Tumores de células pequeñas, redondas y azules: diagnóstico diferencial cuando el tiempo

apremia

Sílvia Bagué Servei de Patologia

Hospital de Sant Pau Barcelona

Soft tissue sarcomas

• Heterogeneous group of rare malignancies • Both rarity and heterogeneity affects

diagnostic accuracy • Most of tissue tumors are classified

according to the type of normal mesenchymal cell or tissue that they most closely recapitulate (“differentiation”)

• Clinical data & radiology • H-E (morphology) • Immunohistochemistry • Molecular and cytogenetics

Approach to diagnosis

1. Age, symptoms, site, size, previous history (cancer, RT…) 2. Associated syndromes or genetic disorders(Li Fraumeni,

Ollier, AFP, NF-1, RB1…)

Clinical & radiological data: essential!!

• Is the lesion benign or malignant? • if malignant, is it a sarcoma

(mesenchymal)? • and what type of sarcoma is it?

(histologic type & grading)

Role of core biopsy (H&E)

Cellular morphology & stroma

Spindle Pleomorphic Lipomatous

Epithelioid Round cell Myxoid

Small round & blue cell tumors

Small round & blue cell tumors • Rhabdomyosarcoma • Ewing sarcoma • “Ewing-like” sarcomas • Desmoplastic SRCT • PD Syn S • Myoepithelial tumors • Mesenchymal Ch • Neuroblastoma • Lymphoma • Small cell carcinoma

Mainly in children & adolescents High-grade by definition Often “translocated-sarcomas”

[50%]

Bone and Soft Tissue Sarcomas: 1996-2005

[15%]

Incidence Rates per Million Population, Children (0-14), Great Britain

Neuroblastoma Clinical history Newborn, 7 m. Abdominal mass

DSRCT Clinical history Boy, 12 y-o. Intraabdominal masses

Mesenchymal chondrosarcoma

•Young adults (15-35 yrs) • <10% chondrosarc • Bone: maxilla, ribs, pelvis, vertebra • 20-30%: soft tissue • Biphasic pattern

Immunohistochemistry • Diferential diagnosis between mesenchymal/non-mesenchymal tumor (carcinoma,

melanoma, lymphoma) • Standard method for establishing the line of differentiation (vascular, neural,

smooth muscle, skeletal muscle, myofibroblastic) • Facilitates the differential diagnosis and classification of a spindle and / or

round cell neoplasms • Detection of underlying molecular alterations

Do not provide information about benign or malignant

h-Caldesmon LMS

Immunohistochemistry of SRCT CD99 Desmin Myogenin CK20 LMWK TdT SYN EMA

a-RMS 15% 95% >90% - - - - - Ewing sarc 95% - - - 20% - 20% 5%

PD Syn Sarc 95% 50% 90%

DSRCT WT1+ 10% 80% - - 90% - 5% 95%

Mesenchymal Ch 80% - - - - - - - Neuroblastoma - - - - - - 80% - TCLL 90% - - - <1% 90% - -

M1 small cell carcinoma (lung) - Age & clinica data! - > 45 yrs; IMAGING! - CD99 (-)

TTF1

Ker AE1/AE3

Merkel cell carcinoma (skin) - Age & clinica data! - Elderly; superficial - CD99 (-)

Ker 20

CAM 5.2

-20-30% extraskeletal

Ewing Sarcoma -3rd most common sarcoma in children

Ewing Sarcoma

FLI-1

Membranous ~ 100% cases low specificity!

Nuclear 71-84% cases

LMW cytokeratins in up to 30% of ES! Vimentin, synaptophysin, HNK1, CAV1, NSE: focally …

Folpe et al. AJSP 2005; 29;1025-33

Immunohistochemical findings

CD99 FLI-1

CD99

TdT

Lymphoblastic lymphoma Clinical history 2 year-old, female. Proximal left humerus

Clinical history 17 y-o, male Thigh mass + inguinal lymph node

Clinical history 17 y-o, male Thigh mass + inguinal lymph node FNA

“rhabdoid cells” rhabdomyosarcoma??

Desmin

Myogenin

Rhabdomyosarcoma (skeletal muscle differentiation)

CAM 5.2

Vim Desmin

DSRCT: IHC & Genetics Malignant small round cell tumor associated with prominent stromal desmoplasia and polyphenotypic differentiation with a consistent translocation t(11;22)(p13;q12) and EWSR1-WT1 gene fusion.

WT1

Molecular and cytogenetics

95% t(11;22)(q24;q12) EWSR1-FLI1 fusion gene < 5% t(21;22)(q22;q12) EWSR1-ERG fusion gene

Ewing’s sarcoma: Genetics

Sarcomas thouhgt to be Ewing but EWSR1 negative: “Ewing-like sarcomas”

t(20;22)(q13;q12) EWSR1-NFATC2 t (4;19)(q35;q13) CIC-DUX4 BCOR-CCNB3

46 y-o female. Right thigh mass + pulmonary mets

Small round cell tumor with hemangiopericytoid pattern

Clinical history

FISH: SS18 gene rearrangement

Desm Myogenin

PAX FKHR + -

PGK + -

PAX FKHR + -

PGK + - bp

247 → 170 →

FNA 17 y-o, male Thigh mass + inguinal lymph node

Genetics 50% a-RMS: t(2;13)(q35;q14) PAX3-FOXO1 25% a-RMS: t(1;13)(p36;q14) PAX7-FOXO1 25% fusion-neg cases biologically similar to e-RMS

FOXO1 rearrangement by FISH

Clinical history

Classification of Rhabdomyosarcoma

Superior prognosis - Botryoid rhabdomyosarcoma - Spindle cell rhabdomyosarcoma Intermediate prognosis - Embryonal rhabdomyosarcoma Poor prognosis - Alveolar rhabdomyosarcoma - Anaplastic rhabdomyosarcoma

Required for patient management and tumor prognostication!

Clinical history Boy, 12 y-o. Intraabdominal masses

Desmoplastic small round cell tumor

DSRCT: IHC & Genetics

FISH: EWSR1 rearrangement

Malignant small round cell tumor associated with prominent stromal desmoplasia and polyphenotypic differentiation with a consistent translocation t(11;22)(p13;q12) and EWSR1-WT1 gene fusion.

Soft tissue tumors: Molecular pathology STT other than Ewing carrying EWS translocation

Ewing sarcoma t(11;22)(q24;q12) EWSR1-FLI1 DSRCT t(11;22)(p13;q12) EWSR1-WT1 AFH t(2;22)(q33;q12)

t(12;22)(q13;q12) EWSR1-CREB1 EWSR1-ATF1

CCS t(12;22)(q13;q12) t(2;22)(q33;q12)

EWSR1-ATF1 EWSR1-CREB1

EMC t(9;22)(q22;q12) EWSR1-NR4A3 Myoepithelioma t(19;22)(q13;q12) EWSR1-POU5F1 Mixoid liposarc

t(12;16)(q13;p11) t(12;22)(q13;q12)

FUS-DDIT3 EWSR1-DDIT3

Final diagnosis

Frozen (biobanking)

Molecular pathology

H&E ME sample

CNB / FNA

Clinical data & imaging

IHC

FNA CNB

Specimen work up

In summary:

• Accurate diagnosis provides appropriate clinical decision making

• Histotype: predictor of outcome • Conventional morphology still powerful tool….although

overlapping histologic features create diagnostic challenges • Integration with immunohistochemistry is a diagnostic

standard • Molecular genetics helpful in increasing situations - only in context with morphology! - same genetic alterations in unrelated entities

Muchas gracias por su atención