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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2021  |  Volume : 32  |  Issue : 2  |  Page : 548-553
Successful chemotherapy with liposomal doxorubicin for metastatic Kaposi’s sarcoma without skin involvement in the kidney transplant recipient

1 Department of Internal Medicine and Oncological Chemotherapy, Medical University of Silesia, Katowice, Poland
2 Department of Nephrology, Transplantology and Internal Medicine, Medical University of Silesia, Katowice, Poland
3 Department of Pathomorphology, Medical University of Silesia, Katowice, Poland

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Date of Web Publication11-Jan-2022


Kaposi’s sarcoma (KS), one of the most typical malignancies after kidney transplantation, is strongly associated with human herpes virus 8 infection. More than 90% of patients had primary skin changes, which make the diagnosis easier and faster. The lack of skin lesions is considered rare, especially in the iatrogenic type of sarcoma, including patients on immunosuppression and may cause a diagnostic challenge due to the variety of organ involvement, imitating other diseases. The aim of this case presentation is to raise attention to the atypical clinical manifestation of this malignancy. Currently, several different therapeutic options are available for patients with KS, including reduction of immunosuppression, conversion of immunosuppression to mTOR inhibitors, or chemotherapy. Here, we present an unusual case of advanced KS human immunodeficiency virus-negative patient after kidney transplantation without primary skin involvement.

How to cite this article:
Kozak S, Gładyś A, Karkoszka H, Pająk J, Wdowiak K, Chudek J. Successful chemotherapy with liposomal doxorubicin for metastatic Kaposi’s sarcoma without skin involvement in the kidney transplant recipient. Saudi J Kidney Dis Transpl 2021;32:548-53

How to cite this URL:
Kozak S, Gładyś A, Karkoszka H, Pająk J, Wdowiak K, Chudek J. Successful chemotherapy with liposomal doxorubicin for metastatic Kaposi’s sarcoma without skin involvement in the kidney transplant recipient. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 Jan 22];32:548-53. Available from: https://www.sjkdt.org/text.asp?2021/32/2/548/335469

   Introduction Top

Kaposi’s sarcoma (KS), one of the most typical malignancies after kidney transplantation, is strongly associated with human herpes virus 8 (HHV-8) infection.[1],[2] Performing serum antibody screening against HHV, two-thirds (8 of 12) of the patients with KS were seropositive.[3]

The prevalence of KS depends on the geographical location and varies from 0.5% in Western countries (USA) to 5.3% in Saudi Arabia.[4],[5]

Usually, KS develops five to 21 months after kidney transplantation.[6] Men, non-white, older age, HHV-8 virus infection, and intensive immunosuppression regimen, including lung transplant recipients and the first year post-procedure are established risk factors for KS occurrence in transplant recipients.[1]

Chemotherapy is considered as the most effective therapy for KS in transplanted patients when the use of immunosuppression reduction does not lead to tumor regression.[7] In addition, the use of mTOR inhibitors in the immuno-suppression schedule may contribute to complete remission (CR) achievement.[2] An example of the effective conversion from calcineurin inhibitors to sirolimus was described by Najafi et al.[8]

Although there is no screening, an early detection, based on skin lesions, can lead to a better outcome.[7] We report a case of advanced disease without skin lesion, which was successfully treated with chemotherapy.

   Case Report Top

A 33-year-old woman, two years after kidney transplant, was admitted to the nephrology ward for the checkup, before planned arteri-venous fistula closure presenting progressive dyspnea and exacerbation of fatigue for 10 months. The medical history included a two-year period of dialysis for the treatment of end-stage kidney disease in the course of focal segmental glomerulosclerosis (the patient was on immunosuppression regimen since the age of 17 years), hypertension, bacterial meningitis, hysterectomy, cholecystectomy, and left ovary resection.

Physical examination on admission revealed enlarged cervical lymph nodes, and noncharacteristic oval shadows were visualized in chest X-ray in November 2010. There were no suspected skin lesions. A cervical lymph node biopsy revealed KS cells, CD34(+), CD31(+), vimentin(+), fascin(+), WT1(+), podoplanin(+), S-100(-), SMA(-), and CD68(-) [Figure 1]. The CD23 and CD21 staining were positive in the dendritic cells of preserved lymphoid follicles of the lymph node. The kidney transplantation allograft function was stable with estimated glomerular filtration rates (eGFR) between 74 and 79 mL/min/1.73 m2. Immuno-suppressive regimen consisted of tacrolimus, mycophenolate mofetil, and prednisone. During the first posttransplant year, frequent infections of the upper respiratory and the urinary tracts with concomitant transient subnephrotic proteinuria were observed. Hypertension was well controlled using β-blocker and angiotensin-converting enzyme inhibitor. When the diagnosis of KS was established, immunosuppressive regimen was modified: tacrolimus and mycophenolate mofetil were discontinued, and everolimus was introduced. Despite of the modified immunosuppression schedule there was no regression of lymph node lesions.
Figure 1: Kaposi sarcoma cells with mitoses. Extravasated erythrocytes between sarcoma cells in hematoxylin and eosin stain (×400). (a) Positive stain of KS cells for D2-40 podoplanin (×200), (b) CD31 (magnification ×200), (c), and D) CD34 (×200).

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The patient was referred to an oncology ward (April 2011) with an overall good clinical condition (ECOG 0). The assessment of disease status revealed the Stage IV of KS. Small cervical lymph nodes were palpable on the left side. An ultrasound examination revealed enlarged peri-aortic lymph nodes (36 × 25 × 24 mm). Computerized tomography (CT) of the chest showed at least 10 regular and irregular nodules in both lungs (the largest was 15 × 15 × 20 mm), and enlarged paratracheal lymph nodes — corresponding with stage IV of the disease [Figure 2]a. There was no infiltration in bone marrow trephine biopsy.
Figure 2: Contrast enhanced computed tomography of patients chest with axial reconstruction with average maximum intensity projection performed before initiation of chemotherapy (a) showing multiple metastatic lesions in the lungs (blue arrows), and after the treatment completion (b) showing scars in the location of metastatic nodules.

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The patient had elevated serum LDH activity and CRP levels.

Chemotherapy (liposomal doxorubicin — Caelyx in a dose of 25 mg/m2 of the body surface in 14-day intervals) was started. During the third cycle, proteinuria and micro-hematuria were found. The consulting nephrologist suggested to maintain the immunosuppression regime, weighting benefits (anti-oncogenic/anti-VEGF effect) against losses (potential pro-proteinuric effect) of everolimus. Brown discolorations appeared on the skin of palms, feet, armpits groins, in striae, and scars. Since the 4thcycle, the patient’s performance was classified as ECOG 1. A brown papular rash appeared on the skin of the lower arm and lateral parts of the back, without pruritus. Skin changes observed during chemotherapy were an adverse reaction to doxorubicin.[9]

Before the 5th Caelyx administration, the chest X-ray examination revealed partial regression of lung metastases. The next (5–9) cycles were administered in 21-day intervals, without dose increase, due to significant weakness reported by the patient, without any abnormalities found during examination and in laboratory tests. During the 5th cycle, the skin changes exacerbated, and pus discharge appeared from the skin between the breasts. The therapy was well-tolerated overall, complicated by sore throat, which was treated with antibiotics prescribed by the general practitioner; constipation; bone pains; and headaches.

At the last chemotherapy (September 2011), the skin changes were healed, but the discolorations remained. There was no lymphadenopathy in clinical examination and no abnormalities in the chest X-ray. The control chest computed tomography (CT) revealed a single nodule in the right lung (13 mm), and there were no lymph nodes enlargement [Figure 2]b. Complete remission was confirmed by a positron emission tomography-CT (PET-CT) scan.

During the third posttransplant year, the patient had two episodes of full-blown nephrotic syndrome and persistent microscopic hematuria. Kidney allograft function has remained stable (eGFR 72–76 mL/min/1.73 m2) the whole time. The kidney allograft biopsy performed was uninformative. Immunosuppressive regimen was modified empirically: everolimus was discontinued, and cyclosporine A was introduced. After four months of the treatment with cyclosporine A, complete remission of nephrotic syndrome was achieved. Since that time, the patient remains incomplete remission. Kidney allograft function is stable.

   Discussion Top

KS with the absence of skin lesions is considered rare,[5],[10] especially in the iatrogenic type of the disease.[11] In 17 (37%) of 47 human immunodeficiency virus (HIV)-positive patients with KS, postmortem examinations showed the presence of organ lesions without skin or mucosal changes.[12] The most common infiltration affected the gastrointestinal tract, lungs, and lymph nodes. Our patient was presented with advanced stage of KS, with an initial involvement of the lymph nodes and pulmonary metastases, but without skin lesions. In a prospective study of kidney transplant recipients, more than 90% of the patients who developed KS had primary skin changes.[10],[13] The lack of skin lesions in KS may be a cause for diagnostic challenge because of the variety of organ manifestations similar to other diseases.[14] There are only a few described cases of KS with organ involvement without primary skin lesions,[15] mainly in mucosal localizations,[10] especially in oral mucosa[5],[10] and gastrointestinal tract.[5] It is worth to note that primary pulmonary localization of the postrenal transplant KS has been reported.[16] KS dissemination to the organs other than lymph nodes is an independent factor of worse prognosis.[17]

The long-term use of immunosuppressive agents for the prevention of acute allograft rejection is associated with the increased risk of a wide variety of malignancies, which is approximately two times higher compared to the general population,[18] with KS being a relatively common type of malignancy. Several approaches have been adapted in the past to treat patients with this condition.[19] In most of the cases, in the early stage, reduction of immunosuppressive therapy was followed by a resolution of KS. Nevertheless, any decision to modify the immunosuppression regimen to lessen the burden of cutaneous malignancy should be weighed against the risk of acute graft rejection.[19] A retrospective study described by Delyon et al have shown that the reduction of immunosuppression allows to achieve complete remission in about 50% of patients with KS. Switching to an mTOR inhibitor was associated with an 80% response rate.[20] However, it should be remember that in the case of the advanced stage of KS, the conversion may be ineffective.[21] In the presented case, the modification of immunosuppression regimen (elimination of calcineurin inhibitor tacrolimus) was followed by glome-rular injury, possibly chronic glomerulonephritis, which is clinically manifested by nephrotic syndrome after completion of chemotherapy. Hopefully, this adverse event was reversible after re-introduction of calcium inhibitor (cyclosporine A).

In patients who do not respond to the above-described management, chemotherapy remains the treatment of choice. According to the National Comprehensive Cancer Network guidelines, the first line of chemotherapy for patients with KS is liposomal doxorubicin or paclitaxel, especially in the case of advanced and disseminated disease.[22] Most of the data come from studies conducted in non-transplanted patients with KS associated with HIV infection.[23],[24] Reports showing the effectiveness of chemotherapy in patients with post-transplant KS are based on small cohorts.[24]A randomized trial comparing the efficacy of paclitaxel and pegylated liposomal doxorubicin showed similar efficacy in HIV-positive KS patients in the objective response rate (ORR; 56% vs. 46%; P = 0.49) and progression-free survival (PFS; 17.5 vs. 12.2 months; P = 0.66). Importantly, paclitaxel was characterized by greater toxicity (grade ≥3; 84% vs. 66%).[25] Valuable options for relapsed and refractory KS are vinblastine,[26] gemcitabine,[27] etoposide,[28] and pomalidomide.[29]

The diagnosis of KS in biopsy requires differentiation from other sarcoma derived from spindle cells, muscle cells, myofibroblasts, peripheral nerve sheath cells as well as histiocytic and dendritic lymph node cells. Numerous of immunostains have high sensitivity but low specificity, including D2-40 (podoplanin), CD31, CD34.[30] This shows the importance of wide panel of immunohistochemistry markers (S-100, SMA, CD68, CD23 and CD21) application for the exclusion of the above-mentioned neoplasms.

In the case presented, due to the advancement of the disease, modification of immunosuppression regiment was insufficient, and the patient started chemotherapy. After nine cycles of liposomal doxorubicin, complete remission was achieved, which was confirmed by PET-CT imaging. After nine years of follow-up, the patient is still in complete remission with preserved graft function.

In conclusion, the presented case demonstrates the effectiveness of chemotherapy with liposomal doxorubicin in a kidney transplant patient with disseminated KS, which had delayed diagnosis due to nonskin location of the primary lesion.

The authors obtained all appropriate consent forms from the patient for the publication of this case report.

Conflict of interest: None declared.

   References Top

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Correspondence Address:
Jerzy Chudek
Department of Internal Medicine and Oncological Chemotherapy, Medical University of Silesia, Katowice
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DOI: 10.4103/1319-2442.335469

PMID: 35017351

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