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Dermatology Diagnosis

Diagnosing A Solitary Purple Lesion On The Fifth Toe

A 55-year-old male presented with a three-month history of a single slow-growing red lesion to the medial aspect of the left fifth digit with notable albeit minimal pain. He is healthy and not of Eastern European descent, is immunocompetent (non-HIV) and has been in a monogamous homosexual relationship for 20 years.

In regard to the examination, the patient appeared well nourished and well developed. He had a normal systemic examination. There was a raised, well-demarcated red lesion measuring 1.0 by 0.8 by 0.4 cm to the medial aspect of the fifth toe. In addition, radiographs revealed the presence of a soft tissue contour and density within normal limits without evidence of any erosion or abnormality of the bone in the area of the soft tissue lesion.

When you hear that a 55-year-old patient in a 20-year homosexual relationship has this lesion, you worry about human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS), and the patient’s survival. In this case, however, there is no HIV and the patient’s immune system is not compromised.

Key Questions To Consider

1. What the diagnosis?
2. What is the differential diagnosis?
3. What is the prognosis for these lesions?
4. What are the treatment options for these lesions?

Answering The Key Diagnostic Questions

1. Kaposi sarcoma
2. Microvenular hemangioma, tufted hemangioma, pseudo-Kaposi sarcoma (acroangiodermatitis), cavernous hemangioma, pyogenic granuloma, hematoma, spindle cell hemangioma, dermatofibroma, purpura, bacillary angiomatosis, allergic reaction, angiosarcoma, basal cell carcinoma, melanoma, and squamous cell carcinoma
3. The prognosis is 100 percent as this is a localized skin lesion and not a sarcoma. The lesions may return but do not mean worsening of any condition unless his HIV status changes.
4. Local treatments include surgical excision, cryotherapy, laser therapy, topical therapy and intralesional/radiation therapy. Systemic treatments include chemotherapy and immunomodulators.

What You Should Know About Kaposi Sarcoma

Kaposi sarcoma is best known as the prototypical AIDS-defining illness. It is caused by the human herpesvirus 8 (HHV-8) and typically results in distinctive, dark-colored skin lesions on the skin or inside the mouth, respiratory or gastrointestinal (GI) tract.1 The HHV-8 virus transmits via sexual contact.

We can categorize Kaposi sarcoma in four groups: classic (typically in middle- or senior-aged men of Mediterranean or Central/Eastern European descent); endemic (sub-Saharan indigenous Africans, not HIV-related); iatrogenic (associated with immunosuppressive therapy related to renal transplantation); and AIDS-associated (epidemic Kaposi sarcoma).2

Lanternier added a fifth group/new variant, which primarily arises in middle-aged, HIV-negative gay men with normal immune function.1 The cases in HIV-negative men were less aggressive and rapidly progressing than those in people with AIDS. Our patient fits into this fifth group.  

There have been several classifications for classic Kaposi sarcoma with the latest attempt classifying the neoplasm in four stages.3 Stage I (macular/nodular stage) consists of small isolated macules and nodules that are primarily confined to the lower extremities. Stage II (infiltrative stage) consists of violet-gray plaques that mainly appear on the lower extremities and sometimes involve a few nodules as well. Stage III (florid stage) entails multiple angiomatous plaques and nodules that are frequently ulcerated and involve one or more lower extremities. Stage IV (disseminated stage) involves multiple angiomatous nodules and plaques that extend beyond the lower extremities. Stages I or II present with a slower rate of progression, fewer complications, and a lower occurrence of GI tract involvement. Stages III and IV present with faster rate of progression, more complications, and greater involvement of the GI tract. This particular study by Hiatt and colleagues involved 300 patients over 20 years and also revealed that the classic Kaposi sarcoma frequency is more common in men (7:1), and arises at a mean age of 74.3

The lesion is typically purplish, reddish blue or dark brown in macules or plaques that are often in the lower extremity. Kaposi sarcoma can also indicate a systemic disease that can present with cutaneous lesions with or without internal involvement. Kaposi sarcoma has been defined as a malignant neoplasm of blood or lymph vessels presenting with multiple vascular nodules in the skin or other organs.4 The disease is multifocal with a course ranging from indolent (with only skin manifestations) to fulminant (with extensive visceral involvement).

At one point, researchers estimated that gastrointestinal Kaposi sarcoma occurred in up to 40 percent of patients with AIDS but more recently, its incidence has declined.4 In addition to occurring in patients with AIDS, visceral Kaposi sarcoma can also arise in organ transplant recipients as well as patients receiving immunosuppressants for other diseases. In these patients, Kaposi sarcoma occurs several months to a few years after the initiation of immunosuppression. Although skin lesions may regress with a reduction in immunosuppression, patients with visceral involvement may succumb to their disease.5

Due to the size of the lesion for this patient, we recommended surgical elliptical excision in order to be able to close the surgical site. Surgical pathology revealed the soft tissue mass to be Kaposi sarcoma with tumor cells positive for CD31, CD34 and HHV8. Margins were negative for involvement. We called the patient’s internist, who rechecked the patient did not have HIV. The internist, who is also an infectious disease specialist, said that once you resect the lesion, it is gone and surveillance is the treatment.

The classic textbook/exam “lesion” is Kaposi sarcoma secondary to HIV. What about Kaposi sarcoma unrelated to HIV? Kaposi sarcoma was once rare as it only affected older men from Eastern European or Mediterranean families, young African men, or people who had undergone organ transplants. Now HIV is the most common cause.

What do the cutaneous lesions look like? Kaposi sarcoma has the ability to develop into lesions of varying morphologic appearance. We normally see the lesions at the patch, plaque and nodular stage, but we can also see anaplastic and telangiectatic Kaposi sarcoma as well as several lymphedematous variants and variants including hyperkeratotic, keloidal, micronodular, pyogenic granuloma-like, ecchymotic, and intravascular Kaposi sarcoma. It is important to be able recognize these variants in order to avoid potential misdiagnosis and improper management of patients with these lesions.6

Is Kaposi Sarcoma A Misnomer?

Despite its name, Kaposi sarcoma is not a true sarcoma, which is a tumor arising from mesenchymal tissue. Data suggest that, at least in the early stage, Kaposi sarcoma may actually be a hyperplastic-proliferative lesion.7 Cells infected with HHV8 produce cytokines, chemokines and growth factors that cause proliferation of endothelial and spindle cells. There is controversy as to whether these proliferative cells truly represent a malignant neoplasia versus an inflammatory hyperplasia.7

A sarcoma is a malignant tumor that forms in the connective or supportive tissues of the body, including bone, cartilage, fat, muscle or blood vessels. Most soft tissue sarcomas occur in the arms, legs, hands or feet.

This is in contrast to a malignant tumor originating from epithelial cells. These tumors are called carcinomas. Human sarcomas are quite rare. Common malignancies, such as breast, colon and lung cancer, are almost always carcinoma.8 Sarcomas represent about 1 percent of the 1.5 million new cancer diagnoses in the United States.

A biopsy is required to make the definitive diagnosis of Kaposi sarcoma.8 The pathological evaluation of all four different types do not differ. Spindle cell proliferation will stain for CD34 and CD31 while one can use the polymerase chain reaction assay to detect amplified HHV8 DNA sequences.9

Relevant risk factors for developing Kaposi sarcoma in this patient include anti-HHV-8 antibodies; a history of immunosuppression that is either iatrogenic (organ transplantation) or acquired (HIV infection); and gender (males have a greater risk than females). A study in 2002 found that smoking cigarettes significantly lowered the risk for Kaposi sarcoma, especially with a higher pack per year and pack year history.10 Classic Kaposi sarcoma risk decreased by 20 percent for each ten pack years of smoking and decreased by sevenfold in men with more than a 40 pack year history.

Pertinent Insights On Treatment For Kaposi Sarcoma

Local treatments for Kaposi sarcoma include surgical excision, cryotherapy, laser therapy, topical therapy and intralesional/radiation therapy. Systemic treatments include chemotherapy and immunomodulators.

Surgical excision has been effective for single Kaposi sarcoma nodules with subsequent topical application of hydrogen peroxide to achieve hemostasis.11 The concern is that new lesions will commonly develop at other sites. Nevertheless, it is a safe, effective and simple lesion treatment.

Cryotherapy and laser therapy can provide local control of small Kaposi sarcoma lesions.12 However, to date, researchers have not evaluated long-term control with these treatment modalities.

Topical therapy includes alitretinoin gel 0.1% (Panretin, Eisai), a Food and Drug Administration (FDA)-approved topical treatment for cutaneous AIDS-associated Kaposi sarcoma. However, there is limited data on classical Kaposi sarcoma.13 Célestin Schartz and coworkers evaluated the use of imiquimod on non-HIV related Kaposi sarcoma and noted a decrease in lesion area.14 Researchers have also evaluated nicotine patches based on the associated reduced risk of Kaposi sarcoma in smokers but did not find this modality to be successful.15

Systemic treatments, including chemotherapy and immunomodulators, have the potential to treat Kaposi sarcoma at all sites. The response to therapy has ranged from 60 to 90 percent.16 The treatments are well tolerated by elder patients at higher risk for classic Kaposi sarcoma and the response duration ranges from four months to over two years.

Patients with classic Kaposi sarcoma usually die of non-neoplastic conditions or uncommonly of lymphoid malignancies.17 Therefore, early diagnosis and treatment are crucial.

Final Words

Kaposi sarcoma is commonly related to HIV infection but one should keep in mind that there are non-HIV-related cases as well.18 Maintain a high index of suspicion for classic Kaposi sarcoma presentations in order to ensure prompt and correct diagnosis with early biopsy, and subsequent initiation of therapy as indicated.

Dr. Santander is a first-year resident at MedStar Washington Hospital Center in Washington, D.C.

Dr. Morse is the President of the American Society of Foot and Ankle Dermatology. He is a Fellow of the American College of Foot and Ankle Surgeons, and the American College of Foot and Ankle Orthopedics and Medicine. Dr. Morse is board-certified in foot surgery. He is an attending at the MedStar Washington Hospital Center in Washington, D.C.

References
1.     Lanternier F, Lebbe C, Schartz N, et al. Kaposi sarcoma in HIV-negative men having sex with men. AIDS. 2008, 22(10):1163-8.
2.     Ruocco E. Kaposi sarcoma: Etiology and pathogenesis, inducing factors, causal associations, and treatments: Facts and controversies. Clin Dermatol. 2013; 31(4):413-422.
3.     Hiatt KM, Nelson AM, Lichy JH, Fanburg-Smith JC. 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. Mod Pathol. 2008; 21(5):572-82.
4.     Ensoli B, Sirianni MC. Kaposi sarcoma pathogenesis: a link between immunology and tumor biology. Crit Rev Oncogenesis. 1998; 9(2):107–124.
5.     Master SS, Carethers JM. Kaposi’s sarcoma. In Johnson L (ed.), Encyclopedia of Gastroenterology, Elsevier, Philadelphia, 2004, pp. 477–78.
6.     Grayson W, Pantanowitz L. Histological variants of cutaneous Kaposi sarcoma. Diagn Pathol. 2008; 3:31.
7.     Hulmani M, Kudur M. Misnomers in dermatology: Time to change and update. Indian J Dermatol Venereol Leprol. 2013;79(4):479-91.
8.     Sen F, Tambas M, Ciftci R, et al. Factors affecting progression-free survival in non-HIV-related Kaposi sarcoma. J Dermatolog Treat. 2016; 27(3):275-7.
9.     Hbid O, Belloul L, Fajali N, et al. Kaposi sarcoma in Morocco: a pathological study with immunostaining for human herpesvirus-8 LNA-1. Pathology. 2005; 37(4):288-95.
10.     Goedert JJ, Vitale F, Lauria C, et al. Risk factors for classical Kaposi sarcoma. J Natl Cancer Inst. 2002; 94(22):1712-8.
11.     Tourlaki A, Bellinvia M, Brambilla L. Recommended surgery of Kaposi sarcoma nodules. J Dermatolog Treat. 2015; 26:354.
12.     Webster GF. Local therapy for mucocutaneous Kaposi sarcoma in patients with acquired immunodeficiency syndrome. Dermatol Surg. 1995; 21:205.
13.     Morganroth GS. Topical 0.1% alitretinoin gel for classic Kaposi sarcoma. Arch Dermatol. 2002; 138(4):542-6.
14.     Célestin Schartz NE, Chevret S, Paz C, et al. Imiquimod 5% cream for treatment of HIV-negative Kaposi sarcoma skin lesions: A phase I to II, open-label trial in 17 patients. J Am Acad Dermatol. 2008; 58(4):585-91.
15.     Goedert JJ, Scoppio BM, Pfeiffer R, et al. Treatment of classic Kaposi sarcoma with a nicotine dermal patch: a phase II clinical trial. J Eur Acad Dermatol Venereol. 2008; 22(9):1101-9.
16.     Krown S, Singh JC. Classic Kaposi sarcoma: Epidemiology, risk factors, pathology, and molecular pathogenesis. UpToDate. Updated April 12, 2017. Accessed November 17, 2017.
17.     Ascoli V, Minelli G, Kanieff M, et al. Cause-specific mortality in classic Kaposi sarcoma: a population-based study in Italy (1995-2002). Br J Cancer. 2009; 101(7):1085-90.
18.     Grigoriou M, Kofina KE, Ioannidis A, et al. Kaposi Sarcoma in an human immunodeficiency virus (HIV)-seronegative Mediterranean female: report of a rare case. Am J Case Rep. 2017; 18: 830–833.

Dermatology Diagnosis
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Israel Santander, DPM, and M. Joel Morse, DPM
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