Uterus

• Undifferentiated uterine sarcoma is a diagnosis of exclusion applied to malignant mesenchymal tumors of the uterus with no lineage specific morphologic or immunohistochemical features and no entity defining molecular alterations

Contributed by Ayse Ayhan, M.D., Ph.D.

Contributed by David B. Chapel, M.D.

• Spindle cell leiomyosarcoma:
  • Long intersecting fascicles of spindle cells with cigar shaped nuclei and eosinophilic cytoplasm
  • SMA, desmin or caldesmon IHC positive, at least focally
  • Mutations in TP53, ATRX, RB1 and MED12 common
• Myxoid leiomyosarcoma:
  • Subset shows brisk mitotic activity, marked atypia and necrosis
  • SMA, desmin or caldesmon at least focally positive (Am J Surg Pathol 2016;40:285, Mod Pathol 2019;32:1688)
  • PLAG1 IHC positive in 50% (Am J Surg Pathol 2019;43:382, Mod Pathol 2019;32:1688)
• High grade endometrial stromal sarcoma with BCOR rearrangement:
  • Uniform spindle cell population with mild atypia in myxoid stroma
  • Cyclin D1 and CD10 IHC consistently positive
  • BCOR IHC positive in ~50%
  • May be focally SMA positive but often desmin and caldesmon negative
  • BCOR fusion (most often with ZC3H7B)
• High grade endometrial stromal sarcoma with BCOR internal tandem duplication:
  • Variably spindle to epithelioid cells with moderate to marked atypia but typically without frank pleomorphism, in myxoid stroma
  • Low grade fibromyxoid component often present
  • Cyclin D1, BCOR and CD10 IHC positive
  • May be focally desmin positive but caldesmon and SMA negative
  • BCOR internal tandem duplication (ITD) in exon 15
• High grade endometrial stromal sarcoma with YWHAE-NUTM2A/B fusion:
  • Often biphasic morphology
    • High grade epithelioid component: uniform population of atypical epithelioid cells, arranged in nests surrounded by delicate capillary vasculature
    • Low grade spindle component: uniform population of bland stubby spindle cells, resembling low grade endometrial stromal sarcoma
    • Relative frequency:
      • Biphasic tumors most common
      • Occasional tumors show only the high grade epithelioid component
      • Rarely, only the low grade spindle component is present
  • Cyclin D1 and BCOR IHC consistently positive in the high grade epithelioid component and negative or focally positive in the low grade spindle component
  • CD10 negative in high grade epithelioid component but positive in low grade spindle component
  • YWHAE-NUTM2A/B fusion on molecular testing
• NTRK fusion uterine sarcoma:
  • Uniform spindle cell population with mild to moderate atypia and haphazard or herringbone architecture
  • Most common in the cervix of young (< 40) women
  • S100 and pan-TRK IHC consistently positive but nonspecific
  • Desmin, ER and PR IHC negative
  • NTRK fusions (most often NTRK1-TPM3) define entity
• COL1A1-PDGFB fusion uterine sarcoma:
  • Exceptionally rare
  • Uniform spindle cell population with mild to moderate atypia and storiform architecture (resembling dermatofibrosarcoma protuberans)
  • CD34 IHC consistently positive
  • S100, desmin, ER and PR IHC negative
  • COL1A1-PDGFB fusion defines entity
• Malignant inflammatory myofibroblastic tumor:
  • Spindle cells with moderate to marked atypia and inflammatory infiltrate
  • Infiltrative borders, brisk mitoses and tumor necrosis may be present
  • ALK IHC positive in almost all cases, most often with granular cytoplasmic staining
  • ALK fusion present in almost all cases
  • Rare uterine IMT may show RET, ETV6-NTRK3 or ROS1 fusions
• Malignant perivascular epithelioid cell tumor:
  • Variable epithelioid to spindle cells, often with frank nuclear pleomorphism, multinucleation and macronucleoli
  • Smooth muscle (SMA, desmin or caldesmon) and melanocytic (HMB45, MelanA, MITF, PNL2) markers positive
  • TSC1/2 alterations or TFE3 fusions on molecular testing
• Epithelioid leiomyosarcoma:
  • Uniform to pleomorphic epithelioid cells with eosinophilic cytoplasm, often with an admixed spindle component
  • SMA, desmin or caldesmon positive
  • PGR fusions present in a subset
    • This subset characteristically shows uniform cytomorphology, with a rhabdoid eosinophilic cytoplasmic inclusion and eccentric nucleus
• Uterine tumor resembling ovarian sex cord tumor with GREB1 fusion:
  • Uniform epithelioid cells with vesicular chromatin and prominent nucleoli, predominantly arranged in solid sheets, often with focal sex cord patterns (sertoliform cords, tubules, retiform structures)
    • Spindled growth may also be present
  • Polyphenotypic: smooth muscle markers, cytokeratin, sex cord markers (calretinin, inhibin, SF1, WT1, CD56, CD99), CD10 and hormone receptors typically positive, though expression is variable
  • Defined by GREB1 fusions (usually with NCOA1/2)
  • Precise clinical and biologic relationship to classic UTROSCT remains unsettled
• Pleomorphic rhabdomyosarcoma:
  • Primary pleomorphic rhabdomyosarcoma of the uterus is exceptionally rare
  • Polygonal to spindle cells with marked nuclear pleomorphism, frequent multinucleation and abundant eosinophilic cytoplasm
  • Desmin, myogenin, MyoD1 IHC positive
  • Must be differentiated from rhabdomyosarcomatous differentiation in carcinosarcoma or adenosarcoma
• SMARCA4 deficient uterine sarcoma:
  • Uniform epithelioid cells with moderate nuclear atypia and eosinophilic cytoplasm, arranged in solid sheets
  • Phyllodiform growth may be present
  • SMARCA4 (or more rarely, SMARCB1 / INI1) IHC negative (i.e. abnormal loss of expression)
  • SMARCA4 loss of function alterations on molecular testing
  • Subset associated with germline SMARCA4 mutations
• Undifferentiated / dedifferentiated or poorly differentiated carcinoma:
  • Extensive sampling may reveal a component of differentiated carcinoma
  • Mismatch repair deficiency in approximately half of cases
  • SMARCA4 or SMARCB1 / INI1 deficiency in approximately 20%
  • May express cytokeratins, epithelial membrane antigen, claudin 4 or E-cadherin (though these have not been rigorously tested in undifferentiated uterine sarcoma)
• Carcinosarcoma:
  • Extensive sampling will reveal a malignant epithelial component
  • In case of complete overgrowth by undifferentiated sarcoma, distinction will not be possible
• Adenosarcoma with sarcomatous overgrowth:
  • Extensive sampling will reveal a component with conventional adenosarcomatous morphology
  • In case of complete overgrowth by undifferentiated sarcoma, distinction will not be possible
• Melanoma:
  • Protean histomorphology; often pleomorphic polygonal cells with macronucleoli
  • Melanocytic markers (MelanA, HMB45, S100, SOX10) IHC positive

A 73 year old woman presents with postmenopausal bleeding. Ultrasound shows a 12 cm, sonographically heterogeneous uterine mass. Gross examination shows extensive necrosis and hemorrhage. A representative photomicrograph from the tumor is shown. Immunohistochemical stains for SMA, desmin, caldesmon, ALK, CD34, S100, cyclin D1, BCOR, ER, PR, SOX10, HMB45, MelanA, MyoD1, myogenin and broad spectrum cytokeratins are negative. SMARCB1 / INI1 and SMARCA4 immunostains show retained / intact expression. A CD10 immunostain shows patchy positivity and a p53 immunostain shows strong diffuse mutant pattern expression. Which of the following is the most appropriate diagnosis?

1. Epithelioid leiomyosarcoma
2. Malignant inflammatory myofibroblastic tumor
3. Melanoma
4. Pleomorphic rhabdomyosarcoma
5. Undifferentiated uterine sarcoma

E. Undifferentiated uterine sarcoma. The clinical history and gross findings are suggestive of a uterine malignancy but they are not specific to a particular diagnosis. Microscopic examination shows a malignant neoplasm with a loose, vaguely spindled background and numerous superimposed pleomorphic tumor giant cells. An extensive immunohistochemical workup shows no identifiable line of differentiation, ruling out epithelioid leiomyosarcoma (negative SMA, desmin and caldesmon), malignant inflammatory myofibroblastic tumor (negative SMA, desmin, caldesmon, ALK), melanoma (negative S100, SOX10, HMB45, MelanA) and pleomorphic rhabdomyosarcoma (negative desmin, myogenin, myoD1). The other stains also rule out malignant PEComa (negative smooth muscle and melanocytic markers) and high grade endometrial stromal sarcoma (negative BCOR and cyclin D1). A novel fusion related uterine sarcoma (e.g. NTRK fusion sarcoma) is unlikely, given the pleomorphic cytomorphology and mutant pattern p53 immunostaining. Having excluded all items on this lengthy differential diagnosis, a diagnosis of undifferentiated uterine sarcoma is most appropriate.

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Reference: Undifferentiated uterine sarcoma

Which of the following statements regarding the diagnosis of undifferentiated uterine sarcoma is true?

1. Patchy CD10 staining rules out a diagnosis of undifferentiated uterine sarcoma
2. Undifferentiated uterine sarcoma characteristically shows a myomelanocytic immunoprofile
3. Undifferentiated uterine sarcoma is a diagnosis of exclusion applied to malignant uterine mesenchymal tumors with no lineage specific morphologic or immunohistochemical and no entity defining molecular alterations
4. Undifferentiated uterine sarcoma is defined by YWHAE-NUTM2A/B fusion
5. Undifferentiated uterine sarcoma most commonly occurs in the cervix of young women (< 40 years old)

C. Undifferentiated uterine sarcoma is a diagnosis of exclusion applied to malignant uterine mesenchymal tumors with no lineage specific morphologic or immunohistochemical and no entity defining molecular alterations. Patchy CD10 staining may be seen in undifferentiated uterine sarcoma (answer A) and is considered nonspecific. PEComa characteristically shows a myomelanocytic immunprofile (answer B), which should not be seen in undifferentiated uterine sarcoma. YWHAE-NUTM2A/B fusions define a subset of high grade endometrial stromal sarcomas (answer D); this fusion is not compatible with a diagnosis of undifferentiated uterine sarcoma. Undifferentiated uterine sarcoma principally affects postmenopausal patients (answer E); in contrast, NTRK fusion uterine sarcomas most commonly occur in the cervix of young women (< 40 years old).

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Reference: Undifferentiated uterine sarcoma