Successful Treatment of Anal Gland Adenocarcinoma With Combined Modality Therapy

CASE REPORT

A 39-year-old Hispanic man presented to the Jackson Memorial Hospital Emergency Room with hematochezia of 6 months duration. He was diagnosed with hemorrhoids and treated with rubber band ligation twice. He had lost 20 pounds in 6 months and had not had a bowel movement for 12 days. On physical exam, he was pale and noted to have a large low rectal lesion. A computed tomography (CT) scan revealed a large rectal lesion with multiple small perirectal lymph nodes, the largest one measuring approximately 1.6 cm in diameter. A colonoscopy showed a large mass in the lower end of the rectum, and a biopsy revealed mostly necrotic tissue. The mass was excised transanally, and the histological examination revealed a very poorly differentiated adenocarcinoma (Figure 1).

Figure 1.

(A) Poorly differentiated tumor undermining the normal squamous mucosa of the anal canal (hematoxylin and eosin [H&E] 20×). (B) Tumor in the upper left corner and normal anal gland in the lower right corner staining positive for CK7 (CK7 immunoperoxidase stain, hematoxylin counterstain, 4×). (C) Tumor (left) growing underneath normal, rectal-type mucosa (H&E, 20×); (D) Poorly differentiated tumor cells show strong membrane immunoreactivity for CK7 (CK7 immunoperoxidase stain, hematoxylin counterstain, 20×).

Immunohistochemical (IHC) staining demonstrated poorly differentiated cells without mucin infiltrating submucosa. IHC staining revealed CK7 positive, CK20, CDX2, p63, and PSA negative cells consistent with anal gland adenocarcinoma (AGA). One month after local excision, an anorectal sonogram showed perirectal lymphadenopathy, and positron emission tomography (PET)/CT demonstrated intense ¹⁸F-deoxyglucose (FDG) uptake at bilateral internal iliac chain lymph nodes (maximum standard uptake value [SUV] 12.0) and at bilateral perirectal/presacral regions (max SUV 10.9) consistent with a high-grade tumor.

Concurrent chemoradiotherapy followed by surgical resection was planned. Due to the extent of disease, the patient was immediately started on chemotherapy with oxaliplatin (130 mg/m² every 3 weeks) and capecitabine (CAPOX; 825 mg/m² twice daily for 14 days every 3 weeks) while waiting for radiation planning. After two cycles, the patient was started on intensity-modulated radiotherapy to the rectal region (total dose 51.25 Gy in 25 fractions in 5 weeks) with concurrent capecitabine (825 mg/m² twice daily for 2 weeks followed by 1 week rest) and oxaliplatin (50 mg/m² weekly on weeks 1, 2, 4, and 5).

Two months after completion of concurrent chemoradiotherapy, a repeat CT scan showed resolution of the perirectal mass and the lymphadenopathy. A complete laparoscopic restorative proctectomy was then performed with a combined abdominal and transanal approach, with the resulting pathology showing adenocarcinoma in only one lymph node out of six lymph nodes resected. The surgical resection margins were negative for malignancy. The patient received four additional cycles of capecitabine/oxaliplatin postoperatively. PET/CT and colonoscopy showed no evidence of disease 7 months after the surgery. The patient's ileostomy was reversed, and he is currently disease-free 21 months after the initial diagnosis.

DISCUSSION

The incidence of anal cancer in the United States is estimated at 5300 cases/year, accounting for approximately 1.9% of all digestive system cancers.¹ Adenocarcinomas make up 2.9%–10% of anal cancers.² Anal adenocarcinoma (AA) is an aggressive disease that is associated with worse overall survival and a higher rate of local and distant recurrences than anal squamous cell cancer.^3,4 AA can be subclassified further by both histology and anatomic location as follows: colorectal type, perianal mucinous type, and anal gland type, with colorectal making up the majority of cases^5,6 Distinction of these subtypes may be clinically important since the treatment for colorectal type is well established while the ideal management for anal gland and mucinous types is still unknown.

Immunohistochemical (IHC) staining with cytokeratins (CK) 7, 20, and CDX2 can be used to distinguish the subtypes of anal adenocarcinomas. AGA is an extramucosal, intramural tumor that stains positive for CK7 and negative for CK20 and CDX2, as opposed to mucinous adenocarcinoma, which is CK7+/CK20+, and rectal-type adenocarcinoma, which is CK7−/CK20+/CDX2+. AGA is also negative for p63 and PSA.^6,7

While long-term survival rates between 30% and 60% were reported in AA patients treated with pre-/postoperative chemoradiotherapy incorporating 5-fluorouracil (5-FU) (± mitomycin or cisplatin), subtypes of the adenocarcinomas were not reported in neither of these retrospective studies.^4,8–10

The clinical presentation of AGA is similar to the presentation of benign lesions of the anus, leading to a delay in diagnosis and treatment. In one case series, erroneous diagnoses were reported to lead to an average delay of 14 months between the patients' first presentation to a physician and AGA diagnosis.¹¹ This was also true for the patient presented above.

The incidence of AGA is likely overestimated in the literature, as there is not an exact histologic definition of AA, and most studies did not incorporate IHC staining to differentiate AA from rectal adenocarcinoma. The largest series included 52 cases based on a questionnaire and no histologic review,² whereas in the only other large study (21 cases), all anal extramucosal adenocarcinomas were assumed to be originated in anal glands/ducts.¹¹ In our case, though the histology was not fully consistent with AGA as per the definition proposed by Hobbs et al,⁷ it was felt to be a case of a poorly differentiated AGA based on its IHC profile and on the tumor's undermining growth pattern beneath the squamous mucosa as well as the rectal mucosa.

Due to its rarity, there is no standard treatment for AGA. Although various retrospective studies have reported promising results after combined multimodality therapy (CMT) with concurrent chemoradiotherapy and surgical resection,^4,10 this may primarily be due to inclusion of patients with rectal adenocarcinoma into the study cohorts, as IHC staining was not performed to exclude rectal adenocarcinoma. While 5-FU has been the most commonly used chemotherapeutic agent used in these series—either alone or in combination with mitomycin or cisplatin—we elected to use a more aggressive regimen (CAPOX concurrent with radiation) due to the extensive nodal involvement.

As anal glands are histologically and embryologically different than anal squamous cell epithelium, we assumed that mitomycin would not be as efficacious as a platin. On the other hand, capecitabine is an oral prodrug that is converted to 5-FU and mimics continuous 5-FU infusion. Despite promising phase II data with preoperative concurrent chemoradiotherapy with CAPOX in patients with locally advanced rectal carcinomas demonstrating pathological complete remission rates between 10% and 23%,^12,13 addition of oxaliplatin to preoperative 5-FU or capecitabine-based chemoradiotherapy in locally advanced rectal cancer did not significantly improve pathologic response in two phase III trials.^14,15 These have been reported in full.¹⁵

Response assessment in our case was difficult since the patient had undergone a transanal excision of the tumor prior to the initiation of therapy; the finding of tumor in only one lymph node in the pathology specimen, as opposed to the multiple FDG-avid lesions evident in PET/CT prior to therapy, suggests that the patient had a good response to preoperative chemoradiotherapy with CAPOX.

We believe that until further studies are available, patients with AGA should be treated with combined multimodality therapy. CAPOX appears to be an active chemotherapy regimen for treatment of AGA.