What Is the Underlying Cause of These Exophytic Lesions?

A 102-year-old African American woman presented to the dermatology clinic for initial management of lesions on her right medial foot. The lesions had been present for several weeks, and the patient was unable to recall any preceding trauma, infections, or other skin changes. The patient denied fevers, chills, night sweats, or other systemic symptoms. Physical exam revealed several grouped exophytic nodules with variable hyperkeratosis and surrounding collarette of scale, inferior to the right medial malleolus (Figure 1).

The patient returned to clinic 1 month later complaining of a new lesion on her right great toe, a similarly exophytic nodule but with less keratosis and a more friable, vascular appearance (Figure 2). Previous lesions on right medial instep appeared unchanged from her initial visit.

What Is The Diagnosis?

Scroll below the ad to find out!

Diagnosis: Classic Kaposi Sarcoma

Kaposi sarcoma (KS) is a human herpes virus 8 (HHV-8)-associated malignancy that is divided into four subtypes and can present in a variety of clinical scenarios. KS was originally described by Moritz Kaposi as “idiopathic multiple pigmented sarcoma of the skin” in the late 1800s and typically presents as violaceous papules, plaques, or polyps. It was historically found in elderly men of Mediterranean decent but gained notoriety in the United States during the peak of the AIDS epidemic. The four subtypes of KS, each associated with HHV-8 but with unique epidemiologic specifiers, include classic KS, African or endemic KS, immunosuppression-associated KS, and AIDS-associated KS.¹ 

Clinical presentation may include pink patches and dark violet plaques, nodules, or polyps, but the etiology of KS determines the disease presentation, distribution, and clinical course. It is now known that KS is caused by a combination of HHV-8 and impaired host immunity, whether AIDS-related, iatrogenic, due to an ageing immune system, or chronic infection and malnutrition.²

Classic KS is known to affect elderly men of Jewish or Mediterranean/Eastern European descent. Most cases develop after the age of 50, and although the male to female ratio was previously estimated at 15:1, newer literature estimates a 3:1 ratio.¹ Additionally, there is evidence that risk groups of individuals presenting with classic KS may be changing. A retrospective cohort study of classic KS in Paris, France, between 2006 and 2015 reported that less than 40% of
patients were of Mediterranean origin.² The classic type predominately favors the lower extremities and presents as red-violet macules that may coalesce to form large plaques or nodules, which typically shows an indolent, protracted clinical course.³ 

The African endemic type has a clear male predominance and has an incidence from 1% to 10%. It also includes a lymphadenopathic variant that primarily affects children. The African endemic type accounts for up to 9% of all reported cancer in equatorial Africa.¹ 

The third type of KS is due to iatrogenic immunosuppression, in which immunosuppression is secondary to systemic medications such as prednisone, calcineurin inhibitors, or cytotoxic agents. These types of lesion may regress following cessation of immunosuppressive therapy. Although this type is typically associated with transplant patients, their incidence is now less than 1% in Western countries.¹ 

The final type is AIDS-associated KS, which occurs primarily in men who have sex with men (MSM) and is the most common type in the United States. Patients with HIV, with advanced immune impairment and CD4⁺ T-cell counts of less than 500 cells/mL³, are at greatest risk. AIDS-related KS may present as faint erythematous macules, papules, or plaques or purple-black tumors and nodules.¹ This type exhibits a more widespread distribution pattern, including the face, oral cavity, gastrointestinal tract, and genitalia and typically demonstrates a more aggressive clinical course if viscera involvement is present.² Occasionally, AIDS-related KS develops in patients with HIV receiving chronic antiretroviral therapy, but overall, the introduction of antiretroviral therapy has led to a marked decrease in the incidence, morbidity, and mortality of HIV-associated KS.¹ 

The differential diagnosis for such an exophytic lesion is broad, including reactive, neoplastic, and infectious processes. The Table features a number of common differential diagnoses.^1,4-7

KS is a type of spindle cell malignancy that originates from vascular endothelium and is associated with HHV-8 infection. Histology is particularly useful in distinguishing KS from its other differential diagnoses. Furthermore, the histologic appearance does not significantly differ among its various subtypes. On hematoxylin-eosin staining, a sieve-like pattern of vascular spaces is considered to be highly characteristic of KS. The neoplastic cells tend to be spindle-shaped and often express many endothelial markers of both vascular and lymphatic differentiation, such as CD31, CD34, and vascular endothelial growth factor receptor 3. Immunohistochemical analysis is often diagnostic and can be performed via latency-associated nuclear antigen (LANA-1). This highly sensitive and specific marker for HHV-8 has proven greater diagnostic utility than polymerase chair reaction (PCR) genomic analysis, being that a small number of non-KS vascular tumors have been found to be positive for HHV-8 by PCR.¹ 

Management of KS differs depending on the patient’s etiology and hinges upon proper diagnosis of the patient’s condition. Treatment of classic KS is typically individualized to the patient and stage at presentation. Solitary or isolated lesions may be observed or treated with local radiotherapy or surgical excision. Conversely, disseminated disease may be treated systemically with a variety of chemotherapeutic agents. In the case of immunosuppression-associated KS, suspension or reduction in the dose of immunosuppressant may lead to resolution. Treatment of HIV-associated KS consists of highly active antiretroviral therapy (HAART) with or without local therapy. Lesion-free survival at 5 years after HAART treatment, with or without local therapy, was reported at 92% in a series of more than 400 cases. The addition of chemotherapeutic agents may be necessary in the case of disseminated disease.⁸

In this case, the patient exhibited a unique presentation of classic KS (Figure 1). She had no history of HIV infection, transplant, or immunosuppressant medication use, and she was not from sub-Saharan Africa. Her biopsy results were consistent with the typical histology of KS, exhibiting slit-like vessels with spindle cell proliferations. Immunohistochemical studies showed diffuse positivity for CD31 and CD34. The tumor was positive for HHV-8, further supporting the diagnosis of KS. 

Although there are a variety of management options of classic KS, the patient’s treatment was limited due to her age and prior medical conditions; therefore, supportive care was recommended with symptomatic local therapy.

Classic KS is known to affect elderly men of Jewish or Mediterranean/Eastern European descent. This patient, instead, was an African American woman. There is limited literature that records the prevalence of KS in this specific population. In North America, classic KS is rare with an incidence of 2.6 to 4.1 cases per 1 million men and 0.6 to 0.9 cases per 1 million women. A case series from Hiatt et al⁹ studied classic KS exclusively in the United States. In this study of 438 patients, 56% were documented to be Caucasian/American, 22% Mediterranean, 18% South American Hispanic, only 10% Black, with the remaining percentages belonging to western European, Middle Eastern, Scandinavian, and other ethnicities. This particular study found classic KS to be more common in men (7:1) with a mean age of 74 years. Most lesions found in the study presented similarly to our patient: in the lower extremity and in the nodular stage. Furthermore, many of the patients were found to have associated second malignancies, which may relate to the etiology of classic KS. The study supported the indolent disease course, which rarely results in patient death.⁹

KS is an HHV-8-associated malignancy originating from vascular epithelium, which may present as a variety cutaneous lesions from pink patches to dark violaceous plaques to nodules and polyps. The clinical presentation and disease progression differ depending on the type of KS; therefore, it is important to be able to recognize classic KS in atypical patient populations to provide proper diagnosis, immunohistochemical identification, management, and treatment.

Mrs Caire is a fourth-year medical student at Louisiana State University Health Sciences Center in Shreveport, LA. Dr Creel is chief resident at Louisiana State University Health Sciences Center in New Orleans, LA. Dr Poche is an attending physician at Louisiana State University Health Baton Rouge in Baton Rouge, LA.

Disclosures: The authors report no relevant financial relationships.