Clinical case
A 62-year-old woman presents to her general gynecologist with a complaint of right-sided vulvar itching and discomfort over the past 2 months. She is an otherwise healthy person who receives age-appropriate, routine health maintenance, and screening. She notes the vulvar discomfort is pronounced with vaginal intercourse. The patient does have a history of a right-sided Bartholin gland infection in her 40s, which was treated with incision and drainage and Word catheter placement ( Fig. 18.1 ). On exam, the gynecologist notes a 2 cm firm, indurated nodule located at 8 o’clock in the labia minora, just cranial to the introitus. The mass is tender to palpation. The remainder of the exam is unremarkable. The clinician does not appreciate any palpable lymphadenopathy in the groins bilaterally. The clinician diagnoses a Bartholin gland abscess, and a plan for Bartholin gland marsupialization is made. In the OR, the surgeon incises the overlying epithelium. Minimal fluid is expressed. A firm, whitish nodule measuring approximately 3 cm is appreciated in the area of the suspected abscess. This nodule bleeds easily to minimal palpation, and a biopsy is taken. The procedure is aborted, given the unexpected intraoperative findings. Pathology demonstrates a Bartholin gland adenocarcinoma. What are the next steps in management? How might the treatment approach to Bartholin gland carcinoma differ from treatment of more common vulvar carcinomas?
Epidemiology
Vulvar cancer is a rare disease which accounts for 5% of all gynecologic malignancies. Approximately 6000 women are diagnosed with vulvar cancer annually. Among vulvar cancers, Bartholin gland carcinomas are rarer still, accounting for 1%–7% of all vulvar tumors and less than 1% of all gynecologic cancers. The Bartholin gland (also known as Bartholin’s gland, or greater vestibular gland) was first described by the Danish anatomist Caspar Bartholin in 1675 and has the normal function of providing vulvovaginal lubrication. The Bartholin glands and ducts are located bilaterally at approximately the 4 and 8 o’clock positions in the labia minora, with duct openings just proximal to the introitus, and with an approximate size of 0.5–1 cm. Bartholin gland carcinomas occur in women with a median age of 53 years. The average tumor size at diagnosis is 39 mm.
Approximately 17% of all patients are diagnosed with stage I disease, and 28% are diagnosed with stage II disease. Another 32% of patients are found to have stage III disease, in which disease has reached the inguinofemoral lymph nodes and 23% of patients are diagnosed with stage IV disease. Among patients who undergo primary surgical treatment, 5-year survival ranges from 70% to 93%.
There are no known etiologies or risk factors for Bartholin gland carcinomas. Prior history of a Bartholin gland abscess or cyst does not seem to be a risk factor for Bartholin gland carcinoma. HPV has been isolated at the site of some Bartholin gland carcinomas, and, in the case of squamous cell carcinomas HPV infection may have an etiological role.
Pathology
Bartholin gland carcinomas encompass a broad variety of histologic patterns, best conceptualized by knowing the histology of the Bartholin gland. The gland is composed of mucinous epithelial lined glands that drain via ducts lined by squamous and transitional cell epithelium. As such, different histotypes may arise from their respective cell lineage, including: squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, adenoid cystic carcinoma, transitional cell carcinoma, small cell neuroendocrine carcinoma, Merkel cell carcinoma (MCC), epithelial-myoepithelial carcinoma, and lymphoepithelioma-like carcinoma.
Gross description
The mean size is 3.8 cm, with a reported standard deviation of approximately 2 cm. The tumors may either have an ulcerated surface or be deep seated with smooth overlying surface.
Microscopic description
As these are rare tumors and the Bartholin gland may be secondarily involved by vulvar tumors, histologic criteria for diagnosis must be met to determine if the carcinoma is a primary from the Bartholin gland. These criteria are: (1) histology of the tumor is compatible with a Bartholin gland origin, (2) there is a transition from normal Bartholin gland elements to tumor and (3) no evidence of other primary tumor in the adjacent structures. In practice, not all criteria are met in a given case and sometimes distinction of a primary tumor from secondary involvement may be challenging. Squamous cell carcinoma is the most predominant histology, comprising approximately 50% of all Bartholin gland carcinomas, followed by adenocarcinoma ( Fig. 18.2 ) and adenoid cystic carcinoma.
All carcinomas that arise in the Bartholin gland show similar morphology to their counterparts elsewhere in the body. Squamous cell carcinomas, for example, show similar histology to that of squamous cell carcinomas from other sites, varying in keratinization and cytologic atypia.
Adenoid cystic carcinomas show similar histology to that in the salivary gland, with uniform small cells arranged in cords and nests with an overall cribriform and cystic appearance, filled with an acellular basement membrane-like material ( Fig. 18.3 ). Perineural and lymphovascular invasion are characteristic findings. Immunohistochemistry shows positivity for c-kit (CD117) and p63, with the latter showing staining in the myoepithelial component.
Neuroendocrine carcinomas involving the Bartholin gland are either small cell carcinomas or Merkel cell carcinoma. Small cell carcinoma has monotonous small cells, ovoid hyperchromatic nuclei with scant cytoplasm ( Fig. 18.4 ), and brisk mitotic/apoptotic activity with foci of necrosis. Some small cell carcinomas of the Bartholin gland have exhibited distinct lobular architecture and/or Flexner–Wintersteiner rosette-like structures. These findings may represent a characteristic histology for small cell carcinomas arising in this area. MCC has a similar morphologic appearance to small cell neuroendocrine carcinoma ( Fig. 18.5 ) but has a different immunophenotype from the latter.
Ancillary testing
As some Bartholin gland carcinomas are HPV associated, they are diffusely positive for p16 immunostain, as well as for HPV by in-situ hybridization. Adenoid cystic carcinoma shows NFIB rearrangement in approximately two-thirds of cases. Merkel cell carcinomas express CK20, CAM5.2 and neurofilament in a paranuclear dot-like or ring-like pattern. MCC are positive for Merkel cell virus polyoma virus, which can be tested for by immunohistochemistry. Small cell carcinomas are typically negative for CK20 and neurofilament. MCC are also distinguished by differing driving viral infections, as previously mentioned.
Differential diagnosis
The differential diagnosis includes benign cysts, abscess, and endometriosis, all of which can be readily distinguished from malignant tumors. Glandular mimics may include hyperplasia or adenoma, but as these are benign lesions, there is no accompanying atypia or mitotic activity. Once a neoplasm has been diagnosed, it needs to be determined if the neoplasm represents metastasis or extension to the vulva from another primary site. Following the previously mentioned histologic criteria for will help rule in or rule out the tumor as a primary Bartholin gland neoplasm.
Diagnosis and work-up
The differential diagnosis of Bartholin gland carcinomas includes benign etiologies, such as Bartholin gland abscess, cyst or vulvar endometriosis; infectious etiologies such as syphilis and chancroid; and other vulvar cancers such as vulvar melanoma, sarcoma and squamous cell carcinoma of the overlying skin. Given the numerous benign etiologies on differential diagnosis and the rarity of these tumors, diagnosis of Bartholin gland carcinoma is often delayed. Frequently patients experience vague or modest symptoms for months, only seeking care when symptoms become more severe or when they are evaluated during routine health maintenance visits. The most common symptom at presentation is a vulvar mass, in 54% of women, followed by pain (9%), bleeding (3%), and burning sensation (2%). As mentioned, prior history of a Bartholin gland abscess or cyst does not seem to be a risk factor for Bartholin gland carcinoma; however, it may add to the diagnostic complexity, as a Bartholin gland carcinoma is often confused with a cyst or abscess, which may be the leading differential in a patient with this history.
Physical exam findings frequently include a palpable, firm mass which may be fixed to the underlying tissue ( Table 18.1 ). Bartholin gland carcinoma may bleed easily when palpated, a finding that may help distinguish it from other, benign etiologies.
| Physical exam | Complete physical exam with pelvic and rectovaginal examinations |
| Laboratories | CBC Liver function tests Renal function tests HIV testing |
| Imaging | PET or CT scan to evaluate for metastatic disease MRI pelvis for surgical or radiation planning |
| Additional testing | Biopsy of primary lesion HPV testing and cervical cytology as indicated |
When a Bartholin gland carcinoma is suspected, careful physical exam is the most important first step in evaluation. Care should be taken to evaluate the size of the mass and its involvement of adjacent structures such as the vagina, urethra, and anus or rectum. Lesions which are fixed and immobile may involve surrounding structures. Groins should be evaluated bilaterally for signs of inguinofemoral adenopathy.
Imaging may be utilized on an individual basis, depending on the tumor’s characteristics on physical exam and the concern for nodal metastasis or extension to surrounding structures. This is particularly helpful when counseling patients on the anticipated extent of surgical resection. Imaging is recommended for patients who present with larger tumors (> 4 cm), have palpably enlarged lymph nodes, have symptoms which suggest metastatic involvement of the lower urinary tract or bowel, or who are not otherwise surgical candidates and for whom non-surgical management is planned. Imaging modality may be selected depending on the clinical scenario. Magnetic resonance imaging (MRI) is most helpful in determining local lymph node metastasis, as well as tumor extension into surrounding structures. Imaging outside of the pelvis with computed tomography (CT) is also useful in evaluating for distant metastases. Positron emitting tomography is utilized by some clinicians, though the clinical benefit over CT is debatable. Finally, exam under anesthesia with or without cystourethroscopy and proctoscopy may be required to evaluate for involvement of the lower urinary tract, bowel, and in cases where patient discomfort obviates adequate examination. Advances in imaging, particularly the use of MRI, to characterize extent of disease has obviated this practice in most cases, however.
While a Bartholin gland carcinoma may be suspected on presurgical evaluation, the diagnosis requires pathologic evaluation. The first diagnostic criteria for Bartholin gland carcinomas was proposed in 1897 by Honan and required that the following be met: the tumor is located in the area of the Bartholin gland, the tumor is located deep to the labia majora, the overlying skin is intact, the histologic type of tumor is consistent with that seen in Bartholin gland carcinoma, there is a transition from normal to invasive carcinoma in the specimen, and there is no evidence of a primary tumor at another site (i.e., the Bartholin gland carcinoma does not represent a metastasis). Given the burdensome extent of these criteria, they were simplified in 1971 by Chamlian and Taylor to include the following: the tumor invades the area histologically matching the Bartholin gland, it has areas which transition from tumor to normal in the sample, and there is no evidence of a primary tumor elsewhere in the vulva.
Staging system
Bartholin gland carcinomas are classified as vulvar cancers, and their staging follows FIGO and AJCC staging systems for cancers of the vulva ( Table 18.2 ). Staging involves a combination of clinical and surgical factors. Clinical factors include tumor size, local extension, gross lymph node involvement, and distant metastases detected by imaging. Surgical factors may include microscopic lymph node metastases, and depth of invasion. The staging system is summarized in the table below.
| Primary tumor (T) | ||
|---|---|---|
| T category | FIGO stage | T criteria |
| TX | Primary tumor cannot be assessed | |
| T0 | No evidence of primary tumor | |
| T1 | I | Tumor confined to the vulva and/or perineum. Multifocal lesions should be designated as such. The largest lesion or the lesion with the greatest depth of invasion will be the target lesion identified to address the highest pT stage. Depth of invasion is defined as the measurement of the tumor from the epithelial-stromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion. |
| T1a | IA | Lesions more than 2 cm, or any size with stromal invasion of more than 1 mm, confined to the vulva and/or perineum |
| T1b | IB | Lesions more than 2 cm, or any size with stromal invasion of more than 1 mm, confined to the vulva |
| T2 | II | Tumor of any size with extension to adjacent perineal structures (lower/distal third of the urethra, lower/distal third of the vagina, anal involvement) |
| T3 | IVA | Tumor of any size with extension to any of the following-upper/proximal two-thirds of the urethra, upper/proximal two-thirds of the vagina, bladder mucosa, or rectal mucosa-or fixed to the pelvic bone |
| T3a | IIIA | Tumor involving the serosa and/or adnexa (direct extension or metastasis) |
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