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Background

This tumor was the first clue to the diagnosis of AIDS in the late 1970's. It was an indolent tumor previously been seen on the lower extremities in elderly men of Mediterranean or Jewish extraction. In contrast, the tumors occurring in this new clinical situation of AIDS had a virulent progressive course. One of the great breakthroughs in microbiology was the discovery of a viral etiology for this sarcoma. Human Herpes Virus 8 (HHV8) has been shown to be the cause of both AIDS-related and non-epidemic cases.

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/Other Diagnostic Testing  
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
Immunohistochemistry/
Electron Microscopy
 
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

EPIDEMIOLOGY CHARACTERIZATION
SYNONYMS KS
INCIDENCE Most common tumor in HIV infected patients
SEX (M:F)
In epidemic type, there is a higher prevalence in men
GEOGRAPHY
In Africa, there is a high frequency of females
Women
Women who have sex with bisexual men
African women
PERU  
Epidemiological and clinical characteristics of classic Kaposi's sarcoma in Peru.

Mohanna S, Ferrufino JC, Sanchez J, Bravo F, Gotuzzo E.

Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.
J Am Acad Dermatol. 2005 Sep;53(3):435-41. Abstract quote  

BACKGROUND: Classic Kaposi sarcoma (KS) occurs predominantly among the elderly, with predominance among Jews, Italians, and Greeks. Classic KS has been seen relatively frequently in Peru.

OBJECTIVE: Our purpose was to outline the epidemiological and clinical profile of classic KS in Peru.

METHODS: Epidemiological and clinical features of all classic KS cases diagnosed between 1969 and 2003 at Hospital Nacional Cayetano Heredia (HNCH) and between 1946 and 2004 at Instituto Nacional de Enfermedades Neoplasicas (INEN) were reviewed and studied retrospectively.

RESULTS: An overall incidence of 2.54 per 10,000 attended patients was obtained at the INEN during the 48-year period (mean, 2.39; standard deviation: 1.99; 95% confidence interval, 2.92-1.86). Twenty-one cases were discovered at HNCH and 106 cases at INEN. A male/female ratio of 2.62:1 was found. Mean age at diagnosis was 68.5 years. Lower limbs were involved in 109 patients (85.8%); the trunk was involved in 11 patients (8.6%). Nodules were the most common type of lesion (85.8%); less commonly found were plaques (27.5%), macules (12.5%), papules (12.5%), and ulcers (8.6%). Sixty-two patients had no symptoms (48.8%). Pain was the most common symptom (26.7%), followed by edema (21.2%), bleeding (14.9%), and pruritus (3.9%). A second primary malignancy was found in 11 patients (8.6%).

LIMITATIONS: These results were obtained from patients with classic KS in Peru and may not be applicable to other populations.

CONCLUSION: Classic KS is quite common in Peru with sporadic cases found throughout the country and some clustering in the coastal region. Classic KS in Peru has a clinical presentation that is very similar, but not identical, to the classic KS described in the Mediterranean region, exhibiting some special clinical and epidemiological characteristics with a nodular, nonsymmetric presentation that usually affects the lower extremities.
SARDINIA  
Classic Kaposi sarcoma in northern Sardinia: a prospective epidemiologic overview (1977-2003) correlated with malaria prevalence (1934).

Department of Dermatology, University of Sassari, Italy.

J Am Acad Dermatol. 2006 Dec;55(6):990-5. Epub 2006 Aug 14. Abstract quote

BACKGROUND: Studies have demonstrated considerable variations in classic Kaposi sarcoma (CKS) incidence within Europe, with some of the highest incidences found in the Mediterranean area. As a Mediterranean area, northern Sardinia has a high CKS frequency.

OBJECTIVE: In order to determine CKS incidence in people born in and residing in northern Sardinia, a clinical prospective epidemiologic study was carried out between 1977 and 2003 by the Department of Dermatology, University of Sassari. We also evaluated a correlation between malaria prevalence in 1934, estimated on the eight historical sub-areas of the Sassari province, and the standardized morbidity ratio from 1977 to 2003.

RESULTS: A total of 332 patients with CKS were identified. Incidence among the northern Sardinian population > or =40 years of age was 4.06/100,000 persons/year and it was almost stable through the years. The male to female ratio showed a significant decline from 3.6 to 2.5 (P = .03). Females had a statistically decreased risk of developing CKS compared to males (adjusted incidence rate ratio = 0.27; 95% CI: 0.21-0.34), and the risk of developing CKS increased exponentially with age. The prevalence of malaria in each sub-area ranged from 9% to 91%. The standardized morbidity ratio for CKS in the years between 1977 and 2003 ranged from 0.27 to 1.76; the regression coefficient was -0.85 (95% CI: -2.94-1.24), yielding a nonsignificant relationship between the two diseases.

LIMITATIONS: These results were obtained from patients with CKS in northern Sardinia and may not be applicable to other populations.

CONCLUSIONS: The northern Sardinian population consistently has a very high incidence of CKS, while in our data, the correlation between malaria and CKS remains open to question.

 

DISEASE ASSOCIATIONS CHARACTERIZATION
GASTRITIS  
Phlegmonous gastritis associated with kaposi sarcoma: a case report and review of the literature.

Yu QQ, Tariq A, Unger SW, Cabello-Inchausti B, Robinson MJ.

Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, Fla 33140, USA.
Arch Pathol Lab Med. 2004 Jul;128(7):801-3. Abstract quote  

We report a case of phlegmonous gastritis associated with Kaposi sarcoma in a 37-year-old, human immunodeficiency virus (HIV)-positive man who presented with an acute abdomen.

Computed tomographic scan revealed free fluid in the abdominal cavity and a thickened gastric wall. A partial gastrectomy was performed. The resected portion of stomach had a hemorrhagic, necrotic thickened wall and showed extensive, acute suppurative inflammation, especially in the submucosa, with focal transmural involvement. Beneath an area of healing ulceration, a focus of Kaposi sarcoma was present. Group A beta-hemolytic streptococcus was grown from peritoneal fluid, and treatment with numerous antibiotics was initiated. After a difficult postoperative course that responded to 8 weeks of antibiotic therapy, the patient was medically stable and discharged from the hospital on antiretroviral therapy for HIV.

Phlegmonous gastritis is a rare and rapidly progressive bacterial infection of the gastric wall. Kaposi sarcoma is one of the most common malignancies in HIV-positive patients, and gastric involvement is relatively common in those patients with systemic Kaposi sarcoma.

To our knowledge, this is the first reported case of phlegmonous gastritis associated with Kaposi sarcoma, and it represents a rare survival following surgical and antibiotic therapy.
LYMPHOMA  


Immunoblastic Lymphoma in Persons with AIDS-Associated Kaposi's Sarcoma: a Role for Kaposi's Sarcoma-Associated Herpesvirus.

Engels EA, Pittaluga S, Whitby D, Rabkin C, Aoki Y, Jaffe ES, Goedert JJ.

Viral Epidemiology Branch, Division of Cancer and Epidemiology and Genetics (EAE, CR, JJG) and Hematopathology Section, Laboratory of Pathology, Center for Cancer Research (SP, ESJ), National Cancer Institute, Rockville.


Mod Pathol 2003 May;16(5):424-9 Abstract quote

Kaposi's sarcoma-associated herpesvirus, the viral agent of Kaposi's sarcoma, is associated with two lymphoproliferative disorders: primary effusion lymphoma and multicentric Castleman's disease.

To identify other lymphoproliferative conditions linked with Kaposi's sarcoma-associated herpesvirus, we studied non-Hodgkin's lymphomas arising in individuals with AIDS-associated Kaposi's sarcoma. Formalin-fixed tissues from 24 such lymphomas were examined.

As expected, two primary effusion lymphomas were Kaposi's sarcoma-associated herpesvirus-positive, with immunohistochemistry demonstrating the Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen in the nuclei of all neoplastic cells. Additionally, three of seven evaluable cases of the immunoblastic variant of diffuse large B-cell lymphoma (immunoblastic lymphoma) showed similar latency-associated nuclear antigen staining.

These Kaposi's sarcoma-associated herpesvirus-positive immunoblastic lymphomas resembled primary effusion lymphoma histologically but were not known to involve body cavities (sites included lymph nodes, soft tissues of the neck, and spleen). Notably, 5-20% of the neoplastic cells in the Kaposi's sarcoma-associated herpesvirus-positive immunoblastic lymphomas also showed cytoplasmic staining for viral interleukin-6, a biologically active cytokine homologue found in primary effusion lymphoma.

We conclude that Kaposi's sarcoma-associated herpesvirus is present in some immunoblastic lymphomas in persons with AIDS-associated Kaposi's sarcoma.

 

PATHOGENESIS CHARACTERIZATION
HHV 8 (Human Herpes Virus 8) N Engl J Med 1995;332:1181-1185
Transmission of
HHV-8

N Engl J Med 2000;343:1369-1377
N Engl J Med 2000;343:1378-1385

Kissing can pass along the virus but does not explain why the virus is not as prevalent in the general population as HHV-1 and Epstein-Barr virus

Only 39% HIV positive, HHV-8 infected men who had sex with men developed KS

In patients who acquired HHV8 infection through organ transplantation in 3 cases,1 patient developed KS

GENERAL  
Detection of HHV-8 in pyogenic granuloma-like kaposi sarcoma.

Department of Dermatology, University of Colorado Health Sciences Center, USA.

 

Am J Dermatopathol. 2006 Aug;28(4):317-21. Abstract quote

Kaposi sarcoma (KS) is a low-grade vascular neoplasm associated with human herpesvirus-8 (HHV-8) infection. Clinically, lesions commence as blue-red macules that may develop into plaques and eventually into nodules. The histologic appearance spans a broad spectrum and varies with the stage of the lesion. At each stage, KS has significant morphologic overlap with other vasoproliferative lesions.

Recently, we encountered 6 KS tumors that histologically mimicked pyogenic granuloma (PG), a common benign vascular tumor of the skin that usually does not figure in the histologic differential diagnosis of KS. We stained 6 PG-like KS and 28 PGs with a mouse monoclonal antibody (13B10) against HHV-8 latent nuclear antigen-1 (LNA-1) to determine the utility of immunoperoxidase staining in distinguishing KS from PG. All 6 PG-like KS demonstrated nuclear staining for HHV-8 LNA-1. No staining was identified in any of the 28 PGs. Histologic criteria often used to differentiate between these two entities were not helpful in our cases. The only distinguishing feature was the presence or absence of HHV-8 LNA-1 staining.

The presence of HHV-8 LNA-1 nuclear staining seems to be a specific marker for KS when comparing PGs and PG-like KS. Immunoperoxidase staining for HHV-8 LNA-1 is a useful diagnostic tool in this setting.
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.

Hammock L, Reisenauer A, Wang W, Cohen C, Birdsong G, Folpe AL.

1Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, GA, USA.
Mod Pathol. 2005 Apr;18(4):463-8. Abstract quote  

Human herpesvirus-8 (HHV-8) latency-associated nuclear antigen (LANA) is expressed in endothelial and spindle cells of nearly all Kaposi sarcomas, and the presence of this antigen in serum is strongly correlated with the risk of developing Kaposi sarcoma in immunocompromised individuals. Studies of vascular tumors occurring in the general population show LANA expression to be specific for Kaposi sarcoma. No study to date, however, has examined whether non-Kaposi sarcoma vascular tumors arising in immunocompromised patients may express LANA, possibly reflecting origin from an HHV-8-infected endothelial progenitor cell.

The objective of this study was to evaluate the specificity of LANA expression for Kaposi sarcoma in immunocompromised patients by LANA immunohistochemistry and real-time polymerase chain reaction (PCR) for HHV-8. A total of 13 cases of non-Kaposi sarcoma vascular tumors (12 hemangiomas and one epithelioid hemangioendothelioma) and 24 cases of Kaposi sarcoma, all from known HIV-positive patients, were immunostained for LANA and evaluated for the presence of HHV-8 DNA by real-time PCR. LANA expression was seen in 22 of 24 (92%) of Kaposi sarcoma cases and in 0 of 13 non-Kaposi sarcoma cases.

Real-time PCR detected HHV-8 in all of the Kaposi sarcoma cases and in four of the non-Kaposi sarcoma cases (all hemangiomas). LANA expression appears to be a highly sensitive and specific marker of Kaposi sarcoma in both the general population and in HIV-positive patients. This is in contrast to HHV-8 PCR, which is positive in a small subset of non-Kaposi sarcoma vascular tumors, most likely due to detection of HHV-8 within intratumoral blood mononuclear cells by the highly sensitive real-time PCR technique.

For this reason, LANA immunohistochemistry is preferable to HHV-8 PCR for the evaluation of problematic vascular proliferations in HIV-positive individuals.
HHV-8/KSHV during the development of Kaposi's sarcoma: evaluation by polymerase chain reaction and immunohistochemistry.

Pak F, Pyakural P, Kokhaei P, Kaaya E, Pourfathollah AA, Selivanova G, Biberfeld P.

Immunopathology Laboratory, Cancer Center Karolinska, Karolinska Hospital, Solna, Stockholm, Sweden.
J Cutan Pathol. 2005 Jan;32(1):21-7. Abstract quote

The human gamma-herpes virus-8 (HHV-8) was first described in AIDS-related Kaposi's sarcoma (KS) tumour samples.

In this study, we report comparative studies on paraffin-embedded biopsies of AIDS-related KS (AKS) and endemic KS (EKS) with regard to HHV-8 content as evaluated using polymerase chain reaction (PCR) and immunohistochemistry. DNA was extracted either using Chelex-100 or using Qia-gene kit and was evaluated with the help of a semiquantitative PCR assay. The PCR detection of HHV-8 was more sensitive to the Chelex method than to Qia-gene. The threshold for PCR test sensitivity with the help of serial dilution of DNA was at the level of five plasmid ORF-26 regions, and DNA from 25 body cavity-based lymphoma-1 cells.

The results expressed as virus load/actin unit showed progressively higher HHV-8 levels in late (nodular) cases, compared to those in early (patch/plaque) stages. Evaluation of HHV-8 DNA levels in tumour tissues, thus, indicates a correlation between virus load and KS stage. Double immunostaining of spindle cells (SC) in KS biopsies for CD34 and HHV-8/latency-associated nuclear antigen (LANA) showed an increase in double-positive SC in the lesions of nodular AKS and EKS cases, compared to that in plaque and patch stages. However, 10-15% of CD34(+)/LANA(-) SC cells were observed during the development from patch to nodular cases of AKS and EKS.

Our results indicate that PCR analysis is a simple and sensitive diagnostic method for HHV-8 evaluation in KS tissues, processed for conventional histopathology.

Human herpesvirus-8 latent nuclear antigen-1 expression in endemic Kaposi sarcoma: an immunohistochemical study of 16 cases.

Schwartz EJ, Dorfman RF, Kohler S.

Department of Pathology, Stanford University School of Medicine, CA 94305, USA.

Am J Surg Pathol. 2003 Dec;27(12):1546-50. Abstract quote  

Human herpesvirus-8 (HHV-8) infection is considered the initiating factor in all forms of Kaposi sarcoma (KS). Latent nuclear antigen (LNA-1) is constitutively expressed in all HHV-8-infected cells. An antibody to LNA-1 has recently become commercially available.

The current study addresses the role of immunohistochemistry in the diagnosis of KS, particularly the endemic form. Seven recent cases of KS, 1 atypical vascular lesion in a patient subsequently diagnosed with KS, and 16 endemic cases collected in South Africa in the early 1960s were stained with an antibody to LNA-1. Nine benign vascular lesions and three angiosarcomas were also stained. All 7 recent cases expressed the antigen as did the atypical vascular lesion. Of particular interest was the finding that 10 of the 16 endemic cases were positive. None of the other vascular lesions showed staining.

A subset of the endemic lesions was stained for CD31, an antigen universally expressed in KS. CD31 staining was reduced compared with a positive control suggesting that the current study may underestimate the sensitivity of LNA-1 immunohistochemistry in endemic KS because of poor antigen preservation in the archival tissue. Our results confirm the utility of LNA-1 immunohistochemistry as an aid in the diagnosis of KS.


Study of HHV-8 DNA sequences in archival biopsies from lesional skin of Kaposi's sarcoma, various mesenchymal tumors and related reactive conditions.

Kazakov DV, Prinz BM, Michaelis S, Schmid M, Muller B, Adams V, Burg G, Kempf W.

Department of Dermatology, University Hospital, Zurich, Switzerland and University Leipzig, Heart Center, Leipzig, Germany.

 

J Cutan Pathol 2002 May;29(5):279-81 Abstract quote

Background: HHV-8 has been identified as the causative agent of Kaposi's sarcoma (KS) and some lymphoproliferative disorders. In addition, there are anecdotal reports on the presence of HHV-8 in other tumors, especially cutaneous epithelial and mesenchymal neoplasms. The aim of the study was to ascertain the value of identification of HHV-8 viral DNA sequences in routinely processed, formalin-fixed, paraffin-embedded tissues for the diagnosis of Kaposi's sarcoma and other mesenchymal tumors.

Methods: The presence of HHV-8 sequences in archival material was studied by nested PCR using specific primers for amplification of a 233-bp long fragment of HHV-8 (ORF 26).

Results: Thirty-three patients with KS (18 classic/sporadic, six post-transplant and nine AIDS-related) and various mesenchymal tumors and related conditions (n = 76) were studied. HHV-8 DNA sequences were detected in 29 of the 33 cases of KS and in one case of multiple eruptive dermatofibroma (MEDF).

Conclusions: Identification of HHV-8 DNA sequences in routinely processed tissue is a useful diagnostic marker for KS. Although other mesenchymal tumors are usually not associated with HHV-8, its presence is not fully specific for KS since HHV-8 sequences were also found in one case of MEDF. Therefore, PCR analysis for the detection of HHV-8 should only be used as an additional diagnostic marker for KS and in the context of other tools such as routine histology.


Kaposi's sarcoma and other manifestations of human herpesvirus 8.

Geraminejad P, Memar O, Aronson I, Rady PL, Hengge U, Tyring SK.

Department of Dermatology, University of Illinois at Chicago; the Departments of Dermatology, Microbiology/Immunology, and Internal Medicine, University of Texas Medical Branch; and the Department of Dermatology, Heinrich-Heine University, Dusseldorf.

 

J Am Acad Dermatol 2002 Nov;47(5):641-55 Abstract quote

Kaposi's sarcoma (KS) was described by Moritz Kaposi in 1872 and was known for an entire century as a rare disorder of older men usually of Eastern European, Mediterranean, and/or Jewish origin. In the early 1980s, the prevalence of KS began to increase dramatically and soon became the most common malignancy in patients with AIDS, especially those who were male homosexuals.

In 1994, a new human herpesvirus (HHV) was found to be present in almost 100% of KS lesions. This virus was found to be a gammaherpesvirus, closely related to Epstein-Barr virus, and was designated HHV-8. Subsequently, HHV-8 DNA was found in almost all specimens of classic KS, endemic KS, and iatrogenic KS, as well as epidemic KS (ie, AIDS KS). It is now believed that HHV-8 is necessary, but not sufficient, to cause KS and that other factors such as immunosuppression play a major role.

The use of highly active antiretroviral therapy (HAART) since 1996 has markedly reduced the prevalence of AIDS KS in western countries, but because 99% of the 40 million patients with AIDS in the world cannot afford HAART, KS is still a very common problem.

Primary effusion lymphoma and multicentric Castleman's disease are also thought to be due to HHV-8. Although HHV-8 DNA has been described in a number of other cutaneous disorders, there is little evidence that HHV-8 is of etiologic significance in these diseases. The mechanism by which HHV-8 causes KS, primary effusion lymphoma, and multicentric Castleman's disease is not well understood but is thought to involve a number of molecular events, the study of which should further our understanding of viral oncology.

CLONAL  

The clonality of tumor-infiltrating lymphocytes in African Kaposiís sarcoma

Minakshi Nihal, etal

J Cutan Pathol 2001;28 (4): 200-205 Abstract quote

Background: African Kaposiís sarcoma (KS) lesions contain human herpesvirus-8 (HHV-8) and Epstein-Barr virus (EBV), both of which are associated with various types of non-Hodgkinís lymphomas and are known to produce several factors suspected of lymphomagenic potential. The aim of this study was to evaluate tumor-infiltrating lymphocytes for the evidence of clonal expansion in African KS.

Methods: We used polymerase chain reaction (PCR)-based assays to determine the clonality of tumor-infiltrating lymphocytes in African KS lesions and compared the results to similar studies of patient-matched uninvolved skin and peripheral blood.

Results: T cells were polyclonal in all samples tested. Peripheral blood B cells were also polyclonal; however, a minority of lesional and uninvolved skin samples exhibited evidence of restricted B-cell clonality. Correlation with immunohistological analysis revealed that this clonal B-cell restriction was secondary to the sparse nature of lesional B cells rather than their clonal overgrowth.

Conclusions: We conclude that, despite the putative lymphomagenic potential of HHV-8 and EBV and their co-existence in African KS lesions, tumor-infiltrating lymphocytes in these cases do not show evidence of clonal expansion that might be an early manifestation of lymphoma. Nevertheless, these studies are a case in point that sparse lymphoid subpopulations in lesional and uninvolved extranodal tissues can give rise to restricted clonal patterns that must be interpreted carefully to avoid the misdiagnosis of occult lymphoma.

CYTOKINES Most likely of mesenchymal origin, possibly a smooth muscle progenitor, with phenotypic markings reflective of early differentiation or transformation.

In situ study of chemokine and chemokine-receptor expression in Kaposi sarcoma.

Uccini S, Scarpino S, Ballarini F, Soriani A, Chilosi M, Montesu MA, Masala MV, Cottoni F, Ruco L.

Department of Experimental Medicine and pathology, University La Sapienza, Roma.
Am J Dermatopathol. 2003 Oct;25(5):377-83. Abstract quote  

Tissue expression of CC and CXC chemokines and chemokine receptors was investigated in 6 cases of classic non-AIDS Kaposi sarcoma (KS) using immunohistochemistry and RNase protection assay (RPA). Immunostaining of frozen sections of KS skin biopsies revealed that KS spindle cells express several chemokine receptors.

In KS nodules, almost all KS spindle cells were intensely stained for CXCR4 and CCR5. Other chemokine receptors as CCR1, CXCR3, and CCR2 were also detected in the large majority of KS spindle cells. A minority of KS spindle cells also expressed the fractalkine receptor (FK-R) CX3CR1.The immunohistochemical findings were confirmed at RNA level. In fact, the RNase protection assay (RPA) revealed in 6 of 6 cases the presence of consistent amounts of mRNAs for CXCR4 and CCR1 and in 5 of 6 cases also for CCR5 and CXCR3.Expression of chemokine receptors by KS cells was associated with chemokine production within the lesions. In the same cases, RPA demonstrated the presence of mRNAs for MCP-1, RANTES, IP-10, MIP-1alpha, and MIP-1beta. Chemokine-producing cells, as detected by immunohistochemistry, were mainly spindle-shaped cells resembling tissue macrophages outside KS lesions and some scattered cells (<5%) present within KS nodules.

The demonstration of chemokine receptors in KS cells raises the possibility that recruitment of KS cells in response to locally produced chemotactic stimuli may be one of the events involved in the pathogenesis of Kaposi sarcoma.
Cytokines needed to promote growth and differentiation

Hematol Oncol Clin North Am 1996;10:1011-1021
Science. 1989 Jan 13;243(4888):223-6

Interleukin-1 alpha and beta (IL-1. and IL-1.)
Tumor necrosis factor alpha (TNF.)
F ibroblast growth factors (FGFs)
Interleukin-6 (IL-6)
Platelet-derived growth factor (PDGF)
Oncostatin-M (onco-M)

Secreted by HIV-infected cells and are produced in high quantities during active HIV replication or as a result of other infections or inflammation

Antibodies to IL-1, basic fibroblast growth factor (BFGF), and PDGF and antisense oligonucleotides to IL-6 can inhibit in vitro KS cell growth

Several cytokines, such as IL-1, TNF., and IL-6, appear to have more specific effects on KS-derived cells than on normal endothelial cells or fibroblasts-primary effect of these cytokines is to enhance the growth of tumors once they have been transformed by another potentially infectious agent

 

Proc Natl Acad Sci U S A. 1990 Jun;87(11):4068-72
J Intern Med. 1991 Jun;229(6):539-42.

Modulation of IL-6 production and receptor expression may be the final pathway by which several cytokines such as TNF., IL-1, Onco-M, the tat gene product, and high dose interferon-gamma promote KS tumor growth

IL-6 is a cytokine normally produced by endothelial mesenchymal cells, and it has multiple effects:
Angioproliferation
Inhibition of apoptosis

High levels of TNF., IL-1., and IL-6 are produced with infection

High levels of IL-6 have been found in patients with KS and may precede the development of these tumors in HIV-infected men

A reduction in IL-6 level has also been reported in patients with KS tumor responding to treatment with recombinant alpha-interferon

Hormonally Sensitive

J Clin Pathol. 1995 Jun;48(6):513-8.

Glucocorticoids as well as androgens can stimulate KS growth

Patients with KS have higher levels of dihydroepiandosterone and testosterone

 

N Engl J Med. 1996 Oct 24;335(17):1261-9.
Nature. 1995 May 4;375(6526):64-8.

Tumor regression has been observed during pregnancy in HIV-infected women

Human beta-chorionic gonadotropin can inhibit KS tumors cells in vitro and slow the growth of KS tumors in mice

Some HCG preparations cause regression of lesions when injected intralesionally

MATRIX METALLO-PROTEINASES  
Matrix metalloproteinases in the progression and regression of Kaposi's sarcoma.

Department of Pathology, Baystate Medical Center, Tufts University School of Medicine, Springfield, MA, USA.

 

J Cutan Pathol. 2006 Dec;33(12):793-8. Abstract quote

Background: Matrix metalloproteinases (MMPs) are associated with Kaposi's sarcoma (KS) tumorigenesis. To date, only a few MMPs have been studied in KS lesions. Their role in KS regression has not been investigated. The aim of this study was to evaluate the expression of multiple MMPs in developing and pharmacologically regressed KS lesions.

Methods: Nine samples of acquired immune deficiency syndrome (AIDS)-related and classic cutaneous KS lesions at various histological stages were studied. Regressing KS lesions from three patients treated with systemic therapy were procured after one and two cycles of chemotherapy. Tissue sections from all specimens were immunostained using monoclonal antibodies to MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, and MMP-14.

Results: KS lesional cells were immunoreactive for all MMPs, except MMP-14. Admixed inflammatory cells were immunoreactive for MMP-1, MMP-2, MMP-7, MMP-9, and MMP-13. The MMP immunoprofile in residual KS lesional cells was unaltered in regressed lesions. Increased extracellular matrix (ECM) and macrophage immunoreactivity for MMPs was identified in regressed specimens.

Conclusions: These data show that developing KS lesional cells express collagenases (MMP-1, MMP-13), gelatinases (MMP-2, MMP-9), stromelysin-1 (MMP-3), and matrilysin (MMP-7) but not the membrane-type MMP-14. This MMP expression profile is retained by residual KS cells and also expressed by infiltrating macrophages in regressed KS lesions.
p45  


Over-Expression of p45(SKP2) in Kaposi's Sarcoma Correlates with Higher Tumor Stage and Extracutaneous Involvement but Is Not Directly Related to p27(KIP1) Down-Regulation.

Penin RM, Fernandez-Figueras MT, Puig L, Rex J, Ferrandiz C, Ariza A.

Departments of Pathology (RMP, MTF-F, AA) and Dermatology (JR, CF), Hospital Universitari Germans Trias i Pujol, Barcelona, Spain.

Mod Pathol 2002 Nov;15(11):1227-35 Abstract quote

F-Box protein p45(SKP2) is the substrate-specific receptor of ubiquitin-protein ligase SCF/p45(SKP2) and is involved in the degradation of p27(Kip1) through the ubiquitin/proteasome pathway. In addition, p45(SKP2) facilitates proteolysis of other molecules related to the cell cycle, is frequently over-expressed in transformed cells, and induces S phase in quiescent cells. The aim of this study was to determine whether p45(SKP2) expression is altered in aggressive lesions of Kaposi's sarcoma and its relation to p27(KIP1)down-regulation.

We performed immunohistochemistry using antibodies directed to p45(SKP2), p27(KIP1), and Ki67 on paraffin blocks corresponding to 47 cases of Kaposi's sarcoma (8 macules, 10 plaques, 12 tumors, and 15 extracutaneous lesions). p45(SKP2) nuclear over-expression was present in all Kaposi's sarcoma stages, being significantly increased in skin tumors (mean +/- 95% confidence interval: 39.2 +/- 18.8) and extracutaneous lesions (25.8 +/- 17.3) as compared with macules (18.9 +/- 8.2) and plaques (29.2 +/- 12.0; P =.0199). On the other hand, Kaposi's sarcoma progression was associated with a decrease in p27(KIP1) expression and Ki67 immunoreactivity was independent of disease stage. No statistically significant differences were found in regard to patients' sex and human immunodeficiency virus status and regression analysis failed to show a correlation among p45(SKP2), p27(KIP1) and Ki67 immunostaining scores.

These findings suggest that p45(SKP2) is involved in Kaposi's sarcoma progression, not only by promoting the degradation of p27(KIP1) but also through other mechanisms still unknown.

 

LABORATORY/RADIOLOGIC/
OTHER TESTS

CHARACTERIZATION
Radiographs  
CT scan and MRI  
Laboratory Markers  

Quantitation of human herpes virus 8 DNA in paraffin-embedded biopsies of HIV-associated and classical Kaposiís sarcoma by PCR

Guntram Bezold, etal.

J Cutan Pathol 2001;28 (3), 127-130 Abstract quote

Background: Kaposiís sarcoma occurs in patients seropositive and seronegative for the human immunodeficiency virus (HIV) and has been associated with human herpes virus 8 (HHV8). The purpose of this study was to determine and to compare the amount of HHV8 DNA in formalin-fixed tissue sections of Kaposiís sarcoma.

Methods: From 27 biopsies of Kaposiís sarcoma patients, tissue sections were taken and deparaffinized. Four patients were HIV seronegative and 13 were HIV seropositive. After extraction of DNA copy numbers of HHV8 and b-globin were determined in every sample by quantitative PCR ELISA using an internal quantitation standard. Results were expressed as HHV8 per b-globin.

Results: No significant differences were found between biopsies from HIV-positive and HIV-negative patients (14.8Ī19.6 HHV8 per 1000 b-globin in HIV-positive versus 18.0Ī23.5 in HIV-negative patients).

Conclusions: These data suggest that HHV8 viral load in Kaposiís sarcoma is relatively low and does not differ in HIV-positive and HIV-negative samples. The importance of viral load determination for prognosis or treatment monitoring remains to be elucidated.

 

GROSS APPEARANCE/
CLINICAL VARIANTS
CHARACTERIZATION
General  
Non-epidemic type

Lower extremities of elderly men of Mediterranean and Eastern European extraction

Indolent tumor with rare systemic involvement

Endemic type

Sub-Saharan Africa and involved younger men with cutaneous, lymphatic, and visceral involvement

Clinical course of this tumor was more aggressive.

Immunosuppressive type

Patients receiving immunosuppressive therapy for organ transplants or other autoimmune diseases

Occasional spontaneous regression of lesions can occur after withdrawal of immunosuppressive therapy

HIV associated Epidemic type
 
Classic Kaposi Sarcoma in the United States over the last two decades: A clinicopathologic and molecular study of 438 non-HIV-related Kaposi Sarcoma patients with comparison to HIV-related Kaposi Sarcoma.

1Dermatopathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

 

Mod Pathol. 2008 May;21(5):572-82. Abstract quote

Classic Kaposi sarcoma is rare and occurs predominantly in Mediterranean and Middle Eastern men. Since the emergence of acquired immune deficiency syndrome (AIDS)-related Kaposi sarcoma, the incidence, clinicopathologic features, and molecular human herpesvirus 8 (HHV-8) association of American Classic Kaposi Sarcoma has not been fully explored.

This study compares Classic Kaposi Sarcoma to AIDS-related Kaposi Sarcoma over the same two decade time period. There were 438 histologically and clinically confirmed Classic Kaposi Sarcoma patients. The ethnic/racial distribution included Caucasian/American (56%), Mediterranean (22%), South American Hispanic (18%), Black (10%), western European (4%), Middle East (4%), Scandinavian (2%), and other (2%).

Classic Kaposi Sarcoma was more common in men, 7:1, with a mean age of 74 years. The lesions presented in the lower extremity (69%), in the nodular stage (83%), and HHV-8 was detected by PCR in 40/41 randomly selected cases. A second, non-Classic Kaposi Sarcoma, malignancy was present in 42% (n=45) of the 108 Classic Kaposi Sarcoma patients with complete clinical information, 73% (33 patients) with a higher incidence over the general population. Follow-up of <1-19 years (mean=4.8 years) revealed that 24% of patients died of second malignancy, 22% died of other medical conditions, 2% died of treatment-related complications, and 2% patients died of widespread disease. Thirty-five percent are alive with no evidence of disease and 15% with persistent disease. Human immunodeficiency virus-related Kaposi Sarcoma was observed in 354 cases. There was a male predominance and more aggressive behavior, with higher rates of visceral and disseminated disease.

While Classic Kaposi Sarcoma in the United States is an indolent disease and rarely accounts for patient demise, predominantly affecting Caucasian/American males on the lower extremity in the nodular phase, it more importantly may denote an underlying other malignancy. Current PCR probes detect HHV-8 in 98% of Classic Kaposi Sarcoma cases. In comparison, AIDS-related Kaposi Sarcoma is predominately multicentric, visceral, and disseminated, with more aggressive behavior.
VARIANTS  

Two Cases of Kaposi's Sarcoma Mimicking Stewart-Treves Syndrome Found to be Human Herpesvirus-8 Positive

Anne E. Allan, M.D.; Toru Shoji, M.D., Ph.D.; Ning Li, M.D.; Ann Burlage, M.D.; Bret Davis, M.D.; Jag Bhawan, M.D.

From Pathology Services, Inc., Cambridge, Massachusetts (A.E.A.); Dianon Systems, Inc., Stratford Connecticut (T.S.); Dermatopathology Section, Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts (N.L., J.B.); South Yarra, Victoria, Australia (A.B.); and Sansum-Santa Barbara Medical Foundation Clinic, Santa Barbara, California (B.D.).

Am J Dermatopathol 2001;23:431-436 Abstract quote

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.

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

Department of Pathology, Faculty of Medicine, Assuit University Hospitals, Assuit University, Egypt.

J Cutan Pathol. 2008 Jun;35(6):575-8. Abstract quote

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.

 

HISTOLOGICAL TYPES CHARACTERIZATION
General

Neovascularization and spindle cells forming characteristic slit-like spaces

Low mitotic index and are euploid

Fibroblasts, extravasated red cells, and inflammatory cells are mixed in with the spindle cells

Patch
Earliest change with subtle vascular changes and rare Promontory signs
Plaque
Increased vascularity and spindle cell proliferation
Tumor
Tumor mass with increased pleomorphism of spindle cells
VARIANTS  
INTRAVASCULAR  
Intravascular Kaposi's sarcoma - a hitherto unrecognized phenomenon.

Department of Dermatopathology, St John’s Institute of Dermatology, St Thomas’ Hospital, London, UK.

 

J Cutan Pathol. 2007 Nov;34(11):861-864. Abstract quote

Background: Based on the spectrum of histological features, Kaposi's sarcoma (KS) is grouped into patch, plaque and nodular stages. The histological changes overlap, especially with lesional evolution. To date, intravascular KS is undocumented.

Methods: A clinicopathological description of six cases of intravascular KS.

Results: Clinical: There were four men and two women (mean age = 65 years). Four patients, who presented clinically with classic (sporadic) KS, developed solitary violaceous nodules on the extremities. Two patients with acquired immune deficiency syndrome-related KS had disseminated cutaneous KS lesions in all stages of evolution. Six months to 3 years follow-up showed no evidence of systemic KS in any of the patients.

Histopathology: Exclusive intravascular growth was seen in five patients. The vascular channels, highlighted by mural immunostaining with desmin and anti-smooth muscle actin, had the histological features of veins. Intravascular growth was characterized by interlacing fascicles of human herpesvirus 8, CD31 and CD34-positive spindle cells with formation of cleft-like spaces, erythrocyte extravasation, hyaline globules and a lymphoplasmacytic infiltrate. One patient had a proliferation of irregular, vascular channels in the desmin in addition to the intravenous growth.

Conclusion: Intravascular KS is a peculiar hitherto unrecognized morphological variant of KS that does not seem to be associated with an increased risk of aggressive behaviour.
LYMPHEDEMATOUS HIV-ASSOCIATED  


Lymphedematous HIV-associated Kaposi's sarcoma.

Department of Anatomical Pathology, Nelson R Mandela School of Medicine, Durban, South Africa.

J Cutan Pathol. 2006 Jul;33(7):474-81 Abstract quote

BACKGROUND: Advanced Kaposi's sarcoma is frequently associated with chronic lymphedema (cLO). The histopathological features of lymphedematous HIV-associated KS (KS) are poorly documented and the co-existence of fibroma-like nodules in lymphedematous KS is under-recognized. The aims of this study were to assess the clinicopathological spectrum and diagnostic difficulties associated with lymphedematous KS and to highlight the clinicopathological profile of fibroma-like nodules. In addition, the pathogenesis of fibroma-like nodules and cLO is revisited.

MATERIALS AND METHODS: Prospective 17-month clinicopathological study of all biopsies from patients with lymphedematous KS.

RESULTS: Seventy-four biopsies, the majority from the lower limbs, from 41 patients were evaluated. Nineteen, 14, five and three patients had one, two, three or four biopsies each, respectively. In 14 biopsies, there was poor clinicopathological correlation of KS stage. Exclusive lesional KS (patch, plaque, nodule or lymphangioma-like) was identified in 29 biopsies; 23 and eight biopsies demonstrated KS or fibroma-like morphology and the adjacent dermis demonstrated cLO. There was variable intratumoral and peritumoral venous compression and lymphatic dilatation. Fourteen biopsies demonstrated cLO exclusively. Smaller fibroma-like nodules lacked KS spindle cells, whereas >5 mm nodules demonstrated focal KS spindle cell proliferation and aggregation on extensive sectioning. The subcutis of 42 biopsies demonstrated variable fibrosis, hemosiderin deposits, lymphocytes, plasma cells, KS, interstitial granular material and pools of lymph fluid. Subcutaneous abscesses were identified in six biopsies. All biopsies had variable epidermal features of cLO.

CONCLUSIONS: cLO influences clinicopathological correlation of KS stage and may also mask the presence of KS and the co-existence of subcutaneous abscesses. Smaller fibroma-like nodules are hypothesized to be a manifestation of cLO that have the potential to acquire the characteristics of KS. Lymphatic and venous obstruction, protein-rich interstitial fluid, tissue hemosiderin and subcutaneous infection are hypothesized to play a combined role in the evolution and perpetuation of cLO.
TREATMENT RELATED CHANGES  
Histological features of kaposi sarcoma in a patient receiving highly active antiviral therapy.

Eng W, Cockerell CJ.

LabCorp, Tampa, FL, USA.
Am J Dermatopathol. 2004 Apr;26(2):127-32. Abstract quote  

The introduction of highly active anti-retroviral therapy (HAART) has changed the clinical presentation of skin diseases in patients with the Acquired Immune Deficiency Syndrome (AIDS). This occurs as a consequence of a newly recognized effect of this therapy known as the "Immune Reconstitution Syndrome," which develops with improvement of immunity. One manifestation of this syndrome is alteration of the natural history of Kaposi sarcoma (KS). While there are multiple reports of KS regression during HAART, there is little documentation of the histologic changes that occur.

We present the case of a 55-year-old homosexual male with KS for over 4 years who underwent 6 biopsies over a 3-year period before, during, and after HAART. Kaposi sarcoma lesions prior to HAART were multinodular with ill-defined borders clinically and demonstrated typical features of nodular stage KS histologically. After initiation of HAART in this patient, lesions became uninodular, well circumscribed, and histologically were noted to be less cellular and surrounded by a dense fibrotic stroma.

Although the mechanisms for these histologic changes are not clear, it may be due to activity of HAART against human herpesvirus type 8 (HHV-8), the causative agent of KS, to reconstitution of immunity due to diminution in HIV viral load, or both.

 

SPECIAL STAINS/
IMMUNOPEROXIDASE
CHARACTERIZATION
Immunoperoxidase Positive for alpha-actin, CD34, CD31, and CD18.
D2-40  


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

Kahn HJ, Bailey D, Marks A.

Department of Pathology, Women's College Campus, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada.

Mod Pathol 2002 Apr;15(4):434-40 Abstract quote

There is controversy over the histogenesis of Kaposi's sarcoma (KS) from lymphatic or blood vessel endothelium. D2-40 is a novel monoclonal antibody to an Mr 40,000 O-linked sialoglycoprotein that reacts with a fixation-resistant epitope on lymphatic endothelium.

We sought to establish the selectivity of D2-40 for lymphatic endothelium in normal tissues and compare its reactivity with the expression of the widely used vascular endothelial marker CD31 in a series of 62 formalin-fixed and paraffin-embedded vascular lesions including KS.

In normal tissues, D2-40 stained the endothelium of lymphatic channels but not of blood vessels, including arteries and capillaries defined by reactivity with the blood vessel endothelial marker PAL-E. In our series of vascular lesions, D2-40 stained lymphangiomas (10/10), benign tumors of undisputed lymphatic origin, but not benign neoplasms or tumorlike lesions of blood vessel origin, including hemangiomas (0/10), glomus tumors (0/3), angiolipomas (0/2), pyogenic granulomas (0/2), vascular malformations (0/2), hemangiopericytoma (0/1), or hemangioendothelioma (0/1). D2-40 stained all cases of cutaneous KS (24/24) at all stages of progression, including patch, plaque, and nodular stages, supporting the concept that this disease originates from a cell type capable of undergoing lymphatic differentiation. D2-40 also stained three of seven angiosarcomas, indicating that a subset of these tumors can undergo at least partial differentiation along the lymphatic endothelial lineage and could be classified as lymphangiosarcomas. In comparison, CD31 was expressed in all benign and malignant vascular lesions, except for glomus tumors (0/3) and 5/10 lymphangiomas, in which staining was absent.

We conclude that D2-40 is a new selective marker of lymphatic endothelium in normal tissues and vascular lesions and is valuable for studying benign and malignant vascular disorders in routinely processed tissue specimens.

FIBROBLAST/
MACROPHAGE MARKER 1B10
 

Expression of the fibroblast/macrophage marker 1B10 by spindle cells in Kaposi's sarcoma lesions and by Kaposi's sarcoma-derived tumor cells

Thierry Simonart, Chantale Degraef, Michel Heenen, Philippe Hermans, Jean-Paul Van Vooren and Jean-Christophe Noel


J Cutan Pathol 2002;29:72-78 Abstract quote

Background
Kaposi's sarcoma (KS) is a tumor whose ontogenic origin remains a matter of contention. KS tissues are characterized by predominant expression of endothelial markers, while KS-derived cell cultures are usually characterized by expression of mesenchymal non-endothelial cell markers.

Aims
In order to clarify the ontogenic origin of KS cells, we investigated the expression of the fibroblast/macrophage marker 1B10 in KS tissues (AIDS-associated KS, n = 9; classic KS, n = 6; iatrogenic KS, n = 6) and in KS-derived cell cultures.

Results
1B10 was expressed by loosely distributed spindle-shaped cells in early patch-stage KS and by a variable proportion of spindle cells in late plaque- and nodular-stage KS. Using immunohistochemistry and immunoblot analysis, we found that, in vitro, reactivity for 1B10 was uniformly evidenced in fibroblasts and in KS-derived spindle cell cultures, irrespective of their histological or epidemiological setting. By contrast, vascular smooth muscle cells and endothelial cells were negative for 1B10.

Conclusions
These results suggest that the KS spindle cells isolated in vitro may represent a particular subpopulation of the KS spindle cell compartment.

 

HISTOPATHOLOGY CHARACTERIZATION

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

Pantanowitz L, Dezube BJ, Pinkus GS, Tahan SR.

Department of Pathology, Department of Medicine (Hematology/Oncology Division), Beth Israel Deaconess Medical Center, and Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

J Cutan Pathol. 2004 Jan;31(1):26-34. Abstract quote  

BACKGROUND: Kaposi's sarcoma (KS) is an angioproliferative lesion that may regress or progress. Progression is related to spindle cell proliferation and the expression of human herpes virus-8 latency genes, including latent nuclear antigen-1 (LNA-1), cyclin-D1, and bcl-2. KS regression has not been well characterized histologically. Therefore, this study was undertaken to characterize the histopathology of pharmacologically induced regressed cutaneous KS.

METHODS: Skin punch biopsies from eight patients with acquired immunodeficiency syndrome (AIDS)-related KS, that regressed following chemotherapy with paclitaxel or the angiogenesis inhibitor Col-3, were investigated by light microscopy. Comparative immunophenotyping on pre- and post-treatment specimens for CD31, LNA-1, cyclin-D1, bcl-2, and CD117 (c-kit) was performed.

RESULTS: Clinical and histologic features of regression were similar for paclitaxel and Col-3 treatment. On clinical examination, lesions flattened, became smaller, and lost their purple-red appearance, resulting in an orange-brown macule. Histological regression was divided into partial (n = 3) and complete (n = 5) regression. Partially regressed lesions had a significant reduction of spindle cells in the dermal interstitium, with residual spindle cells arranged around superficial and mid-dermal capillaries. Complete regression was characterized by an absence of detectable spindle cells, with a slight increase in capillaries of the superficial plexus. All regressed samples exhibited a prominent, superficial, perivascular, lymphocytic infiltrate and abundant dermal hemosiderin-laden macrophages. This clinicopathologic picture resembled the findings of pigmented purpura. CD31 staining correlated with the reduction of spindle cells. Regression was accompanied by a quantitative and qualitative decrease in LNA-1 and cyclin-D1 immunoreactivity, but no change in bcl-2 or c-kit expression.

CONCLUSIONS: Pharmacologically induced regression of AIDS-related cutaneous KS is characterized by a complete loss or decrease of spindle cells, increased lymphocytes, and prominent dermal siderophage deposition. Without any prior knowledge of the history of KS regression following therapy, regressed KS lesions may be misdiagnosed clinically and histologically as pigmented purpuric dermatitis.
VARIANTS  
LYMPHANGIOMA-LIKE  
Lymphangioma-like Kaposi sarcoma.

Ramirez JA, Laskin WB, Guitart J.

Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
J Cutan Pathol. 2005 Apr;32(4):286-92. Abstract quote  

Background: Lymphangioma-like Kaposi's sarcoma (LLKS) is a rare morphologic expression of Kaposi's sarcoma (KS) that occurs in virtually all of the well-recognized clinical subtypes of the disease and has the potential to mimic other pathologic processes. In this study, we present the clinical and pathological features of four patients with LLKS.

Methods: Four cases of LLKS were retrieved from the dermatopathology files of our institution. All four tumours were tested immunohistochemically with anti-human herpesvirus-8 (HHV-8) latent nuclear antigen-1 (LNA-1) and anti-CD34 antibodies.

Results: Clinically, each patient presented with violaceous patches, papules or plaques; one patient presented with bullous lesions. All of the LLKS biopsy specimens revealed areas with characteristic light microscopic features of KS. Lymphangioma-like foci consisted of ectatic, irregularly shaped vascular spaces lined by mildly atypical endothelial cells. All tumour cells, including those associated with LLKS foci, showed a strong and diffuse reactivity for anti-HHV-8 LNA-1 and anti-CD34. KS progressed slowly in two patients with adequate follow-up.

Conclusions: As LLKS can mimic other disease processes, the correct diagnosis relies heavily on the recognition of salient clinical and histological features of conventional KS, including a strong immunohistochemical expression of HHV-8-associated LNA-1 in lesional cells.

 

SPECIAL STAINS/
IMMUNO-HISTOCHEMISTRY
CHARACTERIZATION
HHV-8  

Immunohistochemical detection of human herpes virus-8 latent nuclear antigen-1 is useful in the diagnosis of Kaposi sarcoma.

Patel RM, Goldblum JR, Hsi ED.

Division of Pathology and Laboratory Medicine, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.

Mod Pathol. 2004 Apr;17(4):456-60. Abstract quote

Kaposi sarcoma is a low-grade vascular neoplasm that has been shown by molecular analysis to uniformly express the latent nuclear antigen-1 of human herpes virus 8. Differentiating Kaposi sarcoma from other benign or malignant vascular tumors, as well as other nonvascular spindle cell soft-tissue neoplasms, can be challenging. Thus, detection of human herpes virus 8 in fixed tissues would be diagnostically useful. Recently, a monoclonal antibody to human herpes virus 8 latent nuclear antigen-1 has become commercially available for immunohistochemical analysis.

We sought to study the sensitivity and specificity of this antibody in the detection of human herpes virus 8 latent nuclear antigen-1 in Kaposi sarcoma. Fixed, paraffin-embedded tissue sections from 21 cases of Kaposi sarcoma, nine cases of spindle cell hemangioma, five cases of cutaneous angiosarcoma, five cases of dermatofibrosarcoma protuberans, one case of vascular transformation of a lymph node, four cases of pilar leiomyoma, four cases of stasis dermatitis, four cases of pyogenic granuloma, and three cases of spindled melanoma were examined immunohistochemically using the rat monoclonal antibody to human herpes virus 8 latent nuclear antigen-1, open reading frame-73 (Advanced Biotechnologies Inc.).

Tissue sections were stained with automated immunostainers (Ventana) using heat-induced epitope retrieval and a standard DAB detection kit (Ventana) modified to detect rat Ab. Strong, diffuse, nuclear staining in >10% of tumor cells was considered a positive result.

In all, 21/21 cases of Kaposi sarcoma showed strong, diffuse, nuclear staining for human herpes virus 8 latent nuclear antigen-1 (100%), whereas all cases of spindle cell hemangioma, cutaneous angiosarcoma, dermatofibrosarcoma protuberans, vascular transformation of lymph node, pilar leiomyoma, stasis dermatitis, pyogenic granuloma, and spindled melanoma were negative for this antigen. The monoclonal antibody to human herpes virus 8 latent nuclear antigen-1, open reading frame-73, is a highly sensitive and specific marker of human herpes virus 8 infection in paraffin-embedded tissue sections of Kaposi sarcoma.

As such, it is an extremely useful tool for differentiating between Kaposi sarcoma and other vascular and nonvascular spindle cell lesions, which do not express human herpes virus 8 latent nuclear antigen-1.

 

DIFFERENTIAL DIAGNOSIS CHARACTERIZATION
ACROANGIO-DERMATITIS  
Acroangiodermatitis (pseudo-Kaposi
sarcoma) associated
with verrucous hyperplasia induced by suction-socket
lower limb prosthesis.


Sbano P, Miracco C, Risulo M, Fimiani M.

Department of Clinical Medicine and Immunological Sciences, Section of Dermatology, Universit of Siena, Siena, Italy.
J Cutan Pathol. 2005 Jul;32(6):429-32. Abstract quote  


Increasing use of suction-socket lower limb prostheses has been associated with an increased frequency of dermatological manifestations, linked to the fact that the skin of the amputation stump must adapt to an entirely new environment. In particular, verrucous hyperplasia and rare cases of acroangiodermatitis (pseudo-Kaposi sarcoma) have been described.

We report a case of amputation stump dermatitis, clinically resembling verrucous hyperplasia, but with predominant histological aspects of acroangiodermatitis in a patient with a suction-socket lower limb prosthesis.
ACQUIRED PROGRESSIVE LYMPHANGIOMA  

Benign Lymphangioendothelioma (Acquired Progressive Lymphangioma): A Lesion Not to Be Confused With Well-Differentiated Angiosarcoma and Patch Stage Kaposi's Sarcoma Clinicopathologic Analysis of a Series

Louis Guillou, M.D.; Christopher D. M. Fletcher, M.D., F.R.C.Path.

From the University Institute of Pathology (L.G.), Lausanne, Switzerland; and the Department of Pathology (C.D.M.F.), Brigham and Women's Hospital, Boston, Massachusetts

Am J Surg Pathol 2000;24:1047-1057 Abstract quote

The clinicopathologic features of 12 cases of benign lymphangioendothelioma (acquired progressive lymphangioma) are reported.

There were five male and seven female patients. Age at diagnosis ranged from 17 to 90 years (median age, 54 yrs). Development of a single macular/papular hemangiomatous or pigmented lesion was the main presenting symptom. Symptom duration before diagnosis ranged from 2 months to 20 years (median, 5.5 yrs). Tumor size ranged from 0.3 cm to 10 cm (median, 1.5 cm). Location included skin of the head and neck (n = 5), back (n = 1), breast (n = 1), shoulder (n = 1), forearm (n = 1), plantar aspect of the foot (n = 2), and oral mucosa (n = 1). No patient had any other concomitant vascular anomaly (for example, lymphangiomatosis) or was suspected to have acquired immunodeficiency syndrome.

Treatment consisted of excisional biopsy in nine patients, incisional biopsy in two, and wide excision in one. Follow-up information on nine patients (range, 4Ė40 mos; median, 12 mos) showed two local recurrences in one patient.

Microscopically, the lesions consisted of anastomosing, often widely dilated vascular structures developing in the superficial dermis. As the lesion grew within deeper dermis, the vascular spaces collapsed and dissected the dermal collagen in an angiosarcoma-like pattern. The lining endothelium was flat and monolayered, with little or no cytologic atypia and no evident mitoses. Some vascular structures contained stromal papillary projections resembling papillary endothelial hyperplasia, and intravascular red blood cells were present occasionally. Immunohistochemistry performed in eight specimens showed variable endothelial cell reactivity for CD31 (7 of 8), CD34 (7 of 7), and factor VIII-related antigen (4 of 6). A smooth muscle cell layer was observed focally around the vascular spaces in six lesions.

Benign lymphangioendothelioma (acquired progressive lymphangioma) is an uncommon benign lesion that, in view of major differences in treatment and prognosis, should be distinguished from well-differentiated angiosarcoma and Kaposi's sarcoma, especially the patch stage and lymphangioma-like variants of the latter.

DERMATO-MYOFIBROMA  


Haemorrhagic dermatomyofibroma (plaque-like dermal fibromatosis): clinicopathological and immunohistochemical analysis of three cases resembling plaque-stage Kaposi's sarcoma.

Mentzel T, Kutzner H.

Dermatopathologisches Gemeinschaftslabor, Friedrichshafen, Germany.


Histopathology. 2003 Jun;42(6):594-8 Abstract quote

AIMS: Dermatomyofibroma (plaque-like dermal fibromatosis) represents a distinct clinicopathological entity in the spectrum of cutaneous mesenchymal neoplasms showing a myofibroblastic line of differentiation. These benign neoplasms occur frequently, but not exclusively, in young women, and the shoulder girdle as well as the upper trunk are common locations. Histologically, dermatomyofibroma is characterized by a plaque-like proliferation of cytologically bland spindle-shaped tumour cells containing an ill-defined, pale eosinophilic cytoplasm and elongated, neuroid nuclei. Neoplastic cells are arranged in bundles and fascicles orientated parallel to the skin surface, adnexal structures are spared and elastic fibres are increased and fragmented. Immunohistochemically, tumour cells express vimentin and variably muscle actin and alpha-smooth muscle actin, but are negative for desmin, CD34, S100, and epithelial markers. The main differential diagnosis includes hypertrophic scar, dermatofibroma (fibrous histiocytoma), pilar leiomyoma, neurofibroma, adult myofibromatosis, extra-abdominal fibromatosis and plaque-stage dermatofibrosarcoma protuberans.

METHODS AND RESULTS: We report three cases of dermatofibroma arising in male patients aged 31, 36, and 47 years on the thigh, chest wall and back, respectively. All lesions were completely excised and no local recurrence has been reported. Histologically, the neoplasms showed classical features of dermatomyofibroma; however, in addition abundant extravasated erythrocytes, scattered inflammatory cells, numerous capillaries, and sieve- and slit-like spaces, features resembling plaque-stage Kaposi's sarcoma, were noted. In none of the cases did spindled tumour cells stain positively for CD34, and HHV8 was not detected by polymerase chain reaction.

CONCLUSIONS: The reported cases widen the clinicopathological spectrum of dermatomyofibroma and emphasize plaque-stage Kaposi's sarcoma as an additional differential diagnosis.

DISSEMINATED ANGIOPROLIFERATION  
A unique case of a benign disseminated angioproliferation combining features of Kaposi's sarcoma and diffuse dermal angioendotheliomatosis

Rainer Kunstfeld, MD
Peter Petzelbauer, MD

Vienna, Austria

J Am Acad Dermatol 2001;45:601-5 Abstract quote

A female patient undergoing chronic hemodialysis had disseminated, violaceous, and partly ulcerated plaques develop on the trunk. Lesions had erupted simultaneously over a period of 4 weeks and resolved within 5 months after steroid treatment.

By histopathology, the papillary dermis was densely filled with blood vessels lined by a single layer of differentiated endothelial cells, a growth pattern resembling diffuse dermal angioendotheliomatosis. In some areas, endothelial cells were spindle shaped and formed discontinuous lumina. Red blood cells were interspersed within these slits, giving the lesions a kaposiform appearance. By immunohistochemistry, endothelial cells reacted with the antibodies anti-von Willebrand factor, anti-CD31, and anti-CD34 and with the lectin Ulex europaeus-1.

The course of the disease combined with the unusual histopathology makes this case a unique form of a benign disseminated kaposiform angioproliferation.

GRANULOMA ANNULARE  
Human herpesvirus 8 and iron staining are useful in differentiating kaposi sarcoma from interstitial granuloma annulare.

Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT 84132-2409, USA.

 

Am J Clin Pathol. 2007 Feb;127(2):263-70. Abstract quote

We studied 20 granuloma annulare (GA) cases (10 interstitial and 10 palisaded) and 19 Kaposi sarcoma (KS) cases (9 "early" and 10 typical). Tissue sections were stained for iron, Hale colloidal iron, human herpesvirus 8 (HHV-8), CD31, CD34, CD68, collagen IV, factor XIIIa, and MIB-1. Iron staining of dermal tissue associated with the lesion was confirmed in all KS cases and no GA cases.

Immunohistochemical stains for HHV-8 were positive in all 9 cases of early KS and most cases (9/10) of typical KS. All 20 cases of GA were HHV-8-. CD31, CD34, CD68, factor XIIIa, and MIB-1 were also stained but were difficult to interpret and did not seem specific for GA or KS. Iron staining and immunohistochemical HHV-8 staining in combination were reliable markers for KS compared with interstitial GA. MIB-1 fractions of less than 5% favored a diagnosis of GA, whereas fractions greater than 10% favored a diagnosis of KS.

This study provides novel data characterizing iron staining in KS and details the use of iron staining, HHV-8, and MIB-1 to distinguish KS from GA.
RADIATION INDUCED  
Benign Vascular Proliferations in Irradiated Skin

Luis Requena, M.D.; Heinz Kutzner, M.D.; Thomas Mentzel, M.D.; Rafael Durán, M.D.; José Luis Rodríguez-Peralto, M.D.

From the Department of Dermatology (L.R.), Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain; Dermatohistopathologisches Gemeinschaftslabor (H.K., T.M.), Friedrichshafen, Germany; the Department of Pathology (R.D.), Hospital de Elda, Alicante, and the Department of Pathology (J.L.R.-P.), Hospital 12 de Octubre, Universidad Complutense, Madrid, Spain.

 

Am J Surg Pathol 2002;26:328-337 Abstract quote

Several types of cutaneous vascular proliferations have been described in areas of irradiated skin, including both benign lesions, such as benign lymphangiomatous papules, atypical vascular lesions, or benign lymphangioendothelioma, and malignant neoplasms such as high-grade angiosarcomas.

This report describes the clinicopathologic features of 15 cases of different types of benign cutaneous vascular proliferations arisen within irradiated skin. All patients were female ranging in age from 33 to 72 years, and they had received postoperative external radiotherapy for treatment of breast carcinoma (14 cases) or ovarian carcinoma (one case). In those cases in which the latency interval period between radiotherapy and the development of the vascular lesion was known from the clinical records, the latency interval period elapsed between radiotherapy and diagnosis of the vascular lesion ranged from 3 to 20 years. The most common clinical presentation of the cutaneous lesions consisted of papules, small vesicles, or erythematous plaques on the irradiated field.

Histopathologically, most lesions consisted of irregular dilated vascular spaces, with a branching and anastomosing pattern, thin walls, and lymphatic appearance involving the superficial dermis. A discontinuous single layer of endothelial cells with flattened nuclei lined these vascular channels, and numerous small stromal papillary formations also lined by endothelial cells projected into the lumina of the dilated lymphatic vessels. These cases were classified as benign lymphangiomatous papules or plaques. Two cases showed different histopathologic findings because they consisted of poorly circumscribed and focally infiltrating irregular jagged vascular spaces involving the entire dermis and lined by inconspicuous endothelial cells. In some areas these irregular slit-like vascular spaces dissected collagen bundles of the dermis. These cases were classified as atypical vascular proliferations mimicking benign lymphangioendothelioma or patch-stage Kaposi's sarcoma. All cases showed similar immunohistochemical findings and the endothelial cells lining the vascular spaces expressed immunoreactivity for CD31, but they stained only focally positive for CD34 or were negative for this marker. Immunohistochemical investigations for -smooth muscle actin failed to demonstrate a complete peripheral ring of actin-positive pericytes in most of the neoformed vascular structures.

This immunohistochemical profile also supported the lymphatic nature of these vascular proliferations developed in irradiated skin. Although some of these lesions may mimic histopathologically patch-stage Kaposi's sarcoma or well-differentiated angiosarcoma, the follow-up of the patients of this series demonstrated that the vascular proliferations arisen in irradiated skin invariably showed a benign biologic behavior.

 

PROGNOSIS AND TREATMENT CHARACTERIZATION
TREATMENT

Arch Dermatol 2000;136:1461-1469
Topical treatment of cutaneous lesions using Alitretinoin gel was well tolerated, applied twice daily for first two weeks and up to 4 times daily thereafter in 115 biopsy proven AIDS related KS

Statistically significant clinical response in 27% (31/115)
Responses occurred with low CD4 counts <200 cells/uL and in some patients refractory to previous systemic antiKS medications

RETINOIC ACID  


9-cis-Retinoic Acid Capsules in the Treatment of AIDS-Related Kaposi Sarcoma: Results of a Phase 2 Multicenter Clinical Trial.

Aboulafia DM, Norris D, Henry D, Grossman RJ, Thommes J, Bundow D, Yocum RC, Stevens V.

Section of Hematology/Oncology, Virginia Mason Medical Center, 1100 Ninth Ave, PO Box 900 (H14-HEM), Seattle, WA 98111-0900.

Arch Dermatol 2003 Feb;139(2):178-86 Abstract quote

OBJECTIVE: To evaluate the safety, dose tolerance, and anti-tumor effects of 9-cis-retinoic acid in the treatment of Kaposi sarcoma (KS) related to acquired immunodeficiency syndrome (AIDS).

DESIGN: Phase 2, open-label clinical trial of oral doses of 9-cis-retinoic acid increasing in 40-mg increments every 2 weeks from 60 mg/m(2) per day to a maximum of 140 mg/m( 2) per day.

SETTING: Five hospital or health maintenance organization outpatient clinics.

PATIENTS: Fifty-seven adult male patients with human immunodeficiency virus and biopsy-proven KS.

MAIN OUTCOMES MEASURES: Safety was evaluated by adverse events, physical examination, laboratory test abnormalities, treatment-limiting toxic effects, and reasons for early withdrawal. Response (>/=50% improvement) was evaluated by an overall KS response and by the area and height from 6 index lesions selected at baseline.

RESULTS: Patients tolerated 60 and 100 mg/m(2) per day. Most patients found 140 mg/m(2) per day intolerable owing to headache. Common treatment-related adverse events were headache, xerosis, rash, alopecia, and hyperlipemia. The patient response rate for the overall KS disease was 19% (11/57), including 1 patient with clinically complete response. The response rate assessed by measuring 6 index lesions during treatment was 39% (22/57). Sixteen responding patients (73%) were refractory to at least 1 previous anti-KS therapy. Patients with CD4( +) counts of 150 cells/ micro L or lower were as likely to respond as patients with counts of higher than 150 cells/ micro L. The median time to response was 8.5 weeks (range, 4.0-21.1 weeks). The median duration of treatment was 15.1 weeks (range, 0.14 to >/=62 weeks).

CONCLUSION: 9-cis-retinoic acid capsules have moderate activity and provide durable responses, but substantial toxic effects at higher doses limit its suitability as an anti-KS therapy.

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