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Pedal Presentation of Kaposi's Sarcoma in a Non-HIV Hispanic Female: A Case Report and Literature Review
The Journal of Foot & Ankle Surgery 51 (2012) 365–368
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The Journal of Foot & Ankle Surgery journal homepage: www.jfas.org
Pedal Presentation of Kaposi’s Sarcoma in a Non-HIV Hispanic Female: A Case Report and Literature Review Daniel Basalely, BA 1, Khurram H. Khan, DPM 2, G. Javier Cavazos, DPM 3, Anthony V. D’Antoni, PhD 4, Bradley W. Bakotic, DPM, DO 5 1
Fourth Year Student, New York College of Podiatric Medicine, New York, NY Assistant Professor, Division of Medical Sciences, New York College of Podiatric Medicine, New York, NY Private Practice, McAllen, TX 4 Director of Anatomy, Division of Pre-clinical Sciences, New York College of Podiatric Medicine, New York, NY 5 Dermatopathologist, Bako Pathology Services, Alpharetta, GA 2 3
a r t i c l e i n f o
a b s t r a c t
Level of Clinical Evidence: 4 Keywords: biopsy cancer immunocompromise malignancy surgery toe tumor
Kaposi’s sarcoma is divided into 5 subtypes primarily differentiated by clinical presentation and typical at-risk population. We report the unique case of a 74-year-old Latin American woman who presented with a violaceous lesion on the dorsum of her right second digit, which was diagnosed as Kaposi’s sarcoma but was not easily placed into a discrete subtype. We discuss the factors that usually predispose people to this infection and the lack of those factors in our patient, as well as the subsequent treatment of our patient. The patient remained in complete remission at 4 years follow-up. Ó 2012 by the American College of Foot and Ankle Surgeons. All rights reserved.
Kaposi’s sarcoma (KS) represents about 1% of all diagnosed cancer cases worldwide. The disease is divided into 5 subtypes that are primarily defined by clinical presentation and identified in 4 different at-risk populations, commonly occurring in individuals who are immunocompromised. The disease can also be present in individuals of Eastern European or Mediterranean descent. We report a rare manifestation of the condition in a Latin American woman who did not easily fit into any of these predefined subtypes. Case Report A 74-year-old Latin American woman (of Mexican descent) presented with a violaceous lesion on the dorsum of her right second digit. The mass was present for a period of 6 to 8 months and increased in size over time. The patient denied any recent trauma including incidental trauma from shoe gear including sandals. The patient also denied any pain to the area and had self-treated with topical emollient with no improvement. Past medical history was significant for type 2 diabetes mellitus of <5 years duration, hypertension, coronary artery disease, hypercholesterolemia, hypothyroidism, and degenerative joint disease. Financial Disclosure: None reported. Conflict of Interest: None reported. Address correspondence to: Khurram H. Khan, DPM, Assistant Professor, Division of Medical Sciences, New York College of Podiatric Medicine, 53 East 124th Street, New York, NY 10035. E-mail address: [email protected] (K.H. Khan).
At the time, she was receiving anticoagulation therapy. She denied any history of surgery or cancer. She also denied tobacco or alcohol use. On physical examination, the patient’s dorsalis pedis and posterior tibial pulses were palpable bilaterally. The dermatologic examination showed diffuse hyperpigmentation of the integument with varicosities present. There were 2 slightly raised lesions on the dorsum of the second digit of the right foot. The larger lesion had an irregular border, was <1 cm in diameter (0.9 0.9 0.1 cm), had a dark purplish hue, and a hyperkeratotic area that was granulomatous in appearance but not soft (Fig. 1). Upon light debridement, there was no change of this soft tissue mass. The smaller lesion was similar but <0.5 cm in diameter. There was no dry hemorrhagic tissue noted nor was there evidence of hemorrhagic hyperkeratosis. Radiographic evaluation with dorsoplantar, lateral, and medial oblique views revealed no evidence of bone destruction to the underlying second digit or metatarsal head. Based on the clinical appearance and lack of trauma, it was determined that the lesions were suspicious. An excisional biopsy of the larger soft tissue mass was deemed necessary to rule out malignancy. The patient was taken to the operating room, and the biopsy was performed on the larger lesion via 2 semi-elliptical incisions in a 3:1 pattern down to the subcutaneous level and removed in toto. The 3:1 ellipse was used to allow for wide margins and ease of closure (Fig. 2). The smaller lesion was not removed at the time to prevent the creation of a small skin island that could ultimately lead to skin necrosis.
1067-2516/$ - see front matter Ó 2012 by the American College of Foot and Ankle Surgeons. All rights reserved. doi:10.1053/j.jfas.2012.01.012
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Fig. 1. Predebridement, right foot. The larger lesion had an irregular border, was < 1 cm in diameter, had a dark purplish hue, and had a hyperkeratotic area that was granulomatous in appearance but not soft. The smaller lesion was < 0.5 cm and had a dark purplish hue.
Fig. 3. Hematoxylin and eosin stain, 50. Typical histopathologic features of KS. A dermally based lobulated mass composed of spindled cells with a whorled or vaguely fascicular pattern of growth when viewed under low-power microscopy.
Pathology and Laboratory Reports
mammals (2). Factor VIII, like CD34, is a tissue marker characteristically found in endothelial cells. KS, a vascular tumor, is strongly positive for both of these tissue markers. Histologic and immunophenotypic analyses of this lesion revealed several unique findings and markers, which collectively allowed for unequivocal diagnosis of the disease. Histopathologic analysis of the lesion revealed a dermally based lobulated mass composed of spindled cells with a whorled or vaguely fascicular pattern of growth (3) when viewed under low-power microscopy (Fig. 3). High-power microscopic evaluation revealed a predominantly solid collection of spindled cells with scattered slitlike vascular spaces (4) (Fig. 4). Numerous extravasated erythrocytes were present within the lesion (5). Cytologically, the proliferation was composed of plump, spindled cells with abundant pink cytoplasm (5). Oval to elongated nuclei with coarse chromatin and scattered mitotic figures were evident. Within the cytoplasm of some spindled cells, collections of small pink globules were seen (6) (Fig. 5). An immunohistochemical study directed against CD 34 antigen was diffusely positive amongst tumor cells (2) (Fig. 6). This constellation of histopathologic and immunophenotypic features was diagnostic of KS. Because of the prevalence of KS in patients with HIV, and despite the patient’s denial of HIV exposure, the patient was sent for HIV screening.
There were 2 blocks, 2 slides, and 2 immunohistochemical stains (factor VIII and CD34) performed. An excisional biopsy of the lesion was obtained from the second toe of the right foot. The excision of skin measured 3.5 1 cm with an average thickness of 0.4 cm. The epidermal ulcerated nodule measured 0.9 cm in diameter. Pathologic analysis revealed KS with the edges of the lesion free of malignancy. Immunohistochemical stains are both markers characteristically found in patients with KS (1). CD34 is a cellular membrane glycoprotein characteristically found in cells exhibiting endothelial differentiation (2). It is a specific marker for the hematopoietic cells differentiated at the stem-progenitor stage in humans and other
Fig. 2. Postexcision. Biopsy was performed on the larger lesion via 2 semi-elliptical incisions in a 3:1 pattern down to the subcutaneous level and removed in toto. The 3:1 ellipse was used to allow for wide margins and ease of closure.
Fig. 4. Hematoxylin and eosin stain, 400. High-power microscopic evaluation discloses a predominantly solid collection of spindled cells with scattered slitlike vascular spaces. Numerous extravasated erythrocytes are present within the lesion.
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Fig. 5. Hematoxylin and eosin stain, 1000. Cytologically, the proliferation was composed of plump, spindled cells with abundant pink cytoplasm. Oval to elongated nuclei with coarse chromatin and scattered mitotic figures were evident. Within the cytoplasm of some spindled cells, collections of small pink globules were seen.
Fig. 6. CD 34 stain, 400. An immunohistochemical study directed against CD34 antigen was diffusely positive amongst tumor cells. This constellation of histopathologic and immunophenotypic features was diagnostic of KS.
This decision was made in the interest of medical prudence and removing all doubt. A rapid HIV-1/2 antibody test was performed to rule out HIV. The test is a qualitative immunoassay designed to detect antibodies to HIV type 1 and type 2 in saliva, whole blood, and plasma specimens. In this case, the test failed to detect any antibodies to HIV type 1 or type 2. This test did not exclude acute infection, but given the lack of sexual history in the last few years, there was no need to retest. The etiology and epidemiology of KS were discussed with the patient. A thorough medical history revealed no history of organ transplants or blood transfusions. The patient also denied Mediterranean heritage. Physical examination revealed no other lesions on the patient’s body. After complete healing of the first excisional biopsy, the second lesion was removed in similar fashion without incidence. The patient was referred to a dermatologist for a full body evaluation. She remains in complete remission at 4 years follow-up.
virus do not develop KS (8). Percentages of people infected with KSHV differ on various continents throughout the world, with studies showing a <10% rate of infection in the United States (8). In some areas of Africa, >90% of the population is infected with KSHV, with spread of infection from mother to child (8). Many people infected with KSHV will never show any symptoms of KS. Those HHV-8–infected individuals at highest risk for the development of KS are those who are immunocompromised, particularly those with AIDS, and those who have received organ transplants (8). The disease has been categorized into 5 subtypes defined primarily by clinical presentation and identified in 4 at-risk populations. These 5 categories of KS follow:
Discussion KS was first described by Moritz Kaposi in 1872 as an “idiopathic multiple pigmented sarcoma of the skin” (7). Before the AIDS epidemic, KS was extremely rare in the United States, with 2 new cases discovered per 1 million people each year (8). In 2002, the number of KS cases worldwide was 65,000. This number represents nearly 1% of all diagnosed cancer cases (9). Primary lesions of KS initially emerge as macules or papules most frequently located on the extremities. The most common sites of involvement are the feet, especially the soles and the arches. The legs, hands, and forearms can also be affected. Lesions of KS can be pigmented with a variety of colors ranging from bluish-red to brown. Progression of the disease may be slow with potential periods of remission. As the disease progresses, lesions of KS may coalesce to form firm, rubbery nodules. KS may extend to the viscera, with the gastrointestinal tract most commonly affected (10). The liver, lungs, adrenal glands, lymph nodes, and heart can also be affected (10). Involvement of bone indicates widespread disease, with rarefaction, cysts, and cortical erosion demonstrated on radiographs (10). KS has since been linked to presence of KS-associated herpes virus (KSHV), also known as human herpes virus 8 (HHV-8) (8). This virus has been identified in association with all subtypes of KS, regardless of geographic location or patient demographics. KSHV infection is much more common than KS, however, and most people infected with the
1. Classic KS (elderly men of Mediterranean decent) 2. Endemic KS (African) 3. Immunosuppression-associated KS (after iatrogenic immunosuppression) 4. Epidemic KS (AIDS-associated) (7) 5. Nonepidemic gay-related KS (homosexual men without AIDS) Classic KS occurs primarily in elderly men of Eastern European or Mediterranean origin. The disease’s onset is usually in the fifth to eighth decade with a male predominance of almost 10:1 (10). The disease usually progresses slowly and typically is not fatal (11). Endemic KS is typically found in African children, adolescents, and adults. Endemic KS presents with a high frequency of extracutaneous manifestations and follows a more aggressive course than the classic type (12). Immunosuppression-associated KS predominantly occurs in recipients of organ transplants treated thereafter with immunosuppressive therapy to avoid acute organ rejection (13). The incidence of KS in recipients of solid organs is about 500 times that found in the general population, and the clinical presentation of KS in organ recipients is often limited to skin involvement (13). Epidemic KS characteristically occurs in individuals afflicted with HIV. It is the most common neoplasm found in these individuals (14). Nonepidemic gay-related KS is a fifth subtype that has been more recently reported. This subtype has been reported on several occasions in homosexual men with no evidence of HIV (15). These patients have an indolent and cutaneous form of the disease that usually appears on the extremities and genitalia, but can appear anywhere on the skin (15).
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The case presented here is of particular interest because this patient failed to neatly fit into any of the aforementioned demographic clusters. After extensive research, we have concluded that statistics on the incidence of KS in non-HIV, non-Mediterranean women do not exist. This attests to the rarity of KS in this population. The literature does reveal several other studies that discuss nonconforming cases, however. One such article speaks of a 67-year-old white male patient who presented with bilateral blanching erythema and scaling of the second through fifth digits that extended to the dorsal and plantar aspects of both feet for 2 years (16). The patient was diagnosed with tinea pedis and Tolnaftate cream was applied. After years of treatment with no improvement, a punch biopsy was performed on the dorsum of the foot that revealed KS. Another such study reports a case of KS in a 38-year-old male patient of German descent (17). The patient, who had a history of alcoholism, was admitted to the hospital for treatment of septic shock associated with hepatic failure. On physical examination, the patient presented with ascites, liver and spleen enlargement, and a large subcutaneous nodule on the knee, enveloped by normal skin. The hepatic enlargement was attributed to excessive alcohol consumption initially. Proteus mirabilis was isolated from bullous ischemic skin lesions and 3 blood cultures. An enzyme-linked immunosorbent assay test for HIV came back negative. The patient went on to die within 2 days of admission. Postmortem examination of the subcutaneous nodule as well as the liver revealed extensive infiltration by KS. The author remains uncertain as to whether this was an atypical invasive form of KS or whether it was an atypical variant of the disease caused by immunosuppression. The authors of a 2005 article set out to determine the prevalence of KS in South American countries (18). They compiled 250 cases of KS through 2004, with 3 large case series in Argentina, Colombia, and Peru. Several other cases were noted in Brazil, Chile, and Venezuela. They determined that the confluent exophytic nodules seen in the cases in Peru were most similar to the endemic African presentation of the disease. They also noted that cases in Colombia and Peru were characteristically found in indigenous or mestizo (mixed European and Native American origin) populations, whereas the cases in Argentina were more commonly found in European descendants. The authors went on to describe 6 variants of HHV-8, based on differences in the K1 gene, with subtype E found predominantly in the Amerindian populations of Brazilian and Ecuadorian Amazon regions. The authors conclude that the classic KS found in South America has a distinct clinical presentation that is similar to the classic KS described in the Mediterranean, but not the same (18). They further conclude that this subtype may warrant its own classification (18). This classification can only be described, however, with a better understanding of the precise molecular epidemiology of HHV-8 in South America (18). This can be achieved through the performance of more subtyping of these classic KS cases (18). Several treatment options for KS are described in the literature. For patients who present with only a single lesion, excisional biopsy is usually the best treatment option (7), though cryotherapy has been well described in this context (19). For patients with several lesions over a limited area, radiation therapy represents a very good treatment option as demonstrated by several studies (20,21). Patients with extensive or recurrent KS can be treated with a combination of surgery, chemotherapy, and radiation (7). Included in the choices for chemotherapy are taxanes such as paclixatel and docetaxal (22,23) and liposomal anthracylines such as pegylated liposomal doxorubicin and daunorubicin (21). As stated above, the treatment we selected for our patient was an excisional biopsy of the single lesion (Fig. 6). The biopsy showed that the edges of the lesion
were clear from disease, indicating that the lesion was removed completely. In conclusion, to our knowledge and through extensive research, the case presented is one of the few cases of a pedal manifestation of KS in an HIV-negative immunocompetent Hispanic woman without known Mediterranean descent. Although there have been several studies discussing atypical cases of KS in the literature (16–18), little has been said about the demographic presented in our case, specifically, a pedal presentation (second digit) in this uncharacteristic patient population. Knowledge of atypical presentations of KS on the lower extremity is important for a physician to properly identify, biopsy, and diagnose this condition. Only its prompt recognition will allow for appropriate and timely treatment.
References 1. Jones RR, Orchard G, Zelger B, Jones EW. Immunostaining for CD31 and CD34 in Kaposi sarcoma. J Clin Pathol 48:1011–1016, 1995. 2. Kim YC, Wu Q, Chen J, Xuan Z, Jung YC, Zhang MQ, Rowley JD, Wang SM. The transcriptome of human CD34þ hematopoietic stem-progenitor cells. Proc Natl Acad Sci U S A 106:8278–8283, 2009. 3. Siegel JH, Janis R, Alper JC, Schutte H, Robbins L, Blaufox MD. Disseminated visceral Kaposi’s sarcoma. Appearance after human renal homograft operation. JAMA 207:1493–1496, 1969. 4. Dockery GL. Cutaneous Disorders of the Lower Extremity, W. B. Saunders, Philadelphia, 1997. 5. Steele NP, Sampogna D, Sessions RB. Kaposi’s sarcoma of an intraparotid lymph node leading to a diagnosis of HIV. Laryngoscope 115:861–863, 2005. 6. Kao GF, Johnson FB, Sulica VI. The nature of hyaline (eosinophilic) globules and vascular slits of Kaposi’s sarcoma. Am J Dermatopathol 12:256–267, 1990. 7. Antman K, Chang Y. Kaposi sarcoma. N Engl J Med 342:1027–1038, 2000. 8. American Cancer Society. Kaposi Sarcoma. October 5, 2010. Available at: http://www. cancer.org/acs/groups/cid/documents/webcontent/003106-pdf.pdf. Accessed February 20, 2011. 9. Cassar O, Blondot ML, Mohanna S, Jouvion G, Bravo F, Maco V, Duprez R, Huerre M, Gotuzzo E, Gessain A. Human herpesvirus 8 genotype E in patients with Kaposi sarcoma, Peru. Emerg Infect Dis 16:1459–1462, 2010. 10. Rynkiewicz R, Sanders LJ. Kaposi sarcoma. A report of two cases and literature review. J Am Podiatr Med 76:137–141, 1986. 11. Levi MJ. Classic Kaposi’s sarcoma. J Am Podiatr Med Assoc 95:586–588, 2005. 12. Rappersberger K, Tschachler E, Zonzits E, Gillitzer R, Hatzakis A, Kaloterakis A, Mann DL, Popow-Kraupp T, Biggar RJ, Berger R, Stratigos J, Wolff K, Stingl G. Endemic 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, 1990. 13. Stallone G, Schena A, Infante B, Di Paolo S, Loverre A, Maggio G, Ranieri E, Gesualdo L, Schena FP, Grandaliano G. Sirolimus for Kaposi sarcoma in renaltransplant recipients. N Engl J Med 352:1317–1323, 2005. 14. Stebbing J, Wildfire A, Portsmouth S, Powles T, Thirlwell C, Hewitt P, Nelson M, Patterson S, Mandalia S, Gotch F, Gazzard BG, Bower M. Paclitaxel for anthracycline-resistant AIDS-related Kaposi sarcoma: clinical and angiogenic correlations. Ann Oncol 14:1660–1666, 2003. 15. Moatasim J, Ul Haque A. Kaposi sarcoma involving axillary lymph nodes. Int J Pathol 2:94–99, 2004. 16. Walther RR, Zalar GL, Grossman ME. Tinea pedis masking Kaposi sarcoma. Int J Dermatol 18:751–752, 1979. 17. Freuler CB, Durlach RA, Toblli JE, Cicco J, Casas J. Kaposi sarcoma in young adults without evidence of HIV infection. Medicina (Buenos Aires) 54:145–149, 1994. 18. Mohanna S, Maco V, Bravo F, Gotuzzo E. Epidemiology and clinical characteristics of classic Kaposi sarcoma, seroprevalence, and variants of human herpesvirus 8 in South America: a critical review of an old disease. Int J Infect Dis 9:239–250, 2005. 19. Doherty DC, Doherty SD, Rosen T. Thermotherapy in dermatologic infections. J Am Acad Dermatol 62:909–927, 2010. 20. Huang KM, Hsu CH, Cheng JC, Lai MK, Jeng SC, Ting LL, Huang WT. Radiotherapy of classic Kaposi’s sarcoma in Taiwan, an area where classic Kaposi’s sarcoma is not prevalent. Anticancer Res 26:4659–4663, 2006. 21. Bower M, Collins S, Cottrill C, Cwynarski K, Montoto S, Nelson M, Nwokolo N, Powles T, Stebbing J, Wales N, Webb A; AIDS Malignancy Subcommittee. British HIV Association guidelines for HIV-associated malignancies. HIV Med 9:336–388, 2008. 22. Lee FC, Thornton K, Williams B. Low dose weekly paclitaxel is an effective first line treatment for patients with symptomatic AIDS-KS [abstract]. Proc Am Soc Clin On 22:825a, 2003. 23. Lim ST, Tupule A, Espina BM, Levine AM. Weekly docetaxel is safe and effective in the treatment of advanced-stage acquired immunodeficiency syndrome-related Kaposi sarcoma. Cancer 103:417–421, 2005.
Contents lists available at ScienceDirect
The Journal of Foot & Ankle Surgery journal homepage: www.jfas.org
Pedal Presentation of Kaposi’s Sarcoma in a Non-HIV Hispanic Female: A Case Report and Literature Review Daniel Basalely, BA 1, Khurram H. Khan, DPM 2, G. Javier Cavazos, DPM 3, Anthony V. D’Antoni, PhD 4, Bradley W. Bakotic, DPM, DO 5 1
Fourth Year Student, New York College of Podiatric Medicine, New York, NY Assistant Professor, Division of Medical Sciences, New York College of Podiatric Medicine, New York, NY Private Practice, McAllen, TX 4 Director of Anatomy, Division of Pre-clinical Sciences, New York College of Podiatric Medicine, New York, NY 5 Dermatopathologist, Bako Pathology Services, Alpharetta, GA 2 3
a r t i c l e i n f o
a b s t r a c t
Level of Clinical Evidence: 4 Keywords: biopsy cancer immunocompromise malignancy surgery toe tumor
Kaposi’s sarcoma is divided into 5 subtypes primarily differentiated by clinical presentation and typical at-risk population. We report the unique case of a 74-year-old Latin American woman who presented with a violaceous lesion on the dorsum of her right second digit, which was diagnosed as Kaposi’s sarcoma but was not easily placed into a discrete subtype. We discuss the factors that usually predispose people to this infection and the lack of those factors in our patient, as well as the subsequent treatment of our patient. The patient remained in complete remission at 4 years follow-up. Ó 2012 by the American College of Foot and Ankle Surgeons. All rights reserved.
Kaposi’s sarcoma (KS) represents about 1% of all diagnosed cancer cases worldwide. The disease is divided into 5 subtypes that are primarily defined by clinical presentation and identified in 4 different at-risk populations, commonly occurring in individuals who are immunocompromised. The disease can also be present in individuals of Eastern European or Mediterranean descent. We report a rare manifestation of the condition in a Latin American woman who did not easily fit into any of these predefined subtypes. Case Report A 74-year-old Latin American woman (of Mexican descent) presented with a violaceous lesion on the dorsum of her right second digit. The mass was present for a period of 6 to 8 months and increased in size over time. The patient denied any recent trauma including incidental trauma from shoe gear including sandals. The patient also denied any pain to the area and had self-treated with topical emollient with no improvement. Past medical history was significant for type 2 diabetes mellitus of <5 years duration, hypertension, coronary artery disease, hypercholesterolemia, hypothyroidism, and degenerative joint disease. Financial Disclosure: None reported. Conflict of Interest: None reported. Address correspondence to: Khurram H. Khan, DPM, Assistant Professor, Division of Medical Sciences, New York College of Podiatric Medicine, 53 East 124th Street, New York, NY 10035. E-mail address: [email protected] (K.H. Khan).
At the time, she was receiving anticoagulation therapy. She denied any history of surgery or cancer. She also denied tobacco or alcohol use. On physical examination, the patient’s dorsalis pedis and posterior tibial pulses were palpable bilaterally. The dermatologic examination showed diffuse hyperpigmentation of the integument with varicosities present. There were 2 slightly raised lesions on the dorsum of the second digit of the right foot. The larger lesion had an irregular border, was <1 cm in diameter (0.9 0.9 0.1 cm), had a dark purplish hue, and a hyperkeratotic area that was granulomatous in appearance but not soft (Fig. 1). Upon light debridement, there was no change of this soft tissue mass. The smaller lesion was similar but <0.5 cm in diameter. There was no dry hemorrhagic tissue noted nor was there evidence of hemorrhagic hyperkeratosis. Radiographic evaluation with dorsoplantar, lateral, and medial oblique views revealed no evidence of bone destruction to the underlying second digit or metatarsal head. Based on the clinical appearance and lack of trauma, it was determined that the lesions were suspicious. An excisional biopsy of the larger soft tissue mass was deemed necessary to rule out malignancy. The patient was taken to the operating room, and the biopsy was performed on the larger lesion via 2 semi-elliptical incisions in a 3:1 pattern down to the subcutaneous level and removed in toto. The 3:1 ellipse was used to allow for wide margins and ease of closure (Fig. 2). The smaller lesion was not removed at the time to prevent the creation of a small skin island that could ultimately lead to skin necrosis.
1067-2516/$ - see front matter Ó 2012 by the American College of Foot and Ankle Surgeons. All rights reserved. doi:10.1053/j.jfas.2012.01.012
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Fig. 1. Predebridement, right foot. The larger lesion had an irregular border, was < 1 cm in diameter, had a dark purplish hue, and had a hyperkeratotic area that was granulomatous in appearance but not soft. The smaller lesion was < 0.5 cm and had a dark purplish hue.
Fig. 3. Hematoxylin and eosin stain, 50. Typical histopathologic features of KS. A dermally based lobulated mass composed of spindled cells with a whorled or vaguely fascicular pattern of growth when viewed under low-power microscopy.
Pathology and Laboratory Reports
mammals (2). Factor VIII, like CD34, is a tissue marker characteristically found in endothelial cells. KS, a vascular tumor, is strongly positive for both of these tissue markers. Histologic and immunophenotypic analyses of this lesion revealed several unique findings and markers, which collectively allowed for unequivocal diagnosis of the disease. Histopathologic analysis of the lesion revealed a dermally based lobulated mass composed of spindled cells with a whorled or vaguely fascicular pattern of growth (3) when viewed under low-power microscopy (Fig. 3). High-power microscopic evaluation revealed a predominantly solid collection of spindled cells with scattered slitlike vascular spaces (4) (Fig. 4). Numerous extravasated erythrocytes were present within the lesion (5). Cytologically, the proliferation was composed of plump, spindled cells with abundant pink cytoplasm (5). Oval to elongated nuclei with coarse chromatin and scattered mitotic figures were evident. Within the cytoplasm of some spindled cells, collections of small pink globules were seen (6) (Fig. 5). An immunohistochemical study directed against CD 34 antigen was diffusely positive amongst tumor cells (2) (Fig. 6). This constellation of histopathologic and immunophenotypic features was diagnostic of KS. Because of the prevalence of KS in patients with HIV, and despite the patient’s denial of HIV exposure, the patient was sent for HIV screening.
There were 2 blocks, 2 slides, and 2 immunohistochemical stains (factor VIII and CD34) performed. An excisional biopsy of the lesion was obtained from the second toe of the right foot. The excision of skin measured 3.5 1 cm with an average thickness of 0.4 cm. The epidermal ulcerated nodule measured 0.9 cm in diameter. Pathologic analysis revealed KS with the edges of the lesion free of malignancy. Immunohistochemical stains are both markers characteristically found in patients with KS (1). CD34 is a cellular membrane glycoprotein characteristically found in cells exhibiting endothelial differentiation (2). It is a specific marker for the hematopoietic cells differentiated at the stem-progenitor stage in humans and other
Fig. 2. Postexcision. Biopsy was performed on the larger lesion via 2 semi-elliptical incisions in a 3:1 pattern down to the subcutaneous level and removed in toto. The 3:1 ellipse was used to allow for wide margins and ease of closure.
Fig. 4. Hematoxylin and eosin stain, 400. High-power microscopic evaluation discloses a predominantly solid collection of spindled cells with scattered slitlike vascular spaces. Numerous extravasated erythrocytes are present within the lesion.
D. Basalely et al. / The Journal of Foot & Ankle Surgery 51 (2012) 365–368
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Fig. 5. Hematoxylin and eosin stain, 1000. Cytologically, the proliferation was composed of plump, spindled cells with abundant pink cytoplasm. Oval to elongated nuclei with coarse chromatin and scattered mitotic figures were evident. Within the cytoplasm of some spindled cells, collections of small pink globules were seen.
Fig. 6. CD 34 stain, 400. An immunohistochemical study directed against CD34 antigen was diffusely positive amongst tumor cells. This constellation of histopathologic and immunophenotypic features was diagnostic of KS.
This decision was made in the interest of medical prudence and removing all doubt. A rapid HIV-1/2 antibody test was performed to rule out HIV. The test is a qualitative immunoassay designed to detect antibodies to HIV type 1 and type 2 in saliva, whole blood, and plasma specimens. In this case, the test failed to detect any antibodies to HIV type 1 or type 2. This test did not exclude acute infection, but given the lack of sexual history in the last few years, there was no need to retest. The etiology and epidemiology of KS were discussed with the patient. A thorough medical history revealed no history of organ transplants or blood transfusions. The patient also denied Mediterranean heritage. Physical examination revealed no other lesions on the patient’s body. After complete healing of the first excisional biopsy, the second lesion was removed in similar fashion without incidence. The patient was referred to a dermatologist for a full body evaluation. She remains in complete remission at 4 years follow-up.
virus do not develop KS (8). Percentages of people infected with KSHV differ on various continents throughout the world, with studies showing a <10% rate of infection in the United States (8). In some areas of Africa, >90% of the population is infected with KSHV, with spread of infection from mother to child (8). Many people infected with KSHV will never show any symptoms of KS. Those HHV-8–infected individuals at highest risk for the development of KS are those who are immunocompromised, particularly those with AIDS, and those who have received organ transplants (8). The disease has been categorized into 5 subtypes defined primarily by clinical presentation and identified in 4 at-risk populations. These 5 categories of KS follow:
Discussion KS was first described by Moritz Kaposi in 1872 as an “idiopathic multiple pigmented sarcoma of the skin” (7). Before the AIDS epidemic, KS was extremely rare in the United States, with 2 new cases discovered per 1 million people each year (8). In 2002, the number of KS cases worldwide was 65,000. This number represents nearly 1% of all diagnosed cancer cases (9). Primary lesions of KS initially emerge as macules or papules most frequently located on the extremities. The most common sites of involvement are the feet, especially the soles and the arches. The legs, hands, and forearms can also be affected. Lesions of KS can be pigmented with a variety of colors ranging from bluish-red to brown. Progression of the disease may be slow with potential periods of remission. As the disease progresses, lesions of KS may coalesce to form firm, rubbery nodules. KS may extend to the viscera, with the gastrointestinal tract most commonly affected (10). The liver, lungs, adrenal glands, lymph nodes, and heart can also be affected (10). Involvement of bone indicates widespread disease, with rarefaction, cysts, and cortical erosion demonstrated on radiographs (10). KS has since been linked to presence of KS-associated herpes virus (KSHV), also known as human herpes virus 8 (HHV-8) (8). This virus has been identified in association with all subtypes of KS, regardless of geographic location or patient demographics. KSHV infection is much more common than KS, however, and most people infected with the
1. Classic KS (elderly men of Mediterranean decent) 2. Endemic KS (African) 3. Immunosuppression-associated KS (after iatrogenic immunosuppression) 4. Epidemic KS (AIDS-associated) (7) 5. Nonepidemic gay-related KS (homosexual men without AIDS) Classic KS occurs primarily in elderly men of Eastern European or Mediterranean origin. The disease’s onset is usually in the fifth to eighth decade with a male predominance of almost 10:1 (10). The disease usually progresses slowly and typically is not fatal (11). Endemic KS is typically found in African children, adolescents, and adults. Endemic KS presents with a high frequency of extracutaneous manifestations and follows a more aggressive course than the classic type (12). Immunosuppression-associated KS predominantly occurs in recipients of organ transplants treated thereafter with immunosuppressive therapy to avoid acute organ rejection (13). The incidence of KS in recipients of solid organs is about 500 times that found in the general population, and the clinical presentation of KS in organ recipients is often limited to skin involvement (13). Epidemic KS characteristically occurs in individuals afflicted with HIV. It is the most common neoplasm found in these individuals (14). Nonepidemic gay-related KS is a fifth subtype that has been more recently reported. This subtype has been reported on several occasions in homosexual men with no evidence of HIV (15). These patients have an indolent and cutaneous form of the disease that usually appears on the extremities and genitalia, but can appear anywhere on the skin (15).
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The case presented here is of particular interest because this patient failed to neatly fit into any of the aforementioned demographic clusters. After extensive research, we have concluded that statistics on the incidence of KS in non-HIV, non-Mediterranean women do not exist. This attests to the rarity of KS in this population. The literature does reveal several other studies that discuss nonconforming cases, however. One such article speaks of a 67-year-old white male patient who presented with bilateral blanching erythema and scaling of the second through fifth digits that extended to the dorsal and plantar aspects of both feet for 2 years (16). The patient was diagnosed with tinea pedis and Tolnaftate cream was applied. After years of treatment with no improvement, a punch biopsy was performed on the dorsum of the foot that revealed KS. Another such study reports a case of KS in a 38-year-old male patient of German descent (17). The patient, who had a history of alcoholism, was admitted to the hospital for treatment of septic shock associated with hepatic failure. On physical examination, the patient presented with ascites, liver and spleen enlargement, and a large subcutaneous nodule on the knee, enveloped by normal skin. The hepatic enlargement was attributed to excessive alcohol consumption initially. Proteus mirabilis was isolated from bullous ischemic skin lesions and 3 blood cultures. An enzyme-linked immunosorbent assay test for HIV came back negative. The patient went on to die within 2 days of admission. Postmortem examination of the subcutaneous nodule as well as the liver revealed extensive infiltration by KS. The author remains uncertain as to whether this was an atypical invasive form of KS or whether it was an atypical variant of the disease caused by immunosuppression. The authors of a 2005 article set out to determine the prevalence of KS in South American countries (18). They compiled 250 cases of KS through 2004, with 3 large case series in Argentina, Colombia, and Peru. Several other cases were noted in Brazil, Chile, and Venezuela. They determined that the confluent exophytic nodules seen in the cases in Peru were most similar to the endemic African presentation of the disease. They also noted that cases in Colombia and Peru were characteristically found in indigenous or mestizo (mixed European and Native American origin) populations, whereas the cases in Argentina were more commonly found in European descendants. The authors went on to describe 6 variants of HHV-8, based on differences in the K1 gene, with subtype E found predominantly in the Amerindian populations of Brazilian and Ecuadorian Amazon regions. The authors conclude that the classic KS found in South America has a distinct clinical presentation that is similar to the classic KS described in the Mediterranean, but not the same (18). They further conclude that this subtype may warrant its own classification (18). This classification can only be described, however, with a better understanding of the precise molecular epidemiology of HHV-8 in South America (18). This can be achieved through the performance of more subtyping of these classic KS cases (18). Several treatment options for KS are described in the literature. For patients who present with only a single lesion, excisional biopsy is usually the best treatment option (7), though cryotherapy has been well described in this context (19). For patients with several lesions over a limited area, radiation therapy represents a very good treatment option as demonstrated by several studies (20,21). Patients with extensive or recurrent KS can be treated with a combination of surgery, chemotherapy, and radiation (7). Included in the choices for chemotherapy are taxanes such as paclixatel and docetaxal (22,23) and liposomal anthracylines such as pegylated liposomal doxorubicin and daunorubicin (21). As stated above, the treatment we selected for our patient was an excisional biopsy of the single lesion (Fig. 6). The biopsy showed that the edges of the lesion
were clear from disease, indicating that the lesion was removed completely. In conclusion, to our knowledge and through extensive research, the case presented is one of the few cases of a pedal manifestation of KS in an HIV-negative immunocompetent Hispanic woman without known Mediterranean descent. Although there have been several studies discussing atypical cases of KS in the literature (16–18), little has been said about the demographic presented in our case, specifically, a pedal presentation (second digit) in this uncharacteristic patient population. Knowledge of atypical presentations of KS on the lower extremity is important for a physician to properly identify, biopsy, and diagnose this condition. Only its prompt recognition will allow for appropriate and timely treatment.
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