Synchronous visceral Kaposi sarcoma and extracavitary primary effusion lymphoma in a patient with AIDS

Abstract

While infection should always lead the differential when a patient with AIDS presents with fever, inflammatory and malignant aetiologies should also be considered. With profound immunocompromise, malignancies can develop as sequelae of viral oncogene expression. Human herpesvirus 8 (HHV-8) infection drives several AIDS-related cancers including Kaposi sarcoma (KS), multicentric Castleman disease and primary effusion lymphoma (PEL), which can present simultaneously with variable clinical features. Herein, we describe a case of synchronous visceral KS and extracavitary PEL in a patient with AIDS. The patient was treated with systemic chemotherapy and remains in remission after four cycles. We review other cases of copresenting HHV-8-related malignancies, explore the salient pathomechanisms and clinical features of these cancers and discuss treatment strategies.

Background

An increased risk of certain malignancies, such as aggressive B-cell lymphomas, Kaposi sarcoma (KS) and invasive cervical cancer, was one of the earliest defining features of AIDS. The observation that, among populations at risk for HIV infection, men who have sex with men had increased incidence of KS prompted hypotheses that this tumour had an infectious origin.¹ Following this line of thinking, the first oncovirus, KS-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), was causally linked to both KS and a group of B-cell lymphoproliferative disorders: multicentric Castleman disease (MCD) and primary effusion lymphoma (PEL).² Serology studies suggest that HHV-8 infection is widespread in Africa with 30%–60% seropositivity, but much less prevalent in the USA and Europe, ranging from 3% to 10%.³ However, these rates are much greater in high-risk populations, reaching 38% among patients at AIDS clinical trials centres.⁴ As such, the development of HHV-8-associated malignancies can be a major source of morbidity in this population.

In the beginning of the AIDS epidemic, between 20% and 50% of patients developed KS in the US.⁵ However, the incidence has decreased by up to 80% due to better viraemic control and preservation of immune capacity by combined antiretroviral therapy (cART).⁶ Despite therapy, patients with AIDS-associated KS have an increased risk of death with a median survival after diagnosis of 3 years.^{7 8}

PEL is a rare malignancy associated with HHV-8, accounting for only 1%–4% of all AIDS-related lymphomas.⁵ Unfortunately, morbidity is high with median survival of 3–9 months despite treatment with modern chemotherapeutic regimens.⁹

The copresentation KS and PEL is an even less common occurrence despite the fact that both cancers are driven by the same viral process. Data are lacking to describe the true relationship between these two HHV-8-related malignancies. Herein, we present what is to the best of our knowledge, the first case of disparate, synchronous visceral KS and extracavitary PEL in a patient with AIDS.

Case presentation

A man in his 20s with known HIV presented to the emergency department with 2 weeks of intractable nausea, vomiting, fatigue, dry cough, dyspnoea, neck pain and subjective fevers. He reported significantly decreased oral intake and a 15-pound unintentional weight loss. He denied any headache, chest pain, sputum production, abdominal pain, dysuria or melena. His medical history was significant for HIV with inconsistent cART use, neurosyphilis 1 year prior adequately treated with penicillin, and polysubstance use disorder, particularly heroin and alcohol, though had remained abstinent for over a year. He worked as a busboy and was sexually active with males. On examination, he was febrile to 39.4°C, tachycardic with a heart rate of 154 beats per minute and hypotensive at 84/49 mm Hg, though oxygenating adequately on room air. He was thin, ill appearing and diaphoretic.

Investigations

His initial set of basic labs were significant for a hypoproliferative anaemia, thrombocytopaenia, hyponatraemia and a significant lactataemia. C reactive protein (CRP) was elevated to 16.4 mg/dL (normal <0.3 mg/dL) and erythrocyte sedimentation rate (ESR) to 105 mm/hour (normal 0–22 mm/hour). His immunocompromised state was confirmed with a CD4 count of 19 cells/mm³ (normal 500–1200 cells/mm³) and viral load of 37 000 copies/mL. His ferritin was 5193 ng/mL (normal 20–250 ng/mL) and triglycerides 208 mg/dL (normal <150 mg/dL). Soluble IL2 receptor was detected at 4086.7 U/mL, greater than two SD above the age-adjusted norm. IL-6 was likewise elevated at 22.7 pg/mL (normal 9–16.4 pg/mL). Multiple sets of blood cultures from different draw sites returned negative. Analysis of urine revealed no infectious process. Sputum cultures for both typical and mycobacterial organisms produced only normal flora. Lumbar puncture was non-infectious, with only one nucleated cell per high power field and normal cerebrospinal fluid (CSF) glucose and protein. Herpes simplex virus, John Cunningham virus, varicella zoster virus and Epstein-Barr virus (EBV) nucleic material were not amplified from CSF. Specific bacterial tests like clostridium difficile and mycobacterial polymerase chain reactions were unrevealing. Both fungal cultures and antibodies from blood and CSF showed no evidence of coccidiodes, blastomyces, histoplasma or aspergillus. Viral testing for SARS-CoV-2, hepatitis B and C, parvovirus B19, influenza and RSV were negative. However, very low viral loads of cytomegalovirus (CMV) (1400 copies/mL) and EBV (37 400 copies/mL) were detected in blood as well as a moderate viral load of HHV-8 (181 000 copies/mL).

Cranial CT imaging demonstrated ex vacuo dilation of the ventricles out of proportion to the patient’s age but no infectious or inflammatory focus intracranially. Cross-sectional CT imaging through the thorax showed moderately sized bilateral non-loculated pleural effusions with a minor amount of compressive atelectasis at the lung bases. Sampling determined this fluid to be transudative by Lights’ criteria without leukocytosis or colonisation. Diffuse lymphadenopathy with a 2.4 cm node in the left axilla were also noted (figure 1). Echocardiogram demonstrated normal ventricular motion without valvular abnormalities or vegetations. Imaging of the abdomen demonstrated mild, diffuse lymphadenopathy, splenomegaly, mild anasarca and a non-specific soft tissue density adjacent to the pylorus, which was subsequently interrogated by oesophagogastroduodenoscopy. A large, erythematous polypoid vascular mass was discovered at the lesser curvature and incisura of the stomach and biopsied (figure 2). Pathological analysis revealed whorls of spindle-shaped cells with leukocytic infiltration, neovascularisation with aberrant proliferating small vessels, and presence of HHV-8 (figure 3). The large lymph node in the left axilla was also targeted for excisional biopsy. Microscopic sections showed nodular infiltrates of atypical, large-sized cells with round to mildly irregular nuclei, coarse chromatin, distinct nucleoli and moderate amounts of basophilic cytoplasm, as well as necrosis and mitotic figures. The cells were positive for latency-associated nuclear antigen (LANA)-1, CD138, HHV8, EBV in situ hybridisation and lambda-restricted kappa/lambda in situ hybridisation. They were negative for T-cell markers (CD3, CD5) and B-cell markers (PAX-5, CD20 and CD79a) (figure 4).

Figure 1.

Axial contrast-enhanced CT demonstrating nodular lymphadenopathy in the left axillary space (green arrow).

Figure 2.

Oesophagoduodenoscopy demonstrated a polypoid, vascular tumour located at the incisura of the stomach.

Figure 3.

These histological sections show mildly pleomorphic spindled endothelial cells forming intersecting fascicles with slit-like blood-filled spaces, extravasated erythrocytes and haemosiderin deposition. These cells are positive for HHV8 immunohistochemical staining. (A) H&E, ×100; (B) H&E, ×200; (C) H&E, ×500; (D) HHV8 immunohistochemical stain, ×200. HHV8, human herpesvirus 8.

Figure 4.

These microscopic sections show nodular infiltrates of atypical large-sized cells with round to mildly irregular nuclei, coarse chromatin, distinct nucleoli, and moderate amounts of basophilic cytoplasm. Necrosis and mitotic figures are seen. These cells are positive for HHV8 immunohistochemical staining and EBV in situ hybridisation, indicated by brown nuclear staining and black nuclear staining, respectively. (A) H&E, ×100; (B) H&E, ×200; (C) H&E, ×500; (D) H&E, ×500; (E) HHV-8 immunohistochemical stain, ×200; (F) EBV in situ hybridisation, ×200. EBV, Epstein-Barr virus; HHV-8, human herpesvirus 8.

Differential diagnosis

The differential diagnosis for this immunocompromised patient initially presenting with persistent fevers, bicytopenia, and cachexia covers a broad spectrum of potential pathologies, both unique to his HIV status and independent of it. Infectious aetiologies were thought to be most likely, with meningitis of particular concern given his complaint of neck pain. Respiratory aetiologies were considered in light of his dyspnoea, as were gastrointestinal and urinary pathologies given his nausea and vomiting. As such, a broad infectious workup was undertaken, which ultimately was notable only for detectable HHV-8 in moderate levels, as well as low levels of EBV and CMV. Given these findings, cross-sectional CT imaging of the head, chest, and abdomen were performed to evaluate for a cryptic source to explain his persisting fevers.

With the initial favoured diagnostic category of infection less likely, malignant and autoimmune aetiologies came to the forefront. The persistent, non-proliferative anaemia in the absence of obvious bleeding appeared to have a central origin though without obvious cause for bone marrow suppression beyond generalised chronic disease. While HIV viraemia can cause some degree of myelosuppression, cART was held out of concern for precipitation of immune reconstitution inflammatory syndrome (IRIS) against an as-yet-determined pathological process.¹⁰ Haemophagocytic lymphohistiocytosis (HLH) was proposed as a potential unifying diagnosis and additional serum and flow cytometric tests were performed. The patient met diagnostic criteria according to the HLH-2004 trial with fever, splenomegaly, bicytopenia, hypertriglyceridaemia, elevated ferritin and soluble IL-2. His H-score, a tool developed to predict HLH, indicated a 90% likelihood.¹¹ Bone marrow biopsy looking for haemophagocytosis was proposed, but ultimately decided against provided the existing high likelihood of HLH and poor specificity of the finding. Given his relative clinical stability by the second week of his hospitalisation, immediate initiation of cytotoxic therapy for HLH was deferred. Rather, the search for a triggering condition, such as infection, rheumatological disease, or malignancy, was prioritised.

The finding of a vascular, polypoid mass in the stomach was the turning point of the case. Its appearance was classic for KS, which was confirmed on histological analysis (figure 3). The visceral involvement of his malignancy in conjunction with CD4 count <200 cells/uL and systemic symptoms placed him in the poor risk category according to the AIDS Clinical Trial Group.¹² Indeed, his presentation was consistent with KSHV inflammatory cytokine syndrome (KICS) given his persistent fever, anasarca, gastrointestinal and respiratory symptoms; however, this can only be diagnosed when MCD has been excluded.¹³ The presence of splenomegaly and diffuse lymphadenopathy raise suspicion for MCD. Treatment for KS would necessarily involve systemic chemotherapy. However, before initiating treatment, the presence of concurrent malignancy, particularly MCD, must be determined as it would alter the course of therapy. HHV-8 associated MCD was thought particularly likely given the lymphadenopathy, splenomegaly, and elevated ESR, CRP and IL-6 levels. Additionally, MCD and KS are commonly co-morbid.¹⁴ Therefore, the most accessible lymph node, in this case from the left axilla, was biopsied. Unexpectedly, the cell staining pattern was most suggestive of lymphoma. (figure 4) Given expression of both HHV-8 and EBV was seen, the differential diagnosis included germinotropic lymphoproliferative disorder, PEL, and HHV8-positive diffuse large B-cell lymphoma. As germinotropic lymphoproliferative disorder very rarely occurs in HIV positive patients, this was felt to be unlikely. HHV-8 positive diffuse large B-cell lymphoma was also considered but the EBV positivity and lack of expression of B-cell markers, such as CD20, made this less likely. As such, given the presence of atypical cells with EBV positivity, lack of expression of B-cell markers, the patient’s HIV status and their clinical symptoms, the diagnosis of PEL was felt to be most likely.^{15 16}

Thus, the final diagnosis for this patient was concurrent KS and PEL with likely involvement of HLH. He also met criteria for KICS, though this is a diagnosis of exclusion difficult to make because of significant symptom overlap with PEL. These diagnoses likely explain his systemic inflammatory response syndrome unresponsive to aggressive supportive care, cytopenias, and weight loss. The visceral KS may have further exacerbated his gastrointestinal symptoms, both through inflammatory mediators but also intermittent gastric outlet obstruction. His dyspnoea and cough were likely a result of persistent bilateral pleural effusions, which may have arisen as sequelae of PEL despite the lack of malignant cells found in the pleural fluid.

Treatment

The patient initially received empiric vancomycin, cefepime, ampicillin and acyclovir for presumed infection, possibly meningitis. These were later discontinued after the infectious workup returned negative. Throughout his stay, he required intermittent resuscitation with fluid and blood products.

Once the final diagnosis was determined, definitive treatment was initiated. Best practices for the management of PEL, let alone concurrent KS and PEL, are not well established. The patient was initiated on bortezomib in combination with etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (V-EPOCH) with intrathecal methotrexate, which has recently been demonstrated effective as frontline treatment of PEL.^17–19 The high-dose doxorubicin in this regimen designed for PEL was thought to be effective against the concurrent KS. His cART was re-started subsequent to the initiation of chemotherapy with prophylactic trimethoprim-sulfamethoxazole and valacyclovir.

Outcome and follow-up

His initial course of chemotherapy was complicated by pancytopenia and neutropenic fever, with concern for soft tissue infection at the site of his axillary lymph node biopsy. He received another course of broad-spectrum antibiotics as well as granulocyte colony stimulating factor and recovered. He was discharged 65 days after admission in stable condition with his presenting symptoms having resolved, only taking his combined ART and antimicrobial prophylaxis with atovaquone and acyclovir. He was felt to be in clinical remission after four cycles of chemotherapy but, unfortunately, has a poor long-term prognosis.

Discussion

An extensive literature review was conducted using PubMed for cases with both KS and PEL. A total of 8 cases of copresentation or sequential presentation of PEL and KS in the same patient were found. The oldest by Jones et al reports the development of cutaneous KS in a cardiac transplant patient without HIV. Although these lesions remitted with a decrease in immunosuppression, classical PEL was later found in a pleural effusion.²⁰ Both Lankester and Millet report the synchronous presentation of PEL in pleural fluid alongside disseminated KS in patients with AIDS.^{21 22} Disseminated KS and classical PEL in a patient with AIDS were also depicted by Fung. They managed to successfully treat both malignancies with six cycles of CHOP therapy. Unfortunately, the PEL relapsed in an extracavitary fashion and was refractory to salvage therapy.²³ Duncan describes an interesting case of the trifecta of HHV8-related malignancies in a patient with AIDS: sequential cutaneous KS, then inguinal MCD and finally a hepatic presentation of extracavitary PEL. They also treated with CHOP therapy supplemented by intrathecal methotrexate with successful remission and no recurrence during 3 years of follow-up.²⁴ An unusual intravascular presentation of PEL in a HIV-positive renal transplant patient was described by Cain. The extracavitary PEL was disseminated and KS was incidentally discovered on pathological review of a lymph node. HLH was also noted in the hepatic sinusoids, splenic red pulp and bone marrow.²⁵ Both Bruce-Brand and Kastenoreova also depict intravascular PEL, though present inside cutaneous KS lesions in a patient with AIDS and a man who had undergone long-term immunosuppression for multiple sclerosis, respectively.^{26 27} Finally, a recent report by Vaccher describes simultaneous MCD, KS and PEL in a single axillary lymph node.²⁸

HHV-8 or KSHV was first identified in 1994 by the team of Yuan Chang and Patrick Moore from a KS tumour in a patient with AIDS.²⁹ It has been associated with, and is causal to the formation of, several AIDS-associated malignancies. Besides KS, HHV-8 presents with B-cell lymphoproliferative disorders: MCD, both posttransplant and germinotropic lymphoproliferative disorders, and PEL.^{2 14 16} While these malignancies were initially thought to be unique to patients with AIDS, they can develop with sufficient immunosuppression of any aetiology.

KS is a multicentric, highly vascular tumour that often presents cutaneously with deep violaceous colouring. However, lesions can involve many different organs including the lymph nodes, lungs, bones, oral mucosa and gastrointestinal tract. Driven by HHV-8, KS formation is inversely related to CD4 count, demonstrating the role of immune suppression against this indolent virus. Uniquely, however, the risk for KS remains elevated for patients with AIDS even with adequate ART therapy.³⁰ The aforementioned violaceous colouring forms due to haemosiderin deposition throughout the abnormal vascularity of lesions characterised by proliferation of spindle cells, inflammatory infiltrate, and fibrosis. Spindle cells drive the tumours, with HHV-8 anchored to chromatin by LANA, a viral protein used in histological identification.³¹ KS is staged according to the AIDS Clinical Trials Group, with prognostic implications for therapy. Treatment is centred on re-establishment of immune surveillance through ART. In some patients, however, exacerbations of KS lesions occur with re-initiation of ART, which is thought to be a form of IRIS.³² Further systemic therapy is warranted in patients with visceral, rapidly progressive or KS-associated IRIS. Pegylated liposomal doxorubicin is the mainstay of cytotoxic therapy, though paclitaxel, lenolidomide, bleomycin, vincristine and etoposide have been shown to be effective.^33–35 Therapy continues until lesions regress and immune reconstitution can suppress further development. While clinical symptoms of KS usually arise secondary to the location of lesions, some patients may develop severe systemic symptoms due to KICS.³⁶ In many ways, KICS manifests similarly to MCD and can be difficult to truly identify until B cell lymphoproliferative disease has been excluded.³⁷ Alongside classic B-symptoms of cachexia, high fevers, night sweats, and weight loss, patients develop lymphadenopathy and splenomegaly as well as respiratory, gastrointestinal, and neurological symptoms. Common laboratory findings include anaemia, thrombocytopenia, hyponatraemia and an elevated CRP, likely as a result of HHV-8 encoded viral IL-6.^{37 38} Treatment of the underlying KS is the mainstay of therapy, though KICS is associated with a particularly poor prognosis.

PEL is another HHV-8 related B-cell malignancy that classically manifests as a body-cavity effusion laden with clonal cells but can also appear as extracavitary/solid disease. Malignant effusions may occupy the pleural, pericardial or peritoneal spaces. The underlying pathobiology of PEL is not well characterised, though it may arise from HHV-8 infected mesothelial cells.³⁹ EBV coinfection is found in 80% of cases.⁵ Diagnosis is based on cell surface antigen expression. Malignant cells are CD45 leukocytes with markers (CD38, CD138) suggesting late stage B cell differentiation; however, they lack the classic B-cell markers CD19, CD20 and CD79a. Presence of HHV-8 with or without LANA-1 expression is required.¹⁸ Extracavitary/solid PEL is much more challenging to diagnose than classic PEL given HIV/HHV-8-infected subjects may also concomitantly develop other lymphomas that are HHV-8 positive. EBV positivity, monoclonal immunoglobulin rearrangements, CD138 positivity, and absence of B-cell marker expression can help to clarity to the diagnosis.⁴⁰

Systemic inflammatory symptoms are common with elevated IL-6, IL-10, ferritin, and IgE associated with poor outcomes.⁴¹ Treatment of PEL typically involves conventional chemotherapy regiments for non-Hodgkin’s lymphoma such as CHOP or EPOCH, through median overall survival remains less than 1 year. Methotrexate can be used but will accumulate in effusions, resulting in higher toxicity.⁴¹ Surprisingly, ART alongside chemotherapy hasn’t borne significant results, possibly due to the weaker residual immune function in patients with PEL as compared with KS.¹⁸ The addition of bortezomib has recently shown promising results, though definitive evidence is lacking.¹⁷ Interestingly, rituximab in combination with standard chemotherapy has been effective in a few cases even though PEL tumours cells don’t present CD20.⁴²

To the best of our knowledge, this is the first case of synchronous visceral KS and extracavitary PEL at different sites in a patient with AIDS. The copresentation of KS and PEL is an unusual finding but should be considered in the severely immunosuppressed patient with symptoms of chronic systemic inflammation. While KICS associated with KS could explain such systemic symptoms, the search for an underlying secondary malignancy like PEL or MCD should be undertaken before initiating therapy. Prognosis remains guarded for patients with advanced HHV-8 malignancies, though emerging antiviral therapies targeting HHV-8 provide some hope.¹⁸

Learning points.

• The differential diagnosis for the immunosuppressed patient presenting with signs and symptoms of systemic inflammation is incredibly broad. While it is appropriate to evaluate for and treat infection first, be vigilant not to miss alternative autoimmune, inflammatory or malignant aetiologies.

• In patients with AIDS, systemic inflammation and human herpesvirus 8 (HHV-8) positivity, diagnostic considerations include Kaposi sarcoma/Kaposi sarcoma-associated herpesvirus inflammatory cytokine syndrome, multicentric Castleman disease and primary effusion lymphoma.

• When you see coexpression of HHV-8 and Epstein-Barr virus in tissue of an HIV positive patient concerning for lymphoma, primary effusion lymphoma or germinotropic lymphoproliferative disorder should be the leading considerations.

• In advanced HIV, it is routine to have more than one pathological process at a time—Hickam over-rules Occam.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s)