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Of 1463 liver allograft recipients receiving the combination of FK506 and steroids as their primary immunosuppressive regimen, 2 patients developed Kaposi’s sarcoma. Although previously described as a complication of organ transplantation, this is the first case report of Kaposi’s sarcoma occurring in association with the macrolide immunosuppressive agent FK506. A discussion of the clinical presentation and course of Kaposi’s sarcoma in these 2 patients, as well as a review of the past literature on Kaposi’s sarcoma in organ transplant recipients, emphasizes the therapeutic difficulties encountered. Kaposi’s sarcoma is also compared to lymphoproliferative disorders, another well-recognized complication of immunosuppression, highlighting the differences between these two entities.
Kaposi’s sarcoma is a rare multicentric neoplasm of controversial origin known to occur in individuals who are immune-deficient. It is a recognized complication of organ transplantation, accounting for 6% of post-transplant malignancies (1). From 1 March 1989 until 19 June 1992, a total of 1463 liver allograft recipients received FK506 in combination with steroids as their primary immunosuppressive regimen at the University of Pittsburgh. Approximately 10% of this population are foreign nationals, mainly of middle eastern extraction, in whom there also appears to be a genetic predisposition for Kaposi’s sarcoma.
The literature on Kaposi’s sarcoma in organ transplant patients has focused mainly on renal allograft recipients in whom regression of the disease and patient survival do not necessarily equate with continued graft function (see Table 1). Treatment of Kaposi’s sarcoma has closely paralleled the approach used in post-transplant lymphoproliferative disorders (PTLD) and the two entities are frequently compared. The overall prognosis for Kaposi’s sarcoma in liver allograft recipients has, however, been poor with a 45% mortality rate in a series of such patients presented by Bismuth et al. in 1991 (2). This contrasts markedly with the results of recent review from the University of Pittsburgh of 15 patients with PTLD (13 liver and 2 renal allograft recipients) of whom 10 (67%) have survived with functional grafts (3). The following case reports describe Kaposi’s sarcoma occurring in association with FK506 immunosuppression in 2 liver allograft recipients, and serve to illustrate the therapeutic difficulties encountered in its clinical management.
A 49-year-old Saudi Arabian man was admitted on 24 January 1992, 10 months after successful orthotopic liver transplantation for Laennec’s cirrhosis, with a diagnosis of Kaposi’s sarcoma. He presented with new-onset dark raised purple lesions of his lower extremities which had recently been increasing in number. A biopsy of several of these lesions was performed and confirmed a diagnosis of Kaposi’s sarcoma. The patient’s past history was significant for two episodes of acute cellular rejection, documented by liver biopsies, which were treated with a steroid recycle, a 1 g bolus of methylprednisolone and the institution of azathioprine. Immunosuppression on admission consisted of FK506, 4 mg po bid, prednisone 20 mg po q/day and azathioprine at 100 mg qd; the serum FK506 level was 0.5 ng/ml.
On admission, FK506 was reduced to 2 mg po bid, prednisone to 5 mg po qd and azathioprine was stopped; α interferon at a dose of 5 million units sq qd was started and was increased 4 d later to 10 million units sq qd. Investigations during the patient’s hospitalization included a CT scan of the head, chest and abdomen, and an enteroclysis study, which were all negative for tumor. On esophagogastroduodenoscopy, a moderately inflamed distal esophagus with normal stomach and duodenum were noted; biopsies of the esophagus showed acute and chronic inflammation. A limited colonoscopy was performed which showed no colonic lesions. A right pleural effusion was aspirated and cytologic examination of the fluid revealed no malignant cells.
Viral serologic studies sent on admission included an HIV and a hepatitis C screen which were negative; a hepatitis B serology which was negative for hepatitis B surface antigen, positive for anti-HBs, and negative for anti-HBc. Viral titers included cytomegalovirus (CMV) IgG> 120 (ref. value <20), negative CMV IgM, Epstein Barr Virus (EBV) IgG > 50, EBV IgM < 10 and EBV nuclear antigen 2; herpes simplex IgG was > 200 (ref. value < 8) and herpes zoster IgM < 20 (ref value < 20). Pretransplant CMV IgG was > 120 and CMV IgM was negative. Immunoperoxidase, in situ hybridization and polymerase chain reaction techniques failed to detect CMV particles within the lesions in the skin biopsy. Consecutive multiple CMV shell vial assays and cultures obtained during the patient’s hospitalization from throat, sputum, urine and blood were negative with the exception of one urine specimen positive for CMV by shell vial on admission. The HLA status of the patient was HLA – A2 A24 B35 B51 BW4 BW6 DR4 DR11 DQW3 DRW51 DRW53.
On a regimen of daily α-interferon therapy and reduced immunosuppression, the Kaposi lesions stabilized. Liver function, however, worsened, necessitating a liver biopsy on 3 February 1992, which showed a mixed portal inflammatory infiltrate with low-grade lobular reactivity. The patient was given a 1 g bolus of intravenous methylprednisolone, and maintenance prednisone was increased to 10 mg po/daily.
The liver function tests, however, continued to deteriorate and a repeat liver biopsy was performed which revealed lobular reactivity, single-cell necrosis and chronic bile duct injury. Immunoperoxidase staining for hepatitis B surface antigen was negative.
On 16 February 1992, the patient developed coffee-ground emesis and experienced a melanotic stool with a significant drop in his hematocrit. Esophagogastroduodenoscopy revealed prominent gastric varices along the greater curvature of the stomach and biopsies of the duodenal and gastric mucosa were negative for CMV. Autoimmune markers were positive for thyroglobulin antibodies at 100 (Ref. value < 100) and microsomal antibodies at 400 (Ref. value < 100). With the continued deterioration in liver function, an acute autoimmune hepatitis precipitated by α-interferon was suspected and the α-interferon was discontinued.
Bleeding from the gastric varices continued and an arteriogram was obtained which showed thrombosis of the midportion of the splenic vein with patent superior mesenteric and portal veins. An exploratory laparotomy, splenectomy and gastric devascularization was performed on 21 February 1992.
Ten days later, however, the patient redeveloped upper gastrointestinal bleeding after an initial benign postoperative course and an upper endoscopy revealed severe portal hypertensive gastropathy. Serum bilirubin level was markedly elevated at 26.3 mg/dl and a liver biopsy was obtained which showed mild acute cellular rejection with marked duct damage and bile duct loss, as well as panlobular hepatocyte swelling and disarray. The patient was treated with 1 g methylprednisolone i.v. and FK506 was reinstituted at a dose of 2 mg po twice a day, having been previously held for transiently elevated levels; prednisone was again increased from 5 mg to 10 mg po daily. Repeat thyroglobulin and microsomal antibody titers were 400 and 1600 respectively. Hepatitis B serology and the hepatitis C screen continued to be negative. The Kaposi lesions of the lower extremities were essentially unchanged.
The patient continued to have upper gastrointestinal bleeding which became refractory to all resuscitative efforts; comfort measures were instituted and the patient expired.
A 39-yr-old Saudi Arabian man was admitted to the Presbyterian University Hospital on 10 February 1992, 4.5 months after an orthotopic liver transplant for cirrhosis secondary to hepatitis B virus infection with increasing fatigue and extensive multiple nodular dark skin lesions which had started on his anterior abdominal wall approximately 1 month prior to admission and had rapidly disseminated to involve the rest of his body. On examination, these lesions had the typical appearance of Kaposi’s sarcoma; there was no obvious oropharyngeal involvement and no palpable lymphadenopathy or edema. His past history was significant for excision of a hemangioendothelioma involving the right sixth and seventh ribs on 23 December 1991. Three biopsy-documented rejection episodes had been treated with a pulse bolus of intravenous methylprednisolone and a steroid recycle; the patient was also receiving hepatitis B immunoglobulin every 3 to 4 weeks as part of a research protocol. Medications on admission included FK506 8 mg po bid and prednisone 2.5 mg po qd; the serum FK506 level was 1.7 ng/ml. Liver function was essentially normal and the patient’s HLA status was HLA A2 A30 B44 B51 BW4 DR1 DR11 DQW1 DQW3 DRW52.
A skin biopsy was refused by the patient; the lesions, however, were typical for Kaposi’s sarcoma and not metastatic hemangioendothelioma. This was further substantiated by the Dermatology and Oncology services who were consulted. As a result, FK506 was reduced to 2 mg po bid and α-interferon therapy was started at 10 million units subcutaneously daily. An esophagogastroduodenoscopy performed by the gastroenterology service showed multiple vascular lesions which were most consistent with Kaposi’s sarcoma involving the cardia, body and antrum of the stomach as well as the duodenum to the ligament of Treitz; colonoscopic examinations and radiologic studies were essentially noncontributory. A biopsy of the gastrointestinal lesions was not obtained due to a low platelet count of 33000/mm3. Serologic studies performed on admission included a negative HIV screen; a positive hepatitis C screen, a positive anti-HBc and anti-HBs, and an anti-delta hepatitis screen which was positive. Other viral studies included a CMV IgG > 120 (Ref. value < 20) and EBV IgG 400, EBV IgM < 10, EBV nuclear antigen > 8 and an EBV early antigen of 10. Consecutive CMV shell vial assays and cultures for CMV from urine, throat, sputum and blood were all negative. The patient’s pretransplant CMV IgG was > 120 and CMV IgM was negative.
With the combination of a reduction in immunosuppression and continued α-interferon therapy, the patient developed a progressive rise in his liver injury parameters ultimately requiring a liver biopsy which showed mild acute cellular rejection. The FK506 dose was increased to 2 mg po bid having been previously reduced to 2 mg daily. The patient’s Kaposi skin lesions had diminished, suggesting a partial response to therapy. Liver function, however, continued to deteriorate and it was opted to reduce the α-interferon dose to 5 million units sq per d.
In spite of these measures, liver function deteriorated further with a total bilirubin of 12.3 mg/dl, and a liver biopsy obtained on 17 March showed continued mild acute cellular rejection, with centrilobular cholestasis and a low-grade hepatitis. Immunocytochemical stains for hepatitis B surface and core antigens were negative. One gram of methylprednisolone i.v. was administered, and the daily prednisone dose was increased to 10 mg.
On 24 March, with the total bilirubin continuing to rise, α-interferon was reduced further to 3 million units sq daily and an additional 1 g of intravenous methylprednisolone was given.
A repeat liver biopsy obtained on 28 March showed evidence of chronic rejection as reflected by a paucity of bile ducts and prominent centrilobular cholestasis consistent with a vanishing bile duct syndrome. A lobular inflammatory infiltrate was present, suggesting a low-grade hepatitis. Immunocytochemical stains for hepatitis B surface and core antigens were again negative. All cytomegalovirus stains and cultures were negative. Liver function tests continued to be elevated with a total bilirubin reaching 17.3 mg/dl; the serum FK506 level was 0.9 ng/ml and a 1-g intravenous bolus of methylprednisolone was given on 1 April. The patient was discharged at his request on 4 April 1992. He returned to Saudi Arabia on a regimen of FK506 2 mg po bid, prednisone 10 mg po q daily, and α-interferon 3 million units sq q daily. The Kaposi skin lesions were decreasing in size and number, but had failed to completely resolve. Follow-up from Saudi Arabia later indicated that the patient expired in mid-June 1992.
Kaposi’s sarcoma (KS) is a complex tumor of controversial origin which was first described in 1872 by Moritz Kaposi (4). It is known to occur in immune deficiency states such as in organ transplant recipients and in disorders associated with a defect in T-lymphocyte function (4, 7). In organ transplant recipients, KS is intermediate in its behavior between the classic indolent form and the epidemic AIDS-associated KS: of 214 cases of KS listed in the Cincinnati Transplant Tumor Registry, 59% had local disease involving the skin, conjunctiva and oropharyngeal mucosa, and 41% had visceral disease involving mainly the gastrointestinal tract and lungs (1). Of the 2 patients presented in this report, case 2 had visceral involvement seen on endoscopy.
The incidence of KS appears to be higher in recipients of non-renal organs (4% vs. 2%) (1), probably reflecting the more aggressive immunosuppression used in such patients. An analysis of the type of immunosuppression used in organ transplant recipients with KS showed an incidence of 8% in those receiving the combination of cyclosporine A (CsA) with steroids vs. 3% in those receiving conventional immunosuppressive therapy consisting of azathioprine or cyclophosphamide with prednisone (Penn 1991) (1). To date, this is the first report of KS occurring in association with the use of the new macrolide immunosuppressive agent FK506, which has 100 times the immunosuppressive potency of CsA. From 1 March 1989 until 19 June 1992, a total of 1463 liver allograft recipients have received the combination of FK506 with steroids at the University of Pittsburgh; further follow-up will be needed to determine the long-term incidence of KS within this population of patients.
Although KS in organ transplant recipients has been described as being less aggressive than in the AIDS population in whom a persistence of an immunosuppressed state is a characteristic feature, the overall outcome in transplant recipients has been poor. In reviewing the literature on KS in renal allograft recipients, the patient mortality and graft failure rate has been high despite described regression of KS lesions with reduction or discontinuation of immunosuppression (see Table 1).
The origin of KS is controversial, with theories ranging from a reticuloendothelial origin vs. that it may arise from vasoformative mesenchymal cells (4, 10). On the pathogenesis of KS, there is epidemiologic data suggesting a genetic pre-disposition as opposed to theories that it may be a tissue reaction to an infectious agent, such as a virus, rather than being an autonomous tumor (10). In Sardinia, where there is a high incidence of classic non-HIV related KS (10), Contu et al. (11) reported a greater than expected incidence of the allele HLA DR5 in Sardinians with the disease (p < 0.001). HLA DR5 has also been shown to be common in AIDS patients with KS (4). Neither of the patients in this series had the HLA DR5 allele; both, however, were Arab and were HLA A2 B51 BW4 DR11 DQW3- and DRW52-positive. The A2 allele has been reported, by Qunibi et al. (9) to be significantly increased in their population of Saudi Arabian patients with KS after renal transplantation.
Arguments in favor of an infectious agent in the pathogenesis of KS include the fact that cutaneous anergy is frequently present in patients with classic KS, suggesting the possibility that a transmissible agent is facilitated in its colonization of dermal blood vessels (4). In addition, in transplant recipients, Kaposi lesions may regress completely or at least improve with a reduction in immunosuppressive therapy (1, 5, 8, 9, 13, 14, 15, 16). Cytomegalovirus (CMV), papilloma virus, herpes simplex types I and II (HSV I & II), polyoma virus and hepatitis B virus (HBV), have all been linked to KS (2, 12, 16, 17, 18, 19). Both of the patients in this report had evidence of a prior CMV infection with raised CMV IgG levels. There was, however, no evidence for CMV reactivation, as demonstrated by the negative CMV IgM titers and CMV cultures. Polymerase chain reaction techniques failed to detect CMV particles within the lesions in the skin biopsy of patient 1.
CMV nuclear antigen has been demonstrated in KS lesions of AIDS patients (16, 19), and CMV DNA has been found by dot blot hybridization in cultures of KS cells from a renal transplant recipient (16). Kaposi cells, however, have been shown to proliferate in tissue culture despite the disappearance of CM V-DNA, suggesting that CMV, in the setting of an immunosuppressed state, may be required for the initiation of KS but not for its continued growth (16). On the other hand, in AIDS patients with CMV infection, integrated CMV viral DNA has not been consistently detected, thus raising the question as to whether CMV exists in KS cells merely as a secondary invader (19).
In 1991, Bismuth et al. (2) reported 11 patients with KS after liver transplantation, of whom 7 were hepatitis B surface antigen-positive (2). This was from a population of 397 liver allograft recipients with an overall prevalence for KS of 5.2% in hepatitis B surface antigen-positive liver recipients (2). Hepatitis B virus DNA has also been isolated from tiunor lesions and normal skin in an 80-yr-old man with KS, who was concomitantly seronegative for hepatitis B virus (19, 20). Both patients presented in this report were hepatitis B surface antigen-negative, although case 2 was receiving hepatitis B immunoglobulin for an earlier hepatitis B virus infection.
Kaposi’s sarcoma can be a ubiquitous tumor with a mode of spread which is multifocal and not dissimilar to that of a lymphoma. A parallel has been made in the past between KS and post-transplant lymphoproliferative disorders (PTLD) (13, 21, 22). Both occur in immunosuppressed individuals whose defense mechanisms against oncogenesis and/or a viral infection are impaired (4, 7, 13). The incidence of PTLD in organ transplant recipients is increased relative to the general population by at least 10-fold (13), and the incidence of KS in transplant recipients is increased up to 400 to 500 times that of the general population (7). The link between cytomegalovirus infection and KS, however, has not been as consistent as the association of Epstein Barr virus infection with PTLD (13, 16, 19). Furthermore, although both conditions have been treated with a reduction in immunosuppression, unlike PTLD there appears to be a significant number of grafts lost to rejection in KS (see Table 1). The course of PTLD associated with FK506 was recently reviewed at the University of Pittsburgh where a total of 15 patients (13 liver allograft and 2 renal allograft recipients) were treated by a reduction in immunosuppression and intravenous acyclovir therapy; 10 showed complete remission and all 10 have retained their grafts (3). This report stands in sharp contrast with the series of liver graft recipients presented by Bismuth et al. (2) who were treated for KS with a reduction in their immunosuppression, and experienced an overall 45% mortality rate.
α-interferon was used in both patients in this case. There have been reports of improved results in the treatment of KS using α-interferon (α-IFN) in the AIDS population (8, 23, 24, 25, 26). Its use has also been reported in a bone marrow transplant recipient (15) with encouraging results. In AIDS patients, α-IFN has been shown to have anti-retroviral activity as demonstrated by a reduction in HIV antigen levels and a rise in the number of OKT4+ cells (8, 23, 24, 25). In KS, α-IFN is thought to exert its effect by inhibiting angiogenesis either by a direct effect on endothelial cell proliferation (19, 27, 28) or by inhibition of angiogenesis factors (19) such as interleukin-6 (26). Most recently, it has been used with excellent results in cases of childhood angiomas (28). Improvement was seen with α-IFN therapy in the Kaposi lesions of 1 of the 2 patients in this report. The immunomodulatory effects of α-IFN, however, presented a major problem in the setting of reduced immunosuppression in both patients, as manifested by a marked deterioration in liver function with documented cellular rejection by serial liver biopsies. In case 1, activation of a dormant autoimmune process may also have occurred and contributed to the liver dysfunction.
In conclusion, KS is a disease of unclear etiology to which there appears to be an underlying genetic predisposition. The therapeutic approach in KS has closely paralleled that of PTLD, but with a poorer end result. The use of antiangiogenesis and antiviral agents such as α-IFN requires further evaluation. Early treatment of KS using chemotherapy and radiotherapy in association with reduced immunosuppression needs to be studied further.
Kadry Z, Bronsther O, Van Thiel DH, Randhawa P, Fung JJ, Starzl TE. Kaposi’s sarcoma in two primary liver allograft recipients occurring under FK506 immunosuppression. Clin Transplantation 1993: 7: 188-194.