Uterus

Smooth muscle tumors

Leiomyosarcoma



Last staff update: 6 December 2022 (update in progress)

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PubMed search: Leiomyosarcoma

Ashley Monsrud, M.D.
Gulisa Turashvili, M.D., Ph.D.
Page views in 2021: 34,400
Page views in 2022 to date: 36,030
Cite this page: Monsrud A, Turashvili G. Leiomyosarcoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/uteruslms.html. Accessed December 6th, 2022.
Definition / general
  • Rare, malignant mesenchymal tumor derived from myometrial smooth muscle
  • Most common sarcoma of the gynecologic tract
Essential features
ICD coding
  • ICD-O:
    • 8890/3 - leiomyosarcoma, NOS
    • 8891/3 - epithelioid leiomyosarcoma
    • 8896/3 - myxoid leiomyosarcoma
  • ICD-10: C55 - malignant neoplasm of uterus, part unspecified
  • ICD-11: 2B58.1 - leiomyosarcoma of uterus
Epidemiology
Sites
  • Uterus corpus
  • Cervix, rare
Pathophysiology
  • Derived from smooth muscle
  • Vast array of associated cytogenetic abnormalities but none are consistent or diagnostic
  • Most frequently mutated genes: TP53 (~30%), ATRX (~25%) and MED12 (~20%) (Proc Natl Acad Sci U S A 2021;118:e2025182118)
Etiology
Clinical features
  • Nonspecific symptoms:
    • Abnormal uterine bleeding, pelvic or abdominal pain
  • Rapidly growing uterine mass in a postmenopausal woman
  • Usually an incidental finding, identified in 0.13% of hysterectomies for benign indication and 0.39% of hysterectomies for uterine leiomyomas (Am J Obstet Gynecol 2019;220:179.e1)
Diagnosis
  • Myomectomy, hysterectomy
Laboratory
  • No laboratory values are diagnostic:
    • Some studies suggest leiomyosarcomas have higher levels of lactate dehydrogenase (LDH) versus uterine leiomyoma (BMC Cancer 2020;20:514)
    • Variable success as a predictive marker
Radiology description
  • No pathognomonic findings
  • Difficult to distinguish from benign smooth muscle tumors (Curr Opin Oncol 2021;33:464)
  • TVUS:
    • Most common initial imaging modality
      • Successfully detects uterine leiomyomas
      • Does not differentiate between leiomyomas and leiomyosarcomas
  • CT: not indicated for assessing uterine masses
    • May show irregular central zones of low attenuation, suggesting necrosis and hemorrhage
  • MRI, conventional techniques:
    • Ill defined borders
    • Central nonenhancement
    • T1 weighted images with hyperintensity associated with tumoral hemorrhage or necrosis
    • T2 weighted images show heterogeneous intermediate to high signal intensities
  • Advanced imaging modalities show potential diagnostic improvement:
Radiology images

Images hosted on other servers:

Large intrauterine mass

Heterogeneous mass with irregular borders

Prognostic factors
  • Most important prognostic factor is stage
  • Additional prognostic measures include age, tumor size, mitotic rate and lymphovascular invasion
  • High recurrence rate (50 - 70%) regardless of stage at initial diagnosis
  • Poor prognosis even if the tumor is confined to the uterus
    • More favorable prognosis if tumor is < 5 cm and confined to the uterus
  • 5 year overall survival (OS) rate for all stages is poor, ranging from 15 to 25%
    • OS rates are more favorable at low stages (1 - 2), ranging from 40 to 70%
  • Morcellation is associated with significantly increased risk of recurrence (Gynecol Oncol 2021;160:99)
  • Risk stratification model, including mitoses > 25 per 2.4 mm2 (10 high power fields), atypical mitoses, coagulative necrosis, lymphovascular invasion and serosal abutment, is significantly associated with disease free and disease specific survival in stage I tumors (Mod Pathol 2022;35:794):
    • 3 risk groups include low risk (0- 2 points), intermediate risk (3 - 5 points) and high risk (6 - 13 points)
    • Serosal abutment and lymphovascular invasion can be omitted for myomectomy or morcellated specimens
Case reports
Treatment
  • Surgical resection (hysterectomy) is standard treatment for patients with localized leiomyosarcoma:
    • Adjuvant chemotherapy for early stage disease is controversial
    • Bilateral salpingo-oophorectomy is reasonable in peri and postmenopausal patients
  • Lymphadenectomy is only indicated if there is evidence of concerning lymph nodes (J Adv Pract Oncol 2022;13:70, StatPearls: Leiomyosarcoma [Accessed 26 October 2022])
  • Radiotherapy is indicated for palliative care purposes in advanced or metastatic disease (Cancer Med 2022;11:2906):
    • No evidence for increased overall survival
  • Adjuvant chemotherapy is indicated for metastatic / recurrent tumors
  • Immunotherapy is a potential option for MSI high uterine leiomyosarcoma (Gynecol Oncol Rep 2021;35:100701)
  • Hormonal therapy may be an option in hormone receptor positive tumors
Clinical images

Images hosted on other servers:

Uterus with dilated cervix

Large exophytic intrauterine mass

Large mass

Gross description
  • Often a solitary, bulky, fleshy mass within the myometrium - intramural (majority), submucosal, subserosal or pedunculated:
    • Hemorrhagic, necrotic and cystic areas upon sectioning
    • Grossly invasive / infiltrative
  • Rarely may arise in the cervix (5%)
  • Average diameter is 10 cm:
    • ~25% are < 5 cm
  • Myxoid leiomyosarcoma:
    • Gelatinous cut surface
    • Friable
  • References: Oncol Res Treat 2018;41:680, Arch Pathol Lab Med 2008;132:595
Gross images

Contributed by Ashley Monsrud, M.D.
Formalin fixed, intracavitary leiomyosarcoma

Formalin fixed, intracavitary leiomyosarcoma



Images hosted on other servers:

Large mass

Frozen section description
  • Not usually performed
  • If done, assess:
    • Cellularity
    • Significant cytologic atypia
    • Number of unequivocal mitotic figures
    • Tumor cell necrosis:
      • Karyorrhexis, perivascular cuffs of viable tumor cells in a background of necrosis and ghost cells are diagnostic clues for tumor cell necrosis (Am J Surg Pathol 2021;45:1179)
  • If malignant criteria are met:
    • Best practice is to call "malignant mesenchymal tumor”
Microscopic (histologic) description
  • Conventional / spindle cell type:
    • Essential diagnostic criteria:
      • Requires 2 of 3 histologic features:
        • Marked cytologic atypia
        • ≥ 10 mitoses / 10 high power fields
        • Tumor cell necrosis
          • Identified by abrupt transition from viable tumor cells to necrotic cells (ghost cells, apoptotic bodies may be seen)
          • Granulation tissue surrounding necrosis is absent
    • Growth pattern:
      • Cellular tumor comprised of long intersecting or haphazard fascicles
      • Infiltrative border (common)
      • Rarely, may arise from background leiomyoma
    • Cytologic features:
      • Spindle / elongated cells
      • Eosinophilic cytoplasm
      • Hyperchromatic nuclei often with moderate to severe nuclear pleomorphism (can be deceptively bland and uniform)
      • Atypical mitoses are frequently identified
      • Multinucleated and osteoclast-like giant cells may be seen
      • Coagulative tumor cell necrosis:
        • Identified by abrupt transition from viable tumor cells to necrotic cells (ghost cells, apoptotic bodies may be seen)
        • Granulation tissue surrounding necrosis is absent
  • Myxoid leiomyosarcoma:
    • Diagnosis based on ≥ 1 of the following:
      • Moderate to severe cytologic atypia
      • Coagulative tumor cell necrosis
      • ≥ 1 mitosis / 10 high power fields
      • Infiltrative borders / irregular margins
    • Growth pattern:
      • Hypocellular tumor with abundant myxoid stroma
      • Fascicular or nodular patterns are uncommon
      • Myxoid stroma may be difficult to differentiate from hydropic change in small / limited samples
    • Extensive sampling is generally required for diagnosis
  • Epithelioid leiomyosarcoma:
    • Diagnosis based on ≥ 1 of the following:
      • Moderate to severe cytologic atypia
      • Tumor cell necrosis
      • ≥ 4 mitoses / 10 high power fields
    • Growth pattern:
      • Arranged in nests, cords or sheets
      • May show pseudoglandular spaces
    • Cytologic features:
      • > 50% of round or polygonal cells with eosinophilic or clear cytoplasm
      • Rarely, extensive hyalinization
      • Alternative criteria include ≥ 2 of the following features: moderate or severe atypia, ≥ 4 mitoses / 2.4 mm2 and tumor cell necrosis (Am J Surg Pathol 2022;46:464)
  • Classification systems used:
    • FIGO
    • TNM
  • References: Arch Pathol Lab Med 2008;132:595, StatPearls: Leiomyosarcoma [Accessed 26 October 2022]
Microscopic (histologic) images

Contributed by Ashley Monsrud, M.D. and Paulette Mhawech-Fauceglia, M.D.
Spindle cell mesenchymal neoplasm

Spindle cell mesenchymal leiomyosarcoma

Tumor cell necrosis Tumor cell necrosis Tumor cell necrosis

Tumor cell necrosis

Spindle cell mesenchymal neoplasm

Spindle cell leiomyosarcoma

Atypical mitotic figures

Atypical mitotic figures


Hypercellular tumor

Nuclear atypia

Numerous mitoses

Necrosis


Myxoid mesenchymal, infiltrating border

Myxoid leiomyosarcoma, infiltrating border

Myxoid mesenchymal neoplasm Myxoid mesenchymal neoplasm

Myxoid mesenchymal neoplasm

Mitotic figures in myxoid mesenchymal neoplasm

Mitotic figures in myxoid leiomyosarcoma

Epithelioid mesenchymal neoplasm

Epithelioid leiomyosarcoma


Solid pattern and nuclear atypia

Epithelioid leiomyosarcoma

Infiltration of benign smooth muscle

Infiltration of adjacent myometrium

Solid growth pattern

Solid growth pattern

Nuclear atypia

Nuclear atypia

Epithelioid subtype

Epithelioid subtype

Virtual slides

Images hosted on other servers:

Leiomyosarcoma with extensive lymphovascular invasion

Expanding pelvic mass in 60 year old woman

Positive stains
Negative stains
Molecular / cytogenetics description
Molecular / cytogenetics images

Images hosted on other servers:

Somatic mutational landscape

Videos

Review of uterine leiomyosarcoma

Sample pathology report
  • Uterus and cervix, total hysterectomy:
    • Myometrium:
      • Leiomyosarcoma
      • Tumor size: 15 cm
      • Cytologic atypia: diffuse, marked
      • Coagulative tumor cell necrosis: present
      • Mitotic count: 25 per 10 high power fields
      • Lymphovascular invasion: negative
      • Margin status: negative
      • Other findings: leiomyomata
      • See synoptic report
    • Endometrium: inactive
    • Uterine serosa: benign
    • Cervix: benign
Differential diagnosis
  • Endometrial stromal sarcoma:
    • Low grade endometrial stromal sarcoma:
      • Tumor cells resemble proliferative type endometrial stroma
      • Minimal cytologic atypia and low mitotic index
      • Diffusely positive for CD10 and ER / PR but h-caldesmon typically negative or weak expression
      • Cyclin D1 (focal)
      • ~66% harbor gene fusions:
        • JAZF1::SUZ12 (most common), followed by JAZF1::PHF1, EPC1::PHF1 and MEAF6::PHF1
    • High grade endometrial stromal sarcoma:
      • Round or spindle high grade cells with brisk mitoses and necrosis
      • Infiltrative growth pattern
      • Molecular alterations are: YWHAE::NUTM2A / YWHAE::NUTM2B fusion, ZC3H7B::BCOR and BCOR internal tandem duplication (ITD)
  • Leiomyoma variants:
    • Mitotically active leiomyoma:
      • No cytologic atypia or coagulative tumor cell necrosis
      • 6 - 14 mitoses / 10 HPF
    • Leiomyoma with apoplectic changes:
      • Zonation phenomena (benign smooth muscle away from necrotic areas)
    • Cellular leiomyoma:
      • Increased cellularity but no cytologic atypia or tumor necrosis
    • Leiomyoma with bizarre nuclei:
      • Scattered or diffuse bizarre nuclei with adjacent areas of classic leiomyoma
    • Myxoid leiomyoma:
      • Usually focal myxoid change within a conventional leiomyoma, no coagulative tumor cell necrosis, cytologic atypia or mitotic activity
    • Epithelioid leiomyoma:
        No coagulative tumor cell necrosis, cytologic atypia or mitotic activity
  • Smooth muscle tumors of uncertain malignant potential (STUMP):
    • Some but not all criteria are met for uterine leiomyosarcoma:
      • Spindled smooth muscle tumors: focal / multifocal or diffuse cytologic atypia and 2 - 4 mitoses / mm2 (6 - 9 mitoses / 10 high power fields, 0.55 mm field of diameter, 0.24 mm2 in area) but lacking coagulative necrosis; unequivocal coagulative necrosis but lacking cytologic atypia or elevated mitoses; elevated mitoses at > 6 mitoses / mm2 or > 15 mitoses / 10 high power fields (FD = 0.55, 0.24 mm2 in area) but lacking coagulative necrosis or cytologic atypia; diffuse cytologic atypia and uncertain mitotic count, often due to prominent karyorrhexis but lacking coagulative necrosis
      • Epithelioid smooth muscle tumors: epithelioid morphology with 2 - 3 mitoses / 10 high power fields (FD = 0.55, 0.24 mm2 in area) but lacking moderate to severe cytologic atypia and coagulative necrosis
      • Myxoid smooth muscle tumors: myxoid morphology but lacking mitotic activity, moderate to severe cytologic atypia, coagulative necrosis and infiltrative / irregular borders
  • Inflammatory myofibroblastic tumor:
    • Spindle cell neoplasm with myxoid stroma and associated lymphoplasmacytic inflammatory cells
    • Atypia can range from mild to severe
    • ALK staining is seen in most tumors and ALK rearrangement is seen in 80% of cases (Mod Pathol 2017;30:1489)
  • Perivascular epithelioid cell tumor:
    • Composed of epithelioid or spindled cells with eosinophilic to clear cytoplasm with variable cytologic atypia and mitoses
    • Cells may be organized in a perivascular fashion, short fascicles, sheets or nests
    • Melanin rarely present
    • Typically strongly HMB45 positive and often MelanA or MITF positive
    • Cathepsin K staining
    • A subset harbor TSC1 and TSC2 alterations or TFE3 fusion (Mod Pathol 2022;35:515)
Board review style question #1

What mitotic count per 10 high power fields is used to aid in diagnosing spindle cell leiomyosarcoma of the uterus?

  1. > 1 mitosis per 10 high power fields
  2. ≥ 5 mitoses per 10 high power fields
  3. ≥ 10 mitoses per 10 high power fields
  4. Not a diagnostic criterion
Board review style answer #1
C. ≥ 10 mitoses per 10 high power fields. Uterine spindle cell leiomyosarcomas are diagnosed based on the presence of 2 of 3 morphologic features: a mitotic count of ≥ 10 mitoses per 10 high power fields, moderate to marked cytologic atypia and coagulative tumor cell necrosis.

Comment Here

Reference: Leiomyosarcoma
Board review style question #2

A 62 year old woman underwent a hysterectomy for a uterine mass. Immunohistochemical stains show that the tumor is positive for h-caldesmon and desmin and negative for CD10 and ALK. What is the most likely diagnosis?

  1. Endometrial stromal sarcoma
  2. High grade endometrial adenocarcinoma
  3. Inflammatory myofibroblastic tumor
  4. Leiomyosarcoma, myxoid subtype
Board review style answer #2
D. Leiomyosarcoma, myxoid subtype. The image shows a myxoid mesenchymal tumor with infiltrative borders. The morphologic findings combined with the immunophenotype is consistent with leiomyosarcoma, myxoid subtype.

Comment Here

Reference: Leiomyosarcoma
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