Cervical Embryonal Rhabdomyosarcoma Dr. Robert Soslow New York, NY

Introduction Rhabdomyosarcoma (RMS) is a malignant neoplasm originating from myogenic progenitors cells that show variable stages of skeletal muscle differentiation. RMS is the most common soft tissue tumor found in children, accounting for less than 10% of all pediatric solid tumors. Approximately 20% of pediatric RMSs originate in the genital tract, making this the second most common site. Soft tissue sarcomas in the adult population account for 1% of adult malignancies, and RMS accounts for only a small fraction of these tumors. Although childhood RMS has a predilection for the genitourinary system, this is not the case for adults, making RMS of the adult female genital tract an extremely rare tumor [1, 2, 3] . RMS may be categorized into three major variants based on histomorphology. Identification of the clonal chromosomal translocations t(2;13) and t(1;13) plays an important role in the diagnosis of alveolar rhabdomyosarcoma. It is critical to accurately differentiate the histologic subtypes of RMS since there are significant differences in clinical behavior and prognosis. The most common and generally most favorable variant is embryonal RMS, which encompasses botryoid, spindle cell, and anaplastic histologic subtypes. The other less common histologic variants include alveolar and pleomorphic RMS, which are usually associated with a significantly poorer clinical outcome. Most of the clinical and pathologic data that have been collected on RMS have been through cooperative group trials looking at multimodality treatment for pediatric RMS at multiple anatomic locations, including the female genital tract. The case selected for discussion is very unusual in that the patient is an adult. Clinical characteristics Our group studied the clinical features of adults with rhabdomyosarcomas of the female genital tract [4]. The median age at diagnosis was 48 years (range, 16–69) and the most common presenting symptom was abnormal vaginal bleeding, which included post menopausal bleeding and menometrorrhagia in premenopausal women. The majority of women presented with locoregional disease. Ten women (71%) presented with FIGO stage I/II disease, and 12 (86%) presented with IRSG classification I–III disease. The average size of the tumors at presentation was 34 mm (range, 8–60). The primary site of disease was the cervix in 8 women (53%), making it the most common. The other sites included uterine corpus, 3 (20%); vulva, 2 (13%); fallopian tube, 1 (7%); and ovary, 1 (7%). In this adult population, none of the tumors originated in the vagina. There were 11 (73%) embryonal RMSs, and 8 (73%) of these had classic botryoid features. The other histologic subtypes included 2 (13%) pleomorphic and 2 (13%) alveolar. All cervical lesions were embryonal, and both vulvar lesions were of alveolar histology. There was no distinct pattern of distribution of histologic subtypes at the other gynecologic sites. The majority (80%) of women with embryonal RMS presented with early-stage disease (Intergroup Rhabdomyosarcoma Studies [IRSG] group I); in comparison, 75% of women with non-embryonal RMS presented with advanced-stage disease (IRSG group III/IV). For the entire cohort, the median time to progression was only 9 months and the median disease specific survival was 21 months. The 2-year progression free survival was 15% and the 5-year disease specific survival was 29%. Neither age nor stage correlated with survival. Women with a cervical primary RMS had a significantly increased time to progression compared to women with disease at other gynecologic sites. In addition, women with an embryonal histologic variant had significantly improved progression free survival compared to non-embryonal variants. These survival statistics contrasted sharply with the historically rather positive survival rates in pediatric RMS: 5-year overall survival of 82% compared with 66% for non-embryonal variants and 5-year survival rates of 94% for the botryoid histologic subtype specifically [5]. Morphology Botryoid rhabdomyosarcomas are polypoid tumors with a densely cellular zone of primitive cells in a subepithelial distribution (cambium layer). The substance of the polyps is generally myxoid or edematous, with varying cellularity. The lesional cells are rhabdomyoblasts, which have assorted appearances, ranging from small, round, blue and undifferentiated, to strap-shaped, with eosinophilic cytoplasm and easily appreciated cross striations. Interestingly, cartilaginous differentiation is found in a significant minority of cases. Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer The non-polypoid and infiltrative portions of botryoid rhabdomyosarcomas are histologically indistinguishable from embryonal rhabdomyosarcomas of the usual (non-botryoid) sort. There are commonly cellular zones that contrast with paucicellular zones containing myxoid or edematous matrix. Rarely, cambium layers are found cuffing non-neoplastic endocervical glandular clefts. Like botryoid tumors, these sarcomas contain mixtures of rhabdomyoblasts in different stages of differentiation. Round and spindled cells with brightly eosinophilic cytoplasm are present in nearly every case and are important clues to the diagnosis. Immunohistochemistry The typical immunophenotype includes expression of desmin, muscle-specific actin, myogenin and Myo-D1. These markers are found in 90-100% of RMSs (they are sensitive markers [6, 7, 8, 9]) , but desmin and muscle-specific actin are certainly not specific, as they are commonly found in tissues demonstrating smooth muscle and myofibroblastic differentiation. Myogenin and Myo-D1 are regulatory proteins expressed early in skeletal muscle differentiation and show nuclear localization. In general, the expression of these markers is negatively correlated with differentiation, such that only scattered myogenin positive cells are found in embryonal rhabdomyosarcomas with few strap cells. As will be discussed subsequently, expression of myogenin and Myo-D1 are common to all tumors demonstrating skeletal muscle differentiation, which means that tumors other than rhabdomyosarcoma (e.g. carcinosarcoma containing rhabdomyoblasts) should be excluded before using myogenin immunoreactivity alone to make a confident diagnosis of rhabdomyosarcoma. It should be also be pointed out that small numbers of RMSs have been described to express markers such as CD99 (O13), cytokeratin, S100 and WT1, markers more commonly expressed in histologic mimics of RMS. Diagnosis: Cervical embryonal rhabdomyosarcoma Differential diagnosis The histologic differential diagnosis of embryonal rhabdomyosarcoma in the gynecologic tract in adults [14] includes adenosarcoma, carcinosarcoma, endometrial stromal sarcoma, and leiomyosarcoma. To further complicate matters, adenosarcoma [10, 11, 12], carcinosarcoma and even endometrial stromal sarcoma [13] can demonstrate skeletal muscle differentiation such that isolated microscopic fields are indistinguishable from rhabdomyosarcoma. Myxoid variants of endometrial stromal sarcoma and leiomyosarcoma may resemble embryonal rhabdomyosarcoma, and pleomorphic leiomyosarcoma can appear similar to pleomorphic rhabdomyosarcoma. To diagnose rhabdomyosarcoma and exclude adenosarcoma, one should not find phyllodes-like growth and intraglandular stromal papillae. We make an attempt to exclude stromal-predominant carcinosarcomas by searching carefully for lesional epithelium with a malignant appearance. However, it is generally assumed that some genital pleomorphic rhabdomyosarcomas might represent carcinosarcomas in which the epithelial component is overgrown by stroma or is not sampled. References Hawkins WG, Hoos A, Antonescu CR, et al. Clinicopathologic analysis of patients with adult rhabdomyosarcoma. Cancer. 2001;91:794-803. Ferrari A, Dileo P, Casanova M, et al. Rhabdomyosarcoma in adults. A retrospective analysis of 171 patients treated at a single institution. Cancer. 2003;98:571-580. Little DJ, Ballo MT, Zagars GK, et al. Adult rhabdomyosarcoma: outcome following multimodality treatment. Cancer . 2002;95:377-388. Ferguson SE, Gerald W, Barakat RR, et al. Clinicopathologic features of rhabdomyosarcoma of gynecologic origin in adults, in press, Am J Surg Pathol Arndt CA, Donaldson SS, Anderson JR, et al. What constitutes optimal therapy for patients with rhabdomyosarcoma of the female genital tract? Cancer. 2001;91:2454-2468. Wang NP, Marx J, McNutt MA. Expression of myogenic regulatory proteins (myogenin and MyoD1) in small blue round cell tumors of childhood. Am J Pathol. 1995 Dec;147(6):1799-810. Dias P, Parham DM, Shapiro DN, Webber BL, Houghton PJ. Myogenic regulatory protein (MyoD1) expression in childhood solid tumors: diagnostic utility in rhabdomyosarcoma. Am J Pathol. 1990 Dec;137(6):1283-91. Cui S, Hano H, Harada T, Takai S, Masui F, Ushigome S. Evaluation of new monoclonal anti- Are myogenin and myoD1 expression specific for rhabdomyosarcoma? A study of 150 cases, with emphasis on spindle cell mimics.Am J Surg Pathol. 2001 Sep;25(9):1150-7. Cessna MH, Zhou H, Perkins SL, Tripp SR, Layfield L, Daines C, Coffin CM.Are myogenin and myoD1 expression specific for rhabdomyosarcoma? A study of 150 cases, with emphasis on spindle cell mimics.Am J Surg Pathol. 2001 Sep;25(9):1150-7. Kaku T, Silverberg SG, Major FJ, Miller A, Fetter B, Brady MF.Adenosarcoma of the uterus: a Gynecologic Oncology Group clinicopathologic study of 31 cases. Int J Gynecol Pathol. 1992;11(2):75-88. Zaloudek CJ, Norris HJ. Adenofibroma and adenosarcoma of the uterus: a clinicopathologic study of 35 cases. Cancer. 1981 Jul 15;48(2):354-66. Clement PB. Mullerian adenosarcomas of the uterus with sarcomatous overgrowth. A clinicopathological analysis of 10 cases. Am J Surg Pathol. 1989 Jan;13(1):28-38. Baker PM, Moch H, Oliva E.Unusual morphologic features of endometrial stromal tumors: a report of 2 cases. Am J Surg Pathol. 2005 Oct;29(10):1394-8. Daya DA, Scully RE. Sarcoma botryoides of the uterine cervix in young women: a clinicopathological study of 13 cases. Gynecol Oncol. 1988;29:290-304.