Pathology of Kaposi's Sarcoma

Dr Sampurna Roy MD               2022

Although the exact pathogenesis of KS is not known, infection with HHV-8 / KS-associated herpes virus, combined with other genetic and environmental factors, has been strongly implicated as the cause of this disease.

HHV-8 has been detected in KS cells of patients in all 4 epidemiologic groups, suggesting that the virus is a common pathogenetic factor for all KS types.

(HHV-8 has also been implicated in the pathogenesis of multicentric Castleman's disease and primary effusion lymphomas.)

HHV-8 infects CD19(+) B cells as well as T cells, monocytes, endothelial- derived spindle cells and CD34 (+) cells in the peripheral blood of patients with Kaposi's sarcoma.

There are three subtypes of HHV-8 (A, B and C). 

Type C infection is usually not associated with extracutaneous disease.

The tumour begins as a reactive proliferation but behaves as a multifocal neoplasm in advanced stage. 

The spindle cells in Kaposi's Sarcoma are thought to be the proliferating component while the endothelial cell population is thought to undergo a reactive hyperplasia.

Some authors have suggested that the spindle cell elements show endothelial differentiation.

Chronic stimulation of endothelial cells (possibly by viral infection) can produce differentiation to spindle shaped cells.

Recent studies have indicated that the spindle cells are derived from the lymphatic endothelium.

The Histogenesis of Kaposi's sarcoma cell: immunomorphological comparison with endothelial cells of normal human skin, lymphangioma and hemangioma. Arch Dermatol Res 1994;286:212 ;  

Expression of D2-40 in lymphatic endothelium of normal tissues and in vascular tumours.  

Monoclonal antibody D2-40, a new marker of lymphatic endothelium, reacts with Kaposi's sarcoma and a subset of angiosarcomas.  

1. Classic variant:  Usually affects elderly men of Eastern European and Mediterranean origin ; 

Usually present in fifth and seventh decade  ;

More common in men than in women, with a ratio 15 to 1 ;

Presents as multiple firm, purple-blue or reddish-brown plaques and nodules ;

Typically appear initially on the hands and feet ;

Progress up the arms and legs over a period of years or decades;  

Involve the viscera or mucosa about 10 percent of patients ;

Untreated lesions evolve from flat discolorations or patches to plaques and then to raised nodules that become confluent ;

Histologic features - spindle-shaped tumour cells surrounding hyperemic vascular slits, extravasated erythrocytes, hemosiderin, and fibrosis ;

Increased risk of lymphoma ;

Homosexual men may be at increased risk for classic type Kaposi's sarcoma.

This aggressive and frequently fatal epidemic variant of KS affected homosexual men with AIDS,  20 times as frequently as it did to male patients with hemophilia and AIDS who had similar degrees of immunosuppression ;

This variant is also observed in intravenous drug users ;

Epidemic variant of Kaposi's sarcoma has an extensive distribution and rapid progression.

This type of Kaposi's sarcoma  tends to be aggressive,involving lymph nodes, mucosa, and visceral organs in about half of patients, sometimes in the absence of skin lesions ;

The presence of concurrent lymphoma, tuberculosis, or transfusion-related HIV infection makes it difficult to diagnose KS accurately.

Subtypes:  

Lymphadenopathic type: Usually noted in children. The patients have a poor prognosis.

Nodular disease:  Resembles classic type. 

Aggressive atypical variant : Characterized by generalized, infiltrative skin lesion in adults. This variant responded poorly to conventional treatment.

Multiple clinicopathologic forms of KS, which are not mutually exclusive and can have overlapping features, have been described.

Patch ; plaque ; nodular ;  lymphadenopathic ;  infiltrative ; florid ; telangiectatic ;  ecchymotic ; keloidal ; angiomatous ; inflammatory ; anaplastic ;  lymphangiomatous ;  and generalized lymphedema .

Patch Stage:

Flat lesion characterized by proliferation of numerous jagged vascular spaces in the dermis ;

The vascular spaces are parallel to the epidermis ;

The slit like vessels are present around  preexisting blood vessel , skin adnexa and between collagen fibres. ( 'Promontory sign' ) ;

Vessels are lined by plump, mildly atypical endothelial cells ;

Perivascular lymphocytes and plasma cells ;

Extravasated red blood cells and hemosiderin may be present ;

The features resemble granulation tissue.

Plaque Stage:  

Spindle cells are more prominent than those in the 'patch stage' ; 

Dermal proliferation of the spindle cells together with poorly defined slit-like blood vessels ; 

Involves the reticular dermis and even the subcutis ;

Hemosiderin deposition is prominent ; 

Eosinophilic globules are present .

Nodular Stage:

Well defined lesion characterized by  prominent interlacing bundles of spindle cells  around slit like blood vessels and extravasation of red blood cells ;

These features are more prominent than those in the 'plaque stage' ;

Dilated thin walled vessels are present at the periphery ;

Mitotic figures are present ; 

Eosinophilic hyaline globules are present (intra and extra cellular) ;

These are PAS- positive and stain bright red with Mallory's trichrome.

Lymphangioma-like Kaposi's Sarcoma (LLKS):  

Clinically, the lesions have a bulla like appearance. 

Histologically, the tumour is characterized by permeation of dermal collagen by irregular anastomosing vascular channels lined by a flattened endothelium.

The biopsy specimens also reveal areas with characteristic light microscopic features of KS. 

All tumour cells, show a strong and diffuse reactivity for anti-HHV-8 LNA-1 and anti-CD34.

Anaplastic variant of Kaposi's Sarcoma: 

Cases have been reported in Africa.  

Characterized by :  Greater cellularity ; Nuclear pleomorphism ; Frequent mitotic activity.Kaposi's sarcoma: histopathological study of 159 cases from Malawi;   Kaposi's sarcoma in Uganda: a clinico-pathological study.

Immunohistochemistry:  

Kaposi's sarcoma is positive for both CD31 and CD34.

Some cases are positive for factor VIII-related antigen.

Human herpes virus type - 8 can be detected by PCR in paraffin-embedded tissue.

Recently, a monoclonal antibody to human herpes virus 8 latent nuclear antigen-1 has become commercially available for immunohistochemical analysis. 

Kaposi sarcoma shows strong, diffuse, nuclear staining for human herpes virus 8 latent nuclear antigen-1.

Differential Diagnosis of Kaposi's Sarcoma:

Early vascular lesions should be differentiated from telangiectasia, pigmented purpuric dermatosis , acroangiodermatitis (Acro-angiodermatitis. A simulant of Kaposi's sarcoma. ) and low grade angiosarcoma. 

Vessels in KS are more irregular.

An inflammatory infiltrate which includes plasma cells is present in early lesions of KS.

Regressed KS lesions following therapy may be misdiagnosed clinically and histologically as pigmented purpuric dermatitis if the pathologist is not aware of the previous history.

The histologic differential diagnoses of KS include other vascular tumours, such as spindle cell hemangioendothelioma ,  kaposiform hemangioendothelioma, and angiosarcoma.

Spindle cell hemangioendothelioma: In addition to a solid spindle cell component resembling KS, there are dilated and cavernous vascular spaces. 

Kaposiform hemangioendothelioma is a pediatric tumour composed of multiple lobules, each of which resemble either KS or capillary hemangioma, and is often associated with Kasabach-Merritt syndrome.

HHV-8 has not been associated with kaposiform hemangioendothelioma.

Angiosarcoma is characterized by a complex anastomosing pattern and marked nuclear atypia.

The presence of hyaline bodies and deposits of haemosiderin indicate Kaposi's sarcoma.

The spindle cell predominant type KS may be confused with leiomyoma, leiomyosarcoma, or fibrosarcoma.

The presence of hyaline bodies and the formation of vascular channels between spindle cells point to a diagnosis of Kaposi's sarcoma.

Lymphangioma-like Kaposi's  sarcoma characterized by permeation of dermal collagen by labyrinthine vascular channels lined by a flattened endothelium, must be differentiated from spindle cell hemangioendothelioma , low-grade angiosarcoma,  targetoid hemosiderotic hemangioma (Target-like hemosiderotic hemangioma. Further differential diagnosis of Kaposi sarcoma.) , and benign lymphangioendothelioma .

Other histologic simulators of Kaposi's sarcoma are:

-Intranodal Palisaded Myofibroblastoma;

-reactive angioendotheliomatosis  ;

-bacillary angiomatosis ;

-microvenular hemangioma  ;

-hobnail hemangioma ;

-pyogenic granuloma ;

-aneurysmal fibrous histiocytoma ;

-arteriovenous hemangioma ;

-verrucous hemangioma ;

-nonspecific vascular proliferation;

-angiomatoid  fibrous histiocytoma ;

-dermatofibrosarcoma protuberans;

-vascular transformation of lymph node ;

-pilar leiomyoma ( Piloleiomyoma ) ;  -stasis dermatitis ;  -spindled melanoma.

Dermatopathology Quiz Case 142

Latency-associated nuclear antigen expression and human herpesvirus-8 polymerase chain reaction in the evaluation of Kaposi sarcoma and other vascular tumors in HIV-positive patients.

Aggressive behavior of classical Kaposi's sarcoma and coexistence with angiosarcoma.

Occurrence of tubuloreticular structures and intracisternal paracrystalline inclusions in endothelial cells of tissue from different epidemiological types of Kaposi's sarcoma.

Conjunctival Kaposi sarcoma as the initial presentation of human immunodeficiency virus infection.

C-Kit (CD117) expression in AIDS-related, classic, and African endemic Kaposi sarcoma.

Histological characterization of regression in acquired immunodeficiency syndrome-related Kaposi's sarcoma.

HHV-8 DNA sequences in the peripheral blood and skin lesions of an HIV-negative patient with multiple eruptive dermatofibromas: implications for the detection of HHV-8 as a diagnostic marker for Kaposi's sarcoma.

Benign vascular proliferations in irradiated skin.