HIV-Negative African American Man with Gastrointestinal Kaposi Sarcoma Associated with Adalimumab Treatment for Cardiac Sarcoidosis: A Case Report

Introduction

Kaposi sarcoma is a vascular tumor that can be classified into classic, endemic, acquired immune deficiency syndrome (AIDS)-related, and immunosuppression-associated [1]. Kaposi sarcoma is caused by human herpesvirus-8 (HHV-8), also known as Kaposi sarcoma-associated herpesvirus. Effective T-cell responses are important to suppress HHV-8 reactivation and limit disease progression. In the immunocompromised host, HHV-8 infection results in viral oncogenesis through abnormal cytokine expression, cell survival, proliferation, and angiogenesis [1,2]. Classically, Kaposi sarcoma presents as a cutaneous lesion such as a macule, papule, or nodule. Gastrointestinal involvement may be asymptomatic or present as gastrointestinal bleeding, abdominal pain, or weight loss [3]. The awareness of immunosuppression-related Kaposi sarcoma is still suboptimal. It has been reported in patients receiving tumor necrosis factor-alpha (TNF-α) inhibitors, including adalimumab. The proposed mechanism involves immunosuppression leading to reactivation of latent HHV-8 that in turn causes upregulation of growth factors and uncontrolled proliferation of endothelial and smooth muscle cells. Previously, case reports have described Kaposi sarcoma development primarily in patients treated with adalimumab for autoimmune conditions [4,5]. Given the non-specific and highly variable clinical presentation and the need for endoscopic biopsies, the diagnosis of gastrointestinal Kaposi sarcoma is often missed. Timely diagnosis is essential, as the prognosis in advanced cases is poor. This report describes the case of a 65-year-old HIV-negative man with gastrointestinal Kaposi sarcoma associated with adalimumab treatment for cardiac sarcoidosis.

Case Report

A 65-year-old man presented with a chief complaint of bright red blood per rectum and abdominal pain for 5 days. He also reported nausea and weight loss of 30 pounds in 2 months. His past medical history was notable for cardiac sarcoidosis with cardiomyopathy, for which he was chronically on prednisone 10 mg daily and adalimumab 40 mg subcutaneously every 2 weeks. He was also on apixaban for atrial fibrillation. He had a sinus tachycardia of 108 per minute on presentation and other vital signs were stable. The physical exam was remarkable for pallor and a distended but non-tender abdomen with normal bowel sounds. Laboratory test results revealed a hemoglobin of 10.1 (ref: 13.2–16.6) g/dL from a baseline of 12.4 g/dL, blood urea of 36.8 (ref: 8–24) mg/dL, and serum creatinine of 1.63 (ref: 0.7–1.35) mg/dL. Liver functions were within normal range. A computerized tomography (CT) scan of the abdomen and pelvis without intravenous contrast was unremarkable. Although a contrast study would have provided higher sensitivity for infectious or neoplastic lesions, it was deferred due to the elevated renal functions. He underwent esophagogastroduodenoscopy (EGD) and colonoscopy to investigate the source of the gastrointestinal bleeding. EGD revealed a normal esophagus and 3 localized erythematous spots (Figure 1) with no stigmata or recent bleeding in the gastric body. The colonoscopy identified a 2 mm sessile polypoid lesion in the sigmoid colon (Figure 2). Biopsies were taken with cold forceps. Histopathology from both the gastric body (Figure 3) and the sigmoid colon (Figure 4) revealed lamina propria spindle cell proliferations with mild atypia, scattered slit-like spaces, and extravasated red blood cells. Immunohistochemical staining was positive for CD34 and latency-associated nuclear antigen, detecting the presence of HHV-8, confirming the diagnosis of Kaposi sarcoma.

Following the diagnosis of Kaposi sarcoma, HIV screening was performed, and was negative. Adalimumab was discontinued. Due to the patient’s cardiomyopathy, anthracyclines, which are typically the first-line treatment for Kaposi sarcoma, were contraindicated. Paclitaxel was selected as the primary systemic chemotherapy. He was treated with 9 cycles of paclitaxel (140 mg/m2), administered every 21 days. He developed neuropathy as an adverse effect that required dose reduction for the last 3 cycles and symptomatic treatment with gabapentin (200 mg 3 times a day). Imaging during therapy did not show any disease progression. After completion of chemotherapy, he underwent repeat EGD and colonoscopy. The results demonstrated resolution of previous lesions and no new abnormalities (Figures 5, 6). He is currently on follow-up with active surveillance, 18 months after the completion of paclitaxel treatment.

Discussion

Immunosuppression-associated Kaposi sarcoma can be seen in solid organ transplant recipients or patients on immunosuppressive therapy for other indications, like our patient with sarcoidosis [3]. Adalimumab is a fully human monoclonal antibody that inhibits TNF-α, a key cytokine involved in inflammatory and immune responses. It is widely used to treat autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, and cardiac sarcoidosis [6,7]. Due to its immunosuppressive mechanism, it can increase the risk of infections and malignancies [6], including rare complications like Kaposi sarcoma as described here. The clinical course of Kaposi sarcoma varies between the underlying predispositions. Kaposi sarcoma associated with HIV infection typically follows an aggressive clinical course characterized by widespread mucocutaneous, visceral, and lymphatic involvement [1]. Patients with HIV-associated Kaposi sarcoma often require systemic chemotherapy in addition to highly active antiretroviral therapy (HAART), and the prognosis can be poor if immune reconstitution is not achieved. In contrast, non-HIV Kaposi sarcoma, including immunosuppression-associated Kaposi sarcoma, tends to have a more indolent behavior [8]. In these cases, withdrawal of immunosuppressive therapy alone can lead to significant regression or even complete resolution in mucocutaneous-limited Kaposi sarcoma, while those with other organ system involvement respond well to systemic chemotherapy [8]. Gastrointestinal involvement is seen mostly in men (92–98%) and often involves the age group of 35–45 years. Gastrointestinal involvement in Kaposi sarcoma may occur without cutaneous lesions, making the diagnosis challenging [9]. Prompt investigation with upper and lower gastrointestinal endoscopy is important to make the diagnosis. The endoscopic appearance can vary, including ulcers, macules, nodules, or polypoid lesions [10]. Histopathological examination is the gold standard for diagnosing Kaposi sarcoma, but significant false-negative reports are encountered due to the submucosal nature of Kaposi sarcoma lesions [11]. Without mucosal involvement, superficial biopsies tend to miss the tissue involved. The varied endoscopic appearance and concerns about bleeding during biopsies can further lead to lower yield. Therefore, multiple deep endoscopic biopsies are recommended to improve sensitivity [12]. Endoscopic ultrasound-guided biopsies have also been shown to improve diagnosis [12]. Mucocutaneous Kaposi sarcoma is the common variant seen in immunosuppression-associated cases, while other organ involvement is less common [8,13]. Tabak et al [4] described a patient with rheumatoid arthritis on adalimumab who developed violaceous skin lesions. Histology confirmed Kaposi sarcoma and the lesions regressed after adalimumab was stopped. Amadu et al [5] reported a patient on adalimumab for psoriatic arthritis who presented with hemorrhagic skin nodules in the lower extremities. Histopathology confirmed Kaposi sarcoma, following which adalimumab was discontinued. They were both limited to cutaneous involvement only. Our case of adalimumab-associated Kaposi sarcoma is unique as the patient had upper and lower gastrointestinal Kaposi sarcoma without any skin lesions.

Treatment of Kaposi sarcoma depends on the underlying risk factor. If AIDS-related, prompt initiation of HAART, with or without chemotherapy, is essential. Liposomal doxorubicin, paclitaxel, and vinblastine are the preferred chemotherapeutic agents [14]. Treatment of immunosuppression-associated Kaposi sarcoma includes adjusting or stopping the patient’s immunosuppressive therapy, and administering Kaposi sarcoma-specific chemotherapy. Anti-angiogenic agents like bevacizumab and pomalidomide have recently shown promising results for advanced Kaposi sarcoma [15]. They also alter the tumor microenvironment by regulating angiogenesis, which has been shown to play a key role in immune evasion by malignant cells. Immunotherapy, including interferon and checkpoint inhibitors, is being studied in the management of systemic Kaposi sarcoma [15]. Checkpoint blockage improves cellular immunity against HHV-8 and reduces the proliferation of tumor cells [15]. Standard guidelines for managing Kaposi sarcoma caused by immunosuppression are lacking, highlighting the importance of a multidisciplinary approach [16]. Despite therapeutic advancements, the prognosis of gastrointestinal Kaposi sarcoma remains poor, especially if advanced at the time of diagnosis. A recent large study showed that the overall survival in gastrointestinal Kaposi sarcoma was 98.5 (±6.8) months [17]. Those with large bowel involvement had longer survival than those with esophageal, small bowel, liver, or pancreatic involvement [17]. In summary, gastrointestinal Kaposi sarcoma should be considered in those with risk factors (AIDS, immunosuppression) presenting with gastrointestinal bleeding or other unexplained abdominal symptoms. Timely endoscopy with biopsy and treatment can be lifesaving in the management of this aggressive disease in these vulnerable patient populations.

Conclusions

This report describes the rare association between adalimumab treatment and Kaposi sarcoma. It also emphasizes the importance of maintaining a high index of suspicion for gastrointestinal Kaposi sarcoma in immunocompromised patients presenting with non-specific symptoms, such as intermittent or minor gastrointestinal bleeding. There is significant variability in clinical and endoscopic presentations. Timely diagnosis and treatment are important to improve outcomes in gastrointestinal Kaposi sarcoma. The case also showcases an effective treatment plan using paclitaxel in a patient in whom standard anthracycline-based regimens were contraindicated due to underlying cardiomyopathy. Treatment guidelines are needed in the management of immunosuppression-associated Kaposi sarcoma for standardized care and improved outcomes. A multidisciplinary approach, including internists, gastroenterologists, and oncologists is vital in the care of these patients. Due to the rarity of iatrogenic Kaposi sarcoma associated with TNF-α inhibitors, the need for vigilance in monitoring for malignancies in patients undergoing such therapies is emphasized.