Diagnostic and management considerations in the modern patient with AIDS: a case of concurrent disseminated Kaposi sarcoma and colesional Cryptococcus neoformans
- 1 Tri-Institutional MD PhD Program, Weill Cornell Medical College, New York, New York, USA
- 2 Weill Cornell Medicine Department of Pathology and Laboratory Medicine, New York, New York, USA
- 3 Department of Medicine, NYU Langone Medical Center, New York, New York, USA
- Correspondence to Mr Samuel Clay Williams; scw2008@med.cornell.edu
Abstract
In the era of highly active antiretroviral therapy (HAART), disseminated Kaposi sarcoma (KS) has become much rarer in the USA. We report a case of a 34-year-old man with KS of the skin, oropharynx, lung and rectum. Within the same lung nodule, we discovered significant burden of colesional Cryptococcus neoformans, in the context of a positive asymptomatic cryptococcal antigenemia, which was a previously unreported occurrence. The gold standard of treatment for KS continues to be HAART. The role of chemotherapy is still controversial. In addition, a cryptococcal antigen screen-and-treat approach with fluconazole is still not routinely recommended in the USA to prevent serious meningeal disease despite recent studies showing efficacy and applicability. We discuss both issues here and the outcome of our patient. We also present the patient’s own unique perspective in dealing with the ramifications of these diagnoses.
Background
Kaposi sarcoma (KS) and Cryptococcus neoformans pneumonia have both been routinely described as AIDS-defining illnesses since the beginning of the AIDS epidemic in the 1980s. The discovery and implementation of highly active anti-retroviral therapy (HAART) and early testing has decreased the prevalence of these diseases in recent years. C. neoformans is a yeast that often causes an infectious meningoencephalitis. The fungus can also present with pneumonitis or cutaneous manifestations.
KS, caused by the human herpesvirus-8 virus (HHV-8), is the most common AIDS-related neoplasm. Lesions most commonly occur on the skin but can also present in the oral cavity, lungs and gastrointestinal (GI) tract. Lung involvement typically presents in a diffuse reticulonodular infiltrative pattern on chest radiography. GI lesions are often asymptomatic but can present with bleeding.1 Visceral lesions are uncommon.
Here, we describe a case of a rare phenomenon: disseminated KS of the skin, rectum, oropharynx and lungs with colesional asymptomatic Cryptococcus pneumonitis. In addition, we briefly discuss the screen-and-treat model for cryptococcal antigenemia and its application to current standard of care, as well as literature on the benefits of chemotherapy in disseminated KS.
Case presentation
The patient is a 34-year-old man who has sex with men with no relevant travel history who presented with fatigue, poor appetite, rectal bleeding, oral mucosal lesions and skin lesions for the past 6 months. The patient reported that his skin lesions had grown slowly over the past year but had rapidly increased in number and size over the past several weeks. The patient also reported a recent history of significant weight loss, night sweats, palpitations, as well as sore throat and difficulty opening his mouth fully. He also attested to several days of intense fatigue 1 year ago that prevented him from getting out of bed. HIV serology was negative 2 years prior to the current presentation and the last episode of unprotected intercourse was 1 year prior to current presentation. He had no history of sexually transmitted infections. In addition, he had a recent biopsy of one of his oral lesions with non-diagnostic results.
Physical examination showed trismus, violaceous lesions covering the posterior third of the hard palate, and numerous violaceous, hard skin papules all over his face, neck and torso. There were no ulcerations or bleeding. Lungs were clear bilaterally. Heart rate was regular but tachycardic; no murmurs were heard. No hepatosplenomegaly was identified. Genitalia were unremarkable.
Initial laboratory workup was positive for HIV-1 with a CD4 count of 42, 2.2% cells/mL and viral load of 272 150 copies/mL at the time of diagnosis. A serum CrAg study was positive (1:5). Due to his positive CrAg, a lumbar puncture was performed. Cerebrospinal fluid (CSF) was clear and colourless with normal opening pressure, white blood cell count and red blood cell counts within normal limits (2 WBCs/µL and 8 RBCs/µL). CSF CrAg test was negative. CSF bacterial and fungal cultures showed no growth.
In addition, a skin biopsy was performed of his violaceous nodules (figure 1). The latency associated nuclear antigen 1 (LANA-1) is an HHV-8 specific protein expressed in the nucleus of all HHV-8-infected tumour cells.2 The skin biopsy of our patient showed LANA-1-positive immunohistochemical staining. In addition, an initial chest X-ray was negative.
Skin biopsy material of a violaceous nodule seen with H&E (A) and LANA-1 staining (B). LANA-1, latency associated nuclear antigen 1.
The patient was diagnosed with AIDS, cutaneous KS and asymptomatic cryptococcal antigenemia. He was started on HAART therapy with dolutegravir, tenofovir alafenamide and emtricitabine. He was also started on therapeutic fluconazole 400 mg daily to treat his cryptococcal antigenemia and trimethoprim–sulfamethoxazole for anti-pneumocystis prophylaxis.
Two weeks after starting HAART, his KS lesions appeared more numerous with increased shortness of breath and fatigue. Lungs continued to be clear on exam. A CT scan of the chest without contrast (figure 2) and CT of the abdomen with contrast were performed. The CT chest found ‘innumerable bilateral nodules’ in a peribronchovascular distribution with the largest nodule measuring of 1.2 cm.
Chest CT scan from patient demonstrating innumerable peribronchovascular nodules consistent with Kaposi’s sarcoma.
The CT of the abdomen found mural rectal thickening and prominent perirectal lymph nodes. Patient refused admission for workup of disseminated KS and a plan for outpatient lung biopsy and sigmoidoscopy was made. In addition, the patient had a haematology consultation and was educated about the risks and benefits of chemotherapy with liposomal doxorubicin that he refused.
Flexible sigmoidoscopy was performed 3 weeks after HAART initiation. Multiple 5–12 mm mucosal nodules were observed and biopsied in the rectum. Histologic analysis and immunohistochemical staining with LANA-1-specific staining of biopsy materials established a diagnosis of KS. A biopsy of the lung nodule (now 1.5 cm) was performed 4 weeks post HAART initiation. Histologic review of biopsy material showed granulomatous inflammation, yeast consistent with Cryptococcosis, as well as KS. Immunohistochemical stains for LANA-1 as well as special stains for fungal organisms (figure 3) were performed on biopsy materials and supported these diagnoses.
Lung biopsy material with Kaposi sarcoma as seen with H&E (A) and LANA-1 staining (B). Cryptococcus neoformans was also seen on H&E (C) and mucicarmine staining (D). LANA-1, latency associated nuclear antigen 1.
Outcome and follow-up
The patient was next seen in the clinic 37 days post HAART initiation. His skin and mucosal lesions were still present and had increased in size. His shortness of breath and overall wellness had improved since his last visit 2 weeks after starting HAART. He remained compliant with his medications, including HAART and fluconazole, and maintained his refusal for chemotherapy. After 1 month, his HIV viral load had dropped to 604 copies and by 2 months was near the limit of detection. At 4 months, his CD4 count was 203 cells/µL. His symptoms continued to improve and his skin lesions had begun to regress.
A positron emission tomography CT done at 6 months after initiation of HAART showed diffuse avid lymphadenopathy and nodular lung opacities. These findings were likely consistent with disseminated KS with LANA-1-positive lesions in the lungs, skin and GI tract (whereas Cryptococcus was only found in his lungs and not in rectal biopsy specimens). The patient continues to closely follow-up with oncology and infectious disease and has improved with therapy, gained weight, returned to his full-time employment and has had no subsequent fevers nor other symptoms.
Discussion
To our knowledge, this is the only report of colesional Cryptococcus and KS in the lung. Prior to this case, nine cases had been reported in the literature of colesional Cryptococcus and KS in cutaneous nodules.3 Most of the patients in the literature were severely immunocompromised with CD4 counts of <100 and at least 5/9 of these patients had died within 10 months with others lost to follow-up.4 Five cases were reported in South Africa.4 5 Two-fifths of the patients died within 2 days of cutaneous biopsies with CD4 counts of 10 and 14, one had a CD4 of 108 and was lost to follow-up and one developed lesions after starting HAART but was also lost to follow-up. The latter two patients were coinfected with Mycobacterium tuberculosis in addition to KS and Cryptococcus. The last patient had a CD4 count of 14 and died within 1 month from disease progression.5
Four cases have been reported in the USA. One patient had a CD4 count of 6 with colesional Mycobacterium avium and was deceased within 6 months,6 one patient had no CD4 count reported and died within 10 months from disease progression7 and the other two had limited information with both reporting improvement of status.6 In addition, one case of neuromeningeal Cryptococcus infection was recently reported with gastric KS in a patient with a CD4 count of 394. This patient passed away within 6 days.8 These case reports and ours illustrate that a highly immunosuppressed patient with AIDS may have more than one diagnoses responsible for the clinical findings and reflect the necessity of a procedure such as biopsy for clinching the diagnoses. Despite advent of HAART, KS remains the most common tumour in HIV-infected patients worldwide.9 KS in those with HIV is characterised by widely disseminated cutaneous disease, with advanced cases involving the oral mucosa and viscera (most frequently the lungs and GI tract). Pulmonary KS is the second most common non-cutaneous site of the disease after the GI tract and its most life-threatening form, and can involve the parenchyma, pleura or the tracheobronchial tree.10 Up to 45% of HIV-infected patients with cutaneous KS show pleural or pulmonary manifestations.11 However, overall visceral KS is uncommon and pulmonary involvement is only around 16%.12 In one study, only 10/469 patients9 had both GI and pulmonary KS and other studies have confirmed similar rates.13
It is important to note that pulmonary KS can be remarkably asymptomatic,14 and high index of suspicion is required for diagnosis. For example, our patient never had an abnormal lung exam, had no chronic cough and his initial chest X-ray was clear. Pulmonary KS can have complications such as chylothorax, diffuse alveolar haemorrhage and immune reconstitution inflammatory syndrome in patients treated with HAART.10
It is not clear if chemotherapy is always warranted in patients with AIDS with visceral KS, but when administered, it is often started concurrently or within a month of HAART initiation. A 2014 Cochrane systematic review found no studies which compared outcomes between starting immediately and delaying therapy.14 The six studies comparing HAART with chemotherapy versus HAART alone showed no statistically significant difference in mortality, but suggested that HAART plus chemotherapy can reduce disease progression in patients with advanced KS.14 Cryptococcus pneumonitis is often symptomatic in severely immunocompromised patients but in asymptomatic patients, treatment with 400 mg fluconazole is recommended.15 In 2011, the WHO made a conditional recommendation to screen HAART naïve HIV patients with a CD4 <100 cells/mm3 in populations with a high prevalence of cryptococcal antigenemia.16 Recent evidence suggests that CrAg screening and treatment significantly reduces the rates of meningitis and death.17–19 In 2015, McKenney et al concluded that CrAg in the US HIV population was prevalent enough to warrant screening as an appropriate cost-effective choice. They suggested routine CrAg screening among HIV-infected patients with a CD4 count ≤100 cells/µL to treat early infection and prevent complications such as meningitis.20
In conclusion, we presented here the first case report in the literature of disseminated KS with colesional Cryptococcus in the lung of an HIV-positive patient. It is important to thoroughly investigate all possible pathologies in the immunosuppressed patient. Our patient continued to improve without the addition of chemotherapy. Given the unclear benefits of these drugs, we encourage physicians to maintain an open dialogue with their patients on the risks and benefits of these agents when discussing treatment. In addition, screening for CrAg is an important tool even in lower prevalence areas and can prevent complications.
Patient’s perspective
Because naturally we as humans make emotional choices rather than rational ones when faced with difficult options, it was important for me to weigh all the facts before deciding. I knew that my immune system needed to be strong in order to fight alongside the highly active antiretroviral therapy treatment. I also was aware that chemotherapy would make it more difficult to do so. Even though I was strongly urged by my doctors and assured that I would receive low doses of the recommended drug I hesitated. My health and energy levels seemed to be on the rise again, after being low for so long. I did not want to jeopardise that.
I have witnessed cancer treatment-related fatalities within my family from an early age. Because of this, it was important for me to keep a level head. Ultimately, the decision to forego the chemotherapy treatment came down to a vote among close members of my family. We knew that recovery would be a slow process, but we were willing to bet on my own body to fight it out, rather than taking the risk.
Learning points
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In an immunosuppressed patient, a single biopsy can contain multiple infectious pathologies. It is important to thoroughly investigate to avoid missing potential etiologies.
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Visceral disease in Kaposi sarcoma is rare but can potentially be serious and warrant a high index of suspicion and screening with further imaging.
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Screening for cryptococcal antigenemia and treating with 400 mg fluconazole is warranted in the US population and should be considered as the best practice in newly diagnosed HIV patients to prevent serious meningeal disease.
Acknowledgments
We would like to thank Judy C Stribling, Clinical Medical Librarian, MLS, AHIP for her help in preparing the manuscript, as well as Nicolas J Blobel, Weill Cornell Pathology and Weill Cornell Imaging for providing images. SCW was supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the National Institutes of Health under award number T32GM007739 to the Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program.
Footnotes
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Contributors SCW wrote, compiled and edited the manuscript as well as assisted in care. JS provided Pathology expertise, images of biopsies and editing of the manuscript. LP was the primary physician for the patient’s care, as well as assisted in writing and editing the manuscript.
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Funding This study was funded by National Institute of General Medical Sciences (grant number T32GM007739).
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Competing interests None declared.
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Patient consent for publication Obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.
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