An Overview of Genital Stromal Tumors

By Konstantinos Linos MD, FCAP, FASDP Bone, Soft Tissue and Dermatopathology Assistant Professor of Pathology Dartmouth-Hitchcock Medical Center Geisel School of Medicine at Dartmouth Hanover, NH, USA Financial disclosures

• Book Royalties General • Broad variety of soft tissue tumors exclusively in vulvovaginal and inguinoscrotal sites

• Probably originate from a distinct zone of subepithelial stromal cells or subepithelial mesenchyme extending from the endocervix

• Striking morphologic, immunophenotypic and genetic overlap • Fibroepithelial Polyp • Superficial Myofibroblastoma • Cellular angiofibroma • Mammary-type myofibroblastoma • Angiomyofibroblastoma • Deep/”Aggressive” angiomyxoma • Superficial Angiomyxoma • Prepubertal Vulvar Fibroma • Lipoblastoma-Like tumor of the vulva • Smooth Muscle Tumors of the external genitalia Fibroepithelial Stromal Polyp • Synonyms • Mesodermal stromal polyp • Cellular Pseudosarcomatous fibroepithelial stromal polyp • Pseudosarcoma botryoides • Benign polypoid growth of the vagina, vulva or cervix • Strongly tied to hormonal stimulation • Most often during pregnancy • also in reproductive age women • Postmenopausal women undergoing hormonal replacement

• Regression in the postpartum period is typical

• Typical clinical presentation is one or more polyps that may be symptomatic

• Usually 1-5cm

Immunohistochemistry

• Consistently reactive for • Desmin • Estrogen Receptor (ER) • Progesetrone Receptor (PR) • Sometimes Smooth Muscle Actin

Enbryonal Rhabdo- myosarcoma

Rhabdomyoma Superficial (cervicovaginal) myofibroblastoma • Benign tumor that may arise in the vulva, vagina or cervix

• Nodular or polypoid painless mass in adults most commonly in their 50s

• Grossly well-circumscribed, firm and dense mass from 1 to 6.5cm

Immunohistochemistry

• Desmin in 75-100% of cases

• ER/PR in 80-100%

• CD34 in 50-85%

• SMA in 0-45% Cellular Angiofibroma • Synonym • Angiomyofibroblastoma-like tumor of the male genital tract • Benign neoplasm in vulvovaginal and inguinoscrotal areas • Middle-aged patients with a female predominance • Classically subcutaneous painless nodule usually not exceeding 7cm

Immunohistochemistry

• Inconsistent expression

• Variable expression of CD34, desmin, SMA

• P16 positivity in sarcomatous areas p16 Mammary-type Myofibroblastoma • Initially described in breast • Can arise anywhere in soft tissue • Predilection for inguinal and pelvic region

• Most cases occur in men

• Median age 53

• Range 1-22cm (median size of 6cm)

Immunohistochemistry

• Frequently positive for CD34 and Desmin (~90%)

• Rare cases CD34 Desmin negative for both (~3%) Prognosis

• Benign tumor

• Local excision curative

• No evidence of significant recurrence risk even in the presence of positive resection margins RB1 and Genital Stromal Tumors Mammary-type myofibroblastoma

RB1

Cellular Angiofibroma

RB1 Angiomyofibroblastoma

• Benign mesenchymal neoplasm of the vulva and vagina

• Uncommonly may present as a penduculated lesion

• Most grossly well-circumscribed and smaller than 5cm

Immunohistochemistry

• Positive for Desmin, ER &PR

• Less commonly CD34 and SMA positivity

Desmin

Deep Angiomyxoma

• Synonym: “Aggressive” angiomyxoma • Low Grade, locally infiltrative myxomatous neoplasm specific to the deep vulvovaginal, perineal and pelvic tissues • Strong female predisposition • In men in the analogous inguinoscrotal and perineal regions • Usually 4th decade of life with painless cystic mass often exceeding 10cm • Less aggressive course than initially described if completely excised with negative margins • Potential for local destructive recurrence some times years (often decades) after initial excision • Even tumors as small as 3cm have recurred multiple times • Grossly soft gelatinous tumor with ill-defined margins • In recurrent cases may have more fibrous appearance

Immunohistochemistry • Typically positive for: • Desmin • SMA • ER/PR • Variable CD34 positivity • Structural rearrangements of the region 12q15 • ~30% of tumors, intragenic/extragenic • HMGA2 and CDK4 IHCs positive • When positive, useful in confirming the diagnosis and assessing margins status in a subset of cases Reactive changes Smooth Muscle Tumor

WDL Superficial Angiomyxoma Superficial Angiomyxoma • Can also occur in the genital region of women • Include this entity in the differential of myxoid lesions of the distal female genital tract • Association with Carney complex less clear with lesions in the genital area • Typically polypoid and usually less than 5cm • Potential for local nondestructive recurrence in ~30-40% of cases

Prepubertal Vulval Fibroma

Myxoid Collagenous

Loss of RB1 by IHC

• Lack of PLAG1 and HMGA2 expression suggests it is distinct from “true” lipoblastomas

• Loss of Rb1 suggests possible role of 13q chromosomal alterations

• Possible relationship with the Spindle cell lipoma family Practical approach

• Correct Identification of Aggressive Angiomyxoma is critical • If above has been excluded and definitive classification is not possible you can use label • “Benign Genital Stromal Tumor” Smooth Muscle Tumors of the External Genitalia • Smooth muscle tumors of vulva, vagina, and scrotum have similar gross and pathologic features to soft tissue and uterine counterparts • Criteria for malignancy depend on the specific site • Soft tissue • Superficial (including nipple) • Genital • Deep seated LEIOMYOMA

Epithelioid morphology

Myxoid changes LEIOMYOSARCOMA

Some combination of • cytologic atypia, • increased mitotic activity • Increased size • infiltrative growth Smooth Muscle Tumors of the Vulva • Leiomyomas of the vulva is one of the more common vulvar mesenchymal neoplasms • Present in 4th to 5th decade as a small (<3cm) mass • Mutliple leiomyomas may be manifestation of Alport Syndrome • Hereditary disorder • Glomerulonephritis, ocular abnormalities & hearing loss • Mutation in COL4A3, COL4A4, COL4A5

Smooth Muscle Tumors of the Scrotum • Uncommon and most are leiomyosarcomas • Cytologic atypia, mitotic activity and necrosis • Rare in this location tumors with absence of atypia or mitotic activity • Extensive sample is necessary before apply the diagnosis of leiomyoma • Note long-term clinical follow-up • Any mitotic activity warrants classification as malignant Differential Diagnosis • Neurofibroma • S100-protein/SOX 10 + • Solitary Fibrous Tumor • STAT6 positive • Inflammatory Myofibroblastic Tumor • ALK + in 50-60% of cases • Sarcomatoid Carcinoma • Diffuse cytokeratin expression • Examine for High Grade Squamous Intraepithelial lesion or dVIN • Email: [email protected]

• @ @ KonstantinosLin