Appendicitis Secondary to Metastatic Melanoma: Review of the National Institutes of Health Experience

Importance  Malignant melanoma has an unusual propensity to metastasize to the small bowel; however, malignant melanoma with metastatic spread to the appendix presenting as acute appendicitis has rarely been reported. We describe cases of melanoma of the appendix presenting with appendicitis and review our institutional experience with this entity.

Observations  Medical records were reviewed in patients with melanoma at the National Cancer Institute between January 1, 1953, and December 31, 2010, who underwent appendectomy. Of 5822 cases of melanoma treated at the National Institutes of Health, appendectomies were performed on 31 patients, 2 of whom had acute appendicitis secondary to malignant obstruction and presented with symptoms of vague abdominal pain. Both patients had been heavily pretreated for metastatic melanoma and had multiple sites of intraperitoneal and extraperitoneal disease. On exploratory laparotomy, both patients showed clinical evidence of acute appendicitis, and an appendectomy was performed. Both patients recovered fully from the operation and proceeded to further systemic therapy.

Conclusions and Relevance  Although rare, the diagnosis of appendicitis should be considered in patients with melanoma and acute abdominal pain. Timely surgical intervention may allow palliation and the ability to pursue subsequent systemic treatment.

The incidence of malignant melanoma has been increasing in the past 3 decades, and it was estimated there would be 76 690 new cases and 9480 deaths in 2013 in the United States.¹ Although it is the least common of all cutaneous cancers, malignant melanoma accounts for most skin cancer deaths. This high mortality rate is attributed to the aggressive biological characteristics of advanced lesions, high metastatic potential, and low response rate of currently available systemic therapies.^2,3 Melanoma has an unusual propensity to metastasize to the gastrointestinal (GI) tract, with the small bowel being the most common site of GI metastasis (35%-58%), followed by the colon (14.5%-31.3%), stomach (7%-20%), duodenum (12%), and esophagus (4%).^4-7 Symptoms of GI metastases vary widely, from the asymptomatic lesion to occult or frank bleeding, intussusception, and/or bowel obstruction.^8,9 We present 2 cases of acute appendicitis secondary to metastatic melanoma and review our institutional experience with this entity.

A white woman in her 30s with metastatic malignant melanoma from an unknown primary tumor presented with vague abdominal pain and 2 weeks of fevers. Her disease was diagnosed 1 year earlier from an excisional biopsy of a left breast mass. Staging workup revealed advanced metastatic disease that was subsequently treated with interleukin 2 (aldesleukin) and experimental immunotherapy. Her most recent evaluation revealed a persistent, large soft-tissue pelvic mass in addition to bone, lung, and pancreatic metastases.

Her symptoms were accompanied by abdominal distension, anorexia, and weight loss without nausea, vomiting, or changes in bowel habits. Four weeks before presentation, she was diagnosed as having newly appreciated ascites. At that time, a paracentesis was performed, and cultures revealed Bacteroides and Enterobacter bacterial peritonitis. Blood cultures also yielded Bacteroides bacteremia. She began antimicrobial therapy; however, she continued to experience intermittent febrile episodes. On physical examination, she was in minimal distress, with a slightly distended abdomen with succussion splash and tenderness on deep palpation in the lower abdomen without evidence of overt peritonitis or guarding. Temperature was 37.1°C, and the white blood cell count was 5.03 ×10³/μL (reference range, 3.4-8.5 ×10³/μL) (to convert to ×10⁹ per liter, multiply by 0.001) with 72.6% neutrophils (to convert to a proportion of 1.0, multiply by 0.01). Computed tomography showed a moderate amount of ascites, and the appendix could not be visualized. Progression of her cancer was noted in all known sites, including moderate enlargement of the soft-tissue pelvic mass. She was taken to the operating room for exploratory laparotomy with palliative intention. On exploration, the soft-tissue pelvic mass appeared to originate from the left ovary, and there was evidence of a fibrinous abscess cavity in the right lower quadrant adjacent to the cecum. A hard tumor measuring approximately 4 cm was palpated in the body of the appendix with associated tip edema and erythema, consistent with acute appendicitis (Figure 1). Appendectomy was performed, along with resection of the large pelvic tumor. The patient defervesced postoperatively, with improvement of her abdominal pain and restoration of her appetite. After an uneventful recovery from surgery, she was discharged to home on postoperative day 7. Pathological evaluation of the appendix revealed a 4-cm malignant melanoma with necrosis causing obstruction of the appendiceal lumen and acute appendicitis without evidence of frank perforation. Immunohistochemical staining of the tumor was positive for HMB-45.

A white man in his 50s with metastatic malignant melanoma presented with right lower quadrant pain of 1 week’s duration. Melanoma had been diagnosed 3 years earlier from a 5.94-mm, nonulcerated, left flank cutaneous primary lesion with 1 positive sentinel lymph node. He developed widespread metastatic disease 1 year later and was treated with multiple regimens, including interleukin 2 (aldesleukin), dacarbazine/cisplatin chemotherapy, and experimental immunotherapy. Evaluation of known disease sites disclosed multiple subcutaneous and intraperitoneal nodules.

The patient presented with 1 week of worsening right lower quadrant abdominal pain and mild nausea without vomiting, fever, chills, or changes in bowel habits. On physical examination, he was in moderate distress with abdominal guarding, right lower quadrant tenderness, and rebound. His temperature was 38°C, and the white blood cell count was 8.98 ×10³/μL (reference range, 3.3-9.6 ×10³/μL) with 82% neutrophils. Abdominal ultrasonography showed a large 8 × 9-cm mass in the right lower quadrant. The appendix was not visualized. Computed tomography showed appendiceal wall thickening, an associated fluid collection, and an extensive pelvic tumor (Figure 2). Exploratory laparotomy was performed and revealed dense adhesions in the right lower quadrant. Lysis of adhesions uncovered a large purulent abscess around an indurated appendix with perforation at the tip (Figure 3). The base of the appendix and cecal wall were unremarkable. Appendectomy was performed, the patient recovered uneventfully, and he was discharged on postoperative day 11. Pathological studies revealed metastatic melanoma to the appendix with extensive vascular invasion, acute appendicitis with perforation, and marked serositis. MART-1, S100, HMB-45, and tyrosinase immunohistochemical stains of the appendiceal melanoma were positive.

With an interest in developing experimental protocols for patients with malignant melanoma, the National Cancer Institute at the National Institutes of Health has served for decades as a quaternary referral center for many patients with melanoma. A retrospective review of the prospectively collected database from January 1, 1953, through December 31, 2010, at the Clinical Research Center identified 5822 patients with melanoma. Thirty-one patients underwent appendectomy for appendicitis (3 cases), as incidental appendectomy during laparotomy (16 cases), or as part of a right hemicolectomy or ileocecectomy (12 cases). The patients included 14 men and 17 women, and the median age was 42 years (range, 27-68 years). Of the 3 patients who underwent an appendectomy for acute appendicitis, 2 were secondary to metastatic melanoma and 1 was secondary to nonmalignant causes. Therefore, the 57-year incidence of appendicitis secondary to melanoma in an institution heavily biased toward stage IV disease was 2 (the 2 case reports described above) of 5822 or 0.03%.

Acute appendicitis is the most common intra-abdominal surgical emergency and leads to approximately 250 000 appendectomies performed in the United States every year.¹⁰ Although acute appendicitis can be readily managed with an appendectomy with very little morbidity, it can lead to intra-abdominal catastrophe with high morbidity when misdiagnosed. The exact incidence of acute appendicitis secondary to luminal obstruction from metastatic deposit is unclear and limited to single-institution case reports¹¹; however, the diagnosis of appendicitis may be overlooked in patients with a history of cancer because of vague symptoms, concomitant abdominal conditions or metastases, and side effects of ongoing therapies. Patients with metastatic melanoma may pose a particular diagnostic challenge because melanoma commonly metastasizes to the GI tract, making the diagnosis of acute appendicitis difficult, as demonstrated in this report.

Letovanec et al¹² described a patient with no known history of melanoma who presented with right lower quadrant pain and ultrasonographic findings suggestive of periappendiceal abscess or tumor. The patient underwent appendectomy and right hemicolectomy, and pathological analysis revealed malignant melanoma. Letovanec and colleagues were unable to determine whether this was a primary or metastatic lesion, and additional imaging demonstrated multiple liver metastases. Unlike this first case report, both of our patients had a known history of melanoma and were heavily pretreated with multiple modalities. The pathophysiological features of acute appendicitis in these 3 patients are secondary to luminal obstruction, as in other forms of appendiceal obstruction (eg, lymphoid hyperplasia, fecalith, or foreign body obstruction) leading to acute appendicitis.

Although targeted therapies are being developed, the overall prognosis of metastatic malignant melanoma is extremely poor, with a 10-year survival rate of less than 10% and a median survival of 6 to 9 months.^9,13 Until recently, only 2 agents were approved by the US Food and Drug Administration for treatment of metastatic melanoma: dacarbazine and high-dose interleukin 2, approved in 1975 and 1998, respectively. In 2011, two additional agents were approved for the treatment of metastatic melanoma: ipilimumab and vemurafenib. Available systemic therapy for metastatic melanoma can be categorized broadly into cytotoxic chemotherapy (eg, dacarbazine, temozolomide, and taxanes), immunotherapy (high-dose interleukin 2, ipilimumab), biochemotherapy (interleukin 2 with or without interferon alfa combined with chemotherapy), targeted therapy (vemurafenib), and investigational modalities (adoptive cell therapy, vaccines, antiangiogenic agents, and other targeted therapies using small-molecule inhibitors).^3,13-16 Adoptive cell therapy using lymphodepletion and infusion of autologous tumor-infiltrating lymphocytes has shown an objective response rate in up to 72% of patients with refractory melanoma.¹⁷

The prognosis of patients with GI metastasis who are unresponsive to systemic therapy is poor, with a median survival of only 5 to 11 months.¹⁸ Many of these patients can present with symptoms, such as pain, bleeding, or obstruction, that necessitate surgical intervention. Such patients can derive significant symptom palliation from surgical intervention, with acceptable morbidity and mortality.^9,19 Several institutional reviews suggest a survival advantage of surgical intervention in patients with GI metastases when complete or near-complete resection of metastatic deposits is feasible.^6,8,18-23 Palliative and potentially therapeutic surgery for melanoma metastatic to the GI tract should be pursued in select patients, especially in those with suspected acute appendicitis secondary to a metastatic lesion, as demonstrated in our report. Acute appendicitis should be included in the differential diagnosis in these patients. Such an approach may also serve as a bridging intervention to ever-evolving systemic therapies for treatment of metastatic malignant melanoma.

Corresponding Author: Mio Kitano, MD, Department of Surgery, Albert Einstein College of Medicine, 3400 Bainbridge Ave, MAP4, Bronx, NY 10467 (mkitano@montefiore.org).

Published Online: May 28, 2014. doi:10.1001/jamasurg.2013.4067.

Author Contributions: Drs Kitano and Maker had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Kitano, Maker, Danforth, Kammula.

Acquisition, analysis, or interpretation of data: Kitano, Maker, Lanier, Kammula.

Drafting of the manuscript: Kitano, Maker, Lanier, Kammula.

Critical revision of the manuscript for important intellectual content: Lanier, Danforth, Kammula.

Statistical analysis: Kitano, Kammula.

Administrative, technical, or material support: Kitano, Lanier, Danforth.

Study supervision: Maker, Kammula.

Conflict of Interest Disclosures: None reported.