A 48-year-old female with family history of colon, rectal, and lung cancer (Figure 1.), and a past medical history of obesity and type 2 diabetes mellitus, presented in July 2018 with a several-month history of an enlarging pruritic labial mass found to represent a high grade squamous intraepithelial neoplasm for which a radical right partial vulvectomy was performed. Final pathology demonstrated a stage IB squamous cell carcinoma. Due to the presence of bilateral inguinal lymph node enlargement, a bilateral inguinal lymph node dissection was performed which demonstrated that all 15 lymph nodes removed were negative. At follow-up, the patient complained of fecal incontinence. To evaluate this, upper and lower endoscopies were performed which demonstrated a large rectal mass representing adenocarcinoma characterized by a low probability of microsatellite instability and an anal mass representing a second adenocarcinoma. No polyps were encountered.
In January 2019, colonoscopy revealed a large, circumferential, fungating, infiltrative, ulcerative, non-obstructing rectal mass. (Figure 2.) Biopsies of this mass demonstrated adenocarcinoma. (Figure 3.) In February 2019, further staging work-up included an elevated CEA level of 416.9 ng/ml, a CT chest/abdomen/pelvis, and a pelvic MRI. In addition to demonstrating the rectal and anal neoplasms, (Figure 4.) the CT chest/abdomen/pelvis demonstrated a multinodular thyroid, a 1.5cm right adrenal adenoma, a thin walled pulmonary nodule or cyst, bilateral iliac chain lymph node enlargement, a single enlarged portocaval lymph node, and a large ventral hernia. Staging pelvic MRI re-demonstrated the rectal lesion which was noted to be 15.6cm in size, invading 50mm in depth, extending from above the peritoneal reflection down to within 1cm of the anal verge, possibly involving the pelvic floor musculature, posterior cervix, and vaginal cuff. Local lymph node involvement was radiographically suspected. (Figure 5.) Due to concern for local lymph node involvement and extracolonic extension, the patient was clinical stage IIIC (T4b, N1, Mx). The asymptomatic thyroid mass was evaluated via ultrasonography which demonstrated two TI-RADS 5 left-sided thyroid nodules, and a TI-RADS 4 right-sided thyroid nodule. (Figure 6.) Left lobe thyroid biopsies demonstrated papillary thyroid carcinoma. Due to the presence of multiple primaries, genetic testing was performed, and demonstrated heterozygosity for a p.G396D MUTYH mutation. The patient was negative for a multitude of other mutations including APC, MLH1, MSH2, MSH6, PMS2, BRCA 1&2, MEN1, RET, PTEN, and TP53. Counselling was provided regarding associated risks, and early screening colonoscopy for her offspring was recommended.
The presentation of colorectal cancer alongside extracolonic malignancies raises suspicion for germline mutations and familial cancer syndromes. The presentation of our patient raised concern for Lynch Syndrome, Cowden disease, Familial Adenomatous Polyposis (FAP), and MYH-associated polyposis. The presentation of Lynch Syndrome is characterized by the development of colorectal cancers in addition to other extraintestinal cancer, including ovarian cancer. This, coupled with the relatively low number of intestinal polyps seen in Lynch Syndrome, consistent with our patient, further raised suspicion for this diagnosis. However, immunohistochemical stains for MLH1, MSH2, MSH6, and PMS2, which are used to screen for Lynch Syndrome, were negative. Additionally, though the patient did not demonstrate any germline mutations associated with Cowden syndrome, the diagnosis was considered due to her medical history of colon cancer, papillary thyroid cancer, and thyroid structural disease. However, the patient did not meet diagnostic criteria based on clinical history alone. In the current literature, MAP is most commonly diagnosed within patients suspected of having FAP, but without an APC mutation. While Attenuated FAP (AFAP) is characterized by a low number of polyps, absence of an APC mutation, again, excluded this diagnosis. The finding of a p.G396D MUTYH mutation indicated the most likely diagnosis to be MAP. This disorder is genetically defined by a homozygous mutation, and therefore, our patient, by current standards, should only be carrier and should not phenotypically express this typically Mendelian autosomal recessive disorder. However, the finding of this mutation, coupled with the development of characteristic extracolonic malignancies, calls into question the generalizability of this evolving diagnostic standard.
The patient underwent neoadjuvant chemoradiation prior to undergoing a total thyroidectomy with central lymph node dissection. Papillary carcinoma was found within both lobes, and 3 of 9 lymph nodes were positive for associated metastases. Radioactive iodine ablation was planned. A follow-up CT scan in May demonstrated a response by the rectal tumor to neoadjuvant chemoradiation, with a decrease in size of the rectal tumor from 8.7 x 7.7 x 10.7cm to 6.6 x 5.0 x 6.9cm. (Figure 6.) In June, the patient underwent a posterior pelvic exoneration with a total abdominal hysterectomy and bilateral salpingo-oophorectomy. A sigmoid colectomy with en bloc radical vaginectomy and perineal proctectomy were performed. No gross metastatic foci were encountered, and the tumor was noted to be confined to the anorectum. The wound was closed primarily, a pelvic drain was placed, and a ventral hernia repair was performed. A single hyperplastic polyp was found in the colon. In addition to the two separate adenocarcinomas in the anus and rectum, a left ovarian serous implant of psammocarcinoma (Figure 7.) was identified. Scattered foci of low grade serous carcinoma (psammomatous carcinoma) were found within the ventral hernia sac tissue. All twenty-two lymph nodes were negative for malignancy. The patient was discharged on postoperative day 3 after an uncomplicated hospital stay.
The patient was discharged to a skilled nursing facility for continued wound care. Ongoing plans include adjuvant therapy for her anorectal cancer, as well as further therapy to treat her low grade peritoneal primary serous cancer. This patient’s disease was investigated by both our genetics and dermatology departments thoroughly, and was presented at a multidisciplinary conference to discuss the possibility of Cowden Syndrome. They further recommended obtaining genetic testing for her children which is being considered.