Clinical challenge: cutaneous Kaposi's sarcoma of the lower extremity

Abstract

Kaposi's sarcoma (KS) typically presents as multiple bilateral cutaneous patches or plaques of the lower extremities. This malignancy, however, can evolve with atypical presentation masquerading as a chronic wound. Lesions can mimic venous stasis ulcers, arterial insufficiency, vascular ulcers or chronic‐infected wounds. With acquired immune deficiency syndrome (AIDS)‐associated KS, lesions are even more widespread, and can affect the respiratory tract, lymph nodes, gastrointestinal tract, spleen, liver and, rarely, bone. As the initial diagnosis of KS is generally determined clinically, a high index of suspicion is necessary for all patients with a known or suspected history of HIV/AIDS. Tissue biopsy with histological analysis is essential for all wound types in this patient subset, regardless of wound presentation. The purpose of this report is to review the pathogenesis as well as the typical and atypical presentations of KS with an example of a diagnostic dilemma.

INTRODUCTION

Kaposi's sarcoma (KS) was first described in 1872 by a Hungarian dermatologist, Mortiz Kaposi, who noted five cases of an ‘idiopathic, multipigmented sarcoma of the skin’1, 2, 3, 4, 5. As the multifocal, hyperplastic tumour believed to originate from lymphatic endothelial cells, KS is classified into four clinical variants: classic, endemic, iatrogenic and acquired immune deficiency syndrome (AIDS)‐associated 2, 4, 5, 6, 7. While clinical and histological morphologies among variants are similar, suggesting a common aetiology, the biological characteristics are quite variable, with disease characteristic strongly dependent upon the immunocompetence of the host 8, 9.

KS most commonly presents as cutaneous lesions and may mimic more commonly seen cutaneous wounds such as venous stasis ulcers, arterial insufficiency, vascular ulcers and infected wounds. The purpose of this report is to review the pathogenesis as well as the typical and atypical presentations of KS. An atypical clinical presentation leading to a diagnostic dilemma of AIDS‐associated KS is reviewed. Current recommendations on diagnosis, strategies and treatment options based on involved tissue type are discussed.

CASE REPORT

A 46‐year‐old male with AIDS presented with a 2‐week history of persistent left knee pain following a traumatic fall. Although previously ambulatory with crutches, the patient now required the use of a wheelchair secondary to knee pain following the fall. Physical exam noted bilateral oedema of the lower extremities, with diffuse tenderness surrounding the left knee joint. The knee had a flexion contracture, with a limited passive range of motion of 30–80°. A bilateral subcutaneous nodular rash with ulceration along the surface of the nodules and overlying scaly plaques, extending from the level of the proximal tibia to the distal foot bilaterally, were also noted.

The patient's past medical history includes well‐controlled multi‐drug resistant human immunodeficiency virus (HIV) infection for the past 10 years and a distant history of pulmonary tuberculosis. He was also diagnosed with immunoglobulin G kappa monoclonal gammopathy with no previous radiological evidence of osteolytic bone lesions. In addition, the patient suffered a gunshot wound to the left lower leg 14 years before. This injury led to significant impairment in ambulation and inhibition of full left knee extension. The damage was compounded by pre‐existing Charcot–Marie–Tooth disease which had led to peripheral neuropathy and bilateral Charcot deformities of the ankles. These factors contributed to the development of bilateral severe chronic lymphoedema of the lower extremities for which he was medically managed for the past 2 years with minimal success. The subcutaneous nodular rash noted on physical exam began within the previous 6 months with recent rapid progression (Figure 1A–C).

Figure 1.

Subcutaneous nodular rash with ulceration along the surface of the nodules and overlying scaly plaques, extending from the level of the proximal tibia to the distal foot. (A) Rash extending from the level of the proximal tibia to the distal foot, (B) Arrows showing skin nodules on the left foot and (C) Lymphoedema with fluid accumulation in left resulting in loss of countour of maleoli.

Laboratory evaluation noted a CD4 count of 165 with an elevated viral load of 4286 copies/ml. Radiographic evaluation of the left knee noted a comminuted fracture of the supracondylar left femur with osteolytic changes in the surrounding tibia, as well as findings suggestive of a chronic osteomyelitic process versus an osteolytic neoplastic process of the tibia and femur (Figure 2A). There was no evidence of visceral neoplasm involvement based on imaging studies.

Figure 2.

Comminuted fracture of the supracondylar left femur with osteolytic changes in the surrounding tibia. (A) Radiographic image demonstration of fracture with arrow at fracture site. Medium power view of bone with involvement by Kaposi's sarcoma. Note the vascular space just to the left of the bony trabecula, which is lined by a typical, hyperchromatic and ‘angulated’ endothelial cells (100×).

A punch biopsy of a cutaneous lesion on the left leg was performed. Histology showed uniform vascular proliferation in the dermis representative of KS (Figure 3). A CD34 stain was found positive, as well as a CD31 (+), Warthin–Starry (−), Steiner (−), HHV8 (strong +) and herpes simplex virus (HSV)−1 (−). Bacillary angiomatosis (BA) was effectively ruled out using multiple special stains for micro‐organisms. In addition, Bartonella angiomatosis does not typically present with the extreme destructive involvement of deep tissues as was seen in this case. A CT‐guided percutaneous needle biopsy of the femur at the fracture site, as well as a bone marrow biopsy, was performed. Pathological examination showed focal marked thinning of the cortex with enlargement of the Haversian canals and extensive loss of medullary bone (Figure 2B). It was concluded that the extensive bony resorption present was likely because of a combination of KS involving the bone and osteopenia as a result of disuse.

Figure 3.

High power view of Kaposi's sarcoma malignant endothelial cells located within the dermis. Small, irregular luminal spaces are lined by these enlarged, often ‘angulated’ and hyperchromatic endothelial cells (400×).

Because of poor bone quality, high risk of infection and high probability of skin breakdown, the patient was not a good candidate for operative or casting treatment of the fracture. He was placed in a stabilising lower extremity brace for fracture management and radiation therapy was began for treatment of lower extremity KS. He was not a candidate for systemic chemotherapy because of his underlying immunodeficiency state. As the result of treatment non compliance by the patient, radiotherapy was unsuccessful. The patient additionally developed persistent severe infection, consisting of cellulitis and osteomyelitis, of the lateral malleolus/midfoot of the right leg (Figure 4). Infection was progressive and unresponsive to aggressive wound care and antibiotic treatment. Worsening infection led to an above knee amputation (AKA) of his right leg. Shortly thereafter, a similar progressive infection with skin breakdown and poor wound healing of the left leg ensued. The patient underwent an AKA of the left leg as well. At the patient's 3‐month follow‐up status post‐amputations, lesions consistent with KS were once again evident on the stumps bilaterally. The patient was advised to return for radiotherapy and possible additional surgery, but refused follow‐up treatments.

Figure 4.

Progressive cellulitis and osteomyelitis unresponsive to treatment.

DISCUSSION

Historically, KS was considered a disease of low‐grade malignant potential, with a slow progression and indolent course. These presentations were primarily composed of the classic variant, and were generally found in elderly men of Mediterranean, Jewish or Italian decent 1, 5, 6, 8, 9. Conversely, the endemic form, found predominantly in central Africa, displayed a more aggressive malignant course, which was rapidly progressive over several months to years and would often result in patient fatality 5, 6, 8. The third form, iatrogenic KS, is often seen in patients following solid organ transplants and is secondary to the effects of immunosuppressive medications that are prescribed following transplantation (10).

In 1981, coinciding with the emergence of AIDS in the USA, a fourth and unusually aggressive form of KS was reported among HIV‐positive homosexual males. These sarcomas often arose in bizarre locations relative to previous descriptions, and were found most commonly in a young patient population between the ages of 30–40. Incidence of this KS subtype increased dramatically, occurring in approximately one‐third of all HIV‐positive patients, frequently as the initial symptom of HIV infection 4, 6, 11, 12, 13, 14. With the advent of highly active antiretroviral therapy (HAART) in the management of HIV, rates of KS decreased significantly 4, 6, 11, 12, 13, 14. Today, rates of KS among HIV‐positive patients is 5–7%, making KS the most common neoplasm of this population 2, 4, 6, 11, 13, 15.

An important discovery in the cause of KS occurred in 1994 when DNA from a new and novel herpes virus, human herpes virus 8 (HHV‐8), from the lesion of a KS patient was isolated and sequenced 1, 4, 9, 12, 15. The role of HHV‐8, in conjunction with other essential aetiological factors, in the development of KS was subsequently verified 1, 4, 11, 12. It was later discovered that while HHV‐8 was a necessary factor for KS, viral presence alone was not sufficient for disease to occur. This principle was best illustrated by the worldwide seroprevalence of HHV‐8 being significantly higher than the incidence of KS 5, 6, 15.

KS presentation varies depending on multiple variables, including variant type and the immune status of patient. Typically it presents as multiple mucocutaneous lesions of vascular proliferation, often multifocal in origin, and with coexistent visceral involvement 4, 6, 9, 11, 16. Isolated cutaneous involvement is also common, while visceral disease without cutaneous involvement occurs rarely 4, 6, 11, 13, 17. Lesions are typically patches or plaques, which can become nodular, infiltrative, exophytic, lymphadenopathic, echymotic, telangiectactic or keloidal in nature 5, 6, 17. Bilaterally symmetric patches or plaques of the lower extremities, which progress to nodules, are often the initial presentation of early stage disease (6). Lesions found in AIDS‐associated KS are more widespread than those with classic variant 3, 4, 13. These lesions can be found involving the skin, respiratory tract, lymph nodes, gastrointestinal tract, spleen and liver. Skeletal lesions are rare, and typically arise by invasion from adjacent skin lesions (7). They often appear as a periosteal reactions, irregular cortical erosions or osteolysis. Localisation of KS lesions to specific areas of previous trauma has also been documented, and may or may not occur in the presence of HIV 3, 4, 6, 11, 18. Patients with AIDS‐associated KS tend to rapidly progress to nodular involvement of the head and neck, usually with presence of significant visceral involvement soon after onset of disease 6, 17. Nodules often enlarge rapidly and frequently ulcerate mimicking routine cutaneous wounds, and can lead to secondary infections 4, 13, 14. Tumour progression can inhibit lymphatic drainage, which leads to significant oedema, impairing mobility, predisposing to skin breakdown and facilitating further dissemination of disease 5, 6, 14, 19. Mucous membranes are commonly involved, occurring in 30% of all AIDS‐associated KS cases 5, 6, 14. Massive visceral involvement will ultimately lead to organ dysfunction and subsequent death 5, 6.

Initial diagnosis of KS is made clinically, but histological confirmation is essential for an accurate diagnosis. Initial disease stage histology typically shows a normal epidermis with the dermis displaying increased spindle cells and vascular structure proliferation within a network of collagen and reticular fibres. Polymorphic inflammatory cell infiltrate with prominent plasma cell component can often be seen, along with surrounding proliferation of endothelial‐like cells and fibroblasts. With disease progression, KS lesion histology shows further proliferation resulting in distorted endothelialised vessels, with neighbouring non endothelialised, slit‐like spaces 4, 6, 11, 12, 14, 15, 17. Extravasation of red blood cells leading to haemosiderin deposition in surrounding spaces may be present (17).

Several clinically and histologically similar cutaneous lesions should be routinely considered in the differential diagnosis of KS. Of particular importance is BA, a pseudo‐neoplastic entity that has increased prevalence in HIV patients which can cause lytic lesions of underlying bones 4, 5, 6, 7, 11, 14, 20, 21, 22 BA is easily treatable with antibiotics; however, a missed diagnosis may result in a fatal outcome 6, 22. Special stains, including the grocott‐methenamine silver or Warthin–Starry stains, may be used to delineate questionable cases by assessing for the presence of the BA causative bacteria 6, 20, 22. BA should be ruled out before the definitive diagnosis of KS is made.

Staging is performed at the time of KS diagnosis and should include a complete skin exam and mucosal inspection, with special emphasis on the oral and genital mucosa 4, 5, 6, 14. Abdominal ultrasound, lymph node exam and chest X‐ray are additionally used to assess for disseminated disease 4, 5, 6, 14. Gastroduodenoscopy and colonoscopy should be performed when mucosal involvement is documented (4). AIDS‐associated KS lesion disease stage can be calculated according to the AIDS Clinical Trials Group (ACTG) staging classification for AIDS‐associated KS, which incorporates tumour grade, CD4 count and presence of systemic illness and assigns a specific disease stage which is then used to target appropriate therapy 3, 4, 5, 11, 13, 14.

Therapy for KS is based on lesion size, disease stage, pattern of progression, KS subtype and immune status 4, 6, 14. The management goal involves treatment of disease without impairment of immune system function. If the immune system is already weakened, therapeutic objective involves reconstitution of immune function 4, 14 As with most diseases, prevention is the best treatment. Evidence shows prevention of KS onset by avoidance of primary HHV‐8 and HIV infections, as well as the use of HAART therapy and HHV‐8 sensitive anti‐viral medications such as cidofovir 4, 6, 11, 14, 23.

Treatment of KS includes several FDA‐approved systemic, topical and intralesional chemotherapeutic options, which may be used alone or in combination with laser therapy, radiation therapy and/or surgical excision/amputation 1, 2, 4, 9, 11, 15. Recurrence rates are highest when local therapy is used alone, but surgical excision and laser therapy are sufficient strategies for managing early stage disease involving cutaneous sites only. KS is remarkably radiosensitive, and radiation is an effective alternative for early stage lesions, as well as for treating lymph nodal disease 4, 11. Systemic chemotherapy is usually reserved for documented disseminated disease, widespread cutaneous involvement, especially with facial, palmar and plantar involvement, in addition to disease with coexistent visceral involvement 4, 11.

Once remission has occurred, patient follow‐up should be conducted concurrently with routine HIV exams at regular 6‐month intervals 4, 9, 11. Follow‐up visits should include complete skin and mucosa examination, chest x‐ray and evaluation of gastrointestinal involvement by using occult blood, sonography and endoscopy.

KS is a progressive disease, most commonly presenting as a cutaneous lesion. These cutaneous lesions may mimic more commonly seen cutaneous wounds such as venous stasis ulcers, arterial insufficiency, vascular ulcers and infected wounds. A high index of suspicion is necessary for all patients with a known or suspected history of HIV/AIDS. Tissue biopsy with histological analysis is essential for all wound types in this patient subset, regardless of wound presentation.

ACKNOWLEDGEMENTS

We would like to thank Timothy Westmorland, Medical Media, Bay Pines V.A. Healthcare System for his help and expertise with figures used in this paper. This material is the result of work supported with resources and the use of facilities at the Bay Pines V.A. Healthcare System.

DISCLAIMER

The contents of this work do not represent the views of the Department of Veterans Affairs or the United States Government.