Introduction
The overwhelming majority of cervical cancer cases will be either squamous cell or adenocarcinoma. In a National Cancer Database (NCDB) study of cervical cancer in the United States, 79.5% of cervical cancer cases consisted of the squamous cell subtype, 19.0% were adenocarcinoma, and 1.5% were high-grade neuroendocrine carcinoma. These estimates round to 100% meaning that there are very few cervical cancer cases of the ultra-rare subtypes such as rhabdomyosarcoma, clear cell carcinoma, adenoid cystic carcinoma, or verrucous carcinoma. In fact, the majority of the literature for these subtypes comes from case reports of single patients, small case series that span decades, and population database studies whose data sources lack the details necessary to make any specific treatment recommendations. In this chapter, we will review these ultra-rare subtypes and attempt to make recommendations for treatment based on the current literature as well as drawing from similar histologic subtypes from other primary tumor sites (for clear cell cervical cancer, see Chapter 16 on clear cell vaginal cancer).
Cervical rhabdomyoscarcoma
Rhabdomyosarcoma is a malignancy of the skeletal muscle phenotype with incomplete myogenesis. It is the most common pediatric soft tissue tumor accounting for 50% of the soft tissue malignancies and 3%–4% of all childhood cancers. In children, these tumors are most commonly found in the head and neck region, specifically within the orbit. The genitourinary tract may be the primary site in 20% of pediatric cases; however, most of these will be seen in the bladder or vagina with the cervix as site of origin exceedingly rare. Rhadbomyosarcoma accounts for only 1% of all malignancies in adults and only 5% of all soft tissue sarcomas. Rhabdomyosarcoma of the cervix most commonly occurs in the second and third decades of life in contrast to the more common vaginal rhabdomyosarcoma that occurs more frequently in the first decade of life. The incidence of these tumors in adults is exceedingly rare. Over a 40-year period at Memorial Sloan Kettering Cancer Center, only 8 cases of adult cervical rhabdomyosarcoma were observed and only 6 cases were seen in a 30-year period at MD Anderson Cancer Center. Rhabdomyosarcoma accounts for < 0.5% of all cervical cancers.
For rhabdomyosarcoma of the lower genital tract (cervix, vulva, and vagina), the 5-year overall survival rate approaches 70%. Improved overall survival may be seen with younger age, localized disease with no distant or lymph node metastases, and in patients embryonal histology. The Intergroup Rhabdomyosarcoma Study Group (IRSG) classifies rhabdomyosarcoma into three histologic subtypes: embryonal, alveolar, and undifferentiated. The alveolar and undifferentiated subtypes have a much poorer prognosis than the embryonal subtype. Fortunately, three-fourths of cervical rhabdomyosarcoma will be the embryonal subtype. The embryonal subtype can be further classified into classic, botyroid, and spindle cell subtypes. The majority of cervical cancer patients with rhabdomyosarcoma will have the botyroid subtype.
The only known risk factors for rhabdomyosarcoma are genetic in nature. For rhabdomyosarcoma at all sites, there are well-known links to familiar hereditary syndromes such as Li–Fraumini syndrome, Neurofibromatosis type 1, Beckwith–Wiedemann syndrome, Costello syndrome, and Noonan syndrome. For patients with cervical rhabdomyosarcoma, DICER1 syndromes have been most frequently reported. Other features of DICER1 syndrome include higher rates of pleuropulmonary blastoma, pediatric cystic nephroma, thyroid multinodular goiter, ovarian Sertoli-Leydig tumor, and Wilm’s tumor. The relationship between cervical rhabdomyosarcoma and human papilloma virus (HPV) is unknown but thought to be unlikely.
Grossly, the tumors are often polypoid with an edematous and fleshy cut surface. In some cases, multiple polyps may be present giving a botryoid/grape-like appearance. The most common histologic subtype of rhabdomyosarcoma in the cervix is of the embryonal-type. Microscopically they have a polypoid appearance lined by squamous or glandular epithelium ( Fig. 15.1 A ). The stroma is edematous with alternating hypocellular and hypercellular areas. The condensation of the spindle cells beneath the surface epithelium results in the so-called cambium layer. The tumor cells are composed of short spindle cells and often surround entrapped endocervical glands. Rhabdomyoblasts/strap cells with cross-striations are variably present ( Fig. 15.1 B). Brisk mitotic activity and apoptotic bodies are usually present.
The less common alveolar rhabdomyosarcoma is composed of loosely packed cells with high N/C ratio growing in an alveolar pattern, separated by collagenous stroma. The central discohesion with adherence to the periphery of the nests results in the alveolar pattern. The pleomorphic rhabdomyosarcoma subtype is characterized by large multinucleated cells with bizarre atypia and rhabdomyoblasts are variably present. Rhabdomyosarcomas are positive for desmin, myogenin ( Fig. 15.2 A ) and myoD1 ( Fig. 15.2 B). Alveolar rhabdomyosarcoma can express keratin markers focally.
The differential diagnosis of rhabdomyosarcoma is vast as it can mimic many tumors. The primary differential is an inflamed benign cervical polyp. The inflammation may obscure the rhabdomyoblasts resulting in a benign diagnosis and this is a known pitfall. Distinguishing embryonal rhabdomyosarcoma from adenosarcoma with sarcomatous overgrowth and heterologous rhabdomyoblastic differentiation is particularly challenging, and may not be possible in some cases. The presence of phyllodes-like growth pattern and presence of leaf-like glands with periglandular cuffing will favor a diagnosis of adenosarcoma. Carcinosarcoma with heterologous rhabdomyoblastic differentiation is also in the differential but the presence of malignant glandular component will facilitate the diagnosis. Other sarcomas such as leiomyosarcoma and undifferentiated sarcoma can be differentiated from rhabdomyosarcoma by doing immunohistochemical stains to confirm skeletal muscle differentiation in the latter. Also to be considered in the differential diagnosis is SMARCA4-deficient undifferentiated sarcoma. For these cases, demonstrating loss of SMARCA4 by immunohistochemistry is necessary.
Embryonal rhabdomyosarcoma may show both somatic and germline mutations of DICER1 . These mutations are less common in adenosarcoma; hence absence makes embryonal rhabdomyosarcoma less likely. Alveolar rhabdomyosarcoma shows recurring translocation in t(2;13)(q35;q14) and less commonly t(1;13)(q36;q14) which fuse the FOXO1 gene on chromosome 13 with either PAX3 on chromosome 2 or PAX7 on chromosome 1 , respectively.
The classic description of cervical rhabdomyosarcoma is a friable, polypoid tumor with a “bunch of grapes” appearance. In fact, the term “botyroid” comes from the similar Greek word meaning “bunch of grapes.” Most patients will present with vaginal bleeding or discharge. Other patients may experience vaginal mass or protruding cervical polyps.
For all abnormal cervical masses, a biopsy of the tumor should be performed using biopsy forceps. For pediatric and adolescent patients, there should be a high suspicion for a rare type of cervical tumor as the more common HPV-associated cervical cancers (squamous, adeno, and adenosquamous carcinomas) are almost never seen in women under the age of 18 years old. For adult women, the differential diagnosis includes the more common HPV-associated cervical cancers as well as other benign lesions and rare malignancies.
After a pathologic diagnosis has been established, all patients should undergo imaging. We recommend computed tomography (CT) scan of the chest, abdomen, and pelvis or positron emission tomography (PET) scan to evaluate for metastatic disease and magnetic resonance imaging (MRI) of the pelvis to evaluate extent of the primary cervical tumor. A prospective study showed PET scan increases detection of lymph node and bone metastases. However, the same study showed CT scan is better for detection of lung metastases.
There are multiple staging systems that may be considered for patients with cervical rhabdomyosarcoma. For gynecologic oncologists, the most well-known and commonly utilized system will be from the International Federation of Gynecology and Obstetrics (FIGO). The 2018 staging system allows for clinical, pathologic, and radiologic factors to be considered when assigning stage ( Table 15.1 ). Outside of gynecology, the most frequently used surgico-pathologic staging schema is the Clinical Group (CG) system developed by the IRSG. This system incorporates degree of tumor spread at diagnosis and the amount of disease remaining after initial surgery ( Table 15.2 ). More recently, the IRSG developed a TNM-type system that accounts for other important prognostic factors ( Table 15.3 ).
| Stage | Description |
|---|---|
| I | The carcinoma is strictly confined to the cervix (extension to the uterine corpus should be disregarded) |
| IA | Invasive carcinoma that can be diagnosed only by microscopy, with maximum depth of invasion < 5mm a |
| IA1 | Measured stromal invasion ≤ 3 mm in depth |
| IA2 | Measured stromal invasion > 3 mm and ≤ 5 mm in depth |
| IB | Invasive carcinoma with measured deepest invasion > 5 mm (greater than Stage IA), lesion limited to the cervix uteri |
| IB1 | Invasive carcinoma > 5 mm depth of stromal invasion, and ≤ 2 cm in greatest dimension |
| IB2 | Invasive carcinoma > 2 cm and ≤ 4 cm in greatest dimension |
| IB3 | Invasive carcinoma > 4 cm in greatest dimension |
| II | The carcinoma invades beyond the uterus, but has not extended onto the lower third of the vagina or to the pelvic wall |
| IIA | Involvement limited to the upper two-thirds of the vagina without parametrial involvement |
| IIA1 | Invasive carcinoma ≤ 4 cm in greatest dimension |
| IIA2 | Invasive carcinoma > 4 cm in greatest dimension |
| IIB | With parametrial involvement but not up to the pelvic wall |
| III | The carcinoma involves the lower third of the vagina and/or involves pelvic and/or para-aortic lymph nodes b |
| IIIA | The carcinoma involves the lower third of the vagina, with no extension to the pelvic wall |
| IIIB | Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney (unless known to be due to another cause) |
| IIIC | Involvement of pelvic and/or para-aortic lymph nodes (including micrometastases), irrespective of tumor size and extent (with r and p notations) b |
| IIIC1 | Pelvic lymph node metastasis only |
| IIIC2 | Para-aortic lymph node metastasis |
| IV | The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. (A bullous edema, as such, does not permit a case to be allotted to Stage IV.) |
| IVA | Spread to adjacent pelvic organs |
| IVB | Spread to distant organs |
| International Federation of Gynecology and Obstetrics (FIGO) staging of cancer of the cervix uteri (2018). | |
| When in doubt, the lower staging should be assigned. | |
a Imaging and pathology can be used, where available, to supplement clinical findings with respect to tumor size and extent, in all stages.
b Adding notation of r (imaging) and p (pathology) to indicate the findings that are used to allocate the case to Stage IIIC. Example: If imaging indicates pelvic lymph node metastasis, the stage allocation would be Stage IIIC1r, and if confirmed by pathologic findings, it would be Stage IIIC1p. The type of imaging modality or pathology technique used should always be documents.
| Clinical group | Extent of disease/surgical result |
|---|---|
| I | A: Localized tumor, confined to site of origin, completely resected |
| B: Localized tumor, infiltrating beyond site of origin, completely resected | |
| II | A: Localized tumor, gross total resection, but with microscopic residual disease |
| B: Locally extensive tumor (spread to regional lymph nodes), completely resected | |
| C: Locally extensive tumor (spread to regional lymph nodes), gross total resection, but microscopic residual disease | |
| III | A: Localized or locally extensive tumor, gross residual disease after major resection (≥ 50% debulking) |
| IV a | Any size primary tumor, with or without regional lymph node involvement, with distant metastases, irrespective of surgical approach to primary tumor |
a Although current Children’s Oncology Group (COG) trials include all patients with metastatic disease in the high-risk category, selected patients with favorable site, histology/molecular features (embryonal or alveolar, and FOXO1 fusion-negative), and age (under age 10) with limited metastases may have better outcomes with VAC therapy (vincristine, actinomysin D, and cyclophosphamide) or intensified treatments such as those in the completed ARST0431 protocol.
| Stage | Sites | Tumor | Size | N | M |
|---|---|---|---|---|---|
| 1 | Orbit Head and neck a Genitourinary b Biliary tract | T1 or T2 | A or B | Any N | M0 |
| 2 | Bladder/prostate Extremity Cranial Paramenindeal Other c | T1 or T2 | A | N0 or Nx | M0 |
| 3 | Bladder/prostate Extremity Cranial Parameningeal Other c | T1 or T2 | A or B | N0 or N1 | M1 |
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