Uterus
Smooth muscle tumors
Leiomyoma-general
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PubMed search: leiomyoma[title] uterus review[ptyp]
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Diagnosis | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Positive stains | Negative stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Alran L, Rychlik A, Croce S. Leiomyoma-general. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/uterusleiomyoma.html. Accessed August 11th, 2022.
Definition / general
- Most common uterine tumor (Mod Pathol 2016;29:S104)
- Benign mesenchymal tumor derived from smooth muscle
Essential features
- Benign mesenchymal tumor derived from smooth muscle
- 90% of leiomyomas are the conventional type:
- Conventional / usual leiomyoma:
- Monotonous spindle cells with indistinct borders arranged in intersecting fascicles
- Mitoses: rare (in general < 5/10 high power fields)
- Subtypes:
- Cellular
- Leiomyoma with bizarre nuclei
- Fumarate hydratase (FH) deficient
- Mitotically active
- Hydropic
- Apoplectic
- Lipoleiomyoma
- Epithelioid
- Myxoid
- Dissecting leiomyoma
- Diffuse leiomyomatosis
- Conventional / usual leiomyoma:
Epidemiology
- All ages, especially in fifth decade; third decade for fumarate hydratase deficient leiomyoma
- More common (up to 80%) in African American women
- References: Best Pract Res Clin Obstet Gynaecol 2008;22:571, BJOG 2017;124:1501
Sites
- Uterine corpus
- Less common in vulva, vagina, cervix, broad ligament, ovary
Pathophysiology
- Leiomyomas have a clonal origin
- Several alterations identified (Table 1) (Clin Obstet Gynecol 2016;59:25)
- Risk decreased by oral contraceptives
- May occur in hereditary leiomyomatosis and renal cancer syndrome (HLRCC) and Alport syndrome
Etiology
- Mitotically active leiomyoma: associated ischemia or hormonal stimulation (endogenous or exogenous) (Am J Surg Pathol 2016;40:563)
- Apoplectic leiomyoma: progesterone (or analogues) exposure (contraception or pregnancy and postpartum)
Diagrams / tables
Contributed by Sabrina Croce, M.D., Ph.D.
Table 1: molecular alterations
Table 2: differential diagnosis in uterine spindle cell smooth muscle lesions
| | | | |
| - | + | ≥ 10 | Leiomyosarcoma |
| + | + | ≥ 10 | |
| + | + | < 10 | |
| - | - | > 15** | Smooth muscle tumor of uncertain malignant potential (STUMP) |
| - | + | < 10 | |
| + | - | < 10 | |
| - | - | ≥ 6 and ≤ 15** | Mitotically active leiomyoma |
| * Mitoses/mm2 (mitoses/10 HPF of 0.55 mm in diameter) | |||
| ** > 15 or ≥ 15, cutoff value varies according to the references | |||
Table 3: differential diagnosis in uterine myxoid smooth muscle lesions
| | | | |
| Infiltrative borders | - | - | 1 or more of these criteria:
|
| Atypia | - | - | |
| Tumor cell necrosis | - | - | |
| Mitoses* | - | 1 | |
| * Mitoses/mm2 (mitoses/10 HPF of 0.55 mm in diameter) | |||
Table 4: differential diagnosis in uterine epithelioid smooth muscle lesions
| | | | |
| Atypia | - | - | 1 or more of these criteria:
|
| Tumor cell necrosis | - | - | |
| Mitoses* | < 2 | ≥ 2 and < 4 | |
| * Mitoses/mm2 (mitoses/10 HPF of 0.55 mm in diameter) | |||
Clinical features
- 25% symptomatic; remainder asymptomatic
- Symptoms depend on size and location
- Menorrhagia and pelvic pain in 33% of patients
- Reference: Nat Rev Dis Primers 2016;2:16043
Diagnosis
- Can be established by resection of the whole uterus (hysterectomy), by resection of the leiomyoma if accessible by curetting (if submucosal) or by myomectomy (if subserosal)
- Ultrasound or magnetic resonance imaging (MRI) (guided core biopsy of the leiomyoma is a promising new procedure (Int J Gynecol Cancer 2020;30:A113)
Prognostic factors
- Uterine leiomyomas are benign tumors that may recur, especially after myomectomy
- Fumarate hydratase deficient leiomyomas:
- Recur more frequently
- Genetic counseling should be recommended
Case reports
- 32 year old woman with enlarged uterus with hypervascular lesions likely representing fibroids (Case of the Month #508)
- 32 year old woman with uterine leiomyoma with high stage renal carcinoma in a context of HLRCC syndrome (Am J Surg Pathol 2011;35:1235)
- 58 year old woman with uterine leiomyomas and osteoclast giant cells (Int J Gynecol Pathol 2016;35:30)
- 74 year old woman with uterine leiomyoma harboring KAT6B-KANSL1 gene fusion (Diagn Pathol 2019;14:32)
Treatment
- Asymptomatic: does not require therapy
- Symptomatic leiomyoma:
- Surgery (hysterectomy or myomectomy)
- Hysteroscopic resection
- Medical treatment - progestins / levonorgestrel intrauterine system, gonadotropin releasing hormone (GnRH) analogs or aromatase inhibitors
- Ulipristal acetate; widely used in conservative treatment of uterine leiomyomas but rejected by the FDA due to risk of liver toxicity
- Interventional treatments - uterine artery embolization or radiofrequency myolysis
- Reference: J Obstet Gynaecol Can 2015;37:157
Gross description
- Location in the uterus: intramural, submucosal and subserosal
- Often multiple
- Typically well circumscribed but nonencapsulated
- On cut surface: white or tan-white, whorled, firm, bulging
- Hemorrhage and infarction can be present in large tumors
- Calcifications can be present
- Apoplectic change (foci of hemorrhage) associated with progesterone therapy
- Extensive sampling (to exclude malignancy)
- Especially in leiomyomas that lack the classic gross appearance
- Myxoid areas to exclude myxoid leiomyosarcoma
- Reference: Mod Pathol 2016;29:S104
Gross images
Contributed by Sabrina Croce, M.D., Ph.D.
Submucosal leiomyoma
Intramural leiomyoma
Subserosal leiomyomas
Apoplectic leiomyoma
Conventional / usual leiomyoma
Microscopic (histologic) description
- Conventional / usual leiomyoma (spindle):
- Well defined borders
- Normocellular
- Intersecting fascicles of monotonous spindle cells with indistinct borders, eosinophilic cytoplasm, cigar shaped nuclei (with tapered ends) and small nucleoli
- Atypia: absent or mild
- Mitoses: rare (in general < 5/10 high power fields)
- Blood vessels with thick walls
- With or without infarct type necrosis, hyalinization, calcification, cystic change
- Subtypes:
- Cellular
- Increased cellularity (more cellular than background myometrium)
- Scant cytoplasm without increased mitotic activity and atypia
- May have irregular borders
- Highly cellular leiomyoma is not a WHO diagnosis
- Leiomyoma with bizarre nuclei:
- Bizarrely shaped, hyperchromatic, multilobulated nuclei with nuclear pseudoinclusions
- Arranged in a multifocal to diffuse distribution in a background of a typical leiomyoma (Am J Surg Pathol 2014;38:1330, Mod Pathol 2017;30:1476, Am J Surg Pathol 2016;40:923, Cancer 2014;120:3165, Am J Surg Pathol 1997;21:1261)
- Alveolar edema, staghorn vessels
- Low mitotic activity (< 5 mitoses/10 high power fields)
- Absence of tumor cell necrosis
- Vasculature variable (staghorn vessels, thick walled vessels, fibrinoid necrosis of vessel walls, luminal vascular obliteration)
- Diagnostic key: intermixed normal spindled smooth muscle cells
- Fumarate hydratase deficient leiomyoma:
- Alveolar edema
- Staghorn or hemangiopericytoma-like vessels
- Chain-like growth of tumor cells
- Spindle or epithelioid cells with ovoid nuclei and prominent eosinophilic nucleoli surrounded by perinucleolar halos
- Rhabdoid / eosinophilic cytoplasmic inclusions
- May include multinucleated cells and cells with bizarre nuclei
- Mitotically active:
- Spindle cell leiomyoma without atypia or tumor cell necrosis
- Increased mitotic activity (the mitotic cutoff varies according to the authors 6 - 14 mitoses/10 high power fields or 6 - 15 mitoses/10 high power fields)
- Hydropic:
- Tumor cells separated by watery or eosinophilic and proteinaceous fluid, resulting in a trabecular, nested architecture
- Apoplectic:
- Central zone of hemorrhage and necrosis with increased mitotic activity in its periphery or myxoid changes (zonation phenomenon)
- Usual appearance away from the central necrosis
- Lipoleiomyoma:
- Tumor composed of smooth muscle cells mixed with mature adipocytes (variable quantity)
- Epithelioid:
- Round or polygonal cells with eosinophilic or clear cytoplasm (in general, ≥ 50% of tumor cells)
- Nested or trabecular architecture
- No cytologic atypia or tumor cell necrosis
- Mitotic count is < 2 mitoses/10 high power fields
- Myxoid:
- Hypocellular tumor
- Cells separated by myxoid matrix composed of glycosaminoglycans (Alcian blue+) occupying ≥ 50% of the overall tumor volume
- Well circumscribed borders (most important criteria)
- No cytologic atypia, mitoses or tumor cell necrosis
- Dissecting leiomyoma:
- Nodules of smooth muscle cells dissecting the myometrium; occasionally hydropic changes and intravenous extension can be seen
- Called cotyledonoid leiomyoma if extends outside the uterus
- Diffuse leiomyomatosis:
- Diffuse, poorly circumscribed, innumerable tumor nodules in the myometrium
- No atypia and tumor cell necrosis
- Low mitotic count
- Cellular
Microscopic (histologic) images
Contributed by Sabrina Croce, M.D., Ph.D.
Conventional / usual leiomyoma
Cellular leiomyoma
FH deficient leiomyoma
Leiomyoma with bizarre nuclei
Hydropic leiomyoma
Apoplectic leiomyoma
Epithelioid leiomyoma
Myxoid leiomyoma
Lipoleiomyoma
Contributed by Kristina Doytcheva, M.D. and Jennifer A. Bennett, M.D. (Case #508)
Fumarate hydratase deficient (FH-d) leiomyoma
Virtual slides
Images hosted on other servers:
Leiomyoma
Leiomyoma with bizarre nuclei
Highly cellular leiomyoma
Lipoleiomyoma
Positive stains
- Desmin
- h-caldesmon
- Smooth muscle actin
- Transgelin
- Smooth muscle markers can be weak in epithelioid and myxoid leiomyomas
- Estrogen and progesterone receptors
- WT1
- Up to 40% of leiomyomas are CD10 positive (especially cellular leiomyomas) (Am J Surg Pathol 2002;26:403)
- FH loss of expression and 2SC positivity may be useful to identify fumarate hydratase deficient leiomyoma (Am J Surg Pathol 2016;40:599, Mod Pathol 2014;27:1020)
- FH loss of expression is specific of FH deficient leiomyoma but its sensitivity is low with different results across different leiomyomas of the same patient; for these reasons, the clinical value of FH staining is limited (Am J Surg Pathol 2015;39:1529, Am J Surg Pathol 2019;43:1170, Genes Chromosomes Cancer 2021;60:210)
- 2SC nuclear staining has been reported in FH deficient leiomyomas but is not widely commercially available and experience is limited (Am J Surg Pathol 2014;38:627, Am J Surg Pathol 2015;39:1529, Mod Pathol 2014;27:1020, Genes Chromosomes Cancer 2020 Oct 24 [Epub ahead of print])
Negative stains
Molecular / cytogenetics description
- About 70% of conventional leiomyomas harbor MED12 mutations and nearly 40% HMGA2 / HMGA1 rearrangements, COL4A5 / COL4A6 deletions or FH mutations (Fertil Steril 2014;102:621, Mol Cancer 2017;16:101)
- Other less frequent alterations include 7q22 deletion involving CUX1 gene, 22q deletion with DEPDC5 gene and 1p deletion with NPHP4 gene (Genes Chromosomes Cancer 2013;52:11, Proc Natl Acad Sci U S A 2016;113:1315, N Engl J Med 2013;369:43, Am J Obstet Gynecol 2014;210:572.e1, Cancer Genet Cytogenet 2009;193:54)
- Recently, a novel t(10;17)(q22;q21) KAT6B-KANSL1 fusion has been described in cellular leiomyoma (Diagn Pathol 2019;14:32)
- In leiomyomas with bizarre nuclei, the genomic profiles and genomic index can be more complex compared with that of classic leiomyoma (Mod Pathol 2016;29:1262):
- At a molecular level, leiomyomas with bizarre nuclei are separated in 2 subtypes: FH abnormal and TP53 and RB1 abnormal (Mod Pathol 2017;30:1476, Mol Cancer 2017;16:101)
- Bi-allelic inactivation of FH has been described in up to 33% of leiomyomas with bizarre nuclei (Mol Cancer 2017;16:101)
- For FH deficient leiomyomas, the FH mutation may be somatic or germline (Am J Surg Pathol 2016;40:1661, Mod Pathol 2014;27:1020, Am J Surg Pathol 2019;43:639, Genes Chromosomes Cancer 2021;60:210)
- TPCN2-YAP1 fusion (Genes Chromosomes Cancer 2020 Jul 17 [Epub ahead of print])
Sample pathology report
- Uterus, total hysterectomy:
- Conventional leiomyoma: 5.0 cm (see comment)
- Comment: Microscopic examination reveals a smooth muscle tumor composed of spindle, cigar shaped cells arranged in fascicular pattern without cytologic atypia and tumor cell necrosis. Mitoses are rare (4 mitoses/10 high power fields). Tumor borders are well circumscribed. By immunohistochemistry the tumor cells are positive for desmin, h-caldesmon, ER and PR.
Differential diagnosis
- Smooth muscle tumor of uncertain malignant potential (STUMP):
- Uterine spindle cell STUMP:
- Only 1 morphologic criteria of malignancy (Table 2)
- Myxoid STUMP:
- Mitoses: 1/10 high power fields in the absence of cytologic atypia and tumor cell necrosis (Table 3)
- Epithelioid STUMP:
- Mitoses: ≥ 2/10 high power fields) and < 4/10 high power fields in the absence of cytologic atypia and tumor cell necrosis (Table 4)
- Uterine spindle cell STUMP:
- Leiomyosarcoma:
- Uterine spindle cell leiomyosarcoma (Table 2):
- 2 or more morphologic criteria of malignancy:
- Cytologic atypia
- Tumor cell necrosis
- Mitoses: ≥ 10/10 high power fields
- 2 or more morphologic criteria of malignancy:
- Myxoid leiomyosarcoma (Table 3):
- 1 or more morphologic criteria of malignancy:
- Mitoses: ≥ 2/10 high power fields
- Cytologic atypia
- Tumor cell necrosis
- 1 or more morphologic criteria of malignancy:
- Epithelioid leiomyosarcoma (Table 4):
- 1 or more morphologic criteria of malignancy:
- Mitoses: ≥ 4/10 high power fields
- Tumor cell necrosis
- Cytologic atypia
- 1 or more morphologic criteria of malignancy:
- Uterine spindle cell leiomyosarcoma (Table 2):
- Endometrial stromal nodule (Mod Pathol 2016;29:S104):
- Endometrial stromal nodule versus highly cellular leiomyoma:
- Diffuse arteriolar vascularization
- Absence of thick vessels at the center of the lesion
- Absence of fascicular growth
- Immunohistochemistry:
- Weak to absent smooth muscle marker staining
- CD10 (not specific): can help if diffuse and strong in absence of smooth muscle markers
- JAZF1, PHF1, EPC1, MEAF6, MBTD1 or EZHIP fusions (Genes Chromosomes Cancer 2021;60:160)
- Endometrial stromal nodule with smooth muscle metaplasia:
- Smooth muscle metaplasia in endometrial stromal nodule can be present but is typically a minor component of the tumor
- Endometrial stromal nodule versus highly cellular leiomyoma:
- PEComa versus epithelioid leiomyoma (Genes Chromosomes Cancer 2020 Oct 24 [Epub ahead of print], Am J Surg Pathol 2018;42:1370):
- Thin and delicate vasculature
- Nested and trabecular architecture
- Clear to eosinophilic granular cytoplasm with round nuclei
- Immunohistochemistry: at least 2 melanocytic markers expressed, preferably HMB45 and MelanA (or cathepsin K, PNL2)
- Molecular:
- TSC1 or TSC2 alterations (Am J Surg Pathol 2015;39:813, Oncology 2020;98:905, Genes Chromosomes Cancer 2021;60:168)
- TFE3 fusions (Am J Surg Pathol 2015;39:394, Am J Surg Pathol 2012;36:783, Genes Chromosomes Cancer 2021;60:168)
- Inflammatory myofibroblastic tumor versus myxoid leiomyoma (Int J Gynecol Pathol 2021;40:28, Am J Surg Pathol 2020;44:1441, Mod Pathol 2017;30:1489):
- Presence of lymphoplasmacytic inflammation
- Spindle, myofibroblastic cells embedded in myxoid stroma
- Tissue culture-like pattern
- Immunohistochemistry:
- ALK positive
- Smooth muscle markers not useful: positive in both
- ALK rearrangements / fusions
Additional references
Board review style question #1
A 23 year old woman with multiple recurrent leiomyomas is diagnosed with a FH deficient leiomyoma. Which of the following is true?
- FH deficiency is a risk factor for uterine leiomyosarcoma
- Staghorn vessels, alveolar oedema, macronuclei with perinucleolar halos and cytoplasmic eosinophilic globules are typical morphologic features of FH deficient leiomyoma
- Bizarre nuclei and FH deficient leiomyoma are mutually exclusive
- All FH deficient leiomyomas are 2SC positive and FH negative
- All FH deficient leiomyomas are associated with a germline mutation
Board review style answer #1
B. Staghorn vessels, alveolar oedema, macronuclei with perinucleolar halos and cytoplasmic eosinophilic globules are typical morphologic features of FH deficient leiomyoma
Comment Here
Reference: Leiomyoma-general
Comment Here
Reference: Leiomyoma-general
Board review style question #2
A 44 year old woman presents with 4 cm leiomyoma with bizarre nuclei. Which of the following is true?
- The presence of atypia alone is a sufficient criterion warrant the diagnosis of leiomyosarcoma
- Significant number of leiomyomas with bizarre nuclei harbor FH biallelic inactivation
- Leiomyomas with bizarre nuclei are malignant
- p16 staining is a reliable marker of leiomyomas with bizarre nuclei
- Arteriolarization of vessels is a typical feature of bizarre nuclei leiomyoma
Board review style answer #2
B. Significant number of leiomyomas with bizarre nuclei harbor FH biallelic inactivation
Comment Here
Reference: Leiomyoma-general
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Reference: Leiomyoma-general
