Abstract
Coexistence of multicentric Castleman disease and Kaposi sarcoma is rare and might be missed without an experienced pathologists’ interpretation. A 46-year-old man had been diagnosed with HIV infection and treated with combination antiretroviral therapy of dolutegravir/abacavir/lamivudine (Triumeq) for one year. The latest viral load was 49 copies/mL and CD4 T-cell count was 192 cells/uL. He was admitted due to fever off and on, splenomegaly, general lymphadenopathy, and severe thrombocytopenia for two months. Biopsy of a purplish skin lesion and gastric tissue showed Kaposi sarcoma. The pathology of inguinal lymph nodes revealed coexistence of Kaposi sarcoma and multicentric Castleman disease. The plasma Kaposi sarcoma herpesvirus viral load was 365,000 copies/mL. During hospitalization, progressive pancytopenia and spiking fever persisted, and he died of multi-organ failure before completion of chemotherapeutic treatments with rituximab plus liposomal doxorubicin.
Keywords
Introduction
Classic Kaposi sarcoma (KS) is an indolent tumor that usually occurs in elderly men. Human immunodeficiency virus (HIV)–associated KS may have more rapid progression, dissemination, and mortality. 1 Human herpesvirus 8, also known as Kaposi sarcoma–associated herpesvirus (KSHV), was found to be the causative pathogen of HIV-associated KS. In addition to KS, KSHV is associated with multicentric Castleman disease (MCD) and KSHV inflammatory cytokine syndrome. Herein, we report a rare case of disseminated KS with MCD in an HIV-infected patient under viral suppression.
Case report
A 46-year-old man presented with intermittent fevers for two months, accompanied with chills, dry cough, malaise, dizziness, vomiting, epigastric discomfort, poor appetite, and weight loss of 8 kg in the past six months. He had been an office worker and denied special travel, contact, and cluster history. He was known to have sex with men and was diagnosed with HIV infection one year before. No obvious skin lesions or gastrointestinal discomfort was found or complained of at the time of diagnosis. No opportunistic infections such as pneumocystis pneumonia or pulmonary tuberculosis were found at that time point. He had been followed up at the outpatient department since diagnosis, taking antiretroviral therapy with dolutegravir 50 mg/abacavir 600 mg/lamivudine 300 mg. The HIV viral load had decreased from 620,000 to 49 copies/mL, and the CD4+ T-cell count had increased from 17 to 192 cells/uL in the past one year.
Fever evaluations during outpatient follow-ups were remarkable for progressive cytopenia, elevated values of inflammatory markers, and splenomegaly with bilateral inguinal lymphadenopathy on computed tomography (CT) imaging. The gallium-67 inflammation scan showed no active inflammatory process. He was admitted due to fever of unknown origin. The initial vital signs were as follows: temperature, 39.2°C; pulse rate, 106 beats per minute; respiratory rate, 18 breaths per minute; and blood pressure, 107/65 mmHg. On exam, irregular purplish macules were found on his body (Figure 1(a)). (a) Irregular violaceous macules on the patient’s left shoulder. (b) Hemorrhagic gastritis over the whole stomach. (c) Pathology of gastric biopsy revealed stomach tissue with hemorrhage. Focal spindle cells were seen and highlighted by KSHV immunohistochemical staining (inset), which was consistent with Kaposi sarcoma. (d–f) Pathology of inguinal lymph nodes. (d) Proliferation of spindle cells arranged in whorled and fascicular patterns with slit-like spaces containing red blood cell extravasation. These spindle cells were positive for CD34, ERG, and KSHV (not shown). (e) The lymph node showed prominent interfollicular and mantle zone plasmacytosis. There was also proliferation of plasmablasts (arrows and inset) in the expanded mantle zone. (f) KSHV immunohistochemical staining highlighted the localization of plasmablasts in the mantle zone, which was consistent with multicentric Castleman disease. KSHV: Kaposi sarcoma–associated herpesvirus.
Bone marrow biopsy, done for pancytopenia and suspicion of lymphoma with bone marrow involvement, revealed no evidence of lymphomatous involvement but increased plasma cells with unknown significance. Excisional biopsy of the skin lesion disclosed KS. Esophagogastroduodenoscopy, done for vomiting and epigastric discomfort, revealed hemorrhagic gastritis over the whole stomach (Figure 1(b)); the pathology of the gastric biopsy was consistent with KS (Figure 1(c)). The whole-body CT scan for staging showed diffuse lymphadenopathy from cervical to femoral regions. Excisional biopsy of the left inguinal lymph node disclosed coexistence of MCD and KS (Figure 1(d) to (f)). The plasma KSHV viral load was 365,000 copies/mL by real-time polymerase chain reaction. 2
Since hospital day 15, the patient developed rapidly progressive jaundice and renal impairment, hypoalbuminemia, and severe pancytopenia (white blood cell count, 1360/μL; hemoglobin, 7.9 g/dL; platelet, 5000/μL; creatinine, 3.7 mg/dL; total bilirubin, 32.16 mg/dL; direct bilirubin, 31.50 mg/dL; and albumin, 1.8 g/dL). Disseminated KS with MCD and inflammatory cytokine syndrome was considered. On hospital day 22, he developed sudden coma and died quickly before completion of rituximab and liposomal doxorubicin. Bacterial cultures of blood, urine, stool, and bone marrow; mycobacterial culture of blood, urine, stool, and bone marrow; and fungal culture of blood and bone marrow all yielded no pathogens.
Discussion
We report a case of disseminated KS and MCD in an HIV-infected patient under viral suppression. A strong inverse association between CD4+ count and risk of KS is well established, and the KS incidence among HIV-infected patients has lowered greatly after the introduction of antiretroviral therapy. 1 However, worsening of previous KS lesions has been described as a presentation of immune reconstitution inflammatory syndrome (IRIS) after initiation of antiretroviral therapy. 3 In our case, the seemingly successful HIV treatment course did not preclude a diagnosis of KS, as reported previously.4,5 MCD, arising notably in HIV-infected patients, is characterized by inflammatory symptoms. 1 If left untreated, the cytokine storms can be fatal.1,5 Both KS and MCD are inflammatory and neoplastic conditions associated with KSHV and HIV infections. 6 KSHV viral load may reflect the severity of the two diseases.7,8
There is literature reporting concurrent MCD and KS.9–11 Volkow-Fernandez et al. reported as high as 79% of patients with Castleman disease had coexistent KS in an oncology institution. While the two diagnoses were often made in different tissues, for example, skin and lymph node biopsies, the coexistence of KS and MCD in the same tissue was less commonly reported.12–14 The microscopic foci of KS spindle cells in lymph nodes may be subtle and can be missed on even immunohistochemical staining. 12 The identification of both diseases on pathology is crucial because the therapeutic targets may be different, and patients with untreated MCD are at higher risk of large B-cell lymphoma. 1 Notably, the gallium-67 inflammation scan did not reveal KS and MCD, which was also reported previously.15,16 This characteristic may help differentiate the condition from lymphoma.
In our patient, a poor prognosis was expected due to disseminated KS and concurrent MCD. Systemic chemotherapy was indicated in such condition, and liposomal doxorubicin is the most used agent. 1 Rituximab, a monoclonal antibody targeting CD20, can be applied concomitantly because of the coexistence of MCD. 6 Exclusion of opportunistic infections before chemotherapy is mandatory. Cornejo-Juárez et al. found 20% of blood marrow cultures to be positive for Mycobacterium avium complex or Histoplasma in HIV patients with KS, 17 even in those without cytopenia. A bone marrow study was suggested to detect opportunistic infections in HIV patients with KS before chemotherapy, thus preventing further complications.
This case highlights that KS can occur in patients under viral suppression or appear as a presentation of IRIS. Both KS and MCD could not be detected on gallium-67 scan. While coexistence of KS and MCD in the same tissue could be missed, it is clinically important to identify both diseases because of different treatment strategies. A delay in diagnosis and treatment may lead to prominent inflammatory cytokine syndromes and poor prognosis. Exclusion of opportunistic infections before chemotherapy is suggested.
Footnotes
Acknowledgements
We would like to thank Dr Chien-Ching Hung and Prof Sui-Yuan Chang for their help in the test of KSHV viral load.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a research grant from E-Da Hospital (EDAHP109036). The funder played no role in study design, data collection and analysis, decision to publish, or manuscript preparation.
