March 2017

A 52 year-old male with multiple cutaneous nodules and lymphadenopathy

Matthew W. Auten, MD, PhD and Flavia G. Rosado, MD

Overview
A 52-year-old male with past medical history of hypertension and hyperlipidemia presents to a health care facility with numerous skin “swellings.” He denied fever, cough, diarrhea, weight loss, or other symptoms.  On examination, the “swellings” were described as multiple erythematous nodules across the back, chest, and upper extremities. These lesions were bluish, non-blanching, firm, and ranged from 0.5 cm to 4 cm in diameter. In addition to the subcutaneous nodules, submandibular and cervical lymphadenopathy was noted on physical examination. He tested positive with an HIV-enzyme-linked immunosorbent assay (ELISA), which was indicated due to his history of prior intravenous drug abuse. Initial fine-needle aspiration cytology of a representative subcutaneous nodule and lymph node revealed hypercellular, plump spindle cells arranged in groups within a hemorrhagic background, and diagnosed as a spindle cell neoplasm. He then underwent excisional biopsy of submandibular lymph nodes for definitive histopathologic diagnosis.

Gross and Microscopic Description
The submandibular lymph node biopsy specimen consisted of two firm, tan-red lymph nodes, which measured 0.9 x 0.6 x 0.4 cm and 1.0 x 0.5 x 0.5 cm.  The cut surfaces of the specimens were red-purple and hemorrhagic.  H&E stained sections of the lymph node show the normal nodal architecture is entirely replaced by interlacing fascicles of spindle cells with minimal nuclear atypia and extravasated red blood cells. In some areas, slit-like spaces filled with blood are also noted (Figure 1). Immunohistochemical staining for HHV-8 was also performed (Figure 2).


Figure 1. (H&E 100x) Submandibular lymph node biopsy shows interlacing fascicles of spindle cells without significant atypia and extravasated red blood cells.



Figure 2. (HHV-8 immunohistochemistry, 200x). The spindle cells are positive for HHV-8.

Diagnosis

Which of the following is the most likely diagnosis?

Answer

Please select an answer above.

Discussion

Kaposi Sarcoma (KS) was originally described in 18722 and has been extensively studied since.   Classical KS is an indolent neoplasm most commonly seen elderly men of Italian or Jewish heritage.3-6 At the onset of the HIV/AIDS epidemic, KS took on an entirely new importance as the original AIDS-defining illness.7,8 Following the discovery of Kaposi sarcoma-associated herpesvirus (KSHV), now known as human herpesvirus-8 (HHV-8), in 1994,9 the reasons for the epidemiologic changes seen with HIV-related Kaposi sarcoma would become clearer.

Epidemiology
Human herpesvirus-8 (HHV-8) is the etiologic agent that leads to the development of all forms of KS.  In addition, HHV-8 has been identified as the causative agent of multicentric Castleman disease (MCD), primary effusion lymphomas, solid immunoplastic/plasmablastic lymphomas (SIPLs), and cases of large B-cell lymphoma arising in MCD.9-13 There are four epidemiologic forms of KS recognized: (1) sporadic cases of classic KS; (2) endemic KS, seen in infants and young males of central Africa; (3) iatrogenic KS, secondary to immunosuppression (e.g., post-transplant);  and (4) AIDS-related KS.6,14,15

Clinical Features
KS is an angioproliferative neoplasm that may involve the skin, lymph nodes, or viscera in a varying combinations and severity, often in a multifocal presentation.6,13,16 Morphologically, ten variants of KS have been described: patch, plaque, nodular, lymphadenopathic, exophytic, infiltrative, ecchymotic, telangietactic, keloidal, and cavernous/lymphangioma-like. The progression of disease is similar in all cases with progression from early lesions (patches) to more advanced lesions (plaques) and ultimately nodular lesions. 6,13 In cutaneous KS, early stage lesions appear as violaceous patches, which may resemble junctional melanocytic nevi or nevus flammeus.17,18 Cutaneous KS may rarely become infiltrative or exophytic. However, infiltrative KS is rarely reported outside of Africa. Exophytic KS may erode into underlying bone. Telangiectactic KS appears as an eruption of pink, translucent nodules with prominent telangiectasia.19 Periorbital ecchymoses are seen in ecchymotic KS.20 Brown-to-violaceous keloidal nodules are seen in keloidal KS.19 Lymphangioma-like/cavernous KS is typically seen on the lower leg as a bullous-like eruption of dilated vascular spaces.21 Visceral KS is most prominent in the gastrointestinal tract and lymph nodes.22

Diagnosis
Histologically, the cellular components of KS vary with the stage of disease.13 In early stages, patch lesions are defined by dermal proliferations of vascular spaces composed of irregular endothelial cells alongside normal capillaries. In plaques, there are sheets or fascicles of spindle cells that encircle slit-like vascular space. Finally, in nodular lesions, the spindle cells predominate forming large fascicles often with extravasated red blood cells, and less obvious slit-like vascular spaces.
Spindle cells resemble plump endothelial cells with minimal cytologic atypia, and mitotic activity is usually low to absent. As these spindle cells originate from the endothelium but acquire the phenotype of endothelial lymphatic cells, they are immunoreactive for VEGRF3 and podoplamin (D2-40) as well as other endothelial markers, including CD34, CD31, Factor VIII, actin, and von Willebrand factor (vWF).23,24 Importantly, the presence of HHV-8, often demonstrated by reactivity for HHV-8 latency-associated nuclear antigen-1 (LANA-1) confirms the diagnosis of KS.

Summary
Kaposi sarcoma is a vascular neoplasm defined by its association with HHV-8. As shown in the reported case, KS is frequently seen in association with HIV/AIDS, and is regarded as an AIDS-defining illness. Morphologic and cytologic features that aid in the diagnosis include the identification of groups or fascicles of spindle cells with minimal cytologic atypia and the presence of abundant extravasated red blood cells. Immunohistochemical staining for HHV-8 is crucial in differentiating KS from other vascular tumors, which otherwise show an identical phenotype.

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