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Vulvar cancer is a rare disease, representing only 3-5% of all tumors of the female genital tract and 1% of all cancers in female (5). Ninety to ninety-five percent of them are squamous cell carcinomas (SCC), and the remaining 5-10% being melanomas, sarcomas and basal cell carcinomas (6). Its annual incidence is 1.5 per 100,000 women per year, increasing constantly with age with the average age at diagnosis being 65-75 years old (7, 8). The disease is most commonly observed in postmenopausal women presenting primarily with localized pruritus, vulvar mass, bleeding, or pain (5, 6).
The prognosis is favorable with a 5 - year survival rate of 70 - 90% for patients with negative nodes compared to 25 - 41 % for those with lymph nodes metastasis (7, 8).
The predominant risk factors for the development of vulvar cancer include increasing age, smoking, immunosuppressive disease and chronic skin diseases of the vulva such as lichen sclerosus, or Vulvar Intraepithelia Neoplasia. However, these conditions can most probably be attributed to an increasing wide variety and number of human papillomavirus (HPV) infections (6, 9).
The patient's age and immunosuppressive state might have predisposed the patient to having the disease. And though no histopathologic diagnosis was made, her intermittent vulvar pruritus was suggestive that she might have a chronic skin disease like lichen sclerosus, which is another risk factor for acquiring vulvar cancer.
Treatment of vulvar cancer used to be primarily surgical, but radiation therapy and, to a lesser extent, chemotherapy have been progressively integrated into the treatment protocol over the past 20 years. Surgery may involve different methods depending on the stage and lymph node involvement (10).
Not all patients who undergo radical vulvectomy necessitates extensive reconstructive operation such as that of the patient. Further, neoadjuvant or adjuvant treatment may be indicated based on stage and individual patient factors. The management for vulvar carcinoma has indeed evolved into an individualized multidisciplinary approach (6, 10).
Those cases wherein large denudated defects are expected in the perineum following radical vulvectomy or perineal surgery in which primary closure would likely result in post-operative dehiscence of the wound incision, are best co-managed with Plastic Surgery for better post-operative outcome. For the patient, a myocutaneous flap was done to cover the vulvar defect with a cutaneous structure having its own non-traumatized blood supply that can produce a healed wound with a normal functioning vulva. This was followed by a prophylactic transverse loop colostomy done by the Colorectal Service to prevent infection in the anal area while the wound is still in the healing process. Post-operatively, the patient had wound dehiscence, which is a common complication of a surgical procedure in vulvar carcinoma. Other possible complications include lymphedema and infection, which did not occur in the patient. (10)
The final histopathology revealed primary cutaneous MEC of the vulva. This should be differentiated from a metastatic salivary gland MEC since the latter usually presents with a more aggressive disease and poorer prognosis. In terms of genetic composition, both harbor CREB Related Transcriptional Co-activator 1 (CRCT1) rearrangements. However, Mastermind Like 2 (MAML2) mutations, which were associated with greater metastatic potential and worse prognosis, were only reported in salivary gland MECs (1, 11). In terms of immunohistochemistry, CK7, PanCK, EMA, carcinoembryonic antigen and p63 gene may be used which are all expected to have positive results for primary cutaneous MEC. However, these markers are considered non-specific and of little clinical use (1, 3). Immunohistochemistry was not done in the patient. But review of systems and physical examination, were not suggestive of a primary salivary gland tumor.
Regardless of the primary site, MECs share distinct histopathological features that allow for its straightforward diagnosis (11). Its unique diagnostic criteria are the predominance of atypical squamous cells or epidermoid cells, scattered or clumped intermediate cells which range from small basal cells with basophilic cytoplasm to larger cells which commonly form clusters with eosinophilic cytoplasm, and cells containing intracytoplasmic mucin without any glandular differentiation. Thus, MEC's distinct triphasic cellular morphology includes epidermoid cells, mucus cells, and intermediate cells (1, 2, 3, 11), which were all seen
This complex composition of MEC explains the unmatched results of the patient's vulvar biopsy and review of slides with that of the final histopathology after the radical vulvectomy, implicating that the SCC found in the the first two pathological studies was just a part of the whole vulvar pathology.
Due to its extreme rarity, more precise diagnosis of MEC remains to be a challenge for the pathologists. The most common mimics of MEC are Adenosquamous Carcinoma (ADS) and SCC. MEC may be erroneously interpreted as SCC or ADS when the epidermoid cell population and keratinization were prominent in the tumor (12). But it can be distinguished from the the SCC or from other mucin producing cells by the presence of three cell types as previously mentioned, and also from ADS by the absence of glandular formation (12, 13). Therefore, Chenevert et al. suggested that thorough search for overlying dysplastic squamous mucosa and increased awareness on the different histopathologic features can improve accurate diagnosis of the disease (13). In addition, obtaining sufficient tissue from different parts of the lesion should be made to be able to have a more precise diagnosis for these rare cases (1, 2).
A clinico-pathologic differentiation of MEC from other vulvar diseases is noteworthy since MEC, are usually more aggressive due to its mucin content, which has a value for the prediction of clinical surveillance. Also, MECs generally have a higher potential for metastasizing to regional lymph nodes than non-mucin-secreting tumors (13). There were reported cases of MEC in unusual locations such as the liver, ovary and cervix, all presented with recurrences and mortalities despite adjuvant chemotherapy, with or without radiation (2, 13, 14). These may signify this type of tumor's aggressive behavior, just like in the patient who presented with a high grade carcinoma, an advanced stage disease and positive lymph node metastasis. Thus, the high grade MEC lesions in other sites having poor prognosis may also hold true for the vulva.
On how a salivary gland tumor appeared in the vulva is unusual and is nonetheless unclear. Two hypotheses may explain its etiopathogenesis. First, due to their similarities in embryonic germ layer origin, histologic structures and functions, salivary glands have been suggested to be derived from sweat glands, which are present in labia majora. Thus it can be postulated that the primary cutaneous MEC of the vulva may have been developed from an ectopic salivary gland derived from a sweat gland (1). However, after thorough examination by the pathologist, no salivary gland was found in the patient's submitted specimen.
Another hypothesis, which is a more plausible explanation for the patient's disease, is that High-Risk Human Papillomavirus (HR-HPV), a known risk factor for vulvar carcinoma, may be involved in the etiology of MEC lesions. In 2013, Isayeva et al. reported that the detection rate of HR-HPV in salivary gland MEC has been increasing over time. Their study had demonstrated the presence of transcriptionally active, biologically relevant, HR-HPV in approximately one-third of MEC. HR-HPV oncoproteins were thought to promote MEC as a later event in multistep carcinogenesis. This could be through the additive impact of the HR-HPV E6 and E7 oncoproteins on overall loss of tumor suppression function (15). Their study broadens the scope of associations between HR-HPV and head and neck neoplasia, which can aid in the understanding of the etiology of MEC in other sites, especially in the vulva. The patient was not tested for HPV DNA. However, on histopathology, she presented with koilocytes which are squamous epithelial cells that have undergone several structural changes (Figure 17), suggestive of an HPV infection.
Mucoepidermoid carcinoma in salivary glands may be classified into low-, intermediate-, and high-grade, based on scoring of the cystic component, perineural invasion, cellular nuclear atypia and mitotic activity as suggested by the Armed Forces Institute of Pathology (AFIP) / World Health Organiztion (WHO) (3). Applying this grading system to the patient, she was evaluated to have a high grade tumor due to 4 in ten high power fields and presence of nuclear atypia (Figure 11) (Table 2).
AFIP - Armed Forces Institute of Pathology
Table 2. Basis of high-grade lesion of the patient based on MEC Grading System suggested by AFIP (3)
The histological grade, though there is no single grading system accepted universally, is an important survival prognosticator in MEC of salivary gland tumors. The 5-year overall survival (OS) and disease-free survival (DFS) rates of low-grade and intermediate-grade MEC were 93% and 88%, respectively. Whereas the 5-year OS and DFS rates of high-grade MEC were approximately 40-50% and 20-40%, respectively (3). Whether or not this observation is applicable in primary cutaneous MEC of the vulva is currently unknown. Further investigation is warranted to determine the prognosticating role of the histological grading to this type of carcinoma.
Due to the limited number of cases presented, primary cutaneous MEC of the vulva follows no therapeutic algorithm and prognosis pattern. In 2014, Ng et al. presented 20 reported cases of Primary Cutaneous MEC and their treatment outcome. Only two of which were found in the vulva, both presented in post menopausal age such as in the patient. The first underwent wide local excision and was diagnosed as low-grade with longer survival time and had no evidence of disease until death. The other was evaluated to have high grade tumor. She underwent radiation after tumor recurrence and died of tumor with only 2 month survival time (Table 3) (1, 11).
Due to the rarity of the disease, the specific chemotherapy regimen for primary cutaneous MEC of the vulva has not yet been established. The reported chemotherapy regimens for MEC found in uncommon sites were based on the standards for salivary gland tumors (2). Reported cases and previous experiences help determine the treatment choice of clinicians. For this case, the patient was given a platinum based chemotherapy with Paclitaxel, following the recommended treatment for advanced stage vulvar carcinoma, which are also used in salivary gland MECs (16).
Currently, some researchers are suggesting that molecular targeted chemotherapy including monoclonal antibodies, anti-epidermal growth factor receptor (EGFR) or anti vascular endothelial growth factor (VEGF) based regimen might be a promising strategy for the treatment of MEC in salivary glands (2). In a study by Nakano et al and Lujan et al, all high-grade MECs were found to have either HER2 or EGFR gene copy number gains and were associated with poorer prognosis. In contrast, the vast majority of low- and intermediate-grade MECs were negative for such genetic abnormality (3, 19). A model of CRTC1-MAML2-induced activated AREG-EGFR signaling was presented by Chen et al in 2014, suggesting that inhibiting AREG-EGFR signaling with anti-EGFR-targeted therapies, including antibodies that interfere with ligand-EGFR interaction or small molecules that block EGFR tyrosine kinase may block MEC carcinogenesis (Figure 18) (18). This EGFR signaling was also identified in a recent study by Yan et al, as a promoter of carcinogenesis in MEC, together with p53 mutations. These observations suggest an overall role of EGFR in the pathogenesis of MEC and implicate the pathway as a possible therapeutic target (20).
On the other hand, angiogenesis is an important part in many biological processes, both in physiological and in pathological conditions. Literatures show that the growth and metastasis of solid tumors are dependent on the formation of new blood vessels. And among the known angiogenic factors, it is the vascular endothelial growth factor (VEGF) that has a central role in controlling the neoplastic angiogenic process. VEGF was found to be significantly more expressed in high grade salivary gland malignancies and its high levels predict a poor prognosis. The use of anti-VEGF may lead to regression of existing tumor vasculature and inhibition of new and recurrent tumor vessel growth, both leading to reduction in tumor size and inhibition of tumor growth (21, 22).
These treatment options are more expensive and less available as compared to the more commonly used chemotherapy drugs. However, with further studies, these may eventually lead to good treatment outcome for patients having this rare type of disease.
At present, the patient is ambulatory, voiding freely and with good wound healing. She had her first cycle of chemotherapy with good tolerance and will have her radiation therapy after completion of 6 cycles of chemotherapy. The Colorectal Service will take down her colostomy after 6-8 months.
Table 3. Demographics, clinical pattern and treatment outcomes of reported cases of Primary Cutaneous MEC (11)
This report of a 68 year old woman with vulvar pruritus is an additional case to few incidences of vulvar carcinoma with an extremely rare pathology. Due to limited studies available, tailored management should still be investigated. However, MEC in other primary sites, especially high grade tumors, are reported to be aggressive, have a predilection for metastasizing to lymph nodes and have high risk for recurrence even without any risk factors. For these reasons, the patient was started on adjuvant chemoradiotherapy, as in other histopathologic diagnosis of advanced stage vulvar carcinoma. Other treatment options like monoclonal anti-body, anti-EGFR and anti-VEGF may play a role in the management of this rare case and if possible, should be considered to the patient.
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