Rectal Melanoma: Rare Cancer with Grave Prognosis

Abstract

Malignant melanoma of the rectum is an exceedingly rare type of cancer with an aggressive presentation, comprising up to 4% of all anorectal cancers. Presentation of this cancer tends to occur in individuals in their late 80s, with nonspecific symptoms such as anal pain or rectal bleeding. Diagnosing rectal melanoma, especially in early stages, is difficult due to its amelanotic presentation and lack of pigmentation, which results in poor remission rates and prognosis. Furthermore, surgical treatment is difficult as these types of malignant melanomas tend to spread along submucosal planes; thus, complete resections are impractical, especially if caught later. In this case report, we present the radiological and pathological features as seen in a 76-year-old man diagnosed with rectal melanoma. Based on his presentation of a heterogeneous bulky anorectal mass with extensive local invasion, initial impressions were colorectal carcinoma. However, surgical pathology found the mass to be a c-KIT+ melanoma, with positive SOX10, Melan-A, HMB-45, and CD117 biomarkers. While the patient was treated with imatinib, the melanoma was too widespread and aggressive, leading to progression and ultimately death.

Introduction

Melanomas are broadly characterized as malignant tumors arising from pigmented melanocytes or their precursors, neural crest cells, which migrate extensively during fetal development to the majority of tissues in the body [1]. Most melanocytes migrate to the epidermis and dermis; thus, cutaneous melanomas (CMs) are by far the most common, comprising over 90% of tumors. Of the remaining (<10%) forms of melanoma, 5% are ocular, 2% are of unknown origin, and 1% are mucosal melanomas (MMs) [2]. The rate of MMs has remained steady in the USA with about 2.2 cases per million per year, whereas the rate of CMs has continued to increase [1]. The main sites of origin for MMs include the head and neck, anal tract and rectum, female reproductive tract, or, more rarely, the urinary tract. MMs are more prevalent in women, due to the higher incidence rate in the vaginal canal; these melanomas are associated with poor outcomes and prognosis. Ultraviolet light exposure is the main risk factor for CM, while family history has been shown to be more heavily associated with MM development. Additionally, activating BRAF mutations, a serine-threonine kinase, are classically associated with CMs which arise directly from melanocytes, while activating c-KIT, tyrosine kinase receptor, are more commonly seen with MM. CMs are thought to arise from pigmented melanocytes, whereas MMs are theorized to arise from immature melanoblasts which may contribute to their increased pathogenesis and poorer outcomes [1].

Malignant melanoma of the rectum is an exceedingly rare MM with an aggressive presentation [3]. Rectal MMs are 1% of colon malignancies and usually arise at the squamous and anal transition zones [4]. They typically present around the 8th decade predominantly in women, along with bleeding, pain, or change in bowel habits, and are commonly mistaken for hemorrhoids or colorectal cancers. Prognosis is very poor, with a median survival of 24 months and a 5-year survival rate of 10%, further complicated by the lack of timely diagnosis, with 80% of lesions lacking pigmentation and 20% being histologically amelanotic [4, 5]. Patients with amelanotic melanomas are often misdiagnosed as hemorrhoids [6]. Here, we report the case of a patient with mucosal rectal melanoma highlighting its presentation, complicated diagnosis, and course. Additionally, the CARE Checklist has been completed by the authors for this case report and attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000529434).

Case Report

A 76-year-old male with a past medical history of hypertension, COPD, and kidney stones and a family history of pancreatic and prostate cancer presented to the ED with complaints of painful bright red rectal bleeding for 1 month that had gotten progressively worse. He explained that he had been recently passing blood clots with every bowel movement. Associated symptoms included diarrhea 6–8 times per day and abdominal and rectal pain that worsened with bowel movement. The patient was an occasional smoker, and his last colonoscopy 10 years ago was negative for any concerning polyps.

Initial rectal examination showed an easily friable mass with irregular contour. He had a hemoglobin of 10.3 g/dL and MCV of 71.8 fL, consistent with iron deficiency microcytic anemia. Other abnormal lab values upon admission included ALP 124 U/L, albumin 3.1 g/dL, hematocrit 32.5%, MCH 22.8 pg, MCHC 31.8%, RDW 18.5%, MPV 6.2 fL, and platelet count 659 K/MM3. CT abdomen and pelvis revealed a heterogeneous bulky anorectal mass, measuring up to 6.0 × 4.4 cm in greatest axial dimension. The mass involved the mesorectal fat and likely invaded the mesorectal fascia as well as the anal sphincter. Diffuse metastases involving the visualized lungs and liver were also noted, in addition to diffuse bulky necrotic lymphadenopathy, with notable mass effect on the main portal vein. Based on the presentations, initial impressions were colorectal carcinoma.

One month after initial findings, the patient underwent a biopsy of the mass. The specimen was morphologically and immunophenotypically consistent with melanoma. Further genomic testing showed a positive c-KIT mutation on exon 11 (c. 1727T>C [p.L576P]) but negative for a BRAF mutation. Immunohistochemistry found the mass positive for SOX10, Melan-A, HMB45, and CD117 but negative for S100 (Fig. 1). A PET scan after the biopsy confirmed the mass and metastases to the surrounding mesorectal lymph nodes, in addition to innumerable hypermetabolic foci in the liver with some demonstrating central necrosis, three metastatic lung nodules, and metastatic bone lesions in the T7 spine, left posterior iliac bone, and right sacrum (Fig. 2). Retroperitoneal, periportal, subdiaphragmatic, pelvic, and right inguinal metastatic lymph nodes were found, including a left subdiaphragmatic metastatic lymph node measuring 1.9 × 1.7 cm, a large necrotic periportal lymph node measuring 5.2 × 2.9 cm, a left paracaval lymph node measuring 2.2 × 2.4 cm, and a right inguinal lymph node measuring 3.1 × 1.8 cm.

Fig. 1.

a Pathology slides visualized at ×40 (H&E stain from biopsy). b Immunohistochemical stain positive for SOX-10. c S100-positive stain. d Negative control.

Fig. 2.

PET scan images. a Necrotic portacaval nodal conglomerate. b Retroperitoneal lymphadenopathy in the aortocaval space. c Heterogenous enhancing rectal mass involving the mesorectal fat, fascia, and anal sphincter with scattered colonic diverticuli.

A few weeks after the PET scan, the patient presented to the ED for shortness of breath, weakness, dizziness, syncope, three episodes of passing large blood clots, and rectal pain 10/10. He was tachycardic with his heart rate in the 120 s, normotensive, had an SpO2 of 98% on room air, and afebrile with normal respiratory rate. His initial lactate was 7.9 but increased to 10.6. His hemoglobin level was 10.6 g/dL, consistent with the previous iron deficiency anemia that was found. Other pertinent abnormal lab values included INR elevated to 4.52, PT 37.2, AST 91 U/L, and ALP 298 U/L, consistent with metastatic liver disease. The patient had severe metabolic acidosis with concomitant respiratory acidosis. After treatment and discharge, he was seen for a follow-up regarding management of his rectal melanoma.

The patient was counseled regarding his diagnosis and poor prognosis. Since the patient had a c-KIT mutation, he was a candidate for targeted therapy with imatinib. Due to his widespread and aggressive disease, the patient progressed despite targeted therapy and passed away.

Discussion

Anorectal melanoma is a rare malignancy that differs a great deal from its counterpart of CM. It is diagnosed in an older patient population with 50% of patients presenting after the 8th decade of their life, and women are more likely to be diagnosed [7]. Most patients present with advanced disease following metastasis and have a strong racial association with white patients, although UV exposure is thought to not be a risk factor, especially since darker skin patients have a higher incidence as compared to CMs [8]. Rectal melanomas have been loosely associated with HIV and HPV, indicating a potential immunologic pathogenesis [8, 9]. Anorectal melanomas tend to be located in the anal canal or anal verge in the majority of patients and are found more distally in 35% of patients [9]. As such, patients can present with bleeding, anorectal mass with discomfort or pain, or a change in stool habits including diarrhea. Due to delayed diagnosis, patients may also present with a variety of symptoms related to metastasis and tumor burden including fatigue, weight loss, and anemia [7, 8].

Metastatic spread of anorectal melanomas tends to be via lymphatic ducts, most commonly through the inguinal or inferior mesenteric nodes. Other sites include hypogastric lymph nodes, para-aortic lymph nodes, lung, skin, liver, and brain [10]. When rectal melanomas are diagnosed, distant metastases are discovered in 26–38% of patients [7, 10]. In the case of our patient, he was found to have metastases in the lung, liver, and regional lymphadenopathy, all similar to previous case reports.

Rectal melanomas are exceedingly difficult to diagnose, especially in the early stages. In cases of diagnostic difficulty, which is frequent even on histopathology, melanoma antigens S-100, HMB-45, and vimentin are important immunohistochemical markers. In a study of 19 rectal melanomas histopathology, positive markers for SOX 10 were 100%; Melan-A, 53.3%; S100, 40%; and HMB-45, 38.5% [11].

Genetic sequencing for mutations can also be used to assist with diagnosis and differentiate between MM subtypes. CMs also tend to carry BRAF, CDKN2A, PTEN, or TP53 mutations which are expressed at a significantly lower rate among MMs. However, uveal melanomas depend on activating GNAQ or GNA11 genes for their pathogenesis [1]. Activating KIT gene mutations, which encode for receptor tyrosine kinases, are important for the development and function of melanocytes and are therefore found in both normal and malignant melanocytes. The pathogenesis of malignant rectal melanoma has been associated with these activating KIT gene mutations and between 15% and 40% of MMs carry KIT or increased copies of KIT [1]. The most common site of oncogenic KIT mutation involves exon 11 followed by exon 17 and exon 9 in gastrointestinal stromal tumors. The underlying variability of melanomas indicates the individuality of each type and underlying differences in risk factors and pathogenesis.

Although KIT mutations are mostly associated with anorectal MMs, an analysis of 40 patients with anorectal melanoma found that 40% involved CD117 overexpression compared to 17% of studies with c-KIT point mutations and 5% with BRAF [12]. BRAF is also involved in about 8% of MMs with a high prevalence of non-V600 mutations (37%) compared to MMs with BRAF V6000 mutations [13]. BRAF and c-KIT mutations do not co-occur, indicating an epistatic relationship. Studies have shown that patients with KIT mutations have a shortened survival time compared to non-KIT MMs [14]. Therefore, it is important to sequence patients early in disease course to avoid delays in treatment. Through next-generation genome sequencing, we were able to identify c-KIT mutation in our patient within the first month following diagnosis and treat with targeted therapy.

The treatment of rectal melanoma is limited, and the prognosis is poor. The 5-year survival rate of all patients diagnosed with anorectal melanoma ranges between 16% and 34% and can decrease further if metastasis occurs [7, 8]. These lesions are often dismissed as benign hemorrhoids or polyps, and misdiagnosis of rectal MM is common. In a study of 79 patients eventually diagnosed with anorectal malignant melanoma, more than half were initially diagnosed with hemorrhoids [15].

Due to the rarity of anorectal melanoma, standardized best practices have not been established. Surgery remains the cornerstone for treatment for nonmetastatic rectal melanoma, and abdominoperineal resection is the most aggressive approach. However, 50% of patients develop recurrence locally [16]. Recently, there has been a shift to wide local excision due to its better morbidity, faster recovery, and limited impact on the bowel. Wide local excision has been increasingly used to control anorectal melanomas and has a similar recurrence rate to abdominoperineal resection of 62.5%. Both surgical approaches are used with palliative intent and have been shown to have no impact on survival [8].

Therapies fall into three categories: (1) chemotherapy including dacarbazine, vinblastine, cisplatin; (2) targeted therapies such as imatinib for c-KIT-positive mutations; and (3) immunotherapies such as pembrolizumab. Chemotherapies have limited impacts on anorectal melanoma; however, recent studies have shown positive outcomes when chemotherapy is combined with surgery. Immunotherapies are a growing option for treatment of MMs. Multiple studies have reported less immunotherapy response for MMs compared to CMs. However, pembrolizumab has been shown to have comparable response rates as advanced unresectable MM with an overall response rate of 19% [17]. Additionally, the study by Kim et al. of 164 patients found a similar response rate for metastatic melanoma treated with pembrolizumab, nivolumab, or ipilimumab.

Targeted therapies for c-KIT positive mutations also include sunitinib and masitinib. However, imatinib is the most studied and therefore most commonly used with a response rate of 28% with moderate adverse events including edema, rash, vomiting, and neutropenia [18]. Although imatinib is effective on c-KIT mutations, it has been shown to have limited response to tumors with KIT amplifications and no impact on non-KIT mutations; therefore, treatment needs to be based on c-KIT mutation status rather than the protein expression level [19]. Patients have been shown to develop acquired resistance to imatinib therapy over time, and future studies are considering dual signaling pathway blocking or use of targeted therapy as an adjunct to chemotherapy [18]. One consideration is treatment with nilotinib following disease progress despite treatment with imatinib, which has been shown to benefit patients in a phase II clinical trial [20]. BRAF mutations can be targeted with combination BRAF/MEK inhibitor therapy such as with dabrafenib/trametinib and vemurafenib/cobimetinib, both of which are recommended as per ASCO guidelines [21].

Strengths of this case report include surgical pathology results, highlighting the importance of utilizing appropriate immunohistochemical markers and imaging findings. Limitations involve retrospective chart review.

In conclusion, anorectal melanoma is a rare malignancy that differs a great deal from its counterpart of CM with a very poor diagnosis and limited treatment. It presents nonspecific symptoms, leading to misdiagnosis, and is often dismissed as benign hemorrhoids or polyps. Appropriate histochemical assessment, imaging studies, and tumor mutations are essential for diagnosis and monitoring disease progression. Awareness of anorectal melanoma along with early correct diagnosis utilizing appropriate immunohistochemical markers is necessary for prompt treatment and better patient outcomes.

Statement of Ethics

Ethical approval is not required for this study in accordance with local or national guidelines. Retrospective written informed consent was obtained from the patient’s next of kin for publication of the details of their medical case and any accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

There were no funding sources.

Author Contributions

Khadija Soufi and Rashmi Verma conceived and designed the analysis. Khadija Soufi collected the data. Khadija Soufi, Ferheen Abbasi, MS Dongguang Wei, MD, and Rashmi Verma contributed to draft manuscript preparation. All the authors reviewed the results and approved the final version of the manuscript.

Funding Statement

There were no funding sources.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.