Thirty cases of intestinal-type adenocarcinoma of the vulva or vagina have been reported. The countries and races are diverse, with a mean age of 54.8 (31–80) years (Table 2) [3–30]. This is the first report of primary intestinal-type adenocarcinoma of the vulva with high TMB accompanied by many cancer-associated mutations identified by gene panel testing.
Symptoms of vulvar intestinal-type adenocarcinoma often include pain, itching, and bleeding. In the early stage, as in the present case, the patient may present only with a mass (Table 2). Histopathologically, some tumors are known to resemble colorectal villous adenoma [31]. It is also necessary to exclude metastatic gastrointestinal cancers, such as metastatic colorectal cancer. For diagnosis, IHC is important. Typically, the normal intestinal epithelium is CK7 negative, CK20 positive, and CDX2 positive. Most colorectal cancers are CK7 negative, CK20 positive, and CDX2 positive, while rectal cancers are somewhat more CK7 positive [32]. The present case was also a CK7-positive intestinal-type adenocarcinoma. In previous reports, among 20 cases in which IHC for CK20 and CK7 were performed, 19 cases (95%) were positive for CK20, and 13 cases (65%) were positive for CK7 were positive (Table 2). CDX2 is expressed in the mucosal epithelium from the duodenum to the rectum and is also positive in intestinal-type adenocarcinoma. In previous reports, IHC for CDX2 was positive in all 7 cases in which it was performed (Table 2). ER and PgR were mostly negative, including in the present case (Table 2). Interestingly, p16 was positive in the present case. In addition to this case, there are 5 reports of IHC for p16, 4 cases of which were positive (Table 2). In another report, reverse transcription polymerase chain reaction for HPV in p16-positive intestinal-type adenocarcinoma of the vulva did not detect HPV type 16, but only low-risk HPV [30]. HPV was negative in the present case. The significance of HPV is unclear and further study is needed. In the present case, p53 is a null pattern, which may reflect the TP53 mutation described below.
Although there is one report of a patient who received neoadjuvant chemotherapy followed by surgery [22], most cases are preceded by surgery (Table 2). The most common surgical techniques are wide local excision and radical vulvectomy, with lymph node dissection in some cases (Table 2). In the present case, the lesion was less than 2 cm grossly and there were no suspicious findings of lymph node or distant metastasis on imaging. Since the depth of invasion could not be accurately determined by biopsy, wide local excision was performed. Whether this case was an in situ or invasive lesion was a moot point: well-defined tumor border and overall cystic appearance argued for a possibility that this was an in situ carcinoma that arose within a pre-existing duct or cystic structure; on the other hand, background non-dysplastic epithelium to prove the existence of preceding benign structure was lacking and the tumor was not situated at the site of known major glands such as Bartholin glands or Skene glands; moreover, the underlying stroma of the dysplastic epithelium showed prominent inflammation, which was worrisome for tissue destruction. We considered it a minimally invasive carcinoma for the staging purpose and assigned it FIGO stage IA. There was a sufficient margin, and no adjuvant therapy was performed. Similarly, adjuvant therapy has not been used in most cases that could have been adequately removed by surgery (Table 2). While there is a report that intestinal-type adenocarcinoma of the vulva has a poor prognosis and that endoscopic follow-up of the colon is mandatory given the high propensity for associated gastrointestinal tumors [19], the course is often gradual, and the prognosis is good (Table 2).
In the present case, several cancer-associated mutations were detected. No other reports have performed gene panel testing for intestinal-type adenocarcinoma of the vulva. TP53, KEL, RB1, RNF43, and PTEN showed high variant allele frequency and were considered clonal mutations. The variant allele frequency for PIK3CA and GNAS were very low and were considered to be subclonal mutations. KRAS mutation was not detected. In the gastrointestinal tract, except the colorectum, cancer that histopathology may show the pattern of intestinal-type adenocarcinoma is common in the esophagus [32], stomach [33], and duodenal papilla [34]. Outside of the gastrointestinal tract, it is most common in the sinuses and is the second most common histologic type of primary sinus cancer [35]. Rare cases have been reported of intestinal-type adenocarcinoma of the tongue [36], gallbladder [37], lung [38], bladder [39], and ureter [40] as primary sites. Regarding genetic mutations in cancers with histopathology showing intestinal-type adenocarcinoma, TP53 and KRAS mutations are often detected. TP53 mutations are particularly frequent in intestinal-type adenocarcinoma of the stomach and primary sinus [35, 41]. In intestinal-type adenocarcinomas of the duodenal papilla, TP53 and KRAS mutations were reported in approximately 40% of cases and RNF43 mutations in approximately 15% of cases (32), Another study reported mutations in KRAS, PIK3CA, and SMAD4 [42]. In intraductal papillary mucinous neoplasms of the pancreas of the intestinal type, the frequency of KRAS mutations is approximately 50% [43]. There is also a report of an intestinal-type adenocarcinoma with KRAS mutation arising from a mature cystic teratoma of the ovary [44]. On the other hand, KRAS and BRAF mutations are rare in intestinal-type adenocarcinomas of the sinus [35].
In the present case, TMB was high, at 13 Mut/Mb. TMB is an indicator of response to immunotherapy [45]. The KEYNOTE-158 study showed that advanced solid tumors with TMB ≥ 10 were more likely to respond to pembrolizumab, an anti-PD-1 antibody [46]. The present case was early stage and not treated with adjuvant therapy, but if the patient were in an advanced stage or had a recurrence, an immune checkpoint inhibitor like pembrolizumab could be a treatment option. Therefore, in intestinal-type adenocarcinoma of the vulva, a gene panel test may be helpful to select treatment options. In addition, although the present case was microsatellite stable, there are reports that microsatellite instability (MSI) -high and mismatch repair deficiency is more frequent in gastric intestinal-type adenocarcinoma [47, 48], and microsatellite status and IHC for mismatch repair protein may also be checked in intestinal-type adenocarcinoma of the vulva.
In conclusion, here we report a case of intestinal-type adenocarcinoma of the vulva with multiple cancer-associated mutations and high TMB. In cases of intestinal-type adenocarcinoma of the vulva, it may be helpful to check tumor mutational burden and gene mutations for treatment selection.