Tailgut cyst or retrorectal cyst hamartoma is a congenital remnant of the embryonic tailgut (1). The developing human embryo has a tail caudal to the cloaca (future anorectal canal), and a portion of the hindgut extends into this tail as the tailgut or post-anal gut (Supplementary Figure S1) (2). Failure of the tailgut to involute by the eighth week of gestation can result in cysts. True incidence is under-estimated, as many tailgut cysts are asymptomatic, and it is at least one in 40,000 hospital admissions (3). Patients may present with constipation, perineal pain, blood in stool, perianal fistulas or abscesses, and dysuria. Tailgut cysts are more frequently seen in women, with female-to-male ratios ranging from 3:1 to 9:1 (1, 4, 5).

Malignant transformation of tailgut cysts can occur in 6%–26% of cases (4–7). Varied cancer histologies include mucinous adenocarcinoma, squamous cell, neuroendocrine, transitional cell, endometroid adenocarcinoma, sarcoma, and mixed (such as adenosquamous carcinoma) (7, 8). This histologic diversity is reflective of how the distal hindgut develops (Supplementary Figure S1). By week 4 of gestation, the human embryo develops a gut tube divided into the foregut, midgut, and hindgut (9). Cloaca is the expanded distal portion of the hindgut, which terminates at the cloacal membrane at the junction of the endoderm and ectoderm (proctodeum). The proctodeum develops stratified squamous epithelium of the outer one-third of the anal canal. The urorectal septum grows into the cloaca and divides it into the urogenital sinus anteriorly and the anal canal posteriorly. Neural crest cells migrate into the bowel wall, completing migration into the hindgut in the seventh week of gestation.

Metastatic mucinous adenocarcinoma arising from tailgut cyst (mMATC) is ultra-rare and has been reported with poorly differentiated histology, positive margin resection, and intraoperative cyst leakage (10–15). The reported sites of metastasis of tailgut cyst adenocarcinoma include the lungs, peritoneum, bone, liver, and inguinal lymph nodes (10–15). Literature on the chemosensitivity and radiosensitivity of mMATC is lacking; treatment is extrapolated from rectal cancer management. We are reporting, for the first time, 1.5 years of clinical benefit from gemcitabine, and providing clear evidence of radiosensitivity.

A 57-year-old woman, with obesity (body mass index 40.4 kg/m²) and a history of perianal abscess 4 years prior, presented with a 1-year history of constipation and intermittent perineal pain aggravated by prolonged sitting. Magnetic resonance imaging (MRI) showed a lobulated, multiseptated presacral cystic mass measuring 5.8 × 5.7 × 5.6 cm with mildly nodular enhancement of internal septations, inseparable from the wall of the lower rectum, probable tailgut duplication cyst (Figure 1). Flexible sigmoidoscopy showed extraluminal compression of the posterior midline rectum approximately 5 cm from the anal verge. She underwent surgical excision of the presacral mass with primary coccygectomy. The patient was placed in a padded prone jack-knife position, and a midline presacral incision was made from the tip of the coccyx to just above the anal sphincter complex. Intraoperatively, a large 9-cm presacral mass was found, densely adherent to the rectum and coccyx. The mass was carefully dissected from the rectum, vagina, gluteal muscle, and surrounding subcuticular fat and was removed completely. Pathology confirmed moderate to poorly differentiated adenocarcinoma with mucinous differentiation and perineural invasion (Figure 2A). The area with the suture was also positive for adenocarcinoma. Remnants of a tailgut cyst were present. Immunohistochemistry was positive for CK20, CDX2, and CK7. Progesterone receptor highlighted smooth muscle and rare stromal cells.

This is the first detailed report of mMATC describing sensitivity to gemcitabine and excellent response to radiotherapy at all irradiated sites. We found only six cases of mMATC previously reported in the literature, and these are summarized in Table 1; treatment data are extremely limited. In our patient, the initial site of metastases was the lung, then bone, followed by the peritoneum, distant lymph nodes, pleura, and pancreas. Bone metastases were sclerotic and lytic. CEA and Carbohydrate Antigen 19-9 (CA 19-9) levels correlated with progression, as previously reported (10).

Most tailgut cysts are multicystic, lined by a variety of epithelia, including squamous, columnar, transitional, and cuboidal, with scattered enterochromaffin cells (1). The embryonic cloaca is pluripotent (Supplementary Figure S1). Hence, chemosensitivity of mMATC may resemble that of genitourinary, gynecologic, colorectal, or anal cancer. This was reflected in our patients’ chemosensitivity assay results that showed sensitivity to gemcitabine, mitomycin, and irinotecan. Our patient obtained clinical benefit from gemcitabine, but did not benefit from the colorectal cancer regimens; further investigation is warranted to confirm these findings in other patients.

Optimizing growth conditions for preclinical models of ultra-rare cancers is challenging. Patient-derived xenografts and organoids did not establish successfully from our patient’s cancer. Novel in vitro assays for personalized chemotherapy selection in real-time have the potential to improve patient survival. The in vitro chemosensitivity assay used for our patient required 6 mL of whole blood and generated results in 5–10 days, which was convenient. The detailed methodology and earlier validation studies have been previously described (17, 18). This assay has shown predictive performance for time to progression on chemotherapy and overall survival in small prospective cohorts of patients with metastatic pancreatic cancer and is being further validated (17). Although the assay predicted sensitivity to irinotecan and mitomycin C, our patient did not benefit from these drugs. It is plausible that chemosensitivity changed after the first regimen, and initial results may not accurately predict outcome on subsequent lines of therapy.

This case also illustrates the radiosensitivity of mMATC. Prior literature is limited to adjuvant, neoadjuvant, or locally recurrent settings, without clear response data (10, 19–21). Our patient experienced a rare radiation recall myositis from gemcitabine, characterized by an inflammatory reaction within the irradiated fields during chemotherapy (22). Skin edema and limb pain resolved with initiation of steroids and discontinuation of gemcitabine, but restricted mobility of the left shoulder and hip persisted, requiring physical and occupational therapy.

Genomic analysis showed somatic TP53 inactivating and KRAS activating mutations, implying oncogenesis through the mitogen-activated protein kinase signaling pathway. A germline heterozygous MUTYH p.G396D mutation was seen, which is a loss-of-function mutation annotated as likely oncogenic in the OncoKb database (23). Monoallelic MUTYH germline variants confer a 0.46% risk of colorectal cancer by age 45–49 years, comparable to the average risk (24). Somatic loss of heterozygosity in MUTYH heterozygotes may increase the risk of various cancers (25). However, the association between germline MUTYH variants and tailgut cyst carcinogenesis is unknown.

We acknowledge the limitations of this case report, which include the fact that clinical outcomes related to one case warrant further investigation before treatments can be generalized to other patients with this cancer, and this emphasizes the need for international registries for sharing preclinical knowledge and clinical experiences in ultra-rare cancers. We could not successfully generate preclinical models (patient-derived xenografts and organoids) to pursue in-depth investigation of the mechanisms behind the observed clinical outcomes, and this remains an area for future research. Lastly, the specific algorithm used to create drug sensitivity templates is proprietary to the laboratory that performed the assay and is not included in the manuscript. Nevertheless, this case report meaningfully contributes to the literature on the management of the ultra-rare metastatic mucinous tailgut cyst adenocarcinoma, providing a detailed clinical history and evidence of response to gemcitabine in this patient, which is usually not used in the management of mMATC, as treatment is extrapolated from colorectal cancer management. The case also provides evidence of the radiosensitivity of mMATC, implying the potential role of radiation in neoadjuvant, adjuvant, locally recurrent, and advanced disease settings. These clinical observations require confirmation in larger studies.

mMATC is an ultra-rare cancer that showed sensitivity to gemcitabine and radiation in our patient. The benefit from other chemotherapies is unproven. Further investigation is warranted for the generalizability of outcomes to other patients with mMATC. International registries are needed for sharing preclinical knowledge and clinical experiences in ultra-rare cancers.