Post-transplant kaposi's sarcoma: an unusual presentation and review of clinical presentation, histology and management

Case report

A 65-year-old white female patient was referred from gastro-enterology to the oral medicine out-patient clinic at Bristol Dental Hospital presenting with a severe, sharp pain bilaterally on the palate, associated swelling and a deep burning sensation which had been present for approximately 3 months. She reported difficulty eating and opening her mouth due to the marked pain.

The patient's relevant medical history included a liver transplant in 2011 following jaundice secondary to primary sclerosing cholangitis. On presentation, her immunosuppressant therapy consisted of prednisolone, azathioprine and tacrolimus and her liver graft function was excellent.

Clinical examination revealed no extra-oral abnormalities. Intra-oral examination revealed well-defined, slightly raised purple/red lesions bilaterally on the hard palate. These macular lesions measured approximately 3 cm in length each (Figure 1 − note healing biopsy site is present adjacent to the upper right first premolar). Radiographs, including an upper occlusal and a dental panoramic radiograph, revealed no bony lesions or erosions.

Differential diagnoses based upon clinical presentation of the lesions included oral candidiasis, ecchymoses, haemangioma or Kaposi's sarcoma (KS). Blood-based investigations were undertaken and an incisional biopsy arranged.

Blood-based investigations included virology screening for Cytomegalovirus (CMV), EBV, Herpes simplex virus, HIV, varicella zoster and HHV-8 DNA. The HIV test was negative and the HHV-8 DNA test revealed positivity >100 copies/ml, and it was felt that this would be compatible with a diagnosis of Kaposi's sarcoma. A viral swab of the lesion was also taken which proved negative for Herpes simplex, varicella zoster and CMV.

Microscopic examination revealed ortho-keratinized mucosa, with evidence of a vasoformative process in the corium comprising irregularly-shaped and sometimes slit-like vascular spaces with a proliferation of spindle cells. There was a scanty infiltrate of lymphocytes and plasma cells, together with extravasated erythrocytes and some haemosiderin in the background. The endothelial cells lining the vascular spaces were cytologically bland and immunohistochemical studies demonstrated CD31 (Figure 2) and CD34 reactivity, confirming their vascular origin. Studies for Herpes simplex virus (HSV) 1 and 2, CMV and Epstein Barr encoding region (EBER) were negative but the lesional cells demonstrated strong nuclear reactivity to Human Herpes Virus 8 (HHV–8) (Figure 3) antibody, suggesting a diagnosis of KS.

The definitive diagnosis of PT-KS was discussed and explained to the patient. Following a case conference with gastro-enterology, clinical immunology and the patient's transplant team, a treatment plan was suggested involving alteration of her immunosuppression regimen to allow for recovery of the patient's own cell-mediated immune responses, hopefully leading to regression of the lesions. As such, the patient's azathioprine was stopped, sirolimus replaced tacrolimus and, in the transition phase, an increased dose of prednisolone given. Benzydamine hydrochloride was also prescribed to give topical symptomatic relief.

The change in her immunosuppression seemed to provide some improvement to the patient's symptoms and upon review, at one month, the lesions appeared to have reduced in size.

After 3 months the patient developed a DVT in her right calf − a known but rare association with sirolimus. Her sirolimus was discontinued and tacrolimus restarted at a dose aimed to maintain levels at the lower therapeutic range. Prednisolone was reduced to a baseline 3 mg per day and graft function remained normal and continues to be so. DVT prophylaxis had been initiated by the GP with subcutaneous heparin injections daily. The patient reported that, since her last appointment, she had also been diagnosed with PT-KS affecting her right leg, abdomen and left neck, however, the treatment plan was not modified following discussion with the patient.

She was reviewed 3 months later. Clinically, the lesions on her palate seemed to have reduced in size, although not fully resolved (Figure 4), and she remained asymptomatic. The cutaneous lesions had fully resolved.

Update on PT-KS

Post-transplant malignancies secondary to immunosuppression are not uncommon, with figures ranging from 3−16%.4 These have significant implications as post-transplant malignancies are the second leading cause of mortality following organ transplantation.2 The types of post-transplant malignancies vary, depending on the population studied.4 The greatest incidence of post-transplant tumours seem to be those associated with viruses, such as in KS.2 It is somewhat difficult to ascertain mortality associated with post-transplant malignancies, as there is a lack of long-term follow-up studies for this area. One study reports figures for mortality associated with cancer post-transplant to be 2%, 5% and 15% at 5, 10 and 15 years after transplant, respectively.2 It is thought that the immunosuppressive state rather than the agents used is of most importance when considering the risk of developing PT-KS.2

In Northern Europe, North America and Asia, the prevalence of HHV-8 infection is thought to be around 5%, compared with central and east Africa, where HHV-8 positivity is as high as 50% within the general population. This makes KS still an unusual presentation in Western populations.4 In many cases, PT-KS is thought to arise from re-activation of HHV-8, so it is important to consider the viral status of the recipient prior to transplantation.1

Post-transplant, drug-induced immunosuppression can lead to rapid, uncontrolled viral replication of HHV-8 in the organ recipient. The basis of developing a PT-KS in a transplant patient who was HHV-8 negative is that HHV-8 infected cells and KS progenitor cells can be seeded following transplantation, resulting in PT-KS, often at sites distant to the organ transplant.1 The process of oncogenesis in relation to HHV-8 is not fully understood. It has been suggested that HHV-8's pro-inflammatory proteins may inhibit apoptosis, promoting cellular transformation.5 Up-regulation of vascular growth factors in endothelial cells is also thought to play a role.3

The peak incidence of developing a PT-KS is 0−2 years post-transplant. Following this, the incidence falls significantly (possibly due to a reduction in the level of immunosuppression).1

When the mortality rate of different post-transplant neoplasms is compared, PT-KS has one of the highest mortality rates. Interestingly though, patients with non-iatrogenic KS have a higher rate of mortality than PT-KS patients.2

Clinical presentation of KS

Mucocutaneous lesions are the most common presentation of KS, typically affecting the limbs and trunk. In these cases, oedema can precede the appearance of lesions.6 Owing to the Koebner phenomenon, KS can often occur at scar sites, such as those from the transplant operation.1 Visceral KS typically affects the lymph nodes, gastro-intestinal tract and lungs.1 Kaposi's sarcoma localized to cutaneous lesions typically has a better prognosis than visceral lesions.7

When KS affects the oral cavity, the hard and soft palate and tongue are the most frequently affected sites and they are typically asymptomatic. Should the KS become exophytic, it may be associated with pain, bleeding, suppuration, ulceration, tooth mobility, interference with mastication and poorly fitting prostheses. It has not been previously reported that macular PT-KS can present with pain. In rare cases, KS of the oral cavity can lead to erosion of underlying alveolar bone.8 On clinical presentation, oral KS must be differentiated from other entities that may have similar appearances, such as pyogenic granuloma, peripheral giant cell granuloma, melanoma, naevi, trauma, candidiasis, lymphangioma or haemangioma.8 Rarely, it may also mimic gingival hyperplasia associated with cyclosporine.9 Clinically, the appearance of KS can differ significantly, with colours varying from brown to purple due to the extravastation of erythrocytes and the deposition of haemosiderin. The lesion may be papular, macular, exophytic or nodular,8 which can make clinical diagnosis even more difficult.

An incisional biopsy should be undertaken to obtain a histopathological diagnosis to help confirm any clinical suspicion that a lesion is indeed PT-KS.

Histology of KS

Kaposi's sarcoma usually evolves through three different stages, which gradually change the appearance of the lesion as it develops:

Staining for CD31 (Figure 2) shows strong positivity, highlighting the endothelial-lined channels classically seen within Kaposi's sarcoma. HHV–8 positivity (Figure 3), along with the histological appearance, confirms the vascular lesion to be Kaposi's sarcoma.

Treatment for KS

Treatment for Kaposi's sarcoma should be initiated with a reduction in immunosuppression, and altering immunosuppressant regimens to include sirolimus or another mTOR (mammalian target for rapamycin) inhibitor. Single lesions could be surgically resected if an alteration in the patient's immunosuppressant regimen provides no resolution. Unfortunately, metastases tend to respond poorly to standard therapy and clinical trials would be the most reasonable option for these patients.11

Chemotherapy can be considered in some cases, usually in the form of vincristine, vinblastine or belomycine, but there are few studies to support this and mixed results have been found.12,13 For multiple, actively progressing lesions, paclitaxel or liposomal doxorubicin could be considered.11 Radiotherapy is generally avoided owing to local side-effects, such as severe mucositis, oedema, ulceration and the risks coupled with radiation-associated osteonecrosis of the jaw.10,11,13

Sirolimus has shown significant anti-neoplastic properties in vitro.14 This activity is thought to arise from its inhibition of P70S6 kinase in endothelial cells. P70S6 is involved within the signalling pathways associated with angiogenesis.15

Overall, sirolimus is considered to be beneficial in reducing the incidence of PTKS.14,15 However, some emerging studies are showing it may not be completely effective in avoiding the development of PT-KS.16,17 If the switch to an mTOR is not rapid and complete, temporary or partial remission may occur.18

Sirolimus has a known association with thrombosis. The increased risk of thrombosis is thought to be due to reactive oxygen species production, leading to the dysfunction of endothelial cells.19

It has been suggested that mycophenolate mofetil, used in place of calcineurin inhibitors, may also help with regression of PT-KS, however, it is difficult to assess whether anecdotal improvement of lesions is secondary to a reduction in the immunosuppression or active antineoplastic qualities.18

More research into alternative immunsupressive agents would be beneficial to provide alternative treatment options.

Conclusion

This case is a more unusual presentation of PT-KS, as the macular lesions on the palate were associated with significant pain. The authors believe this to be the only reported case of oral ‘plaque stage’ Kaposi's sarcoma presenting with pain. Macular PT-KS has traditionally been described as painless, but as this case highlights, the presentation or absence of symptoms should not be a determinate in establishing a diagnosis of PT-KS.

PT-KS is a rare entity intra-orally but has significant implications in terms of patient management. As such, it is imperative to consider it as a differential in susceptible patients.

It is unfortunate that the patient has experienced complications from the immunosuppression and transplant. Although sirolimus has been proved to be largely beneficial in treating Kaposi's sarcoma while maintaining a level of immunosuppression, it does increase the possibility of thrombosis and, as such, is not suitable for all patients.

In this case, it is difficult to say whether the patient developed HHV–8 infection from the transplant or whether the lesions arose due to re-activation of the virus. The management of the patient's immunosuppression seems to have improved her symptoms, as she is now in significantly less pain. The lesions have reduced in size and overall the clinical picture is more favourable.

No conflicts of interest are reported and no funding was used in the production of this article.