KSHV/HHV8-associated primary cutaneous plasmablastic lymphoma in a patient with Castleman's disease and Kaposi's sarcoma

Abstract:  We report a unique case of Kaposi's sarcoma (KS)-associated herpesvirus (KSHV)/human herpesvirus (HHV)8-associated lymphoma in a 56-year-old man with a history of acquired immune deficiency syndrome, Castleman's disease, KS, and idiopathic thrombocytopenic purpura. Three months following the diagnosis of KS affecting a left cervical lymph node and Castleman's disease with bone marrow involvement, he presented with a subcutaneous, tender lesion on his left arm. A skin biopsy demonstrated a superficial and deep, interstitial-nodular infiltrate of severely atypical lymphoid cells showing plasmacytoid features, numerous mitotic figures, and frequent individual apoptotic tumor cells. The morphologic features were those of plasmablastic lymphoma (PBL). Immunohistochemical study showed that the lymphoma cells strongly expressed CD45, CD30, and KSHV/HHV8 latency-associated nuclear antigen. KSHV/HHV8 was also detected in the biopsy sections of the patient's KS and Castleman's disease. Epstein–Barr virus in situ hybridization was diffusely positive. In situ hybridization demonstrated κ-light chain restriction. Although KSHV/HHV8 has been individually associated with KS, Castleman's disease, and PBL, this appears to be the first reported case in which all three entities were present simultaneously in one person, suggesting a critical role of KSHV/HHV8 as a common denominator in the pathogenesis of these diseases.     

Two cases of Kaposi's sarcoma mimicking Stewart-Treves syndrome found to be human herpesvirus-8 positive.

Although angiosarcoma is the most frequent tumor arising in the clinical setting of chronic lymphedema, as in Stewart-Treves syndrome, Kaposi's sarcoma has also been reported in this setting, although rarely. We describe two women who developed Kaposi's sarcoma in the lymphedematous arm many years after surgery for breast cancer. Case 1 is a 92-year-old and Case 2 is an 81-year-old; they underwent left total mastectomy and axillary node dissection for infiltrating breast carcinoma in 1981 and 1982 respectively. At that time, neither patient received further treatment. Except for persistent lymphedema, both women did well until over fourteen years later when each noted the development of several purple asymptomatic plaques on the edematous arm. In both, the clinical diagnosis at the time of biopsy was angiosarcoma. However, histologic findings in both cases were typical for Kaposi's sarcoma. In addition, a nested polymerase chain reaction (PCR) for the detection of a 233bp segment of KSHV/HHV8 was performed on DNA extracted from the paraffin-embedded specimens and both cases were positive for this sequence. Histologic sections of both cases were also tested for KSHV by in situ hybridization and demonstrated a positive signal in the lesional cells in each case.     

Kaposi sarcoma associated with systemic corticosteroid therapy

Kaposi sarcoma (KS) was first described in 1872 by Moritz Kaposi. Its epidemiology is suggestive of an infectious disease and in 1994 Chang and coworkers identified DNA sequences corresponding to a previously unidentified herpes virus--human herpes virus 8 (HHV-8)--in AIDS-associated KS biopsies. It is now believed that the presence of HHV-8 is a necessary condition but not sufficient on its own to cause KS. Other factors such as immunosuppression should also be considered and it is known that immunosuppressive therapy increases the risk of KS. We describe a patient who developed KS after prolonged prednisone therapy for temporal arteritis.     

Lymphedema: an immunologically vulnerable site for development of neoplasms

Lymphedema is the result of accumulation of protein-rich interstitial fluid (lymph stasis) caused by a failure of lymph drainage in the face of a normal capillary filtration. Whether the origin is congenital or acquired from infection, radiation, trauma, or surgery, chronic lymph stasis impairs local immune surveillance by disrupting trafficking of the immunocompetent cells in the lymphedematous district and stimulates vicarious angiogenesis by promoting development of a collateral lymphatic and hematic network in the lymphedematous district. When the local mechanisms of immune surveillance begin to fail, the lymphedematous region becomes an immunologically vulnerable area, predisposed to malignancy, chiefly vascular tumors such as Stewart-Treves syndrome and Kaposi's sarcoma, because of the continual angiogenic stimulus.     

Cutaneous and lymphadenopathic Kaposi's sarcoma: a case report and review of literature

Kaposi's sarcoma (KS) of childhood is an extremely rare and unexplained disease. It is usually associated with immunosuppression and human herpes virus 8 (HHV-8) infection. It can involve skin, mucous membranes, lymph nodes and viscera. This investigation describes a case of a 3-year-old boy with cutaneous and lymphangiopathic KS. Initially, the patient presented with cutaneous lesions of KS behind the right ear. Two months later, the disease disseminated not only cutaneously but also to the cervical, axillary and inguinal lymph nodes. Immunological evaluation showed severe lymphocytopenia but without evidence of human immunodeficiency virus infection. The vascular nature of the lesion was supported by positive staining for CD31 and CD34. This study examines the clinicopathologic features of KS in children and summarizes the relevant literature.     

Primary effusion lymphoma presenting as a cutaneous intravascular lymphoma

Primary effusion lymphoma (PEL) is a rare and aggressive lymphoma that arises in the context of immunosuppression and is characterized by co‐infection with Epstein–Barr virus (EBV) and human herpesvirus‐8/Kaposi sarcoma‐associated herpesvirus (HHV‐8/KSHV). It was originally described as arising in body cavity effusions, but presentation as a mass lesion (extracavitary PEL) is now recognized. Here, we describe a case of PEL with an initial presentation as an intravascular lymphoma with associated skin lesions. The patient was a 53‐year‐old man with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) who presented with fevers, weight loss and skin lesions concerning for Kaposi sarcoma (KS). A skin biopsy revealed no evidence of KS; however, dermal vessels contained large atypical cells that expressed CD31 and plasma cell markers but lacked most B‐ and T‐cell antigens. The atypical cells expressed EBV and HHV‐8. The patient subsequently developed a malignant pleural effusion containing the same neoplastic cell population. The findings in this case highlight the potential for unusual intravascular presentations of PEL in the skin as well as the importance of pursuing microscopic diagnosis of skin lesions in immunosuppressed patients.     

Classic Kaposi sarcoma mimicking chilblains

Kaposi Sarcoma (KS) is a low-grade vascular tumor associated with human herpes virus-8 infection. It usually presents in elderly patients as violaceous plaques of the lower limbs. However, KS may present in a wide spectrum of atypical clinical forms, leading to misdiagnoses. We report a case of classic KS mimicking chilblains.     

Penile intraepithelial neoplasia overlying Kaposi's sarcoma lesions: role of viral synergy?

Several viral agents have been detected in the lesional tissue of Kaposi's sarcoma (KS). Their precise oncogenic role remains to be determined. A 32-year-old heterosexual man with acquired immunodeficiency syndrome (AIDS) who had penile lesions of KS with overlying epithelial changes characteristic of intraepithelial neoplasia associated with concurrent infection by human papillomavirus (HPV) and human herpesvirus 8 (HHV-8) is reported. The absence of viral DNA from uninvolved skin suggests that this coinfection is more than coincidental and may involve synergy between these viruses, as has already been suggested for HPV and herpes simplex 2 virus.     

Treatment of Disseminated Classic Type of Kaposi's Sarcoma with Paclitaxel

Classic Kaposi sarcoma (KS) is a rare human herpes virus 8-associated angioproliferative disease, and the disseminated classic type of KS in Korea is even rarer. The treatment options for classic KS vary and range from surgical excision to ionizing irradiation or chemotherapy. Recently, there have been a few reports of treating classic KS with paclitaxel, which has been used to treat AIDS-associated KS and post-transplant KS. We herein report a case of disseminated classic type KS in a 78-year-old Korean male patient who showed dramatic response after only two cycles of paclitaxel treatment.     

A case of classic Kaposi's sarcoma in a Japanese man: detection of human herpes virus 8 (HHV-8) infection by means of polymerase chain reaction and immunofluorescence assay

The recently discovered human herpes virus 8 (HHV-8) has been implicated in the pathogenesis of Kaposi's sarcoma (KS). Because classic KS in Japan is rare and the detection of HHV-8 DNA by polymerase chain reaction (PCR) has been successful only in limited cases, the frequency and role of HHV-8 infection in KS in Japan remain unclear. Herein we report a case of classic KS in a Japanese man whose HHV-8 infection was confirmed by the detection of lesional viral DNA and serum antibodies against lytic antigen.     

Recurrent and self-healing cutaneous monoclonal plasmablastic infiltrates in a patient with AIDS and Kaposi sarcoma

Infection with human immunodeficiency virus (HIV) increases the risk of developing non-Hodgkin lymphoma. Plasmablastic lymphoma (PBL) is a rare variant of diffuse large cell lymphoma that often involves the oral cavity of HIV+ patients. It is characterized by immunoblastic morphology and plasma cell phenotype. Cutaneous involvement in PBL appears to be rare. We report a 44-year-old man with AIDS and Kaposi sarcoma (KS) previously treated with doxorubicin who, following treatment with highly active antiretroviral therapy, developed an erythematous infiltrated nodule on the right arm. Histology showed subcutaneous fat necrosis and clusters of atypical large plasma cells (plasmablastic cells). Immunohistochemistry revealed lambda light chain restriction. Epstein-Barr virus (EBV) mRNA was detected by in situ hybridization within the plasmablastic cells. Polymerase chain reaction amplification with specific primers for human herpesvirus 8 (HHV-8) performed on the skin biopsy specimen detected a specific band. A complete screening (bone marrow biopsy, computed tomographic scan, radiological survey) disclosed no abnormalities. The lesion resolved spontaneously after 3 months. Two years later an infiltrated plaque developed on the abdominal wall. The clinical and histopathological features of this new lesion were similar to those observed 2 years previously. No evidence of extracutaneous involvement was detected. The lesion again resolved spontaneously after 25 days. PBL may be seen in patients with transplants or receiving chemotherapy, but is usually observed in patients with advanced AIDS. The observation of recurrent self-healing EBV- and HHV-8-associated cutaneous monoclonal plasmablastic infiltrates, in a patient with AIDS and KS, expands the clinical spectrum of AIDS-associated plasmablastic lymphoproliferative disorders.     

HIV-associated Kaposi's sarcoma

Kaposi's sarcoma (KS) is a multifocal vascular tumor that occurs most commonly in patients who have immunosuppression caused by HIV. KS-associated herpes virus (human herpes virus 8, KSHV) has been identified as the causative agent. There are marked geographic differences in the prevalence of both KS and seropositivity to KSHV. The incidence of the tumor has shown a marked decline in first-world countries with the widespread use of effective antiretroviral therapy. The most effective anthracycline is pegylated liposomal doxorubicin; however, few developing countries, where KS prevalence is highest, can afford to use these agents.     

PGP 9.5 neuronal marker may differentiate immunohistochemically HIV-related from Mediterranean and immunosuppression-associated Kaposi’s sarcoma

Mediterranean Kaposi’s sarcoma (MKS), HIV-related KS (HIV-KS) and immunosuppression-associated KS (IS-KS), caused by human herpes virus 8 (HHV-8), share similar histological features. The aim of this study was to investigate differences in epidermal nerve fibers (ENFs) between the three KS types and controls. Skin biopsies from 23 HIV-KS, 16 MKS, 28 IS-KS patients and 18 controls, age-gender matched, were immunostained with PGP 9.5; ENFs in upper epidermal layer (EL) and penetrating the basement membrane were measured. The mean number of nerve fibers penetrating ENFs was significantly lower in HIV-KS (p < 0.001) compared to all other groups. MKS and IS-KS had comparable ENFs but lower than controls (p < 0.00 1). In the upper EL all groups had comparable ENFs and lower than controls. In conclusion, HIV-KS can be distinguished histologically from other types, by counting ENFs. Moreover, KS is associated with decreased ENFs, which may be a histological reflection of nerve damage. This is even more pronounced in HIV-KS patients and could be explained by a neurotoxic action of HHV-8, HIV, and their co-existence.     

Stewart-Treves pseudo-syndrome caused by cutaneo-lymphatic metastases of contralateral breast carcinoma

The pathogenesis of Stewart-Treves syndrome remains controversial: angiosarcoma or epithelial cell metastases from a mammary carcinoma? The case reported here, with clinical signs of Stewart-Treves syndrome on one side and mastectomy for carcinoma on the other side of the body, revives the debate. Case-history. The patient was an 89-year old woman whose left breast had been removed in June, 1981 for carcinoma with lymph node involvement. One year after the operation, multiple lymphadenopathy developed in her right armpit and subclavian region. In December, 1984, her right arm became swollen by lymphoedema, while Kaposi-like and nodular skin lesions appeared on her right upper chest and upper back and on her right shoulder and arm. Radiography of the chest showed right pleural effusion, bronchial lymph node enlargement and a reticulate image in the right lung. In spite of chemotherapy, the patient died in April, 1985. Pathology. Pathological examinations included standard histology (HPS, PAS and Gordon-Sweet staining), immunohistochemistry, using anti-factor VIII, anti-keratin KL1 and anti-EMA antisera, and electron microscopy. Results. Irrespective of the skin area biopsied, the histological images were always the same, showing carcinomatous lymphangitis with a varying degree of invasion of the surrounding dermis. Staining of the reticulum enhanced the vascular basal membranes but did not mark the intraluminal tumoral cell population. Post-mortem examination confirmed that the malignant lymphangitis extended to the lung tissue, the oesophageal wall and the adrenal glands, and that the axillary and subclavian lymph nodes were invaded by metastases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Angiosarcoma in chronic lymphedema

Angiosarcoma that develops on a limb with chronic lymphedema is called Stewart-Treves syndrome. This typically appears as a complication of a long course lymphedema located on the arm, after mastectomy and/or radiotherapy due to breast cancer. There are cases of Stewart-Treves syndrome in chronic lymphedema in the upper limb contralateral to the breast treated for cancer and in chronic lymphedema of the leg. We present two cases of this syndrome. The first corresponds to a typical syndrome of Stewart-Treves in an 83-year-old woman who was diagnosed of angiosarcoma in a chronic lymphedema territory secondary to mastectomy and radiotherapy due to breast cancer. The second case is much rarer, since it is a case of diffuse angiosarcoma of the leg in a 42-year-old man with a history of lymphedema. Due to the aggressive nature of this syndrome, knowledge and research on its treatment are necessary.     

Humanes Herpesvirus 8 (HHV-8) und Kaposi-Sarkom

The Kaposi sarcoma-associated herpes virus (KSHV) or human herpesvirus 8 (HHV-8) is a gamma-herpesvirus (Rhadinovirus) present in all clinical cases of Kaposi sarcoma (KS). HHV-8 can be transmitted by blood and blood products, as well as in saliva during mother-child transfer. Sexual transmission is also possible although not conclusively proven. Actually the goal of treating KS is to reduce symptoms and, not to produce complete tumor remission. In patients with HIV- and posttransplant-associated KS; an improved immune status is essential. In addition, specific topical or systemic approaches are available. Therapeutic strategies to treat HHV-8 infection, in order to prevent the development of KS are currently investigated.     

Herpetic syringitis associated with eccrine squamous syringometaplasia in HIV-positive patients

Herpetic syringitis has been described as a rare manifestation of herpes virus infection in patients with an immunodeficiency, usually secondary to human immunodeficiency virus (HIV) infection. Eccrine squamous syringometaplasia (ESS) is an infrequent alteration of the eccrine duct epithelium reported in association with several conditions, including chronic ulcers, inflammatory processes, and patients receiving chemotherapy. The association of herpetic syringitis with ESS has not been reported before. We identified 3 cases of herpetic syringitis associated with ESS in patients with the acquired immunodeficiency syndrome. In 2 of 3 cases the signs of herpetic syringitis were limited to the meta-plastic duct epithelium, but in 1 case there were also herpetic alterations without ESS.
The histological features of herpetic infection in HIV-positive patients may be atypical and lack the typical epidermal alterations, observing only an extensive epidermal necrosis. In those cases, the alterations of the eccrine ducts may be a diagnostic clue in the diagnosis of herpetic infection. ESS of the ductal epithelium is probably secondary to the herpetic infection, although it might also stimulate the extension of the herpetic infection. Futher studies are needed to elucidate the association of ESS and herpes virus infection.     

Angiosarcoma of the abdominal wall after dermolipectomy in a morbidly obese man. A rare form of presentation of Stewart-Treves syndrome

Angiosarcoma is a rare malignant tumor, with a predilection for skin in the head and neck region, although it has been described in many other locations. Its association with chronic lymphedema is well known, mainly in the setting of postmastectomy lymphedema of the arm in breast cancer patients (termed Stewart-Treves syndrome). However, angiosarcoma can appear in lower limbs with chronic lymphedema and rarely in other locations such as the abdominal wall. Herein, we present a unique case of angiosarcoma developing in the abdominal wall of a morbidly obese patient after extensive dermolipectomy.     

Cutaneous Kaposi sarcoma during treatment with superpotent topical steroids and methotrexate for bullous pemphigoid: three cases

Background

Iatrogenic Kaposi sarcoma (KS) has previously been reported in patients with bullous pemphigoid (BP), in relation to systemic steroids.

Objectives

To report three cases of previously unreported cutaneous KS during treatment with superpotent topical steroids (STS) and methotrexate (MTX).

Patients and Methods

All patients were elderly men with BP treated with STS for 2 to 32 months (cumulative doses: 2,700-9,150 g) beforeMTXwas introduced (dosage: 10-12.5 mg/week).

Results

KS occurred one to nine months after the combined therapy. In one case, KS rapidly resolved after withdrawal of MTX. In two cases, vinblastine and/or radiotherapy were required to achieve regression of KS. Human herpes virus 8 (HHV8) latency-associated nuclear antigen was not expressed in BP lesions biopsied prior to development of KS (n = 3), but HHV8 DNA was detected in BP lesions from the patient with the most aggressive KS.

Conclusion

Several predisposing factors were identified, including sex and age, high cumulative doses of STS, combination with MTX, and impaired immune status. In such cases, serum antibodies against HHV8 infection may be investigated in BP patients before introduction of MTX in order to guide clinical monitoring.