Isolated Kaposi sarcoma of the upper aerodigestive tract in immunocompetent individuals,an underrecognized entity with favorable prognosis

Abstract

Kaposi sarcoma (KS) is a rare vascular neoplasm that most commonly arises in the setting of immunosuppression, in areas with high prevalence of Human Herpesvirus-8 infection, and when both situations coexist. Most cases affect the skin, isolated involvement of the upper respiratory tract without skin involvement is extremely rare with only a few cases reported in the literature. We present a case of isolated nasopharyngeal KS in an immunocompetent patient who achieved remission after multimodality therapy. Recent advances in KS-therapy are discussed.

Introduction

First described by the Hungarian dermatologist Dr. Moritz Kaposi in 1872, Kaposi Sarcoma (KS) is a low-grade vascular sarcoma associated with human herpesvirus-8 (HHV8) infection. ¹ KS affects immunocompromised individuals in the context of AIDS or iatrogenic immunosuppression, and in the form of endemic disease in regions with high prevalence of HHV8 infection. ² KS typically affects the skin; however, extracutaneous and/or systemic involvement may occur in children and severely immunocompromised individuals. Isolated involvement of the upper respiratory system in immunocompetent patients is extremely rare, and information regarding biologic behavior and optimal treatment in this subset of patients is scarce.^3-6 We report a case of an incidentally identified nasopharyngeal KS in an immunocompetent 41-year-old man and compiled similar cases from the literature.

Case presentation

A previously healthy 41-year-old man born and raised in Mongolia, who went to college in Turkey and then moved to the US, was referred for evaluation of a medium-sized, midline nasopharyngeal mass incidentally found during esophagogastroduodenoscopy for reflux symptoms (Figure 1A). On review of symptoms, the patient described nasal itching, congestion, ear ringing, and blood-tinged mucus. Magnetic resonance imaging (MRI) and computerized tomography (CT) scans showed a 2.6 cm, well circumscribed, lobular, avidly enhancing mass filling the nasopharynx (Figures 1B and 1C). The biopsy of the lesion showed intersecting bundles of relatively bland spindle cells separated by slit-like pseudovascular spaces containing lymphocytes and leukocytes. Hyaline intracellular globules were focally present (Figures 1D and 1E). Immunohistochemical stains showed that the lesion was positive for the vascular markers CD34 and ERG and for HHV8 confirming the diagnosis of KS (Figure 1, lower right). Testing for human immunodeficiency virus and hematologic evaluation for immunodeficiency were negative. The patient was treated with endoscopic resection followed by fractionated intensity-modulated radiation therapy (IMRT) with a total dose of 30 grays (Gy). A full dose was given to the nasopharynx, 19 Gy to the brain stem, 15 Gy to the spinal canal, 9–15 Gy to the left and right inner canals, respectively, and 7–10 Gy to the left and right parotid areas, respectively. The patient remains in remission, asymptomatic and without post-therapy complications after a follow-up period of 1 year. During this interval he has been followed regularly with MRI and a multidisciplinary head and neck team.

Figure 1.

Nasopharyngeal mass. Upper panel: Gross and radiologic images: (A). Endoscopy, (B). Axial MRI, (C). Sagittal CT scan. Lower panel: Histologic images: (D). At low power the mass consists of intersecting bundles of spindle cells. (H&E, 100X magnification) (E). At higher power, bland spindle cells with occasional intracellular hyaline globules (arrowheads) separated by slit-like vascular spaces containing red cells and scattered leukocytes are apparent. (H&E, 400X magnification). The nuclei of the tumor cells are uniformly positive for the vascular marker ERG and human herpesvirus 8 immunostains. (200X magnification).

Discussion

Kaposi sarcoma is a virally mediated low-grade vascular sarcoma associated with HHV8, also known as Kaposi sarcoma herpesvirus. Four epidemiological types of Kaposi sarcoma have been described: classic (Mediterranean), endemic (sub-Saharan African), epidemic (AIDS-associated), and iatrogenic (transplant-related). These groups comprise 2 populations: immunosuppressed individuals and populations with high prevalence of HHV8 infection; unfortunately, both conditions frequently coexist together. The course of the disease is influenced by the immune status of the host and the age at which the viral infection is acquired: it is localized and indolent in immunocompetent patients, and more aggressive in children and severely immunocompromised individuals, in whom dissemination may occur. ² This patient was born and raised in Mongolia. Although epidemiologic information about HHV8 prevalence in Mongolia is not available, a high prevalence of HHV8 infection and a high incidence of Kaposi sarcoma has been reported in the Uygur ethnic group in the Xinjiang region of China, which borders with Mongolia, suggesting that the present case represents an endemic type of Kaposi sarcoma. ⁷ The possibility of endemic remote exposures can be overlooked in today’s world where long-distance mobility and international travel and relocation are common. Kaposi sarcoma of the upper aerodigestive tract in immunocompetent individuals is uncommon but well described in patients with concomitant cutaneous disease, with several case series and literature reviews available.^3,5,8,9 As expected, most cases are from endemic regions, saliva is the main route of transmission and requires prolonged and repeated exposure; most cases are presumed to be the result of mother to child transmission. ⁹ The most affected sites are the palate and oropharynx; the latter has been reported as the site with the highest level of viral replication.^3,10 Isolated involvement of the upper aerodigestive tract without skin involvement in immunocompetent is exceedingly rare; in our review, we identified only 9 patients, including the current report (Table 1).^3-6 The cases were extracted from other head and neck series that included immunosuppressed patients and patients with cutaneous or multifocal involvement. Sex distribution was similar (M:5, F:4), except for our patient all were older than 50 years (range 41–78), 4 affected the oral cavity, 1 the oropharynx, and 4 the nasal cavity/nasopharynx. Tumor size ranged from 0.9 to 10 cm, patients were treated with either surgery alone, radiation alone, surgery & radiation, and chemotherapy alone with all patients achieving remission. Follow-up was variable ranging from 2 to 48 months. No recurrences, metastases or deaths were reported. Despite the small number of patients, these results suggest that isolated upper aerodigestive disease in immunocompetent patients is very indolent and that the least morbid therapeutic approach according to the clinical scenario should be favored.

Table 1.

Isolated Kaposi sarcoma in the upper aerodigestive system in immunocompetent patients.

Reference #, country	Age/range (yr)	Sex (n)	Location (n)	Size (cm)	Treatment	Follow-up (mo)	Outcome	Metastasis or death
3, AFIP, USA	53–75	M (2),	Oral cavity (2)	0.9-10	Surgery or surgery + radiation	4-16	Remission	No
		F (2)	Oropharynx (1)
			Nasal cavity (1)
4, Greece	59	F (1)	Nasal cavity (1)	NA	Surgery	48	Remission	No
5, Greece	55–78	M (2)	Oral cavity (1)	1-3	Radiation	2-38	Remission	No
			Hard palate (1)
6, Morocco	56	F (1)	Nasal cavity (1)	7.7	Chemotherapy (IFO + DOXO)	12	Remission	No
Mongolia	41	M (1)	Nasopharynx (1)	2.6	Surgery + radiation	12	Remission	No

Abbreviations: AFIP, Armed Forces Institute of Pathology; DOXO, doxorubicin; IFO, ifosfamide.

There are no standardized treatment guidelines for Kaposi sarcoma. Therapy is usually guided by the tumor stage, symptoms, immune status, and comorbidities. ⁹ Treatment of immunocompromised patients is primarily geared towards immune restoration whenever possible. Regardless of immune status, non or minimally symptomatic, stable disease, usually does not require intervention, just follow-up. Progressing or symptomatic mucocutaneous lesions can be treated with topical agents such as alitretinoin or imiquimod, intralesional vinblastine, cryotherapy, and photodynamic therapy. Symptomatic, mass-forming, extracutaneous localized disease is usually treated with surgical excision, with adjuvant radiotherapy for unclear, close, or positive margins, as was done in our case. Disseminated and/or symptomatic irresectable disease is usually treated with single agent chemotherapy with or without radiotherapy. Commonly used agents include pegylated liposomal anthracyclines and paclitaxel. ¹¹

Advances in the understating of the oncogenic effects of HHV8 on endothelial cells have led to the identification of several potential targeted therapies, which at the time of the publication of this article have not been approved for clinical use.

Targeted therapies

PD-L1 inhibitors : PD-1/PD-L1 mediated tumor escape has been documented in KS by various investigators.^12,13 Pembrolizumab and Nivolumab have been shown to achieve complete remission in advanced KS cases.^14,15 Numerous clinical trials using checkpoint inhibitors for the treatment of advanced KS are registered at the ClinicalTrials.gov database. ¹⁶

Angiogenesis inhibitors: KS is a vascular neoplasm. Overexpression of HIF1/2-alpha proteins with subsequent VEGFR-1 upregulation has been shown in cell cultures of endothelial cells infected with HHV8, providing a rationale for the use of antiangiogenic agents. ¹⁷ Preclinical trials using DLX 1008/brolucizumab, a single-chain variable fragment anti-VEGF approved for age-related macular degeneration has demonstrated significant in vivo tumor activity in animal models. ¹⁸ Treatment of KS in animal models with the cyclooxygenase-2 inhibitor celecoxib was associated with a significant reduction in tumor size. ¹⁹

Immunomodulating agents: Pomalidomide, a thalidomide derivative approved for treatment of multiple myeloma has been shown to have immunomodulatory effects in the production of TNF-alpha, IL-6, and VEGF, that result in antiangiogenic and antiproliferative activity. Two phase I/II studies showed that Pomalidomide was well-tolerated and was more effective in HIV-negative subjects, achieving sustained partial or complete responses. ²⁰

Tyrosine kinase inhibitors: Multikinase inhibitors have shown antiproliferative and antiangiogenic effects in Kaposi sarcoma through inhibition of VEGF, PDGF, and C-KIT receptors. Anecdotal off-label use of sorafenib and pazopanib in patients with advanced recurrent Kaposi sarcoma reported complete sustained regression of the lesions.^21,22

Anti-HHV8 Vaccination: Immunization of at-risk populations would probably be the most effective and meaningful way to prevent KS. Vaccines may also help boost the immune response in patients with immunodeficiency associated progressive disease. A multivalent KS vaccine capable of eliciting high titers of neutralizing antibodies in immunized rabbits has been developed; however, a vaccine prototype for clinical studies is not yet available. ²³

Conclusions

Isolated involvement of the upper aerodigestive tract by KS in immunocompetent patients is exceedingly rare. The limited number of cases reported to date have shown an indolent biologic behavior and were successfully treated with surgery, radiation, chemotherapy, and combination surgery/radiation without significant complications; however, follow-up is limited. Several reports of successful treatment of advanced KS with targeted therapies suggest that this neoplasm is amenable to be treated with non-invasive, less morbid therapeutic modalities. Adoption of these newer therapies will likely be delayed by the effectiveness of existing conventional therapies.