Abstract
Background/Aim: Chemoradiation is the recommended initial treatment for locally advanced squamous anal cancer. However, there is still no consensus on the course of treatment for anal canal cancer with distant metastasis, and the significance of surgical resection of distant metastases is also unclear. Case Report: A 48-year-old woman presented to the referral hospital complaining of prolonged bleeding for the past 6 months. On examination, a mass was identified in the anal canal and the upper part of the rectum that was diagnosed as squamous cell carcinoma. Liver, ovarian, and right internal iliac lymph node metastases were found on further examination, and the patient was referred to our department for treatment. Systemic chemotherapy was planned, and six courses of modified FOLFOX6 were administered. After chemotherapy, the liver and right internal iliac lymph node metastases tended to shrink, and no new lesions appeared. Therefore, a total posterior pelvic resection and a bilateral lymph node dissection were performed for the primary tumour and ovarian metastases, and a simultaneous laparoscopic right partial hepatectomy was undertaken for the liver metastases. R0 resection was achieved, and the final diagnosis was T3N3M1a(H) stage IV. The patient remains alive 2 years after the surgery without recurrence. Conclusion: We report a rare case of anal canal cancer with distant metastases who achieved R0 resection after modified FOLFOX6 chemotherapy.
Anal cancer is a rare malignancy, accounting for only 0.5% of new cancer cases annually, and its incidence continues to rise by approximately 2% annually. In the USA, most anal cancers are squamous cell carcinomas, whereas most anal cancers in Japan are adenocarcinomas. Adenocarcinoma accounts for 78.3% of anal canal cancers, whereas squamous cell carcinoma accounts for only 18.0% (1). The recommended initial treatment for anal canal cancer without distant metastases is chemoradiation with mitomycin/5-fluorouracil (FU) or mitomycin/capecitabine combined with radiotherapy (2-4).
According to the Surveillance, Epidemiology, and End Results Program (SEER) database, at the time of diagnosis, in approximately 30% of patients anal cancer has already spread to the inguinal lymph nodes, and 12% have distant metastases (5). Extrapelvic metastases occur in 10%-20% of patients with anal cancer (6), the most common sites being the liver, lungs, and distant lymph nodes. Currently, the National Comprehensive Cancer Network (NCCN) guidelines lack recommendations for the role of surgery in metastatic disease. However, the benefit of resection of hepatic metastases in colorectal cancer is well known. Most series have reported 5-year overall survival rates ranging from 25% to 37%, and median survival ranging from 24 to 40 months following hepatic metastasectomy. The treatment of anal cancer with distant metastases is mainly systemic chemotherapy. The 5-year survival rate of anal canal cancer with distant metastases is 30.5%, and a regimen based on fluoropyrimidines with the addition of cisplatin has been reported to be of some benefit (5). The median overall survival for resected anal canal cancer patients with metastases was reported to be 34 months, which compares favourably with non-resected patients (5).
We here report our experience of a case of squamous cell carcinoma (SCC) anal canal cancer with distant metastases treated with modified FOLFOX6 (mFOLFOX6) followed by resection.
Case Report
A 48-year-old woman presented to the referral hospital with a complaint of prolonged melena for the past 6 months. She underwent a colonoscopy, which revealed a mass lesion at the anal canal (Figure 1A) and upper rectum 15 cm from the anal verge (Figure 1B). The patient was referred to our hospital for multidisciplinary treatment, and the examination and treatment were started. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. This study was performed in accordance with the principles of the Declaration of Helsinki.
Primary tumour and metastatic tumours of anal squamous cell cancer. A) Anal canal; moderate squamous cell carcinoma. B) Lower rectum at 5 cm from the anal verge; moderate squamous cell carcinoma. C) Thickening of the wall of the rectum (⇨) and an enlarged right ovary metastasis (▶), and an enlarged right internal iliac lymph node (→). D) Liver metastasis at S3 section (○).
Pathological examination of biopsies taken from each lesion revealed a moderately differentiated SCC. Immunohistochemistry showed that the malignant cells were positive for cytokeratin (CK)-5/6 and p40 but almost negative (partially positive) for CK-7/20, oestrogen receptor (ER), and WT-1. Furthermore, computed tomography (CT) scan revealed right internal iliac lymph node metastasis, ovarian metastasis (Figure 1C), and liver metastasis in the S3 section (Figure 1D).
Contrast-enhanced magnetic resonance imaging showed a 7 cm cystic lesion in the right ovary with an irregular mass dorsal to the ovary in continuity with the rectum. In addition, positron emission tomography (PET)-CT showed an abnormal accumulation in the anal canal, the primary lesion, an irregular mass continuous from the ovary to the rectum, right internal iliac lymph node metastases, and an abnormal accumulation in a single metastatic lesion in liver S3 (Figure 2). On the basis of the above observations, this case seemed technically feasible for surgical R0 resection if simultaneous resection was performed.
Pretreatment positron emission tomography-computed tomography. A) SUVmax=11.2 at anal canal. B) SUVmax=19.6 at rectum (⇨), and SUVmax=18.8 at right internal iliac lymph node (→), but there was no accumulation at right ovary (▶). C) SUVmax=20.1 at liver metastasis at S3 section.
First, chemotherapy was planned, and six courses of mFOLFOX6 were administered. After chemotherapy, the primary tumour had shrunk, and the liver metastasis and right internal iliac lymph node metastases tended to shrink (Figure 3), while no new lesions appeared. Furthermore, the tumour marker SCC decreased from 8.1 ng/ml to 1.6 ng/ml (normal value: ≤1.5 ng/ml), and hence we planned a radical resection. The preoperative diagnosis was anal canal carcinoma T4N1M1b (liver, ovary) stage IV. The patient underwent abdominoperineal resection, hysterectomy, bilateral adnexectomy, and laparoscopic partial hepatectomy to achieve R0 resection. The pathological results of the surgical specimen showed that the cancer had invaded the surrounding tissues beyond the intrinsic muscularis propria and that there was venous invasion. The surgical margins were negative, and the response to chemotherapy treatment was judged to be grade 2 (Figure 4). In addition, metastases to the internal iliac and closed lymph nodes were found, and liver metastases were postulated to be from squamous cells and diagnosed as pN3, pM1a (H), but no neoplastic changes indicative of malignancy were observed in the right ovary. Therefore, no adjuvant chemotherapy was administered. Two years and nine months have passed since the surgery, which was undertaken at the patient’s request, and the patient is alive without recurrence.
Enhanced-computed tomography images before and after chemotherapy. A) Primary tumor (⇨) and right internal iliac lymph node metastasis (28×25 mm) (→) before mFOLFOX6 treatment. B) Liver metastasis at S3 section (23×20 mm) before mFOLFOX6 treatment. C) Primary tumor (⇨) and right internal iliac lymph node metastasis (15×11 mm) (→) after FOLFOX6 6 courses. D) Liver metastasis at S3 section (13×8 mm) after FOLFOX6 6 courses.
Resected specimens and histological examination. A) Surgical removal specimen of rectum and anal canal. B) Liver metastasis at S3 section. C) Surgical removal specimen of right ovary. D) Hematoxylin-eosin (HE) stain (×200) revealed moderately differentiated squamous cell carcinoma at anal canal. E) HE staining (×200) revealed liver metastasis from squamous cell carcinoma. F) No neoplastic changes indicative of malignancy were observed in the right ovary by HE staining (×200).
Discussion
In this case, we found that mFOLFOX6 effectively controlled disease in metastatic squamous cell anal canal carcinoma with liver and ovarian metastases. We also found that R0 resection, including distant metastases, helped prolong the prognosis and was one of the treatment options.
In 1974, Nigro et al. assessed the tumours of patients with locally advanced anal cancer who received a combination of chemotherapy, including mitomycin or porfiromycine based on 5-FU before surgery and radiation therapy (combination chemotherapy with radiotherapy) (7). Regression indicated that anal cancer could be cured without surgery or permanent artificial anus construction. Currently, the recommended initial treatment for anal canal cancer without distant metastases is chemoradiotherapy with mitomycin/5-FU or mitomycin/capecitabine at the same time as radiation therapy (2-4, 8).
However, systemic chemotherapy is the primary treatment for anal cancer with distant metastases. Anal cancer itself is a rare cancer type. Additionally, extrapelvic metastases occur in 10%-20% of patients, which limits the data on these patients (6). Although there is some evidence that a regimen of adding cisplatin based on fluoropyrimidines is beneficial for anal cancer patients with distant metastases, there is no evidence to support the resection of metastases (6, 9-12).
Several clinical trials have been conducted to determine the treatment of patients with distant metastases. An international randomized phase II trial (Inter AACT study) in the first-line setting of advanced anal cancer was initiated to compare and validate the efficacy of cisplatin plus fluorouracil and carboplatin plus paclitaxel in patients with advanced chemotherapy-naive anal squamous cancer to establish an optimal regimen. The Inter AACT study demonstrated no difference in objective response between cisplatin plus FU and carboplatin plus paclitaxel (13). However, carboplatin plus paclitaxel was associated with a more favourable toxicity profile and a significant trend toward prolonged OS. Median progression-free survival was 5.7 months for cisplatin plus FU compared with 8.1 months for carboplatin plus paclitaxel. Median overall survival was 12.3 months for cisplatin plus FU compared with 20 months for carboplatin plus paclitaxel (13). These data support the consideration of carboplatin plus paclitaxel as a new standard of care in untreated advanced anal cancer and as a cytotoxic platform for developing future phase III trials. The NCCN guidelines recommend chemotherapy for metastatic anal canal cancer as (i) carboplatin and paclitaxel, (ii) folinic acid, fluorouracil, and oxaliplatin (FOLFOX), (iii) leucovorin, fluorouracil, and cisplatin (FOLFCIS), and (iv) docetaxel, cisplatin, and fluorouracil (DCF) (14). mFOLFOX is widely used as one of the standard chemotherapy regimens for colorectal cancer, but there are few reports of treatment with mFOLFOX6 for SCC of the anal canal.
Although there is still no consensus on the treatment strategy for patients with SCC of the anal canal with distant metastases, multidisciplinary treatment with chemotherapy and surgery, rather than random chemotherapy, can be expected to improve the long-term prognosis of patients whose disease is controlled and in whom R0 resection is possible. In this case, the patient wanted to continue outpatient chemotherapy, and the regimen of carboplatin plus paclitaxel was not approved in Japan; hence, outpatient treatment with mFOLFOX6 was started.
This case was well controlled after 3 months (six courses) of chemotherapy, and the surgical technique seemed to be R0 resectable, including liver metastases. The histological evaluation of the resection specimen was Grade 2. There are few reports of SCC of the anal canal with hepatic metastases that can be controlled by mFOLFOX6 and resected R0 with no recurrence for 2 years. However, in patients with controlled disease and R0 resection, chemotherapy and surgery may provide a better long-term prognosis.
Conclusion
We here report a rare case of anal SCC with distant metastases that was able to undergo R0 resection after mFOLFOX6 chemotherapy.
Acknowledgements
The Authors thank H. Nikki March, PhD, from Edanz Group (https://en-author-services.edanz.com/ac) for editing a draft of this manuscript.
Footnotes
Authors’ Contributions
CM described and designed the article. YM edited the article. HB supervised the editing of the manuscript. The other remaining co-authors collected the data and discussed the content of the manuscript. All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
- Received August 30, 2022.
- Revision received October 15, 2022.
- Accepted October 17, 2022.
- Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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