Kaposi Sarcoma

Primary Classic Kaposi Sarcoma of the Parotid Gland in an HIV-Negative Patient

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Introduction

Kaposi sarcoma (KS) is a multifocal vascular tumor first described by dermatologist Moritz Kaposi in 1872.1 It is associated with human herpesvirus 8 (HHV-8) and typically affects mucocutaneous sites and skin of the lower extremities and face.2 KS is classified into 4 clinical forms: (1) classic, (2) endemic, (3) AIDS related, and (4) iatrogenic or transplant related.3 Classic KS (CKS) predominantly affects immunocompetent elderly men of Mediterranean, East European, or Jewish origin, typically causing cutaneous lesions.2 Although all forms of KS have been reported in atypical anatomic locations in patients with HIV,2 primary CKS in the parotid gland without cutaneous involvement in an HIV-negative patient is exceptionally rare.4,5 To date and to our knowledge, only a handful of such cases have been reported.5 We present a rare occurrence of primary CKS in the parotid gland of an HIV-negative patient.

Report of a Case

A White man in his 60s of Mediterranean (Italian) origin with a medical history notable for hypertension, Hashimoto thyroiditis, nephrolithiasis, and gout presented with an 8-month history of a lump on his right face. He had previously tested positive for COVID-19 infection in November 2021 and was treated with monoclonal antibodies. In February 2022, he developed a painful lump on the right side of his face. A computed tomographic (CT) scan of the neck in August 2022 revealed a 2.3-cm enhancing mass in the right parotid gland as shown in Figure 1. An ultrasound-guided biopsy confirmed histopathologic findings consistent with KS. HIV infection was ruled out and all other laboratory blood test results were unremarkable. No cutaneous lesions were identified. The patient underwent a planned right superficial parotidectomy with no complications. Final pathologic findings confirmed KS arising in the intraparotid lymph node with a strong nuclear staining for HHV-8 immunohistochemical analysis as shown in Figure 2. The patient exhibited intact facial nerve function and was discharged on postoperative day 3. At the 6-month follow-up, he showed a well-healed incision with no signs of recurrence.

Figure 1.  Computed Tomographic (CT) Images

Computed Tomographic (CT) Images

A, Axial view on CT scan of the neck. B, Coronal view of the parotid mass on CT of the neck. The arrowheads indicate a 2.3-mm mass in the right parotid gland. 3D indicates 3 dimensional.

Figure 2.  Histopathologic Images

Histopathologic Images

A, Low-power view shows a well-circumscribed nodule composed of intersecting fascicles of spindle cells, arising within a periparotid lymph node, evidenced by a rim of residual lymphoid tissue and parotid gland parenchyma (hematoxylin-eosin stain). B, High-power view of the tumor shows intersecting fascicles of uniform spindle cells with mild cytologic atypia, and numerous slitlike spaces filled with erythrocytes (hematoxylin-eosin stain). C, Palely eosinophilic hyaline globules are characteristic of Kaposi sarcoma and can be intracytoplasmic or extracellular (hematoxylin-eosin stain). D, Tumor cells display strong nuclear staining for human herpesvirus 8 immunohistochemistry.

Discussion

KS is typically associated with men with HIV, presenting as cutaneous lesions on extremities. Head and neck KS is rare, especially within a salivary gland in an HIV-negative patient, with fewer than 10 such cases reported.5 We present a case of CKS in an HIV-negative patient’s intraparotid lymph node. The unique location of CKS in this patient with negative HIV test results and no cutaneous involvement makes this an informative case for head and neck surgeons. Clinical suspicion for KS in HIV-negative patients is limited due to the rarity of HHV-8 infection in such patients.2 The cause of CKS in this patient remains uncertain. Given this patient is of Italian origin, one possibility is the reactivation of a latent HHV-8 after administration of monoclonal antibodies for COVID-19 treatment. Although immunosuppressive drugs such as prednisolone used for COVID-19 treatment have been linked to the iatrogenic form of KS,6 this patient did not receive steroids and was not immunocompromised at diagnosis. Clinicians should elevate their index of suspicion for rare malignant abnormalities like KS in unconventional locations among Mediterranean populations in the setting of new masses or lumps given the relatively higher prevalence of latent HHV-8 infections in these populations.6

Conclusions

We present a rare case of KS in the intraparotid lymph node of an HIV-negative patient, discovered after painful facial swelling following months after COVID-19 treatment with monoclonal antibodies. The patient successfully underwent right superficial parotidectomy with no signs of recurrence at the 6-month follow-up. Clinicians should be vigilant for KS in unusual locations, even in the absence of HIV or immunocompromised status, for patients of Mediterranean origin.

Cancer-Causing Viruses Hijack Human Protein to Evade Immune Response

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Viruses have evolved with humans for millions of years, so it’s no surprise they’ve evolved tricks to evade our natural, or innate, immune responses. Unfortunately, it’s often unclear what these tricks are. But now, thanks to researchers at the University of North Carolina (UNC) School of Medicine, one of these tricks has been revealed. It is particular to gammaherpesviruses, which include Kaposi sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV).

These viruses, which are DNA viruses, have been linked to several cancers and establish lifelong latency in the human population. According to the UNC researchers, these viruses use a human protein called barrier-to-autointegration factor 1, or BAF, to evade our innate immune response, allowing the viruses to spread and cause disease.

The researchers suggest that BAF and related proteins could prove to be valuable therapeutic targets. Indeed, if these targets can be engaged, it may be possible to prevent virus-instigated cancers such as Kaposi sarcoma, non-Hodgkin lymphoma, Hodgkin lymphoma, multicentric Castleman disease, nasopharyngeal carcinoma, and gastric cancer.

Details about the new research appeared in Nature Communications, in an article titled, “Barrier-to-autointegration factor 1 promotes gammaherpesvirus reactivation from latency.”

“We report that barrier-to-autointegration factor 1 (BAF)-mediated suppression of the cGAS-STING signaling pathway is necessary for reactivation of KSHV and EBV,” the article’s authors wrote. “We demonstrate a role for BAF in destabilizing cGAS expression and show that inhibiting BAF expression in latently infected, reactivating, or uninfected cells leads to increased type I interferon-mediated antiviral responses and decreased viral replication. Furthermore, BAF overexpression resulted in decreased cGAS expression at the protein level.”

The research was led by Blossom Damania, PhD, the Boshamer distinguished professor of microbiology and immunology and member of the Lineberger Comprehensive Cancer Center. She stated, “Viruses are in a constant battle with the cellular immune system, which includes the protein cyclic GMP-AMP synthase, or cGAS, which binds to viral DNA and sounds the alarm to trigger immune responses and fight the viral invaders. We’ve discovered that KSHV and EBV use a different host cell protein, BAF, to prevent cGAS from sounding the alarm.”

In the case of KSHV and EBV, the expression of BAF is increased upon infection, suggesting that these viruses take advantage of this host protein to blunt the immune response to infection. In a series of experiments, Damania’s laboratory found that BAF contributes to the degradation of the cGAS DNA sensor. With less cGAS protein available in the infected cell to detect DNA, the cells mount weaker immune responses, which allows these two viruses to replicate and spread more efficiently.

“BAF enables EBV and KSHV to reactivate from latency, replicate, and make more of themselves,” said first author Grant Broussard, a graduate student in the genetics and molecular biology curriculum at UNC Lineberger. “Our study highlights the prominent role that DNA detection pathways like the cGAS pathway play in controlling viral infection.”

He stressed that disrupting BAF activity with targeted therapies could reduce its immunosuppressive effects, thus restricting replication of these viruses to prevent the spread of disease.

Damania, who is a Leukemia and Lymphoma Society scholar and a Burroughs Wellcome Fund investigator in infectious diseases, added, “Preventing lytic replication will prevent transmission of these viruses and also reduce the global cancer burden associated with these two viruses.”

Safety, Activity, and Long-term Outcomes of Pomalidomide in the Treatment of Kaposi Sarcoma among Individuals with or without HIV Infection

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Abstract

Purpose:

Kaposi sarcoma (KS) is caused by Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8). KS, which develops most frequently among people with HIV, is generally treated with chemotherapy, but these drugs have acute and cumulative toxicities. We previously described initial results of a trial of pomalidomide, an oral immunomodulatory derivative of thalidomide, in patients with KS. Here, we present results on the full cohort and survival outcomes.

Patients and Methods:

Participants with KS with or without HIV were treated with pomalidomide 5 mg once daily for 21 days per 28-day cycle with aspirin 81 mg daily for thromboprophylaxis. Participants with HIV received antiretroviral therapy. Response was defined by modified version of the AIDS Clinical Trial Group KS criteria. We evaluated tumor responses (including participants who had a second course), adverse events, progression-free survival (PFS), and long-term outcomes.

Results:

Twenty-eight participants were enrolled. Eighteen (64%) were HIV positive and 21 (75%) had advanced (T1) disease. The overall response rate was 71%: 95% confidence interval (CI) 51%–87%. Twelve of 18 HIV-positive (67%; 95% CI, 41–87%) and 8 of 10 HIV-negative participants (80%; 95% CI, 44%–97%) had a response. Two of 4 participants who received a second course of pomalidomide had a partial response. The median PFS was 10.2 months (95% CI: 7.6–15.7 months). Grade 3 neutropenia was noted among 50% of participants. In the follow-up period, 3 participants with HIV had other KSHV-associated diseases.

Conclusions:

Pomalidomide is a safe and active chemotherapy-sparing agent for the treatment of KS among individuals with or without HIV.

Treating KSHV-Associated Multicentric Castleman Disease .

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Name of the Trial
Pilot Study of Tocilizumab in Patients with Symptomatic Kaposi Sarcoma Herpesvirus (KSHV)-Associated Multicentric Castleman Disease (NCI-11-C-0233).

Principal Investigator
Dr. Thomas Uldrick, NCI Center for Cancer Research

Why This Trial Is Important
Multicentric Castleman disease (MCD) is a group of rare diseases of the lymphatic system. One form is associated with infection by a virus called human herpesvirus 8. This virus is also associated with a type of cancer called Kaposi sarcoma, so it is sometimes known as Kaposi sarcoma herpesvirus (KSHV). Kaposi sarcoma and KSHV-associated MCD are much more common in people who are infected with the human immunodeficiency virus (HIV).

People with KSHV-associated MCD often have Kaposi sarcoma, and some treatments for KSHV-associated MCD can make Kaposi sarcoma worse. NCI researchers in the HIV and AIDS Malignancy Branch at NCI’s Center for Cancer Research are studying new approaches to treating KSHV-associated MCD and are trying to find better ways to manage it in patients who have both conditions.

People with KSHV-associated MCD may develop a variety of symptoms, such as low blood-cell counts (cytopenias), low levels of albumin (hypoalbuminemia), fever, fatigue, weight loss and muscle wasting (cachexia), fluid buildup (edema) in the legs and abdomen, and enlarged lymph nodes and spleen. Untreated, these inflammatory symptoms can be life threatening.

Currently, KSHV-associated MCD is usually managed with one of two treatments: the biological agent rituximab or antiviral therapy. Rituximab may improve symptoms, but it can also cause considerable side effects and lead to worsening Kaposi sarcoma. Virus-activated cytotoxic therapy, which was developed at NCI and consists of high-dose zidovudine (AZT) and valganciclovir, is one type of antiviral therapy that has shown some effectiveness against KSHV-associated MCD.

Although antiviral treatment targets the cause of the disease, it may not rapidly control the inflammatory symptoms. Therefore, doctors want to explore new approaches that may offer more effective and less-toxic treatment.

A monoclonal antibody called tocilizumab (Acterma) interferes with a molecular pathway that is important in MCD. The disease and many of its symptoms are driven by abnormal production of an inflammatory cytokine called interleukin-6 (IL-6). Tocilizumab attaches to the IL-6 receptor and prevents the molecular signaling that leads to IL-6-associated inflammation. This antibody was initially evaluated in the United States to treat rheumatoid arthritis and is approved by the Food and Drug Administration for that condition.

In this pilot study, patients with KSHV-associated MCD will receive intravenous tocilizumab every other week for up to 12 weeks. Patients who do not benefit from tocilizumab therapy alone may go on to receive high-dose AZT and valganciclovir in addition to tocilizumab. Doctors will assess the safety and effectiveness of tocilizumab alone and in combination with virus-activated cytotoxic therapy.

“Tocilizumab has been evaluated in other forms of MCD not related to KSHV and was effective in controlling the symptoms of the disease, including rapid resolution of hypoalbuminemia and anemia,” said Dr. Uldrick. “However, KSHV-associated MCD and other types of MCD are distinct diseases with overlapping clinical features. Tocilizumab may or may not be sufficient therapy in this setting, and that’s why we’re studying it, both alone and in combination with virus-activated cytotoxic therapy,” he said.

“The safety of tocilizumab is part of what we want to evaluate here; the major side effect we’d like to avoid is worsening Kaposi sarcoma in response to treating MCD,” Dr. Uldrick explained. “With rituximab, about half of the patients treated end up with worsening Kaposi sarcoma. That’s the yin-yang of treating these diseases; trying to manage KSHV-associated MCD without making Kaposi sarcoma worse.”

Source: NCI.