Kaposi sarcoma (KS) is a vascular lesion of low-grade malignant potential that is associated with Human Herpesvirus-8 (HHV8) infection. KS is a multifocal tumor that manifests most frequently in mucocutaneous sites, typically the skin of the lower extremities, face, trunk, genitalia and oropharyngeal mucosa (Table 1). KS also commonly involves lymph nodes and visceral organs, most notably the respiratory and gastrointestinal tracts. Peculiar presentations of KS reported in relation to the gastrointestinal tract involvement include primary KS of the appendix 1, isolated rectal KS 2, and KS with mesenteric localization 3. Scores of authors have reported on the occurrence of KS in numerous unusual sites (i.e. anatomic locations other than the aforementioned sites). This review discusses the manifestation of KS in several of these unusual regions of the human body, and highlights what can be learned from these perceptive published observations.

KS involvement of the musculoskeletal system is a rare occurrence 4. Nevertheless, around 70 such cases have been reported. Dr. Moriz Kaposi was the first to document KS involvement of the skeletal system. He described ulcerating KS lesions on the extremities of his patients that penetrated into underlying bone 5. Limited early literature, pre-dating the AIDS epidemic, reported that skeletal involvement was a frequent (~20%) finding in African (endemic) KS 678. The largest review to date on KS involvement of the musculoskeletal system included 66 previously published cases reported from 1925 to 2006 9. Only three cases in this review included KS within skeletal muscle, all AIDS-related KS, that had infiltrated the gastrocnemius muscle 10, intercostal muscles with associated rib destruction 11, and the masseter muscle in association with oral KS 12. Within the musculoskeletal system, osseous KS lesions are more frequently encountered than KS in skeletal muscle. Involvement of bone marrow, without causing an osseous lesion, is far more common in AIDS-related KS 13141516. In a series of 45 HIV-positive patients manifesting with musculoskeletal abnormalities, researchers found that only two individuals had KS of the bone 17. Most of the patients in this series had infections and several had bone lymphomas.

The musculoskeletal system has been shown to be involved by all KS epidemiological forms, including AIDS-related, Classic, African (endemic), and infrequently transplanted-associated KS 918192021. Reports of African KS bone lesions originated mainly from central Africa (e.g. Uganda), but also from Northern African countries (e.g. Algeria, Morocco) and from South Africa. Despite an extensive literature search, we were able to identify only a single case of transplanted-associated KS involving bone. This particular 40 year-old female transplant recipient, who was being treated with cyclosporine, died 8.3 months after her kidney transplant of disseminated KS, diagnosed only by post-mortem examination 22.

African and Classic KS lesions tend to involve the peripheral skeleton, whereas AIDS-related KS more commonly involves the axial skeleton (vertebrae, ribs, sternum, and pelvis) and/or maxillofacial bones 923242526272829303132. KS of the skull has been noted in the parietal and temporal bones, paranasal sinus, maxilla, hard palate and mandible. Other bones reported to be involved by KS include the vertebrae (T11 to L4), ribs, sternum, pelvis, long bones of the extremities (humerus, radius, ulna, femur, tibia, fibula), as well as those of the hands (metacarpals) and feet (talus, calcaneus, and the 3^rd, 4^th and 5^th metatarsals). Asymmetric bone involvement by KS appears to be the rule. Joint involvement is unusual, but has been reported 33.

Osseous KS lesions are more likely to be associated with long-standing and locally aggressive cutaneous African and Classic KS lesions, or with AIDS-associated mucosal KS lesions that penetrate underlying bone 9. Patients with osseous KS may complain of bone pain with limited mobility. Serious sequelae have occurred, such as acute spinal cord compression 3435. KS of the jaw bones can cause pain, headache, increased tooth mobility, paresthesia, or can present with an intraoral tumor mass. Infrequently, osseous KS lesions may be asymptomatic and remain undetected, or may be discovered only incidentally or at autopsy. Pathological fractures in afflicted patients do not seem to be a problem. KS involvement of bone without KS disease elsewhere is exceptional 9. Patients with osseous KS usually have concomitant non-osseous KS lesions, particularly those with AIDS. Very few cases, all AIDS patients, have had primary intraosseous KS 253637. Most of the cases reported in the literature to date were due to KS arising in overlying skin or mucosa, in which KS eroded into underlying bone 49. Those with AIDS-associated osseous KS often present with a CD4+ T-cell count of <100 cells/mm³9. AIDS-related KS that involves bone usually portends an unfavorable prognosis 938.

Most osseous KS lesions are osteolytic, with cortical and at times almost complete bone destruction (osteolysis). KS of the bone does not present well on plain radiographs, despite their frequent osteolytic nature 383940. CT scan and MRI appear to be superior for the detection of KS bone lesions 911. Biopsy of a suspected KS lesion is essential, because other conditions such as bacillary angiomatosis can present with similar clinical and radiological findings 41. Radiation therapy has provided patients with prompt relief of bone pain 132131. Treatment of osseous KS whether by surgery, chemotherapy and/or radiation seems to have limited success 19. Nevertheless, individual case reports describing improvement of patients following radiation and/or systemic chemotherapy have been published 263642. Patient's response to therapy requires monitoring radiological changes in addition to routine clinical observation. With intraosseous KS involvement, successful management generally requires a multidisciplinary approach 43.

Head and neck involvement of KS is not unusual. However, laryngeal involvement is somewhat of an infrequent manifestation. There have been approximately 25 accounts of KS of the larynx 626364656667686970717273. Most patients have had AIDS-related KS, although HIV-negative persons with laryngeal KS have also been noted 7274. Of the AIDS cases reported, the majority (91%) were males of mean age 35 years (range 24–56 years), with advanced HIV disease, that were antiretroviral naïve 73. This may explain why many afflicted persons also had oropharyngeal, as well as cutaneous and visceral KS.

Presenting symptoms may include hoarseness, throat discomfort, urge to cough, aphonia, dysphagia, stridor or complete airway obstruction. Examination may reveal laryngeal edema or more likely a purple vascular mass lesion. The lesion's surface can appear verrucous in nature, due to deposits of dry secretion 62. The diagnosis can be established by laryngoscopy or radiologic studies. A CT scan of the larynx may help delineate laryngeal mass lesions. While a diagnostic biopsy in several patients was performed without complications, biopsy of such vascular laryngeal lesions has been associated with brisk and potentially fatal bleeding 65.

Therapeutic options for this scenario include low-dose local irradiation, intralesional chemotherapy or laser ablation, and systemic therapy, particularly if there is disseminated KS. For laryngeal KS lesions producing acute or impending airway obstruction urgent intervention is necessary. However, depending on the location of the KS lesion, tracheostomy may contribute to mortality as a result of fatal hemorrhage 66. Therefore, cricothyrotomy has been recommended by some authors as an alternative approach to life-threatening emergencies in this setting.

Periorbital edema may occur with KS of the face 7576. External ocular KS lesions are also not uncommon. KS of the conjunctiva and ocular adnexa has been reported in association with Classic and AIDS-related KS 7778798081828384858687. Isolated bulbar conjunctival and eyelid KS has been noted 8889. In a study of 6,552 AIDS patients from Buenos Aires in Argentina, ocular KS was diagnosed in 17 (0.25%) individuals 90. Lesions in this study predominated in eyelids, most with the inferior eyelid affected. A similar study from Zaire in Africa (1962 – 1991) reported on 11 patients with ocular adnexal KS, representing an incidence of 1.25 for 10,000 cases 91. In this study, 9 of the patients had AIDS. It has been previously pointed out that ocular KS may be the first manifestation of HIV infection 85.

External ocular KS may manifest as a mass lesion or simply as a subconjunctival hemorrhage. Interestingly, increased sludging of conjunctival blood-flow has been shown in patients with KS 92. Epiphora (overflow of tears) due to KS of the nasolacrimal duct has been seen 93. Far less common, KS may involve the internal structures of the eye. In one case with widely disseminated KS, tumor involving the choroid of both eyes was identified at autopsy 46. A case of widely disseminated AIDS-associated KS localized in the patient's orbit has been previously described 94. Despite intensive chemotherapy, progression in this patient was aggressive with a fatal outcome. While regression of conjunctival KS has been documented in some cases 95, so to has recurrence following surgical treatment and cryotherapy of ocular adnexal KS in AIDS patients 80.

KS can involve the parenchyma and/or intraparenchymal lymph nodes of the major salivary glands 96. Both the submandibular and parotid glands have been involved. The parotid is the only salivary gland with substantial lymphoid tissue. This explains why most case reports of KS were of intraparotid lymph nodes, particularly in the setting of AIDS 979899. Excluding intraparotid lymph node involvement, around 10 cases have been reported in which KS was identified infiltrating the acinar tissue of major salivary glands 100101102103. Patients with KS of their salivary glands have been reported to present clinically for evaluation primarily because of a 1 cm to 4 cm mass or swelling of the major salivary gland that was present from 1 to 70 months 103. Findings of HHV8 DNA in saliva prompted investigators to study the presence of this virus in several salivary gland neoplasms 104. They found that HHV8 does not appear to infect the salivary gland in HIV-seronegative patients, nor does it not seem to play a pathogenic role in non-KS vascular and epithelial salivary gland neoplasms.

Cardiac involvement has been reported in the various epidemiologic forms of KS. The results of autopsy studies conducted from 1959–1986 identified KS of the heart in 18% of African (endemic), 17% in AIDS-related (epidemic), and 15% of Classic (sporadic) KS 8. Cardiac dysfunction directly due to KS involvement has not been noted 8. In Classic KS, heart involvement has been reported to occur more likely in patients without cutaneous disease 107113. Surprisingly, primary cardiac KS has been found in a Haitian woman with AIDS 114. The epicardium (subepicardial adipose tissue) appears to be more commonly involved than the myocardium or endocardium 8115116117.

Chylothorax is a known, but rare manifestation of KS involving the thoracic duct and adjacent mediastinal structures 118119120121122123. KS related chylothoraces frequently develop with concomitant upper airway KS disease 122. Interestingly, a case of chylous ascites caused by KS has been previously documented 124. Although KS-related chylothorax formation was initially postulated to develop due to metastatic KS to the thoracic duct 118, more recent findings suggest that this may arise due to development of in-situ KS in this region 123.

Genital KS lesions are common. Infrequently, urethral meatal lesions may cause outlet obstruction and urinary retention 125126. However, KS of the urinary system has only been rarely reported, despite the fact that HHV8 is shed in urine from infected patients 127. There have been three accounts of KS of the urinary bladder 128129130. Interestingly, all three patients were renal transplant recipients. In one patient KS involved a transplanted kidney, ureter and urinary bladder 129.

Since HHV8 can be detected in breast milk 131, it is not unexpected that KS may arise within mammary tissue. KS development on lymphedematous arms following radical mastectomy has been reported in two patients 132133. KS within the breast may involve breast parenchyma or intramammary lymph nodes 134. There have been three cases reported of mammary KS 135136137. Breast involvement has been reported without evidence of KS disease elsewhere, and also in the setting of disseminated cutaneous KS. KS can present as a small deep palpable mass or as a cutaneous lesion. KS axillary lymphatic involvement in one HIV infected patient produced lymphatic obstruction, causing a peau d'orange appearance of the breast 136.

Localization of KS to sites of previous iatrogenic trauma has been documented 138139, several with underlying immunosuppression 140. One publication describes oral KS arising after minor surgery in a transplant patient 141. KS in this particular case developed soon (within 6 days) after the patient's trauma. A similar case of KS occurring de novo in the surgical scar of a heart transplant recipient has been published 142. A case of primary intraosseous KS developed in the tibia of an HIV-negative 20-year-old man at the exact same site of a prior traumatic bone injury and operative scar 20. Another osseous lesion in the mandible of a 52-year-old man with AIDS arose in the area of previously extracted teeth 23. Moreover, there have been cases noted of KS arising in tissue grafts 143144. Around 10 cases of KS associated with pemphigus lesions have been described, mainly with pemphigus vulgaris and less commonly foliaceus and erythematosus variants 145146. KS occurring in a dermatome previously involved by herpes zoster has been shown 147, as well as primary KS due to prior radiation 148.

A case of transplant-related KS restricted to the site of a previous deep venous thrombosis has been documented 149. This 72-year-old male patient with a renal transplant had received immunosuppressant drugs including sirolimus, mycophenolate mofetil, tacrolimus and steroids. His KS developed 11 months after transplantation, in relation to deep venous thrombosis and withdrawal of sirolimus due to toxicity. Progressive withdrawal of prednisone was accompanied by full remission of this patient's KS.

It is clear from the aforementioned review that KS has been reported in virtually all anatomic sites. KS involvement of other unusual sites not discussed in this chapter include the gonads (e.g. testis) 150, endometrium 46, and external auditory meatus 151. The rarity of KS reports in uncommon regions may be due be to underreporting, asymptomatic lesions, declining number of current autopsies being performed, and/or under recognition of signs by health care providers. Many of these patients were reported to have AIDS in the pre-HAART era (<1996), with widely disseminated disease. While KS has been documented in infants as young as 6-days-old 152, KS of the placenta does not appear to have yet been reported.

As a result of HIV, a significant increase in anatomically disseminated KS cases was evident. The anatomical distribution of KS lesions also changed during the AIDS period. Soon after the onset of the AIDS epidemic, head and neck AIDS-related KS became one of the most common manifestations of AIDS 153. In a study involving Tanzanian children, investigators noted that in approximately 12% of children KS appeared in anatomical sites that were usually not involved in cases of the pre-AIDS period, viz. the eyelid, ear, lip, face and genitalia 154. Furthermore, researchers also reported a significant increase in upper limb cases and a decrease in lower limb and lymph node involvement 154. The manifestations of KS have also changed considerably with the advent of HAART. As a result of HAART, a smaller proportion of KS patients appear to present with visceral disease 155. In particular, gastrointestinal tract and pulmonary involvement are less frequent among KS-HAART patients 155. The frequency of mucosal and lymph node involvement do not appear to be appreciably altered by HAART 155.

The occurrence of KS in any of these atypical sites may prove difficult to diagnose, particularly if patients are asymptomatic, lesions go unrecognized on routine imaging studies (e.g. osseous KS on plain x-ray films), and/or clinician's are unwary of their existence 156. Awareness that KS can occur in any of these unusual locations may avoid potential misdiagnosis with serious consequences (e.g. spinal cord compression) and/or mismanagement (e.g. biopsy of laryngeal KS with subsequent life-threatening hemorrhage). Also, the possibility of occult HIV infection should be entertained in a young person with an unusual clinical presentation (e.g. subconjunctival hemorrhage), as KS may mimic common lesions and represent the initial presenting sign of AIDS.

In several cases, there was limited available clinical data. Pathologic verification of a diagnosis of KS by means of biopsy and/or autopsy was not available in some cases. In their review of 66 cases of reported osseous KS, the authors noted that histological proof of actual bone involvement by KS was only obtained in 53% of cases 9. Very rarely was HHV8 demonstrated within any of these lesions. Therefore, it is plausible that some published cases may not truly represent KS. KS involvement of infrequent sites may not be considered in the differential diagnoses. In HIV infected persons, for example, brain lesions and salivary gland enlargement are frequently identified and more likely to be attributed to other non-KS causes. Hence, in the setting of HIV/AIDS, it is important to always consider KS in the differential diagnosis.

It is interesting to hypothesize why KS is rarely encountered in the aforementioned anatomic locations. Moreover, why KS involvement of sites like the bladder and breast are uncommon when HHV8 is shed in urine and breast milk, respectively, from infected patients is intriguing. A urinary protein called ANUP (antineoplastic urinary protein) has certainly been shown to inhibit KS growth in a murine model 157. Conversely, investigators have shown that nerve growth factor, possibly related to HHV8 infection, may be involved in KS progression 158. Moreover, KS cells secrete a neurotrophic growth factor 159. One would expect these findings to support more frequent KS involvement of neural tissue.

It is also unclear if isolated KS lesions in some of these sites represent primary or disseminated disease. Some authors have considered the occurrence of KS in unusual locations to represent metastatic disease 54160. Alternatively, KS may arise in numerous sites via multicentric development. It is widely believed that since the eyes and brain are relatively devoid of lymphatic endothelium, these organs are unlikely to be sources of primary KS if KS tumor cells are indeed derived from lymphatic endothelium 160161162. Direct histological evidence of the development of early (in-situ) KS from lymphatic vessels in the setting of chronic lymphedema has been shown 123.

KS lesions develop as a result of the following combination of factors: HHV8, altered immunity (immunosuppression), and an inflammatory/angiogenic milieu. This may explain why, in the appropriate clinical setting, KS develops in traumatized tissue or pemphigus lesions 145. Some authors believe that post-traumatic KS lesions represent the Koebner phenomenon (the appearance of a skin lesion as a result of trauma) 141147. The Koebner phenomenon has been reported by several authors to develop in Classic, AIDS-related and transplant-associated KS 163164. Although still controversial, pemphigus has been associated with HHV8 165. Trauma may precipitate inflammatory changes that recruit HHV8 to the injured site. Finally, specific inflammatory cytokines like interleukin-6, shown to be increased in both serum and blister fluid of pemphigus patients 166, are essential for KS tumorigenesis.

The authors declare that they have no competing interests.

LP and BJD contributed equally to all aspects of this paper.