Soft Tissue and bone Flashcards
Molecular alteration common in Myoepithelial Carcinoma of Soft Tissue
INI-1 deficiency (SMARCB1 deficiency) - confers a rhabdoid architecture, as does INI-1 loss in other entities
Immune profile in Myoepithelial carcinoma
Combinations or limited panels are most useful
Positive: CK5/6 (CKWSS too), p63, p40, S100 protein, GFAP, SOX-10, S100, calponin
Characteristic translocation for Synovial Sarcoma
X;18 –> SS18-SSX1 (more common) or -SSX2 (less common)
Synovial sarcoma, whether monophasic or biphasic, is characterized by this translocation
X;18 translocation…
Synovial sarcoma. Usual gene fusion is SS18-SSX1 (could be with SSX2)
t(2;13)…
PAX3-FOXO1 –> alveolar rhabdomyosarcoma
also PAX7 (3 is worse prognosis than 7)
PAX 7 is t(1;13)
t(7;16)…
FUS-CREB3L2 –> Low grade fibromyxoid sarcoma (LGFS)
t(X;17)…
ASPSCR1-TFE3 –> alveolar soft part sarcoma
H3F3 K36M immunohistochemical stain…
Chondroblastoma, which is a fairly common primary bone benign tumor. A positive stain is fairly sensitive and specific
K=Kondroblastoma
USP6 translocations….
primary ABC (aneurysmal bone cyst), if it’s a secondary feature next to a chondroblastoma, probably won’t have the gene rearrangements
t(16;17)(q22;p13), CDH11-USP6 fusion….
Primary aneurysmal bone cyst (definately remember USP6 gene translocations, but this is the most common partner)
what do nodular fasciitis, myositis ossificans, and ABC all have in common?
USP6 gene translocations
t(2;2)(p23;q13) RANB2-ALK fusion…
aggressive subtypes of pediatric inflammatory myofibroblastic tumors
t(4;19)(q35;q13) CIC-DUX4….
undifferentiated Ewing-like round cell sarcomas (these have aggressive behavior)
t(7;16)(q33,p11) FUS-CREB3L2….
LGFMS (low-grade fibromyxoid sarcoma)
inversion of chromosome 12 with NAB2-STAT6 fusion…
Solitary Fibrous Tumor (get STAT6 and CD34 on everything with spindled cells)
MDM2 in bone tumors…
MDM2 can be amplified in low grade osteosarcomas, both parosteal and central (though MDM2 in non-bone forming tumors is probably de-diff liposarc)
*don’t forget intimal sarcoma
Large, deep seated mass somewhere in the pelvic girdle (such as gluteus maximus muscle)
Look for INI-1 staining. If lost…epitheliod sarcoma, proximal type. Should be EMA and cytokeratin positive with CD34+ about 1/2 the time
TLE1 immunohistochemical stain positivity
synovial sarcoma (probably would get it on a poorly differentiated sample of synovial sarcoma)
Characteristic t(17;22)(q22;q13) leading to COL1A1-PDGFB fusion product….
DFSP (dermatofibrosarcoma protuberans)
CD99
Traditionally Ewing Sarcoma/PNET - but also mesenchymal chondrosarc! Ewing sarcoma/PNET exclusively shows a reciprocal translocation t(11,22)
Ewing sarcoma/PNET exclusively shows a reciprocal translocation….
t(11,22)
reciprocal translocation t(11,22)
Ewing sarcoma/PNET exclusively shows a reciprocal translocation t(11,22)
Extra target you can use for chondrogensis and therefore chondrosarc dx if you need it
Mesenchymal chondrosarcoma typically shows nuclear expression of Sox9, the master regulator of chondrogenesis.
What is Li-Fraumeni syndrome?
Li-Fraumeni syndrome (caused by an inherited mutant p53 allele) is associated with a greater risk of sarcomas (and other malignancies), in particular, a 500 times greater risk of osteosarcoma.
Inherited germline mutation of what allele gives you a 500x increased risk of osteosarcoma?
Li-Fraumeni syndrome (caused by an inherited mutant p53 allele) is associated with a greater risk of sarcomas (and other malignancies), in particular, a 500 times greater risk of osteosarcoma.
X;18 translocation leading to…
X;18 translocation leading to a fusion of the SYT gene (chromosome 18) and the SSX1 or SSX2 gene (chromosome X) is characteristic of synovial sarcoma. This translocation leads to the formation of the SYT/SSX1 or SYT/SSX2 chimeric transcripts diagnostic of synovial sarcoma.
SYT/SSX1 or SYT/SSX2
X;18 translocation leading to a fusion of the SYT gene (chromosome 18) and the SSX1 or SSX2 gene (chromosome X) is characteristic of synovial sarcoma. This translocation leads to the formation of the SYT/SSX1 or SYT/SSX2 chimeric transcripts diagnostic of synovial sarcoma.
Characteristic t(12;16) with FUS-DDIT3 fusion
Myxoid liposarcoma; thigh, never retroperitoneal primary
myxoid liposarc CAN (infrequently) have a …..with DDIT3?
EWSR1 (yes, that dumb gene)
CHOP and what gene are the same?
DDIT3 - myxoid liposarc
MDM2
chromosome 12, gene location
*don’t get it confused with the supernumerary ring form amplification
*liposarc
*osteosarc (low grade)
*intimal sarcoma
what do these have in common?
Li-Fraumeni syndrome
Beckwith-Wiedemann syndrome
Lynch syndrome
Multiple endocrine neoplasia type 1
Familial adenomatous polyposis
Carney complex
Neurofibromatosis type 1
adrenal cortical carcinoma
Positive for SF1, α-inhibin, melan-A, calretinin, synaptophysin
Negative for chromogranin, cytokeratins, EMA, CEA
adrenal cortical carcinoma IHC
differentiate by stains medulla and cortex in adrenal
chromo and melan-A and sf1
HEY1-NCOA2 fusions
Mesenchymal chondrosarcoma
*Jaw and ribs, younger patients
*terrible prognosis
SOX9 + in all components
HEY1-NCOA2 fusions → t(8;8)(q13;q21)
HEY1-NCOA2 fusions → t(8;8)(q13;q21)
Mesenchymal chondrosarcoma
*head and neck of young people
*watch out for NCOA fusion with PAX3 for biphenotypic sinonasal sarcoma
t(8;8)(q13;q21)
Mesenchymal chondrosarcoma
*Jaw/head and neck and ribs, younger patients
*terrible prognosis
SOX9 + in all components
HEY1-NCOA2 fusions → t(8;8)(q13;q21)
MDM2 not liposarc
MDM2 amplification → arises from low-grade central osteosarcoma
*intimal sarcoma (great vessels)
most osteosarcomas are de novo, but have what molecular abnormalities?
Molecular: Typically arise de novo, but will have mutations in RB1 and TP53
IHC for conventional osteosarcoma
- IHC: Positive for SATB2, CD99, S100 (cartilaginous areas); variable keratins
Typical patient information for conventional osteosarcoma
Usually seen in ages 10-20 and males are slightly more common
* Most common to arise in long tubular bones
➢ Femur > proximal tibia > proximal humerus
* Presents as a painful, enlarging mass and overlying skin may be erythematous
* Metastasis is hematogenous and most frequently to the lung
The most frequent genetic abnormality in Ewing Sarcoma
reciprocal translocation between chromosomes 11 and 22 [t(11;22) (q24;q11)] resulting in the fusion of the Fli-1 and EWS genes
Molecular: Various fusions with NR4A3 are reported
* Most common: EWSR1-NR4A3 → t(9;22)(q22;q12.2)
extraskelatal myxoid chondrosarcoma
epitholoid sarcoma
smarcb2 or ini loss
clear cell sarcoma/ melanoma of soft parts
ewsr1 and atf-1 or creb
alveolar soft part sarcoma
Characterized by ASPSCR1-TFE3 gene fusion
alveolar soft part sarcoma
Rare malignant mesenchymal neoplasm frequently composed of large, polygonal cells with abundant eosinophilic cytoplasm, a nested or pseudoalveolar growth pattern and PASD+ intracytoplasmic rhomboid or rod shaped crystals
Predominantly affects the deep soft tissues of the extremities (thigh and buttock) in young adults and head and neck region (tongue and orbit) in children
HEY1-NCOA2 fusions (90%), IRF2BP2-CDX1 fusion
Mesenchymal Chondrosarcoma
Mesenchymal chondrosarcoma molecular
HEY1-NCOA2 fusions (90%), IRF2BP2-CDX1 fusion
Common and less common Ewing Sarcoma translocations
Most common (95%): EWSR1-FLI1 → t(11;22)(q24;q12)
Less common: EWSR1-ERG → t(21;22)(q22;q12)
*anything els is rare
ETV’s and E1AF
*remember NKX2.2 staining and don’t get confused with prostate
hSNF5/SMARCB1 is located on what chromosome?
Loss of 22q11.2
(INI-1) –> think about tumors with INI-1 loss
hSNF5/SMARCB1 is located here, and is the gene responsible for AT/RT. INI-1 shows the absence of the gene product in tumor nuclei.
Any recurrent molecular abnormality in Embryonal Rhabdomyosarcoma?
No characteristic translocation has been described, but there is consistent loss of heterozygosity (LOH) at chromosome 11p15 in the region that harbors the IGF-2 gene that is the result of loss of maternal and duplication of paternal chromosomal material.
Cytogenetic analysis revealed a t(12;15) translocation in a kidney mass
ETV6-NTRK, cellular mesoblastic nephroma
*The cellular variant is the most common type of mesoblastic nephroma, accounting for nearly two-thirds of these neoplasms.
*Mesoblastic nephroma is the most common renal neoplasm identified in the first 3 months of life.
t(9;22) –> EWS-NR4A3
t(9;17) –> RBP56-NR4A3
*NOTE: NR4A3 –> also known as CHN and also known as TEC
Translocations that define extraskeletal myxoid chondrosarcoma
Infantile fibrosarcoma
t(12;15)
ETV6-NTREK
NOTE: ETV6 is also known as TEL
*shares with cellular CMN and secretory carcinoma of breast and salivary gland
Translocations of 2p23 can result in what spindled cell tumor?
this results in ALK1 fusions
Inflammatory myofibroblastic tumor
ALK+IHC in only 30% of cases
ALK rearranged in 50% of cases
*don’t be confused with t(2;5) ALK rearrangements for ALCL
t(2;5)
ALK rearrangements in ALCL
t(7;16)
FUS-CREB3L2
low grade fibromyxoid sarcoma
*evans tumor
*also t(11;16)
*16 is FUS
t(11;16)
FUS-CREB3L2
low grade fibromyxoid sarcoma
*evans tumor
t(7;16)
*16 is FUS
Myxoid and round cell liposarcomas
FUS-DDIT3 (t(12;16))
EWS-DDIT3 (t(12;22))
*NOTE: DDIT3 is also known as CHOP
t(12;22)
*do NOT click ewing sarcoma
*this is EWS-DDIT3 (t(12;22))
myxoid liposarcoma or round cell liposarcoma
t(12;16)
myxoid liposarcoma
FUS-DDIT3 (t(12;16))
EWS-DDIT3 (t(12;22))
*NOTE: DDIT3 is also known as CHOP
Beckwith-Wiedeman syndrome has what chromosome loss and what soft tissue tumor?
11p15 loss
embryonal rhabdomyosarcoma
t(2;13)
PAX3-FOXO1
alveolar rhabdomyosarcoma
*NOTE: FKHR is also known as FOXO1
t(1;13)
PAX7-FOXO1
alveolar rhabdomyosarcoma
*NOTE: FKHR is also known as FOXO1
*the other option for this entitiy is t(2;13), with PAX 3 which has a worse prognosis than PAX7
*living 3 years is worse than 7
*2 and 3 year olds are harder on life than 7 year olds
t(12;22)
*do NOT click ewing sarcoma
*this can result in a EWS-ATF1 translocation that gives you clear cell sarcoma of tendon sheath
*melanoma of soft parts
*also t(2;22) for EWS-CREB1
t(2;22) –> EWS-CREB1
clear cell sarcoma of tendon sheath
*melanoma of soft parts
the other option is t(12;22) for EWS-ATF1
Alveolar soft parts sarcoma translocation
t(X;17)
ASPL-TFE3
ASPL-TFE3
t(X;17)
Angiofibroma of soft tissue molecular
t(5;8)(p15;q13), NCOA2- AHRR fusion
*other NCOA2 fusion is mesenchymal chondrosarc, with HEY1-NCOA2, from a del(8)
BCOR-CCNB3 gene fusion
Sarcomas with BCOR-CCNB3 gene fusion are recently described tumors that have a preference for the bones of adolescent males
WWTR1-CAMTA1 fusion → t(1;3)(q36;q25) (majority of cases)
Epitheloid hemangioendothelioma
*malignant, but not as aggressive as angiosarcoma
*TFE3 IHC is positive in the MINORITY of cases, since that is a YAP1-TFE3 fusion
YAP1-TFE3 fusion
Epitheloid hemangioendothelioma
*malignant, but not as aggressive as angiosarcoma
*TFE3 IHC is these, which are the MINORITY of cases
EWSR1-CREB3L1 translocation
sclerosing epithelioid fibrosarcoma
* Rare, occurs in middle-aged or older individuals in lower limbs/girdles
* Prognosis → poor, metastasis to CNS, bone, lung/pleura
* IHC: MUC4+, +/- EMA; negative for keratins, SATB2, S100, SMA, CD34
* Molecular → EWSR1-CREB3L1 fusions
Two tumors with an t(11;22) clasically
Ewing (EWSR1-FLI1)
DSRCT (EWSR1-WT-1)
*it’s DSRCT with the n-terminal vs. c-terminal epitope thing where you can miss it’s WT-1 positivity
Darier disease
*ATP2A2 gene mutation
*clinical presentation of numerous greasy papules on a seborrheic area
*biopsy of a hyperkeratotic lesion with acantholytic dyskeratosis of in the upper epidermis.
*Darier disease can also present with punctate keratoses of the palms and soles. Additional cutaneous depigmentation, cutis verticis gyrata, mucosal lesion, ocular disorders and bone cysts have been reported.
Intimal sarcoma molecular
IHC: (+) MDM2. Molecular: Amplification of MDM2/CDK4
*epithelioid looking sarcoma in great vessels
*pleomorphic look, highly malignant
CSF1-COL6A3 fusion gene
Tenosynovial giant cell tumor (TGCT)
* benign neoplasm composed of histiocytoid cells typically with eccentric nuclei and moderate amounts of cytoplasm often with a peripheral ring like distribution of pigment.
*Osteoclast-like giant cells are typically intermixed and randomly distributed.
*The neoplastic cells are the mononuclear histiocytoid cells and often harbor a CSF1-COL6A3 fusion gene resulting in production of CSF1 (colony stimulating factor 1) by the neoplastic cells.
clear cell chondrosarc, good or bad?
Low-grade malignancy that is seen in adults in 4th decade
* Usually effects the epiphysis or apophysis of long tubular bones
* IHC: strong S100 in clear cells
MORPHOLOGY
* Clear cells centrally placed nuclei, abundant glycogen-rich cytoplasm, and well-defined cytoplasmic borders
* Woven bone and osteoclast-like giant cells
* Minimal atypia and low mitotic activity
* Half of cases have conventional low-grade chondrosarcoma component
Molecular for biphenotypic sinonasal sarcoma
This is a low grade sarcoma with mixed myogenic and nerve sheath differentiation, and is limited to the sinonasal tract. Its biological behavior is characterized by a tendency for local recurrence, without distant metastasis. These tumors often harbor gene fusions involving PAX3 and MAML3 (up to 60% of cases). Other reported gene fusions are PAX3-FOXO1, PAX3-NCOA1 and PAX2-NCOA2.
Biphenotypic sinonasal sarcoma
- Rare neoplasm, only in sinonasal region, typically middle-aged females
- Locally aggressive (with bone infiltration) but non-metastatic
- Immunohistochemistry:
➢ Variable staining S100, SMA, nuclear β-catenin (focal to diffuse), desmin and myogenin; Negative for CD34 - Molecular: PAX3-MAML3 fusion → t(2;4)(q35;q31)
➢ Other partners: NCOA1, FOXO1, WWTR1, NCOA2
molecular for deep/aggressive angiomyxoma
- Benign tumors occurring mainly in women in a wide age range
- Clinically presents as a slow-growing mass in the pelvicoperineum
- Recurrence is seen in ~40% of cases
- IHC: positive for ER, PR, and desmin
- Molecular: Rearrangements in HMGA2 (12q13-15) → t(8;12) or t(11;12)
can you discover the SFT gene fusion by karyotype?
*no, it’s all in one chromosome and would be cytogenetically cryptic
*SFT is characterized by the NAB2-STAT6 gene fusion, resulting from inversion of the two genes both located on chromosome 12q13. STAT6 is a highly sensitive and specific immunohistochemical marker for SFT, and typically shows strong and diffuse nuclear staining. STAT6 immunostain is diagnostically very valuable as conventional cytogenetic methods cannot detect the intrachromosomal NAB2-STAT6 fusion.
Synovial chondromatosis molecular
Molecular: FN1-ACVR2A fusions
MORPHOLOGY
* Multiple hyaline cartilage nodules within synovium or loose joint space, chondrocytes cluster together in groups
* Minimal atypia is seen in the chondrocytes
* If significant atypia seen including loss of chondrocyte clustering, bone invasion, increased mitoses – increased concern for malignant status
OTHER HIGH YIELD POINTS
* Rare and peak age is 5th decade with a 2:1 male to female predominance
* Locally aggressive and can be multifocal
* Involves large joints (knee is most common) but can involve any joint
molecular chondromyxoid fibroma
Molecular: GRM1 fusions/upregulation
CHONDROMYXOID FIBROMA
MORPHOLOGY
* Benign lobulated lesion with sharp margins
* Chondroid and stellate cells embedded in a chondromyxoid matrix
* Peripheral spindled cells and admixed giant cells
OTHER HIGH YIELD POINTS
* Benign lesion and typically seen in young adults
* Occurs in many sites, but often long bones near the knee
