Uterine Cervix

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2019, Case 09, and is embryonal rhabdomyosarcoma of the uterine cervix.

Sections show multiple polypoid fragments of edematous, hemorrhagic, and focally necrotic soft tissue with occasional entrapped endocervical glands. The glandular epithelium is bland endocervix with some areas of squamous metaplasia. The stromal component shows some hemorrhage and normal-appearing small vessels. Scattered throughout the edematous stroma are small round to spindled cells with indistinct cytoplasm. Near the epithelial surfaces there is dense condensation of the small cell component into a distinctive cambium layer. This supports a diagnosis of embryonal rhabdomyosarcoma (ERMS).

ERMS represents the most common subtype of rhabdomyosarcoma and the most frequent sarcoma of the pediatric population. The majority of ERMS occur in sites other than soft tissue; the head and neck region and the genitourinary or gynecologic tracts are particularly favored areas. In the latter site, there is a special variant of ERMS known as sarcoma botryoides or botryoid rhabdomyosarcoma that typically presents as a fleshy, "bag of grapes"-like lesion on clinical exam.

Sarcoma botryoides represents the most common malignant mesenchymal lesion of the cervix and is most often identified in young women between the ages of 12 to 26 years (average age: 18 years), with rare cases in older women. It frequently appears as a polyp-like lesion that protrudes through the cervical os or occasionally into the introitus. The prognosis for this variant of rhabdomyosarcoma is generally favorable. Patients of child-bearing age can often be treated with a fertility-sparing procedure.

Immunohistochemically, ERMS will express markers of muscle differentiation including desmin, actins, myogenin, and MyoD1. ERMS as a group do not show specific reproducible cytogenetic or molecular aberrations that translate into an ancillary diagnostic test. Structural and numeric copy number changes of chromosomes 2, 8, and 13 are frequent findings.

The differential diagnosis of ERMS/sarcoma botryoides includes other stromal and mixed epithelial and stromal neoplasms of the gynecologic tract.

Aggressive angiomyxoma (also called deep angiomyxoma) is a neoplasm that tends to arise in the deeper soft tissues of the pelvic or perineal regions of adult women. Aggressive/deep angiomyxomas are lobulated lesions that tend to grow around other structures (rectum, vagina) but do not infiltrate. They are hypocellular and contain an abundance of matrix that appears myxoid but actually represents intralesional edema. Scattered throughout the lesion are a few small to medium sized vessels with very thin walls. The predominant cell type is a very small spindle cell with indistinct cytoplasmic processes. Nuclear atypia and pleomorphism are absent.

Unlike ERMS, aggressive/deep angiomyxomas are frequently immunoreactive for estrogen receptors (ER) and progesterone receptors (PR). They may also express smooth muscle actin but desmin staining is usually negative. Although they do not metastasize, they have a propensity to recur and may be associated with morbidity because of their deep-seated location. Because these tumors express ER and PR, patients can be treated with hormone agonists and can often delay surgical excision.

Adenosarcoma may closely mimic sarcoma botryoides but tends to occur in older women (average age: 58 years). They most frequently arise in the endometrium, with rare cases arising in the cervix. They commonly present with abnormal bleeding and generally have a polypoid appearance. Unlike sarcoma botryoides, they lack the “bag of grapes” gross appearance. The overall prognosis for adenosarcoma is fair. Patients with tumor confined to the endometrium tend to do well after hysterectomy. Women with higher-stage lesions are more likely to experience recurrence and metastases.

On histologic examination, adenosarcomas tend to have a phyllodes or “leaf-like” pattern. They are biphasic neoplasms comprised of a benign epithelial component (usually endometrial-type glands) and a spindled stromal component. The stroma may condense around the epithelial glands, creating a “cambium layer-like” configuration. The stroma of adenosarcomas is usually bland but can occasionally become pleomorphic and, in some instances contain rhabdomyoblasts. The latter will express muscle markers including desmin and myogenin.

Differentiating adenosarcoma from ERMS may be difficult because of these histologic similarities. In general, ERMS arise in young patients whereas adenosarcomas typically occur in older women. In addition, adenosarcomas usually originate in the endometrium, where ERMS seldom occurs. Benign glands are an integral feature of adenosarcoma but are often present as entrapped elements in rhabdomyosarcoma. In addition, the mesenchymal element of adenosarcoma will express CD10, WT1, ER, and PR, whereas ERMS seldom do.

Alveolar rhabdomyosarcoma (ARMS) is the second most common subtype of rhabdomyosarcoma, accounting for about 20% of all cases. This subtype is usually seen in a slightly older population than the embryonal subtype, but there is a significant age overlap of patients. Although ARMS is more likely to arise in the soft tissue of the extremities or paraspinal region, it may occasionally arise in the pelvis.

In its classic form, ARMS is characterized by small nests of tumor cells separated by thin fibrovascular septae. The cells themselves are small, primitive-appearing rhabdomyoblasts. Pleomorphism is usually more apparent in alveolar rhabdomyosarcoma and large cells with abundant eosinophilic cytoplasm, occasionally with visible cross striations (rhabdomyoblasts), are often found. However, ARMS is histologically variable and can often closely resemble ERMS, especially with the so-called “solid” variant of ARMS. In this subtype, the characteristic fibrovascular septae are absent, resulting in a solid sheet of tumor cells with very little rhabdomyoblastic differentiation. Like ERMS, ARMS will stain with markers of muscle differentiation.

ARMS is an aggressive neoplasm treated with a multimodal approach. Individuals with ARMS tend to be higher stage at presentation and the tumor is often metastatic by the time it is discovered. Because the treatment for ERMS and ARMS differ significantly, it is important to establish a definitive diagnosis of ARMS prior to initiation of therapeutic intervention. Fortunately, ARMS is characterized by a recurrent translocation in about 80% of cases. This involves a fusion of the FOXO1 gene (formerly known as FKHR for forkhead in rhabdomyosarcoma) with either a PAX3 (t(2;13), most common) or PAX7 (t(1;13)) gene. Because of the differences in prognosis, current recommendations include molecular confirmation of rhabdomyosarcoma subtype whenever possible.

Carcinosarcoma, also known as malignant mixed Müllerian tumor (MMMT), is another malignancy of the gynecologic tract that may resemble sarcoma botryoides. Carcinosarcoma occurs almost exclusively in postmenopausal women and preferentially arises in the endometrium. Patients present with abnormal bleeding, an enlarged uterus and elevated CA125. On histology, carcinosarcoma is characterized by the presence of both a malignant epithelial component (carcinoma) as well as a malignant sarcomatous stroma.

The carcinomatous element is usually endometrioid or serous but occasionally can be squamous, clear cell, or another subtype. The sarcomatous component is most often high grade. About 50% of carcinosarcomas will show heterologous differentiation which manifests as foci of rhabdomyoblastic (most common), chondroblastic, osteosarcomatous, or liposarcomatous differentiation. The rhabdomyoblastic elements will stain for muscle markers, but the remainder of the stroma will typically express CD10, p16, and WT1, markers that are usually negative in ERMS. The prognosis for carcinosarcoma is poor and it is treated aggressively with surgery and adjuvant therapy. Survival rates are related to stage at presentation.

1. Which of the following features best distinguishes embryonal rhabdomyosarcoma (botryoid subtype) from adenosarcoma??
   
   
   1. Absence of staining for CD10, WT1, ER, and PR
   2. Positive staining for desmin and myogenin
   3. Presence of a condensed layer of cells around glands
   4. Presence of a reproducible cytogenetic translocation
   5. Presence of rhabdomyoblasts
2. Which of the following features best separates embryonal subtype of rhabdomyosarcoma (ERMS) from the alveolar subtype of rhabdomyosarcoma (ARMS)?
   
   
   1. ARMS has an alveolar pattern with fibrovascular septae.
   2. ARMS has a characteristic gene translocation.
   3. ARMS is a soft tissue-based lesion.
   4. ERMS is more likely to have numerous rhabdomyoblasts.
   5. ERMS is more pleomorphic than ARMS.
3. Which of the following scenarios is most consistent with sarcoma botryoides?
   
   
   1. A 15-year-old with a pelvic mass and metastases to the lung
   2. A 25-year-old with a deep soft tissue lesion surrounding the rectum
   3. A 25-year-old with a polypoid lesion protruding through the cervical os
   4. A 35-year-old with an endometrial polyp and abnormal bleeding
   5. A 65-year-old with uterine enlargement and abnormal bleeding

1. Dehner LP, Jarzembowski JA, Hill DA. Embryonal rhabdomyosarcoma of the uterine cervix: a report of 14 cases and a discussion of its unusual clinicopathological associations. Mod Pathol. 2012;25(4):602-614.
2. Li RF, Gupta M, McCluggage WG, Ronnett BM. Embryonal rhabdomyosarcoma (botryoid type) of the uterine corpus and cervix in adult women: report of a case series and review of the literature. Am J Surg Pathol. 2013;37(3):344-355.
3. McCluggage WG. Mullerian adenosarcoma of the female genital tract. Adv Anat Pathol. 2010;17(2):122-129.
4. Parham DM, Barr FG. Classification of rhabdomyosarcoma and its molecular basis. Adv Anat Pathol. 2013;20(6):387-397.
5. Rudzinski ER, Teot LA, Anderson JR, et al. Dense pattern of embryonal rhabdomyosarcoma, a lesion easily confused with alveolar rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group. Am J Clin Pathol. 2013;140(1):82-90.
6. Sharma NK, Sorosky JI, Bender D, Fletcher MS, Sood AK. Malignant mixed mullerian tumors (MMMT) of the cervix. Gynecol Oncol. 2005;97:442-445.
7. Soslow RA, Ali A, Oliva E. Mullerian adenosarcomas: an immunophenotypic analysis of 35 cases. Am J Surg Pathol. 2008;32(7):1013-1021.
8. van Roggen JF, van Unnik JA, Briaire-de Bruijn IH, Hogendoorn PC. Aggressive angiomyxoma: a clinicopathological and immunohistochemical study of 11 cases with long-term follow-up. Virchows Arch. 2005;446(2):157-163.
9. Wexler LH, Ladanyi M. Diagnosing alveolar rhabdomyosarcoma: morphology must be coupled with fusion confirmation. J Clin Oncol. 2010;28(13):2126-2128.

Leslie G Dodd, MD
Surgical Pathology Committee
University of North Carolina
Chapel Hill, NC

1. Absence of staining for CD10, WT1, ER, and PR (a)
2. ARMS has a characteristic gene translocation. (b)
3. A 25-year-old with a polypoid lesion protruding through the cervical os (c)