ELSEVIER
Double Endocrine Neoplasia in a Renal Transplant Recipient: Case Report and Review of the Literature
A.I. Lo Monte, V.D. Palumbo, G. Damiano, C. Maione, A.M. Florena, M.C. Gioviale, G. Spinelli, M. Bellavia, F. Cacciabaudo, and G. Buscemi
ABSTRACT
Introduction. The incidence of cancer compared for age groups is 3-4 times higher in transplant recipients than the general population. The increased risk is related to immunosuppressive therapy as well as the use of increasingly older donors and recipients. Although cardiovascular disease with a functioning transplant is the leading cause of death (47%), cancer mortality is significant especially among older patients. However, the most frequent posttransplantation cancers relate to hemolymphopoietic organs and skin, whereas the occurrence of solid tumors elsewhere is rare. Herein we have described a rare case of synchronous double malignancy of endocrine organs (thyroid-adrenal) in a young woman who underwent renal transplantation.
Case Report. A 37-year-old woman with end-stage renal disease for 18 years underwent transplantation when she was 30 years old with a 17-year-old standard cadaveric donor receiving immunosuppressive therapy with mycophenolate mofetil, cyclosporine, and steroids. Follow-up demonstrated good indices of renal function with negative tumor pathology at 79 months when, at an annual ultrasound monitoring, we found a lesion in the right lobe of the thyroid and left adrenal neoplasm of dubious interpretation. The cytology for the thyroid was highly suspicious of papillary carcinoma, whereas the histological examination after surgery diagnosed a thyroid multifocal papillary microcarcinoma (mpT1NxMx) and an oxyphil cell adrenocortical carcinoma (pT2, N0).
Results. Six months after total thyroidectomy with central lymphadenectomy and left kidney and adrenal gland removal the patient showed no evidence of recurrent lesions and stable graft function.
Conclusions. The rare occurrence of solid tumors after transplantation has no known etiopathogenetic relation. Despite the young age of the patient and the double neoplasm that could have produced an unfavorable outcome for the patient and the graft, careful follow-up for tumor pathologies and multidisciplinary management achieved an early diagnosis of both tumors with a surgical eradication without adjuvant therapy, preserving the life of the patient and the function of the graft.
From the Dipartimento di Discipline Chirurgiche ed Onco- logiche (A.I. L.M., V.D.P., G.D., C.M., M.C.G., G.S., M.B., F.C., G.B.), and Dipartimento di Patologia Umana, (A.M.F.). Facoltá di Medicina e Chirurgia, Universitá degli Studi di Palermo, Palermo, Italy
Address reprint requests to Attilio Ignazio Lo Monte, Associate Professor of Surgery, Dipartimento di Discipline Chirurgiche ed Oncologiche, Università degli Studi di Palermo-Facoltà di Medicina e Chirurgia, Via del Vespro, 129, 90127 Palermo, Italy. E-mail: ailomonte@unipa.it
0041-1345/-see front matter doi:10.1016/j.transproceed.2011.02.040
T HE incidence of cancer compared for age groups, is 3-4 times higher in transplant recipients than in the general population.1 In particular, the overall incidence of de novo malignancies after kidney transplantation ranges from 6%-11%,2-5 reaching, 20% among long-term 10-year kidney transplant recipients, and even 30% at 20 years from transplantation.6-9 Although cardiovascular disease should be the leading cause of death, as reported for the general population (47%), cancer mortality is significant. It is even comparable with the cardiovascular death rate, especially among older patients.6,10,11 The chronic immunosuppres- sive therapy to prevent acute rejection episodes increases the long-term risk of cancer dues to modifications in immunosurveillance for neoplastic cells, viral reactivation, or increased viral infections,12-15 resulting in addition from the increased mean age of both donors and recipients.1-4,16 Therefore, an effective immunosuppressive treatment that prolongs graft function also increases tumor risk. The most frequent neoplasms among transplanted adults are skin and lip tumors, posttransplantation lymphoproliferative disor- ders (PTLD), and tumors of the lung, cervix, colon, and kidney.15 Their occurrence is proportionate to the time and intensity of the immunosuppression.4 Among solid tumors, thyroid carcinoma incidence in renal transplant recipients, considering the contribution of all histopathological sub- types, has not been the object of studies, despite its prognostic importance. Only a few studies have reported incidences ranging from 0.02%-0.74% among renal allo- graft recipients.17-22 When dimensions of such neoplasms do not exceed 1 cm in diameter, they can be considered to be papillary microcarcinomata of the thyroid gland (micro- papillary thyroid cancer or micro-PTC), a mild variant of the classical type. This form is notable for its relatively less aggressive biological behavior, so that it has been recog- nized in 2.7%-14% of consecutive autopsies or among routine thyroidectomy specimens.23-27 In 1987, Kasai and Sakamoto28 proposed a classification system in which “tiny carcinomas” are considered to be from 6 to 10 mm in size and “minute carcinomas” are 5 mm and smaller. The minute carcinomas represent a lower risk of developing lymph node metastases as compared with tiny carcinomas. Micro-PTC, as reported by Nemes et al, presents an important incidence in the renal transplant population.1 Adrenal tumors are not frequent lesions, especially if we refer to malignant types, adrenocortical carcinomas (ACC),29-33 neoplastic lesions almost universally character- ized by an aggressive behavior and poor prognosis34,35 with steroid hormone secretion in 60% of cases.34 Most ACCs arise sporadically; however, ACC does develop as part of a constellation of tumors in inherited familiae cancer syn- dromes. The risk of developing ACC synchronous with other malignant tumors is exceedingly rare.36-40 Multiple tumors occur among 44% and more frequently than in the background population,1 but the contemporary presence of 2 solid endocrine tumors, such as adrenocortical carcinoma and micro-PTC, may be considered, to our knowledge, a unique case. Herein, we have described a rare case of a
synchronous double malignancy of endocrine organs (thyroid-adrenal) in a young female renal allograft recipi- ent.
CASE REPORT
A 37-year-old woman underwent transplantation from a standard 17-year-old cadaveric donor at age 30 years after an 18-year clinical history of idiopathic end-stage renal disease (ESRD). She under- went periodic follow-up in September 2009. Blood tests showed alterations in the hormone panel. The patient had a familial history of thyroid diseases and Technetium (99mTc) sestamibi scintigraphy of the gland was suspicious for a multinodular goiter. Due to the presence of a cold nodule, high-resolution ultrasonography (US) of the neck and cytological examination using fine-needle aspiration biopsy (FNAB) were followed by measurement of serum thyroid markers (thyroid stimulating hormone, thyroglobulin, and antithy- roglobulin antibodies. Neck US showed an enlarged right thyroid lobe (right lobe anteroposterior diameter, 2.15 cm; left lobe anteroposterior diameter, 1.3 cm; isthmus, 0.35 cm) and a dysho- mogeneous structure suggestive of the presence of a complex nodule 2.1 x 1.3 cm with well-defined margins in the middle third of the right lobe with calcific inclusions and peripheral vasculariza- tion. Another complex nodule of 1.4 × 1 cm was recognized in the paraisthmas with peripheral vascularization. In the right lateral cervical region, we identified 2 lymph nodes of 0.6 and 0.4 cm in diameter at the 4th level and a small 1 cm one at the 3rd (Fig 1). Upon FNAB we strongly suspected a papillary thyroid carcinoma. Histological examination of the thyroid after total thyroidectomy with laterocervical lymphadenectomy showed a bilateral, multifocal micro-PTC: 0.7 cm diameter right lobe and a tiny 1 mm carcinoma in the left lobe (Fig 2). The regional lymph nodes were not affected (mpT1aNxMx). Two parathyroid glands accidentally excised were of normal aspects. We administered replacement therapy with L-thyroxin. The patient was under an immunosuppressive regimen with cyclosporine, steroid, and mycophenolate mofetil. Taking into account the neoplasm, it was decided to switch the therapy toward everolimus plus cyclosporine, since this is a less oncogenic regimen. After a few days, the patient showed an elevation of body temper- ature to 40°C, which was not sensitive to drugs. Since this side effect was not known in the technical leaflet on the drug, the event was reported to the authorities and the immunosuppressive regimen was switched back to the previous one. But Four months later, an US performed for periodic follow-up showed good graft function but the presence of a round mass under the left native kidney with a maximum diameter of 7.5 cm. Multiphase contrast-enhanced abdominal computerized tomography (CT) showed an oval mass of coronal 8.3 cm and transverse 6 cm diameters, with parenchymal density and hypervascularity in the arterial phase, findings compat- ible with a primitive neoplasm of the adrenal gland (Fig 3). The patient underwent a laparoscopic left renal adrenalectomy at Istituto Clinico “Humanitas” (Rozzano, Italy). Histological exam- ination showed an adrenal carcinoma with large oxyphil cells, sometimes containing multiple nuclei and nuclear pleomorphism with a wide cytoplasm. Overall the solid organization had multiple foci of necrosis. A fair number of mitoses, sometimes typical, were observed with a mitotic index of 6/50 high power field. Immuno- phenotype was positive for synaptophysin, melan A, calretinin, inhibin, and vimentin and focal cytokeratin (CK) 34 beta E12. In contrast, chromogranin A, S100, Human Melanoma Black 45 (HMB45), and CK pool were negative. Proliferation index (ki67) was 15%. No angio or capsule invasion were observed (pT2N0). At 6 months after total thyroidectomy with central lymphadenectomy
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and left kidney and adrenal gland excision, the patient showed no evidence of recurrent lesions and stable graft function.
DISCUSSION
The incidence of neoplasms among transplant recipients is high, especially for hematologic malignances. The most frequent solid organ tumors are skin and lip carcinomas. They seem to display more aggressive features than among the general population. Moreover, the most frequently occurring malignant tumors in the normal population, such as carcinomas of the colon, rectum, breast, and prostate, are not seen more frequently after renal transplantation.41 This could be explained because the origin of these tumors is not related to immunosuppression, whereas an important group of transplantation-related tumors are lymphoproliferative disorders, often related to oncogenic viruses that are un- mesked as a consequence of immunosuppressive therapy.4 Micro-PTC is the most frequent thyroidal carcinoma among the rare thyroidal tumors in transplant recipients.1
In contrast, ACC is quite rare and, considering only the organ transplant population, the above cited case repre- sents, to our knowledge, the first case of adrenal gland malignancy in a young organ transplanted patient. The incidence of synchronous carcinomas is rare. Our patient had already underwent a retroperitoneal neuroma removal in 1994, and a mammary fibroadenoma had been discov- ered in July 2010. The age of the patient was another remarkable factor; in fact, if mean age of tumor occurrence for organ recipients ranges from 47 to 55 years,11,17 the 37 year age of our patient could lead to important consider- ations involving hypothetical undiscovered genetic factors. The synchronous presence of these solid tumors- micro- PTC, ACC, retroperitoneal neuroma, and fibroadenoma- reinforce this idea. Unfortunately, we did not perform genetic tests. However, attention must be paid to the 7 years of immunosuppression, which may have influenced tumor development. Pretransplantation dialytic age and subse- quent ESRD years are important factors, too; in fact, they are associated with a higher incidence of posttransplanta- tion tumors;15 immunosuppressive therapy probably played a facilitatory role. Regarding immunosuppressive drugs, patients treated with tacrolimus show an increased risk for cancer (hazard ratio, 4.4) when compared with cyclospor- ine, probably because tacrolimus is a more powerful immu- nosuppressant associated with lower rejection rates and prolonged graft survival.42 It was not possible to switch immunosuppressive therapy toward a less oncogenic one by administering everolimus, because that maneuver caused severe hyperpyrexia, a side effect not yet described in the literature. The rarity of such a clinical picture makes it difficult to identify a specific syndrome that can explain the contemporary presence of these particular malignancies. Multiple endocrine neoplasia type 1 (MEN-1) could be the answer. MEN-1 is an autosomal dominant inherited disor- der, characterized by the occurrence of more than 20 different endocrine and nonendocrine tumors, but classi- cally characterized by neoplasms of the parathyroid glands, of the pancreatic islets, of the pituitary gland, and of the
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adrenal glands, as well as by neuroendocrine carcinoid tumors.43 The incidence of adrenal cortical tumors (involv- ing one or both adrenal glands) in MEN-1 patients has been reported to be approximately 20%-40%,43,44 however, ACCs are rare,33 the majority of them being nonfunctioning tumors. Thyroid tumors, consisting of adenoma, colloid goiters, and carcinomata, have been reported to occur in more than 25% of MEN-1 patients.45 In the literature, there are no reports of double synchronous neoplasms of solid organs. Unfortunately, the absence of major criteria did not allow us to state that the whole clinical picture could be referred to as a MEN-1 syndrome. Early diagnosis and treatment of malignancies after organ transplantation re- main a challenge for clinicians involved in the long-term care of transplant recipients. Therefore, only accurate clinical and instrumental surveillance guarantees the cor- rect approach in the management of such a delicate patient as a transplant organ recipient bearing malignancies this afflict “sensitive targets.” Early detection is important be- cause better survival can be achieved even among immuno- suppressed patients. Nearly total or total thyroidectomy, L-thyroxin, and/or radioiodine treatment may be consid- ered to be adequate therapeutic approaches for occult papillary cancer also in immunosuppressed patients.46 A surgical adrenalectomy should be considered for those patients with functioning lesions or those with nonfunc- tional lesions larger than 4 cm in diameter or with features suspicious for malignancy on CT.47-49 Micro-PTC was easily detected thanks to serum thyroid markers and neck US alterations, which are simple and rapid examinations than contributed, together with FNAB, to a timely diagno- sis. ACC detection was indeed more difficult; in fact, despite
several ecographic examinations, the tumor was discovered only when it was of large dimensions, during a postthyroid- ectomy US control. Then, contrast-enhanced CT scan con- firmed the suspicion. In fact, as stated by Burgess et al, CT scan has the peculiar feature to detect adrenal lesions even when US results are negative, demonstrating better sensi- tivity, especially among cases of nonfunctioning neoplasms with an indolent clinical courses.50
In conclusion, the rare occurrence of solid tumors after transplantation has no known etiopathogenetic relation, but remains crucial for transplant recipient survival. Despite the young age of our patient and the double neoplasia that could have produced an unfavorable outcome, careful follow-up for tumor pathologies and multidisciplinary man- agement allowed an early diagnosis of both tumors with surgical eradications without adjuvant therapy, preserving the life of the patient and the functionality of the graft. With improved long-term recipient and graft survivals posttransplantation tumors have become the most impor- tant cause of morbidity and mortality. Immunosuppressive treatments particularly expose patients to this risk, necessi- tating accurate pretransplantation and posttransplantation surveillance.12
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