Anorectal disease BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2021-000661 on 9 July 2021. Downloaded from

Anal adenocarcinoma: case report, literature review and comparative survival analysis

Cynthia J Tsay,1,2 Thomas Pointer,3 Jocelyn B Chandler,4,5 Anil B Nagar,1,2 Petr Protiva ‍ ‍ 1,2

To cite: Tsay CJ, Pointer T, ABSTRACT a firm perianal nodule, with several adja- Chandler JB, et al. Anal Introduction Anal adenocarcinoma is a rare malignancy cent papules, thought to be an inflamed adenocarcinoma: case with a poor prognosis. external hemorrhoid. The patient reported report, literature review Methods We present a case of rare anal adenocarcinoma and comparative survival noticing a lump near the anus 1 month in a patient with normal screening colonoscopy. Using analysis. BMJ Open Gastro prior to presentation. He also described the Surveillance, Epidemiology and End Result database 2021;8:e000661. doi:10.1136/ serosanguineous anal drainage for multiple bmjgast-2021-000661 between 2000 and 2016, we performed survival analysis among individuals>20 years old comparing anal and rectal years, but no haematochezia or melena, ►► Additional supplemental cancers. which he had attributed to internal haem- material is published online Results Survival analysis showed that anal orrhoids. His screening colonoscopy 5 years only. To view, please visit the adenocarcinoma is associated with worse outcomes prior had demonstrated findings of diver- journal online (http://dx.​ ​doi.​ compared with rectal adenocarcinoma and anal squamous ticulosis and internal haemorrhoids with no org/10.​ ​1136/bmjgast-​ ​2021-​ cell carcinoma. 000661). anorectal lesion documented by high reso- Discussion This case and survival data illustrate

lution images. CT scan demonstrated pelvic copyright. the importance of prompt investigation of symptoms lymphadenopathy. PET scan revealed hyper- Received 24 March 2021 irrespective of colorectal cancer screening status with metabolic uptake at the rectum extending to Accepted 11 May 2021 careful attention to examination of the anal area. the anal verge, gluteal fold, posterior scrotal sac, lymphadenopathy in the abdomen and pelvis from the iliac chain to external femoral nodes, and a hepatic lesion suspicious for INTRODUCTION metastatic disease. Primary adenocarcinoma of the anus is a A shave perianal biopsy was performed. http://bmjopengastro.bmj.com/ rare disease accounting for only 5%–10% of © Author(s) (or their Immunohistological stains were positive for employer(s)) 2021. Re-­use anal canal malignancies compared with the CK7 and negative for CK20, CDX2, SOX-10 permitted under CC BY-­NC. No anal squamous cell carcinoma accounting commercial re-­use. See rights 1 consistent with adenocarcinoma. The patient for 85%. Approximately 0.2% of men and and permissions. Published underwent repeat colonoscopy and the women will be diagnosed with anal cancer by BMJ. local exam revealed a large mass outside the 1 at some point during their lifetime, based Medicine, Section of Digestive rectum arising from anus which was palpable Diseases, Yale University School on 2016–2018 US data. We aim to present a on digital rectal exam. An ulcerated anal of Medicine, New Haven, clinical case report of anal adenocarcinoma, Connecticut, USA mass invading the squamocolumnar junction 2 provide a review of the pertinent literature, Medicine, VA Connecticut and perform a comparative survival analysis of the anorectal area was seen on retroflexion

Healthcare System—West on October 2, 2021 by guest. Protected of anal neoplasms. (figure 1, top part). Biopsy of the lesion Haven Campus, West Haven, obtained during colonoscopy demonstrated Connecticut, USA 3Yale University Undergraduate invasive moderately to poorly differentiated Program, New Haven, CLINICAL CASE PRESENTATION anal adenocarcinoma with an unusual immu- Connecticut, USA We report the case of a 70-­year-­old man with nohistochemistry pattern for rectal cancer 4 Pathology, Yale School a medical history of seropositive rheumatoid (weakly positive CK7 and negative CK20, of Medicine, New Haven, figure 1, middle part). The initial treatment Connecticut, USA arthritis, anaemia, hypertension, hyperlipi- 5Pathology, VA Connecticut daemia, gastro-­oesophageal reflux disease, plan was aggressive cytoreduction with induc- Healthcare System—West and lung nodules who was admitted for tion chemoradiation and surgery; however, Haven Campus, West Haven, scrotal swelling and erythema thought to be surgical evaluation was delayed given the Connecticut, USA cellulitis. Given no improvement with antibi- patient’s reluctance for anorectal resection. Correspondence to otics, dermatology was consulted. The exam After further review of pathology and given Dr Petr Protiva; was notable for penile/scrotal lymphedema the intra-abdominal­ lymphadenopathy in petr.​ ​protiva@yale.​ ​edu with elephantiasis nostras verrucosa and the staging PET scan, the tumour board

Tsay CJ, et al. BMJ Open Gastro 2021;8:e000661. doi:10.1136/bmjgast-2021-000661 1 Open access BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2021-000661 on 9 July 2021. Downloaded from copyright. http://bmjopengastro.bmj.com/

Figure 1 Top part: colonoscopy showed large anal mass with extension above the anorectal junction. Patient had previous screening exam 5 years prior to diagnosis with documented normal anorectal junction on high-r­esolution endoscopic photography. Middle part: histology, (A) cribriform and glandular architecture (H&E, 100×); (B) weakly positive CD7 stain (200×); (C) negative stain for CD20 (200×) and (D) positive stain for CDX2 (200×). Bottom part: overall and cancer-specific­ survival experience for the three types of cancer. The adjusted HR and P values are shown directly in the figure. The anal adenocarcinoma shows the worst prognosis. recommended treatment of the lesion as a rectal adeno- decrease in size of some intra-abdominal­ lymphade- carcinoma with extension into the perianal skin rather nopathy suggestive of response to immunotherapy with on October 2, 2021 by guest. Protected than as an anal adenocarcinoma. Subsequent tumour stability on restaging scans. Prior chemotherapy regi- profiling demonstrated a high microsatelliteinstability mens included modified Folinic acid“FOL”, Fluorouracil and was KRAS/NRAS/BRAF wild type. Definitive chemo- “F”, and Oxaliplatin which was complicated by coronary radiation was planned, pending response to induction vasospasm (after 5-Fluorouracil­ bolus) and coronary arte- therapy. Surgical interventions, including resection and rial disease requiring placement of a drug eluting stent. a diverting colostomy, were deferred given lack of stool Oxaliplatin, irinotecan, panitumumab were stopped due incontinence. Palliative care was consulted for support to diarrhoea and the development of a gluteal abscess. throughout treatment course. He also developed a DVT and remains on life-­long anti- coagulation. The patient’s functional status remains good CLINICAL CASE FOLLOW-UP with an Eastern CooperativeOncology Group of 1. Given Over a year after diagnosis, the patient is alive and his reports of ongoing mild intermittent rectal bleeding managed with pembrolizumab. Surveillance imaging per the oncology clinic notes, there are tentative plans after 6 cycles of pembrolizumab demonstrated a for a future sigmoidoscopy.

2 Tsay CJ, et al. BMJ Open Gastro 2021;8:e000661. doi:10.1136/bmjgast-2021-000661 Open access BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2021-000661 on 9 July 2021. Downloaded from

LITERATURE REVIEW following diagnosis were estimated with Cox propor- Risk factors for anal adenocarcinoma have not been tional hazards. The independent effect of cancer type studied widely given the small sample sizes. Nevertheless, was assessed using a Cox model adjusted for covariates it is thought the immunosuppression, perianal Crohn’s identified above. Data were analysed using SAS V.9.4 and disease, and older age may be associated with increased R. The p value for significance was set at <0.01 for a two-­ risk. Unlike anal squamous cell carcinoma which has sided test. been associated with the human papilloma virus, no such association with anal adenocarcinoma has been estab- SURVIVAL ANALYSIS lished.1 2 Differentiating between distal rectal adenocar- We identified a total of 93 706 cases: 1660 cases of histo- cinoma with local spread and primary anal canal tumours logically confirmed anal adenocarcinoma, 12 591 cases is challenging. Anal adenocarcinoma is associated with of anal squamous carcinoma, and 79 455 cases of rectal higher mortality compared with rectal adenocarcinoma adenocarcinoma with complete set of covariates. Online or anal squamous carcinoma.3 A recent classification supplemental table 1 shows descriptive statistics for the suggests that anal adenocarcinomas can be subdivided cohort by type of malignancy. into two types: (1) colorectal from mucosa above the Next, we analysed and compared survival by tumour dentate line and (2) extramucosal from anorectal fistulae type. Anal squamous carcinoma exhibited the best overall or anal glands. Given challenges with classification and and cancer-specific­ survival compared with both anal the low number of overall cases, most of the literature is and rectal adenocarcinomas (p<0.001) (figure 1). Anal limited to case reports or observational studies focused adenocarcinoma had a significantly worse survival when on management and outcomes; often times in compar- compared with anal squamous and rectal neoplasms ison or together with the more prevalent anal squamous (p<0.001). The adjusted HRs by the type of neoplasm are cell carcinoma or rectal adenocarcinoma. Historically, shown directly (figure 1); the complete result of the multi- anal adenocarcinoma was treated like rectal cancers variate Cox regression analysis for independent effect with abdominoperineal resection. A follow-up­ study of the three types of anorectal cancers are presented in recommended that chemoradiation provided compa- the online supplemental tables 2,3. Several other covari- rable outcomes and that abdominoperineal resection be ates were also associated with survival. Not surprisingly, used as salvage therapy. A large database study looking at copyright. advanced stage and grade, and the absence of surgical, survival outcomes of anal adenocarcinoma noted that a radiation or chemotherapy interventions were associated shift in the treatment paradigm to neoadjuvant chemo- with worse survival experience (p<0.001). In addition, radiation followed by surgery, similar to management 4 male sex, year of diagnosis, age≥55 years, unmaried status of rectal cancer. Recent larger administrative database and persons identifying as black or American Indian/ studies and a systematic review have confirmed that a Alaska Native were also associated with significantly worse multimodal approach for anal adenocarcinoma incorpo- survival (p<0.001). Full list of covariates with associated rating surgery with chemoradiation rather than chemo- HRs are detailed in online supplemental tables 2,3. radiation alone leads to improved overall survival, with http://bmjopengastro.bmj.com/ highest median survival noted after neoadjuvant chemo- 2 5–7 radiation. DISCUSSION This case highlights the challenges of early diagnosis of anal malignancies and the importance of prompt METHODS evaluation of anorectal area by anoscopy and colonos- We used the Surveillance, Epidemiology and End Result copy if symptoms of rectal bleeding or serosanguinous (SEER18) database to identify patients with anal or rectal anal discharge are reported. The lesion presented as an malignant neoplasms aged 20 years or older between anal neoplasm in a patient with a documented normal 2000 and 2016. The SEER database includes data from 18 anorectal junction on screening colonoscopy 5 years population-­based registries covering approximately 26% prior. The anal malignancy was poorly differentiated and on October 2, 2021 by guest. Protected of US patients with cancer. We used a combination ICD10 the possibility of low rectal adenocarcinoma with large (C20.9, C21.0 and C21.1) and ICD-­O-3 histological codes extension into the perianal skin rather than primary anal to identify cases of anal adenocarcinoma, rectal adeno- adenocarcinoma is not entirely excluded. This case illus- carcinoma and anal squamous carcinoma. We excluded trates the difficulties in diagnosis of poorly differentiated cases where the data on stage, grade, histology were anal carcinomas extending to the rectum. The lesion missing and cases with more than one primary malig- likely developed in the interim; therefore, the colonos- nancy. We used the SEERStat software (V.8.1.5) to collect copy result was probably not a false negative. Anal cancers covariates including age at diagnosis, year of diagnosis, can be detected during routine screening colonoscopy of sex, race, primary cancer site, tumour stage and grade, asymptomatic patients. However, new symptoms such as survival in months, cause of death, marital status, surgery, rectal bleeding or serosanguinous anal discharge should chemotherapy and radiation treatments. prompt careful rectal and anal examination. This should We compared survival using the Mantel-Haenszel­ Log-­ include patients who are up to date on their colorectal Rank Test. Relative HRs for death in the 5-year­ period cancer screening.

Tsay CJ, et al. BMJ Open Gastro 2021;8:e000661. doi:10.1136/bmjgast-2021-000661 3 Open access BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2021-000661 on 9 July 2021. Downloaded from

Survival analysis showed that anal adenocarcinomas of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and exhibit the worst prognosis. Using the National Cancer responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability Database research, others have previosuly shown that anal of the translations (including but not limited to local regulations, clinical guidelines, 3 adenoracinoma carries poor prognosis. We used a similar terminology, drug names and drug dosages), and is not responsible for any error approach using the SEER database and analysed a larger and/or omissions arising from translation and adaptation or otherwise. set of anal adenocarcinomas cases and additional covariates Open access This is an open access article distributed in accordance with the such as ethnic backround, marital status, year of diagnosis Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which and the type of treatment. The SEER database is associated permits others to distribute, remix, adapt, build upon this work non-commercially­ , and license their derivative works on different terms, provided the original work is with incomplete entries and self-­reported data such as ethnic properly cited, appropriate credit is given, any changes made indicated, and the background and race. The precision of adjusted hazards use is non-commercial.­ See: http://creativecommons.​ ​org/licenses/​ ​by-nc/​ ​4.0/.​ for some individual covariates could be limited due to small ORCID iD sample size. However, large number of cases with complete Petr Protiva http://orcid.​ ​org/0000-​ ​0002-5566-​ ​8820 set of covariates allowed adequate precision of hazard esti- mates for the independent effect of cancer type on survival.

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4 Tsay CJ, et al. BMJ Open Gastro 2021;8:e000661. doi:10.1136/bmjgast-2021-000661