder regions of middle aged men • Present as a painless, mobile, solitary mass within the superficial soft tissues (often with a long history) • Rare cases described elsewhere (limbs, oral cavity, breast, larynx, spermatic cord etc) and also in the dermis • Very rarely multiple and familial • Usually less than 5.0 cms in diameter & circumscribed • Oval or discoid, yellowish or greyish-white, may be mucoid

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SCL(3) • IHC: spindle cells strongly +ve for CD34. Also CD10, Bcl2+ve(50%) Adipocytes + ve for S100 protein AR positivity in both spindle and adipocytic cells in almost all cases (Syed S et al. Arch. Pathol.

Lab. Med. 2008;132;81-3)

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Variants of SCL • Myxoid • Pseudoangiomatous • Angiomatous (haemangiopericytic, cavernous/capillary or curvilinear +/- perivascular hyalinization) • Low fat or fat free (Billings SD & Folpe AL Am. J. Dermatopathol.

2007;29;437-442) • Fibrous/collagenous • Plexiform • Composite • ? Inflammatory

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D/D of Spindle Cell Lipoma • Spindle cell liposarcoma and ALT (those with pleomorphic lipoma component) • Dendritic fibromyxolipoma (Suster S. et al. Ann. Diagn.

Pathol. 1998;2:111-20)

• • • • •

Peripheral nerve sheath tumour Mammary type myofibroblastoma Cellular angiofibroma Myxoid liposarcoma ( myxoid SCL) Lipomatous hemangiopericytoma

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Myxoid SCL vs. Myxoid Liposarcoma(MLS) • Difference in sites (neck, upper back and shoulder for SCL; extremities and trunk for MLS) • Subcutaneous (SCL) vs deep (MLS) • Cells are spindly in SCL; round, oval or stellate in MLS. Also lipoblasts in MLS • Prominent chicken wire vascularity in MLS

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Myxoid SCL vs Myxoid Liposarcoma(MLS) - cont • Microcystic lymphangioma-like areas in many MLS; not seen in SCL • CD34 more strongly and diffusely positive in SCL; only a small number of CD34 +ve cells in MLS (Suster S, Fisher C. Am. J. Surg. Pathol.

1997;21;195-200) • CHOP/DDIT3 and FUS or EWS gene fusion t(12;16) or t(12;22) in MLS

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MLS

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PL

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Case 28 • 48M; Retroperitoneal mass

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DIAGNOSIS • Spindle cell liposarcoma

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Mostly Superficial Myxoid Soft Tissue Tumours • • • • • • • • • •

“Ganglion” Myxoid NF Myxoid Nodular Fasciitis Myxoid Spindle cell lipoma Myxoid Neurothekeoma Sup. Angiomyxoma OFMT Myoepithelioma Agg. Angiomyxoma Digital myxoma

• Myxofibrosarcoma • Myxoid DFSP

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Mostly Deep Myxoid Soft Tissue Tumours • Intramuscular myxoma • Cellular myxoma • Juxta-articular myxoma

• • • • • •

Myxoid Liposarcoma EMC LGFS Chordoma Myxoid MPNST Myxopapillary Ependymoma • Myxoid Leiomyosarcoma • Synovial sarcoma • Solitary Fibrous Tumour The Christie NHS Foundation Trust

Case 30 • 68M; Mediastinal mass

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DIAGNOSIS • Dedifferentiated Liposarcoma

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Case 14 • 66F; Retroperitoneal mass

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CD34

DOG 1.1

CD117

h-Caldesmon The Christie NHS Foundation Trust

DIAGNOSIS • GIST

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GIST

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GIST

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Rhabdomyosarcomatous differentiation in GIST post tyrosine kinase inhibitor therapy

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GIST Immunohistochemistry • • • • • • • • • •

DOG1 (99%) CD117 (95%) CD34 (70%) PKC theta (96%) SMA (30-40%) S100 (5%) h-caldesmon (80%) Desmin (<1%) CK (<1%) MUC4 -ve The Christie NHS Foundation Trust

DOG1 positivity in LGFMS Thway K et al. Int J Surg Pathol. 23(6):454-60

• 5/11 showed varying amounts of DOG1 expression, ranging from weakly in approximately 5% of cells to strongly in up to 100% of cells

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Features of Lipoblasts • Cytoplasmic vacuoles (one or more): large round empty

• Nucleus indented

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Lipoblasts

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GIST

EMC

CARCINOMA

MYXOFIBROSARCOMA

LMS

CHORDOMA

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Case 18# • 56 Female – parametrial mass

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• h-caldesmon

• SMA

• Melan-A The Christie NHS Foundation Trust

DIAGNOSIS

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Angiomyolipoma • PEComas -

AML Clear cell “sugar” tumour of the lungs LAM PEST(primary extrapulmonary sugar tumour) Clear cell myomelanocytic tumour

The Christie NHS Foundation Trust

PEComas • Ass. With tuberous sclerosis complex (– usually multiple AMLs) • Criteria for malignancy - >/=70% atypical epithelioid cells - >/=2mitoses per 10HPFs - Atypical mitotic figures - necrosis

The Christie NHS Foundation Trust

Case 3 • 61M; sacral tumour

The Christie NHS Foundation Trust

The Christie NHS Foundation Trust

The Christie NHS Foundation Trust

The Christie NHS Foundation Trust

The Christie NHS Foundation Trust

Galectin

CK

S100 The Christie NHS Foundation Trust

DIAGNOSIS

The Christie NHS Foundation Trust

Chordoma • 50% sacrococcygeal region • 35% base of skull Variants Chondroid Chordoma Dedifferentiated Chordoma

The Christie NHS Foundation Trust

D/D • Chondrosarcoma • Myxopapillary ependymoma • Parachordoma

The Christie NHS Foundation Trust

The Christie NHS Foundation Trust