Pathology genetics

t(11;22) FLI1/EWS and t(21;22) ERG/EWS - FLI1 in ETS trsc factor family

<20 yrs, pediatric SRBCT, #2 bone sarcoma, lytic destructive marrow lesion, onion skinning periosteal rxn, 50% cure

Round cell sarcoma with varying neuroectodermal diff. Uniform round cells, round nuclei, clear to eos cyto, indistinct membranes. PAS positive glycogen cyto.

Strong diffuse membranous CD99 staining, PAS positive glycogen, NSE, vimentin, Leu7/CD57, variable LMWK and synapto. Negative for S100, CD45, vascular and muscle markers.

DDx- metastatic neuroblastoma, lymphoma, desmoplastic small round cell tumor, embryonal rhabdomyosarcoma

del(1p), +17, n-MYC amplification

Most common tumor <1 yr, median age 21 months, rare after 4 yrs. Ped SRBCT, Assoc w/ Beckwith-Wiedemann syndrome, Hirschsprung, NF1, fetal hydantoin syndrome,opsoclonus/myoclonus, heterochromia iridis, Cushing’s syndrome.

IHC Positive: chromo, synapto, NSE, vim, neurofilament. Negative: p53, CD99, FLI1, desmin, myogenin, keratin, CD45, variable EMA/WT1

• Histology Favorable: <1 yr age, hyperdiploid, lack of n-myc
• Unfavorable: 1p36 del (n-myc amplification >10 times), diploidy, del(14p), high Mitosis-Karyrhexis index, >1 yr age

t(2;13) PAX3 / FKHR and t(1;13) PAX7 / FKHR - PAX3 and 7 members of paired box family trsc factors, FKHR member of forkhead trsc factor family. Fusion protein is potent trsc activator.

Occur in all ages, more often in juven and adult. Arise in extremities, no favored site.

Three histologic subtypes: typical, solid and mixed embryonal and alveolar. All mimic lymphoma but with primitive myoblastic diff. Typical with fibrovasc septae separate tumor cells into nests. Cell align septae in picket fence pattern, discohesion in center.

High grade, more aggressive than embryonal.

t(11;22) WT1/EWS- fusion of the Ewings sarcoma gene with the wilms tumor gene. WT-1 expressed in mesodermal tissues- hence serosal lining involvement. EWS- trsc modulation, WT-1 - DNA binding domain

Children and young adults, widespread abdominal serosal involvement, striking male predominance.

Small round cell tumor with prominent stromal desmoplasia and polyphenotypic diff. Epithel, muscle, and neural diff characteristic

IHC: strong positive with cytokeratin, desmin, NSE. Myogenin negative. WT1 usually positive.

Prognosis very poor.

t(X;17) ASPL/TFE3 - TFE trsc factor fused with ASPL gene, localize to nucleus and activate trsc.

Most common 15 - 35 yrs. Extremities, deep soft tissue of thigh. Children - head and neck region

Organoid nesting pattern composed of large, uniform, epithelioid cells with granular eosinophilic cytoplasm. Nests separated by thin sinusoids. PAS w/diastase stains rhomboid crystals in cytopl. Also seen in EM.

IHC: nuclear staining positive for TFE. Otherwise, no consisent positive findings

Prognosis: Slow growing yet highly metastatic.

t(17;22) COL1A1/PDGF beta- fused collagen gene with platelet derived growth factor- fusion protein is potent growth factor.

Young to middle aged adults, trunk or extremities.

Infiltrative, deep dermal and subcutaneous proliferation of monotonous, bland spindle cells in a distinct storiaform pattern. Infiltrate subq fat in lace-like pattern. Wrap around adnexa. Pigmented variant - Bednar tumor with melanin-laden dendritic cells.

IHC: CD34 positive, s100 and F13a negative

Childhood variant - giant cell fibroblastoma

Prognosis- locally aggressive, mets uncommon (5%)

t(12;15) same as infantile fibrosarcoma, ETV6(TEL)/NTRK3- activation of NTRK3 receptor tyrosine kinase. Infantile fibrosarcoma arising within kidney.

<1 yr age, most common congenital renal neoplasm

Densely cellular, plump spindle cells, poorly formed fascicles. Prominent staghorn vessels, abundant mits, necrosis present. Infiltrates adjacent tissue.

Classic (non-cellular) type not related to infantile fibrosarc, insecting bundles of spindle cells, less dense, thin walled vasc spaces, less mitotic activity, sharply demarcated border.

IHC: actin and vimentin positive, cd34/s100/keratin negative

t(12;15) ETV6(TEL)/NTRK3- activation of NTRK3 receptor tyrosine kinase. Also trisomies 8,11,17 and 20.

<2 yrs age, superficial and deep soft tissue of distal extremities

Intersecting fascicles of primitive ovoid to spindle cells with herringbone pattern. Zone necrosis and hemorrhage frequent. Little pleomorphism.

IHC nonspecific, vimentin positive

Favorable outcome when compared to the adult fibrosarcoma.

t(9;22) CHN(NR4A3)/EWS in approx 50% of cases, produces fusion oncoprotein.

Rare, adulthood, deep soft tissue of prox extremities and limb girdles.

Multinodular architecture, abundant myxoid matrix and malignant chondroblast-like cells arranged in cords, clusters, or delicate networks. No convincing evidence of chondroid diff. Cells typically show low grade cyto features.

IHC: vimentin positive, no other consistent.

Possible of prolonged survival, but known to have high risk local recur and mets.

t(12;16) FUS/CHOP - present in >90% cases. Fusion oncoprotein.

Second most common liposarcoma, young adults, deep soft tissue of extremities, thigh.

Uniform round to oval primitive non-lipogenic mesenchymal cells and variable small signet ring lipoblasts in a prominent myxoid stroma with characteristic branching vascular pattern (pulmonary edema like). Round cell areas (>=5%) defined as solid sheets of back to back primitive round cells with high NC ratio and no intervening stroma.

High grade - round cell diff, necrosis, Tp53 overexpression predicts unfavorable outcome.

t(12;22) ATFI/EWS- fusion protein represses p53 activation

Rare, young adults, extremities with predilection for foot/ankle. Usually deep seated around tendons (malignant melanoma of soft parts)

Typical uniform, nested or fascicular growth pattern of polygonal to spindle cells with abundant eosinophilic/clear cytoplasm. Thin fibrous septae around nests.

IHC: positive for s100, HMB45 and other melanoma antigens.

EM: melanosomes

Poor prognosis.

• t(X;18) SSX1/SYT and SSX2/SYT
• SSX1 biphasic, SSX2 monophasic

del(1p36), del(19q13.3)

• -22 or del(22q)
• del(1p) or (14q) - anaplastic

del(3p) VHL

-Y, +7, +17, t(X;1)

t(X;1) PRCC/TFE1 and t(X;17) ASPSCR1/TFE1

• FAVORABLE
• t(8;21) (RUNX1T1)ETO/(RUNX1)AML - M2 morphology/with maturation, younger pts, and good response to tx, longterm dz-free survival
• Characteristic high expression CD34/HLA-DR/MPO and CD13, weak CD33. Frequent CD19 and PAX5

inv(16), t(16;16) CBFB/MYH11 - M4 morphology?/Monocytic and granulocytic diff and abnl eos granules in BM, younger patients more common, good prognosis in young, worse in older pts

• t(15;17) PML/RARA - M3 morphology, hyper and hypogranular (WBC very high) types, good response to ATRA, DIC, best prognosis of AML
• Hypergranular: low expression CD34, HLA-DR, CD11a, 11b and CD18 and bright expression CD33, heterogenous CD13, CD117 (sometimes weak).
• Hypogranular: frequent expression of CD34 and CD2
• CD56 expression associated with worse outcome

• UNFAVORABLE
• t(11;17) PLZF/RARA - variant APL, poor response to ATRA

t(6;9) DEK-NUP214 - with or without monocytic features, basophilia and multilineage dysplasia, nonspecific phenotype, poor prognosis

t(3;3) or inv(3) RPN1-EVI1- nl or elevated plts, atypical megakaryocytes, arise from MDS or de novo, adults most common, poor prognosis

• INTERMEDIATE/UNKNOWN
• t(1;22) RBM15-MKL1- maturation in megakaryocyte lineage (M7), infants with Downs female, prognosis unclear
• CD41 (glycoprot 2b3a), CD61 (glyco 3a), CD42 less frequent, myeloid may be positive, 34, 45 and DR often negative. CD36 positive

• t(9;11) MLLT3-MLL - monocytic features, more common in young, 11q23abnl, DIC, tissue infiltration, intermediate survival, CNS involvement
• Strong expression of CD33, CD65, CD4 and HLA-DR, low expression of CD13,34 and 14. Plus markers of monocytic origin

Sole genetic abnormality is del(5q). Elderly women, with severe macrocytic anemia and occasional thrombocytosis. Medial survival 145 months (>10yrs), transformation <10%

t(9;22) BCR (chr 22)/ABL (chr 9) fusion gene p210 (90-95%) on Ph chromosome, increased tyr kinase activity. Imatinib competes for ATP binding site of fusion protein. Indolent chronic phase, accelerated phase and blast phase. Older adults. Neutrophil leukocytosis in different stages of maturation, no sig dysplasia, absolute basophilia. Progression to blast phase associated with clonal evolution: extra Ph chr, +8, +19 or i(17q).5 yr progression free survival 80-95%.

• FAVORABLE
• Hyperdiploidy (>50 chromosomes and usually <66 chromosomes) - very favorable prognosis, cures >90% of children
• CD10/19/34 positive, often CD45 negative

• t(12;21) TEL(ETV6)-AML(RUNX) - common in children ~25% B-ALL, very favorable prognosis, >90% cure
• CD10/19/34 positive, CD9/20/66c negative, CD13 frequently expressed

• UNFAVORABLE
• Hypodiploidy - blasts with <46 chromosomes, children and adults, poor prognosis, 44-45 chromosomes do better then less
• CD10/CD19 positive

• t(v;11q23) most common t(4;11) MLL - most common leukemia in <1 yr, CNS, neonates and infants, poor prognosis
• CD10 negative, CD24 negative, CD15 and CD19 positive

• t(1;19) E2A(TCF3)-PBX1- children, poor prognosis?
• CD10/19/ mu heavy chain positive

• t(9;22) BCR-ABL - worst prognosis in patients with ALL, p190 kd BCR-ABL fusion protein (in all kids and 1/2 adults)
• CD10/19/Tdt positive, occ CD13,33, 25

• t(8;14) cMYC/IgH and t(8;22) cMYC/IgLambda and t(2;8) IgKappa/cMYC (up to 10% of cases lack MYC translocation)- endemic form: equatorial africa, most common childhood malig, EBV in all patients. Sporatic form: worldwide, children and young adults, EBV in 30%.
• CD10, CD19, CD20, CD22, CD38, CD43, CD77, BCL-6, weak or negative BCL-2, Tdt negative. Near 100% ki67 index. High cure rate in low stage disease.

t(14;18) BCL2/IgH (90% cases) - widespread dz at dx, US and West Europe, adults, paratrabecular involvement in BM, grade 1-2 indolent, grade 3 more aggressive.

• t(11;14) BCL1 (cyclin-D1)/ IgH - mid to old adults, LN spleen BM plus upper GI tract. Blastoid and pleomorphic variants- poor prog. Survival 3-5 yrs.
• CD5, FMC-7, cyclin D- and CD43 positive, weak to negative CD23, negative for CD10 and BCL-6.

• t(11;18) MALT/API2 in pulmonary and gastric tumors, t(1;14), t(14;18) in ocular adnexae and salivary gland, and t(3;14) in thyroid, skin, orbit- indolent nature, t(11;18) resistant to H.pylori eradication
• CD20, CD79a and weak CD43, 11c positive, CD5, CD10, CD23 negative. CD21 and CD35 also expressed.

• Hyperdiploidy >45 and <65 chromosomes - good prognosis
• t(11;14) CCND1/IgH - most common, good prognosis
• del(13), del(17p), t(4;14), t(4;16) or t(14;20) - poor prognosis
• t(8;14) cMYC/IgH - poor prognosis
• hypodiploid - poor prognosis

• t(2;5) ALK-NPM, strong nuclear and cytoplasmic ALK staining, 85% of cases
• t(1;2) TPM3-ALK, 13% of cases
• ALK+ patients have favorable prognosis(80% 5yr) compared with ALK negative cases (48%)
• Hallmark cells - eccentric kidney shaped nuclei, large cells, abundant cytoplasm
• CD30 positive on membrane and golgi
• CD3, CD8 negative in most cases, CD2, 4, and 5 positive as well as granzyme B and perforin. CD45 variable