Anal Melanoma: An Aggressive Malignancy Masquerading as Hemorrhoids.

ABSTRACT: Anal melanoma is a devastating malignancy easily confused with benign hemorrhoids. Physician unfamiliarity with this bleeding rectal lesion can lead to delays in diagnosis and therapy. Four cases of anal melanoma, all initially mistaken for hemorrhoids, have been documented in the past 4 years at our institution. Despite surgical intervention and chemoimmunotherapy, each patient succumbed to widely metastatic disease. Average survival was 15.2 months. The clinical, pathologic, surgical, and oncologic features of anal melanoma are reviewed to enhance physician recognition of this unusual

anorectal disorder. HEMORRHOIDS are the most frequently diagnosed anorectal lesion and the most common cause of rectal bleeding.' Up to 50% of the adult population in the United States may be affected. [2] Typical symptoms are pain, pruritus, bleeding, and prolapse. Conservative therapies may provide symptomatic relief, while surgical techniques such as rubber band ligation, sclerotherapy, electrocoagulation, and hem orrhoidectomy allow definitive resolution. In the past 4 years at our institution, four cases have been encountered in which apparent hemorrhoids refractory to conservative management were subsequently diagnosed as anal melanoma. This alarming disease is rarely considered in patients thought to have benign, common hemorrhoids and carries a grave prognosis.3 While surgical and oncologic publications pertaining to anal melanoma are numerous, only one article4 is available for primary care clinicians who, in our opinion, are often unaware of the significance of this neoplasm. We present four cases (Table).

CASE REPORTS Case 1. A 26-year-old black male bricklayer from central Georgia was seen in December 1995 with 6 months of painful defecation and rectal bleeding, diagnosed as internal hemorrhoids and refractory to medical management. A palpable, tender 5 cm mass was detected on digital rectal examination (DRE), thought to be a thrombosed hemorrhoid, and excised transanally in January 1996. Pathology of the resected specimen revealed anal melanoma with 8 mm of tumor thickness. No evidence of distant metastasis was present. He received adjuvant interferon-alpha (IFN-[alpha]) immunotherapy. In July 1996, a left groin mass developed. At excision, necrotic metastatic melanoma was detected. One of 31 inguinal nodes was positive for melanoma. At follow-up in August 1997, at least 10 pulmonary metastases 1 to 3 cm in diameter were found. He received radiation therapy, interleukin-2 (IL-2) and IFN-a immunotherapy without tumor response. Relendess clinical deterioration followed, with widespread metastases to lungs and bone. The patient died in February 1999, 37 months after diagnosis.

Case 2. A 58-year-old white male prison inmate from eastern Georgia had 6 months of rectal pain and bleeding, diagnosed as hemorrhoids in April 1998 and refractory to medical management A 20-lb weight loss was documented. A tender, pigmented, prolapsing mass was palpable by DRE (Fig 1). Colonoscopy in May 1998 showed a 5 cm fungating, ulcerated mass 2 cm from the anal verge in the anterior position. Biopsies revealed anal melanoma with 18 mm of tumor thickness, deeply invasive into intestinal wall and vascular structures (Fig 2). Hepatic and pulmonary metastases were observed on computed tomography (CT). The patient had abdominoperineal resection (APR) in June 1998 for palliation of severe anal pain, bleeding, and near obstruction by the mass located just above the dentate line (Fig 3). Biopsy of pigmented liver nodules and 14 perirectal lymph nodes was positive for metastases. He received three cycles of dacarbazine, cisplatin, and carmustine, with tamoxifen. Disease progression was rapid despite aggressive intervention. He died of widespread metastatic melanoma to liver and lungs in March 1999, 10 months after diagnosis.

Case 3. A 58-year-old white male nuclear engineer from western South Carolina was seen in November 1998 with 3 months of rectal bleeding and a prolapsing mass, diagnosed as hemorrhoids and refractory to medical management. A pedunculated, nontender mass was palpable within the anal orifice on DRE (Fig 4). Colonoscopy showed a 4 cm ulcerated, fungating mass (Fig 5). Biopsy confirmed amelanotic melanoma. Multiple liver metastases were detected by magnetic resonance imaging (MRI) (Fig 6), with increased signal intensity on Ti-weighted images consistent with melanin within the lesions. Wide local excision of the rectal mass was done to control bleeding and prolapse. Pathologic specimens revealed 7 mm of tumor thickness. Three cycles of biochemotherapy with cisplatin, tamoxifen, IFN-a, and IL-2 were administered. At follow-up, more extensive hepatic metastases were detected by MRI, with new metastases in right inguinal nodes, lungs, and multiple ribs. High-dose IFN-[alpha] was administered for 4 weeks. He was eva luated for high-dose IL-2 immunotherapy at the National Cancer Institute, but his condition deteriorated rapidly and he died in July 1999, 8 months after diagnosis. At autopsy, widespread metastases were detected in liver, spleen, periaortic and inguinal nodes, lungs, vertebral column, ribs, pons, and the cerebral cortex.

Case 4. A 59-year-old white male utilities worker from eastern Georgia was seen in June 1999 with 4 months of rectal fullness and bleeding, diagnosed as hemorrhoids and unresponsive to medical management. Bilateral inguinal adenopathy was present. On DRE, a 6 cm tender, partially pigmented, prolapsing mass (Fig 7) was palpable at 2 cm inside the anal canal. Biopsy of the mass showed anal melanoma with tumor thickness exceeding 5 mm. Needle biopsy of inguinal lymph nodes showed metastatic melanoma, and chest CT scan showed multiple pulmonary metastases. Despite chemotherapy and radiotherapy, widespread metastases developed, metastases to the gastric fundus resulted in massive gastrointestinal hemorrhage, and he died in December 1999, 6 months after diagnosis.

DISCUSSION

Anorectal melanoma comprises 0.25% to 1.25% of malignancies originating in this anatomic region. [5] Of all melanomas, anal melanoma represents 0.4% to 1.6% and is the third most common site of origin, following the skin and eye. The malignancy occurs more frequently with advancing age, with peak incidence in the sixth and seventh decades and no apparent sexual predilection. [6] Cases in whites outnumber those in African-Americans. [7]

The majority of these tumors arise near the dentate line in the anal canal (Fig 3) and have polypoid and pigmented features. Many are nodular masses that prolapse through the anal orifice and ulcerate, as in our patients. Microscopically, tumor cells are arranged in nests, and individual cells may be epithelioid or spindled. These clusters of tumor cells invade overlying squamous mucosa in a pagetoid manner (Fig 2) and are characteyized by immunostaining specific for the melanosome protein HMB-45 (Fig 2, inset).

In normal individuals, melanocytes are readily identified within the squamous mucosa of the anal canal distal to the dentate line. [8] Melanomas of the anorectum are thought to arise from these cells. Ultraviolet light, a common carcinogen in cutaneous melanoma, is obviously not a provocative factor in this anatomic region. [9] Additionally, this tumor is more common in patients residing north of 40[degrees] latitude, in contrast to cutaneous melanoma cases. Some authors believe these malignancies originate from melanocytes indigenous to the overlying glandular mucosa of the anus. [10,11] A recent analysis [12] of 117 cases spanning 20 years in the National Cancer Institute registry showed a sharp rise in incidence in young men in San Francisco between 1988 and 1992, suggesting a possible association with HIV infection. All 4 patients in our series were HIV-negative.

In various series, [7, 13-15] 20% to 62% of patients had metastatic disease at the time of initial diagnosis. The abundant lymphatics of the anorectum probably facilitate the high rate of inguinal and iliac lymph node metastastes. The rich vascular network in this area promotes hematogenous spread to liver, lung, bone, brain, and other organs. In addition, anorectal melanomas often achieve large size and nodular growth before clinical detection. The occult, widespread distribution of metastases before definitive evaluation of the symptomatic anorectal mass is apparent in our four patients. It is uncertain whether the pronounced tendency to metastasize implies a more aggressive tumor biology or is due to plentiful lymphatic and hematogenous channels of the anal canal. In our cases, as in other published series, the prognosis at presentation is generally poor, with expected survival usually expressed in months.

Optimal surgical therapy in the management of anorectal melanoma is uncertain and controversial. Procedures include the conservative approach of wide local excision (LE) and the more radical approach of APR. However, the rarity of this tumor, advanced stage at presentation, and poor prognosis have confounded attempts to clarify optimal surgical intervention. In 19 published series totaling 610 patients worldwide between 1929 and 1995, [5-7, 12-28] no statistically significant difference has been consistently demonstrated for APR (with or without inguinal node dissection) compared with wide LE. Poor prognosis was evident in each series, with 5-year survival of less than 20%, regardless of operative method. Surgical decisions must therefore be individualized according to severity of local symptoms, prevalence of distant metastases, and overall health of the patient. Recent reviews [13,24] advocate sphincter-sparing LE, because patients tend to succumb to metastases regardless of surgical therapy. Others [14,26 ] recommend proceeding with APR, but only if distant metastases are absent or for palliative relief.

From the oncologic standpoint, a limited number of chemotherapeutic agents have shown effectiveness in metastatic cutaneous melanoma. Dacarbazine, carmustine, and cisplatinum have shown single-agent tumor responses in up to 25% of cases. [29] The combination of IFN-[alpha] IL-2, and cytotoxic drugs, termed "biochemotherapy" or "chemoim-munotherapy," seems to be more active than any agent alone. A recent meta-analysis [30] of IL-2 and/or IFN-[alpha] added to chemotherapy, in 154 studies involving 7,341 patients with metastatic cutaneous melanoma showed improved tumor response rates over chemotherapy alone. No published randomized trials are available for anal melanoma due to the small number of patients requiring several decades to recruit in most series. Hence, all treatment regimens are extrapolated from trials involving metastatic cutaneous melanoma. Future options will likely incorporate combined modalities of chemotherapy, immunotherapy, and radiation therapy.

The use of vaccines to treat patients with melanoma is based on the unique immunogenicity of this solid tumor. The most extensively studied melanoma vaccines are whole-cell (allogenic and autologous), cell-lysate formulations containing multiple antigens, shed-antigen derivatives, carbohydrate antigens (including gangliosides), and purified antigen preparations capable of stimulating an immune response in the melanoma patient. [31,32] To date, however, no reported phase III trial comparing vaccine with chemotherapy in cutaneous melanoma, has shown a statistically significant survival benefit. [32,33]

Despite the dismal prognosis in the vast majority of cases of melanoma, some reports have included isolated instances of surprisingly lengthy survival. In 390 cases from 11 series [5,13,14,16,20,21,23,25,26,28,34] in which cases of prolonged survival were mentioned, 29 patients (7%) lived for more than 10 years after diagnosis. The factors predictive of prolonged survival in these unusual cases of anal melanoma are unknown but may be correlated with initial depth of tumor invasion, as shown in cutaneous melanoma, [35] or with absence of distant metastases at time of diagnosis. [13,15]

The average survival time in our series of four patients was 15.2 months despite surgical and oncologic therapy in each. This is consistent with the findings in previous series and may reflect the aggressive biologic behavior of bulky melanomas arising in the richly vascular and lymphatic region of the anus. Our case density of 1.0 per year is consistent with that of larger series at other referral institutions, where experts have seen 85 cases in 64 years, [14] 15 in 16 years, [15] 32 in 36 years, [24] 72 in 57 years, [26] and 24 in 15 years. [27] The patient in case 2, at age 26, represents the second youngest patient reported in the literature [36]; to our knowledge, his is only the sixth case of anal melanoma reported thus far in an African-American patient.

How can practicing clinicians reduce the devastating morbidity and mortality of anal melanoma? We suggest four measures: (1) perform routine annual rectal examinations in the group at highest risk, those aged 45 to 80 years; (2) biopsy anorectal lesions atypical for hemorrhoids based on induration, pigmentation, ulceration, or refractory nature; (3) include anal melanoma in the differential diagnosis of rectal bleeding in adults; (4) seek early diagnosis to allow timely surgical management and prompt entry into combination chemotherapy and immunotherapy regimens before the metastatic burden of disease is excessive. As Pack and Oropeza [5] stated so accurately 34 years ago, the rectum is "a region infrequently inspected with minute care by either patient or physician." Practitioners in a broad variety of specialties must be aware that some cases of hemorrhoids may not be so benign after all.

Acknowledgment. We thank Phil N. Jones for photographic assistance.

From the Departments of Family Medicine, Surgery, and Medicine (Section of Medical Oncology), Medical college of Georgia, and the Department of Pathology, Veterans Affairs Medical Center, Institute of Molecular Medicine and Genetics, Augusta, Ga.

References

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TABLE

Characteristics of the Four Patients


                               Case 1

Age (years)                    26
Race/sex                       African/American male
Duration of symptoms (months)  6
Size of mass (cm)              5
Tumor thickness (mm)           8
Metastases (at diagnosis)      None
Therapy                        Local excision,
                               immunotherapy,
                               radiation therapy
Metastases (later)             Lung, nodes, bone

Survival (months)              37



                               Case 2              Case 3

Age (years)                    58                  58
Race/sex                       White male          White male
Duration of symptoms (months)  6                   3
Size of mass (cm)              5                   4
Tumor thickness (mm)           18                  7
Metastases (at diagnosis)      Liver, lung, nodes  Liver
Therapy                        Abdominoperineal    Local excision,
                               resection,          chemotherapy,
                               chemotherapy        immunotherapy
Metastases (later)             Same                Lung, ribs, spleen,
                                                   brain, nodes.
Survival (months)              10                  8



                               Case 4

Age (years)                    59
Race/sex                       White male
Duration of symptoms (months)  4
Size of mass (cm)              6
Tumor thickness (mm)           5
Metastases (at diagnosis)      Lung, nodes
Therapy                        Chemotherapy
                               radiation therapy

Metastases (later)             Liver, kidney,
                               adrenal, stomach
Survival (months)              6

KEY POINTS

* Anal melanoma is easily confused with hemorrhoids in the initial diagnosis of bleeding anorectal lesions.

* At the time of diagnosis, anal melanoma is often widely metastatic and carries a grave prognosis.

* Current surgical and chemoimmunotherapeutic combinations may be effective for disease control, and there are rare reports of prolonged survival.

* Apparent hemorrhoids that enlarge, are pigmented, ulcerated, or indurated, and persist despite conservative therapy, should be evaluated for melanoma.