Kaposi's sarcoma (overview) C46.-

Authors: Prof. Dr. med. Peter Altmeyer, Prof. Dr. Dr. H. c. Peter Karl Kohl

All authors of this article

Last updated on: 08.08.2021

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Synonym(s)

angiomatosis Kaposi; Angioreticulomatosis; idiopathic multiple pigment sarcoma Kaposi; Kaposi's disease; Kaposi's sarcoma; Kaposi's Sarcoma; M. Kaposi; Pigmentary sarcoma Kaposi idiopathic multiple; Pseudosarcoma teleangiectatic; Sarcoma idiopathicum Kaposi; Sarcoma idiopathicum multiplex haemorrhagicum; teleangiectatic pseudosarcoma

History
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Kaposi, 1872

Definition
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Rare multifocal angioproliferative neoplasia occurring primarily in the skin and secondarily also in other organs. Kaposi's sarcoma occurs spontaneously or as part of an HIV infection.

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Classification
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Clinical forms:

  1. Classic/sporadic Kaposi's sarcoma: Occurring mainly in men from southeastern Europe; association with HLA DR5; onset beyond the age of 50. Localization on distal extremities, centripetal spread, organ or mucosa involvement in 5-20% of cases. Usually progression over decades.
  2. African/endemic Kaposi's sarcoma: V.a. in African children; skin and lymph node types are differentiated; usually fulminant aggressive course.
  3. HIV-associated epidemic Kaposi's sarcoma: In AIDS patients(especially male homosexuals). Disseminated skin involvement (extremities, trunk, acras) and mucosal involvement in 30% of patients. Usually variable course, frequent organ involvement (lymph nodes, gastrointestinal tract, lungs). See Table 1.
  4. Kaposi 's sarcomain immunosuppressed patients (also iatrogenic Kaposi's sarcoma): Iatrogenic, after organ transplantation (0.5-5.3% of organ-transplanted patients) or in various diseases, e.g. lupus erythematosus, systemic or severe atopic dermatitis. V.a. in men, similar course as HIV-associated Kaposi's sarcoma.

Staging according to Mitsuyasu and Groopman (stage and clinical findings):

  • Stage I: Circumscribed cutaneous (< 10 foci or one anatomic region).
  • Stage II: Disseminated cutaneous (> 10 foci or > 1 anatomical region)
  • Stage III: Exclusively visceral
  • Stage IV: Cutaneous and visceral
    • Stage IV A: Without general symptoms
    • Stage IV B: With fever and/or weight loss.

ACTG staging of HIV-associated Kaposi's sarcoma, see Table.

Occurrence/Epidemiology
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Incidence (classic Kaposi sarcoma): 1/10 million inhabitants/year. Incidence of HIV-associated epidemic Kaposi's sarcoma: Kaposi's sarcoma is the characteristic disease of MSM. In 5-7% of HIV infected persons. Before cART, 20% of men were affected.

Etiopathogenesis
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Vascular proliferation whose aetiology has not yet been clearly clarified. Among others, genetic disposition (association with HLA-DR5; frequent occurrence in Mediterranean populations), expression of growth factors (especially Oncostatin M, IL-1 beta, Basic Fibroblast Growth Factor), viral genesis (HHV-8) and immunosuppression are discussed. The prevalence of KS in organ transplant patients is 0.5-5.3%, which is 500 times higher than in control groups, and the prevalence of HHV-8 is 20%! In HIV-infected patients with HIV-associated epidemic Kaposi's sarcoma, associations with the tat protein of HIV-1 have been described.
Molecular pathologically, HIV-induced Kaposi's sarcoma is preceded by an inflammatory response due to infection with HHV-8. HHV-8 suppresses the expression of p53 (see below tumour suppressor genes) via its LNA-1 (latent nuclear antigen). Furthermore, it inhibits proliferation blockade by the RB protein (retinoblastoma protein; see below tumour suppressor genes) and transforms endothelial cells with the Ras oncogene(proto-oncogene). As a result, a number of inflammatory cytokines are produced (e.g. TNF-alpha, IL-1 and other interleukins), which initiate the expression of the angiogenic growth factor bFGF (= basic fibroblast growth factor; see growth factors below) by the endothelia, forcing them to proliferate continuously. However, endothelia do not only need a proliferation signal for their growth, but also a topological orientation signal (e.g. fibronectin). The tat protein(= trans-acting transcriptional activator) expressed by HIV-1 viruses mimics this fibronectin effect. Endothelial cells express certain integrins(belonging to the adhesion molecules) which act as tat receptors. At the same time, the tat protein is able to initiate the formation of collagenases so that the neoplastic endothelial cells can infiltrate the collagenous tissue.

Clinical features
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Initially brown-red to violet spots, from which plaque-like and nodular tumours develop. Tendency to confluence and formation of new foci in the marginal area. Tendency to ulceration (especially mucous membrane lesions). In case of trunk infestation mostly exanthematic spread of the skin lesions with characteristic arrangement along the skin cleft lines. Disturbed lymph drainage leads to elephantiasis-like oedemas. Infestation of lymph nodes, more rarely of the gastrointestinal tract, liver, lungs or heart is possible.

Histology
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In the patch and plaque stage , there are in the upper and middle dermis under a mostly unchanged epidermis with orthokeratotic keratinization, blurred proliferates of endothelial cells and fibroblasts; formation of atypical slit-like vascular structures with erythrocyte extravasations and hemosiderin deposits; furthermore, a lymphocytic and macrophagocytic infiltrate is usually detectable.

In the plaque stage spindle cell formations are in the foreground, which are bundled into fascicles or strands that penetrate the entire dermis. The tumor cells are HHV-8, vimentin, in early lesions also factor VIII and CD31 and CD34 positive. Frequently, immunohistological staining is the only way to determine the complete extent of vascularization.

In the nodular or tumor stage , a cell-rich nodule is made up of densely packed turflike fascicles that penetrate the entire dermis. Included are slit-shaped endothelium-free clefts with erythrocyte clusters. Only moderate nuclear atypia. Mitoses are common.

In the lymphangioma-like variant of Kaposi's sarcoma the "angiomatous character" of the new formations is more strongly expressed. There are irregular, partially anastomosing vessels with prominent "hobnail" endothelials. In paraffin sections, HHV8-LNA (latent nuclear antigen) can be detected very reliably in all forms of Kaposi's sarcoma by immunohistiochemical means.

Diagnosis
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Clinic, histology, skin sonography, exclusion of infestation of internal organs (especially lungs).

Detection of Kaposi's sarcoma herpesvirus (HHV-8) serologically or from the tissue by means of PCR (diagnostically not necessarily conclusive, as neoplasms such as Castleman's lymphoma or body-cavity based B-cell lymphoma can also be associated with HHV-8).

Differential diagnosis
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Clinical image/localization/histology Differential diagnoses
Clinical Solitaire cutaneous, angiomatous (vascular, livid) Cell-rich or thrombosed angiomas; granuloma teleangiectaticum; haematomas; angiokeratomas; angiosarcomas
Solitary cutaneous spindle cell (spindle cell-rich, skin-coloured, reddish) dermatofibroma; dermal melanocytic nevi; lymphomas; more rarely: melanomas; pigmented basaliomas; on the lower legs: acroangiodermatitis
Oral Oral angiomas, bleeding, amalgam tattoo
Lymphatic Lymphomas; Syphilis II; EBV infection
Disseminated cutaneous cutaneous T-cell lymphoma; cutaneous B-cell lymphoma; syphilis II; bacillary angiomatosis
Histological Angiomatous and spindle cell forms Various benign and malignant vascular tumors: angiomas; angiokeratomas; angiosarcomas; granuloma teleangiectaticum; inflammatory granulation tissue; acroangiodermatitis Mali; Stewart's bluefarb syndrome; bacillary angiomatosis

Therapy
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Classical/sporadic KS:

  • Compression bandaging with short-stretch band ages to eliminate lymphedema (see compression therapy).
  • Excision if necessary (often only palliative), local recurrence rate high.
  • Radiation therapy: Fractionated soft X-ray therapy is used for large or grouped lesions. The KS is very sensitive to radiation; single dose (ED) 3-5 Gy 3 times/week, total therapeutic dose (GHD): 20-30 Gy (30-60 kV); X-ray irradiation of larger foci with a GHD of 30-50 Gy, ED: 5 Gy.
    Linear accelerator (or circulating accelerator): indicated for large Kaposi's sarcomas with a penetration depth < 2 cm and secondary lymphedema due to lymphatic outflow obstruction.
    In case of rapid tumor progression with multilocular occurrence, chemotherapy if necessary (see treatment of HIV-associated KS). Based on our own experience, treatment with liposomal doxorubicin may be recommended in extensive, otherwise refractory, progressive cases.
  • Topical application of alitretinoin gel 0.1% (Panretin) for the treatment of manifest classic KS and its relapses.

African KS: Same as classic/sporadic Kaposi's sarcoma.

HIV-associated KS:

  • In case of skin involvement only and < 10 lesions:
    • Camouflage (e.g. Dermacolor), especially in cases of cosmetically disturbing changes and lack of desire for therapy.
    • Laser therapy(argon laser) is only suitable for small macular lesions.
    • Cryosurgery (open spray, 2 cycles, 30-60 sec.) only suitable for macular lesions, wound healing 6-8 days, not plantar or genital.
  • Soft X-ray therapy: (GD 30 Gy, 43 KV, FHA 15 cm):
    • Fractionation: trunk or extremities: 6 times 5 Gy; face: 10 times 3 Gy; penis: 15 times 2 Gy.
    • In the following cases, a break of at least 2 weeks should be taken after 50% of the total dose: In the area of problematic localizations (plantar, enoral, penis/scrotum, tongue, eyelids, conjunctiva).
    • After and during chemotherapy (risk of increased radiosensitivity).
    • Limits of dermopan irradiation:
    • Diameter > 12 cm
    • Thickness > 1,5 cm
    • Extensive lymphedema
    • Strongly curved surface
    • Enoral: diameter > 2,5 cm
    • Posterior third of the tongue.
    • Side effects: radiodermatitis (2-3 weeks), pigmentary shift, alopecia. Prophylaxis of pigmentation: No simultaneous intake of β-carotene, no UV exposure during and 4 weeks after therapy! Therapy of pigmentation: Vitamin A acid (e.g. Cordes VAS cream) locally.
  • Cobalt irradiation: lesions in the area of the oral mucosa and pharynx. Total dose 20 Gy, ED 2 Gy. After 50% of the total dose, at least 2-week break due to risk of mucositis.
  • Rapid electron irradiation: Large Kaposi's sarcomas (lower leg, groin region, face, occasionally accompanied by lymphoedema). 20 Gy GHD, ED 2 Gy.
  • Intralesional interferon: Only in patients with > 200 CD4 cells/μl. Injection 3 times/week at 1 ml/cm2 for 4 weeks.
  • Intralesional chemotherapy (vinblastine or vincristine): dilution 1:9 with 1-2% xylocaine solution. Intralesional injection of 0.5-1 ml/cm2, max 2 mg total dose/session at 3-week intervals. I.d.R. 3 sessions are required.

    Caution. Pain, sensory disturbances, occasionally superficial necrosis. Not indicated in acral localized Kaposi's sarcoma.

  • Chemotherapy:
    • Interferon alfa-2a (e.g. Roferon; evidence level B III; remission rate 40-50%): 3-6 million IU s.c./day 3 times weekly. Only in patients with > 200 CD4 cells/μl, as the response rate with fewer CD4 cells is only 7% and always in combination with HAART. Due to influenza NW, administration of paracetamol (ben-u-ron) 1000 mg 1 hr before injection is recommended.
    • Liposomal doxorubicin (e.g. Doxil; evidence level AI; remission rate: 60-80%): 20 mg/m2 KO i.v. every 2 weeks.
    • Alternative: Liposomal daunorubicin (e.g. DaunoXome; evidence level AI; remission rate: approx. 60%) 40 mg/m2 KO i.v. every 2 weeks.
    • Paclitaxel (e.g. Taxol; evidence level BII; remission rate: 50-60%): 100 mg/m2 KO i.v. every 3 weeks.
  • Antiretroviral therapy (in HIV infection)
    :Especially after initiation of highly active antiretroviral therapy (HAART), regressions of Kaposi's sarcoma have been described. Since HAART has become available, the incidence of KS as an AIDS-defining disease has decreased.
  • In organ transplant recipients, ciclosporin-based regimens appear to be associated with a higher risk of KS than azathioprine-based regimens. Switching to mycophenolate mofetil may lead to regression of KS (off-label use).

Progression/forecast
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According to recent studies, CD4 cell count does not affect the prognosis of Kaposi's sarcoma on HAART.

S. Table 2

Tables
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Stage classification of HIV-associated epidemic Kaposi's sarcoma according to ACTG (AIDS Clinical Trial Group)

Risk

Early stage (good prognosis)

Late stage (poor prognosis)

If all the following conditions are met:

If any one of the following conditions applies:

T0 (good forecast)

Tumor (T0): Kaposi's sarcoma limited to skin and/or lymph nodes; minimal oral involvement if any (non raised lesions on the hard palate)

Tumor (T1): Pulmonary or gastrointestinal Kaposi sarcoma; extensive oral involvement; tumor-related edema or ulceration

T1 (poor prognosis)

I0 (good prognosis)

Immune status (I0): CD4 cells > 200/µl

Immune status (I1): CD4 cells < 200/µl

I1 (poor prognosis)

S0 (good prognosis)

Symptoms (S0): No opportunistic infections, no oral thrush, no B symptoms (b) of HIV infection

Symptoms (S1): In the medical history opportunistic infections, oral thrush, malignant lymphoma or HIV-associated neurological diseases, B-symptomatic (b) of HIV infection

S1 (poor prognosis)

(b) B-symptoms of HIV infection = unclear fever, night sweats or diarrhoea lasting longer than 2 weeks, weight loss > 10%.


Clinical type

Survival time after initial manifestation

Classical/sporadic Kaposi sarcoma

years - decades

African/endemic Kaposi sarcoma

Few months - years

HIV-associated, epidemic Kaposi sarcoma

Depending on the stage of HIV infection and the effectiveness of antiretroviral therapy options: Few months - years

Kaposi sarcoma (KS) in immunocompromised patients

months - years


Therapeutic agent

Dosage

Requirement

Remission rate (%)

Side effects

Level of evidence

References

Interferon alfa-2a or interferon alfa-2b

3 times/week 3-6 million IE s.c. (dose escalation possible depending on tolerance)

> 200 CD4 lymphocytes/μl

40-50

Fever. Rare: muscle aches, arthralgia, depressive moods

BIII

T1, I0, S0-1

(Pegylated) liposomal doxorubicin

20 mg/m2 KO i.v. at 2-week intervals

T1, I1, S0-1

60-80

Neutropenia, anemia. Rare: sensation of heat, shortness of breath, back pain, palmoplantar erythrodysesthesias

AI

Goebel, 1996; Nunez, 2001

daunorubicin liposomal

40 mg/m2 KO i.v. at 2-week intervals

T1, I1, S0-1

approx. 60

Neutropenia, anemia. Rare: sensation of heat, shortness of breath, back pain, palmoplantar erythrodysesthesias

AI

Rosenthal, 2002

Paclitaxel (Taxol)

100 mg/m2 KO i.v. in 2-week intervals or 135 mg/m2 KO i.v. every 3 weeks

T1, I1, S0-1

50-60

Neutropenia, peripheral neuropathy, allergic skin reactions. Rare: hypotension, ECG changes, alopecia

BII

Saville, 1995; Tulpule, 2002

* (if possible always in combination with antiretroviral combination therapy according to the currently valid guidelines)


Tumor size

Therapy

Reference

Small area (≥ 1 cm² macular, nodular)

Cryosurgery

Schöfer, 1991; Tappero, 1991

vincristine intralesional

Schöfer, 1991; Odom, 1987

vinblastine intralesional

Newman, 1988; Epstein, 1993; Ramirez-Amador, 2002

Interferons intralesional

Trattner, 1993

Alitretinoin Gel 0.1% (Panretin)

Walmsley, 1999; Duvic, 2000; Bodsworth, 2001

Excision

Medium size (1-4 cm diameter; macular, nodular)

vinca alkaloids intralesional

Schöfer, 1991; Newman, 1988

Dermopan irradiation (fractionated)

Schöfer, 1991; Kaliebe, 1994

Large surface (> 4 cm diameter; nodular, infiltrating, oral)

Fast electrons, cobalt irradiation (fractionated)

Nisce and Kaufman, 1993; Stelzer and Griffin, 1993

on the lower leg additional compression treatment

All predominantly macular Kaposi sarcomas

Camouflage

Hundeiker and Kehling, 1985

Intraoral

Vinblastine intralesional, 3% sodium tetradecyl sulfate intralesional

Ramirez-Amador, 2002


Active principle

Substances

References

angiogenesis inhibitors

AGM 1470, TNP 470

Dezube, 1998

Glufanide disodium, IM 862

Tulpule, 2000

Thalidomide

Little, 2000

Metalloprotease inhibitors

Cianfrocca, 2002

Aromatic Retinoids

9-cis-retinoic acid, oral

Aboulafia, 2003; Miles, 2002

Liposomal tretinoin, oral

Amber, 2002

Hormonal agents

Urinary HCG, or HCG fractions

Pepper, 2002

Antiviral substances (against HHV-8)

Cidofovir

Little, 2003

Chemotherapeutics

Cidofovir

Little, 2003

Etoposide

Sprinz, 2001, Evans, 2002

Vinorelbine

Nasti, 2000

Aftercare
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  • HIV-associated, epidemic Kaposi sarcoma:
    • 3-monthly checks of the skin, mucous membranes, lymph nodes
    • 6-12-monthly check of the lungs (X-ray thorax) and the GI system (sonography, endoscopy).

Literature
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  1. Antman K, Chang Y (2000) Kaposi's sarcoma. N Engl J Med 342: 1027-1038
  2. Brenner B et al (2002) Classical Kaposi's sarcoma: prognostic factor analysis of 248 patients. Cancer 95: 1982-1987
  3. Campistol J et al (2007) Kopsi`s sarcoma in renal transplant recipients-the impact of proliferation signal inhibitors. Nephrol Dial Transplant 22 (Suppl 1) i17-i22
  4. Chundriger Q et al. (2021) Retiform hemangioendothelioma: a case series and review of the literature. J Med Case Rep 15:69.

  5. Kaposi M (1872) Idiopathic multiple pigmentary sarcoma of the skin. Arch Derm Syph 4: 265-273
  6. Rappasberger K, Tschachler E, Zonzits E et al (1990) Kaposi's sarcoma in human immunodeficiency virus type 1-seronegative persons: demonstration of retrovirus-like particles in cutaneous lesions. J Invest Dermatol 95: 371-381
  7. Schöfer H, Brockmeyer N (2002) German guideline: Kaposi's sarcoma.
  8. Rogena EA et al. (2015) A review of the pattern of AIDS defining, HIV associated neoplasms and premalignant lesions diagnosed from 2000-2011 at Kenyatta National Hospital, Kenya. Infect Agent Cancer 10:28.

  9. Rohner E et al. (2016) HIV and human herpesvirus 8 co-infection across the globe: Systematic review and meta-analysis. Int J Cancer 38: 45-54.

  10. Rohrmus B et al (2000) Outlook in oral and cutaneous Kaposi's sarcoma. Lancet 356: 2160
  11. Schulz TF et al (2015) Kaposi's sarcoma-associated herpesvirus: mechanisms of oncogenesis. Curr Opin Virol14:116-128.

  12. Webster-Cyriaque J (2002) Development of Kaposi's sarcoma in a surgical wound. N Engl J Med 346: 1207-1210.

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