Fine-Needle Aspiration Biopsy Findings of the Thyroid Gland in Renal Transplant Patients.

OBJECTIVES: For patients with end-stage renal disease, thyroid diseases are common due to altered hormone excretion and transport, and for renal transplant recipients this is due to immunosuppressive drugs. We investigated the prevalence of thyroid disorders, including thyroid cancer, by fine-needle aspiration biopsy in kidney transplant candidates and recipients and estimated the outcomes. MATERIALS AND METHODS: For 305 thyroid fine-needle aspiration biopsies performed from January 2000 to December 2020 in patients with end-stage renal disease, we recorded patient demographics, thyroid ultrasonography, and biopsy findings. RESULTS: Of biopsy results from 305 patients, 272 (89.2%) were benign, 24 (7.9%) showed atypia of undetermined significance/follicular lesion of undetermined significance, 2 (0.7%) had suspicion for malignancy, and 7 (2.3%)were malignant.Thyroid surgery was performed for 13 patients with benign results, 6 with atypia of undetermined significance/follicular lesion of undetermined significance, 2 with suspicion for malignancy, and 7 with malignancy. In 13 patients with benign cytology, the histopathology finding was also benign in lobectomy specimens. In 6 patients with atypia of undetermined significance/follicular lesion of undetermined significance, the final diagnosis was papillary thyroid carcinoma in 3 patients, adenomatous hyperplasia in 2 patients, and Hurthle cell adenoma in 1 patient. For all 9 patients for whom fineneedle aspiration biopsy was suspicious for malignancy or malignant, histopathologic examination showed papillary thyroid carcinoma in total thyroidectomy materials. Among 12 papillary thyroid carcinoma patients, 4 underwent renal transplant after thyroidectomy, and survival for these 4 patients was 116.25 ± 29.30 months after transplant without tumor recurrence or distant metastases. CONCLUSIONS: Thyroid diseases are more frequent in patients with end-stage renal disease or renal transplant versus the normal population and also affect morbidity and mortality at higher rates in these patients. Fine-needle aspiration biopsy is a useful diagnostic modality in evaluation and treatment of thyroid nodules in both kidney transplant candidates and recipients.

The Overexpression of Programmed Death-Ligand 2 in Uterine Adenosarcoma: Correlation with High-Grade Morphology, Mutant Type TP53 Expression and Clinical Outcomes.

Immunotherapy involving the programmed death-1 (PD-1)/the programmed death-ligand (PD-1/PD-L) blockade is an understudied tumor therapy approach in cases of adenosarcoma. PD-L1 and PD-L2, and tumor protein p53 (p53) were examined in 20 uterine adenosarcoma cases, and tumor-infiltrating lymphocytes and tumor-associated macrophages were counted in tumor tissue using immunohistochemistry. While CPS PD-L1 positivity with 1% and 10% cut-off values was observed in 40% and 10% of tumors, respectively, CPS PD-L2 positivity with 1%, 10% and 50% cut-off values was observed in 100%, 85% and 50% of the tumors, respectively. The CPS PD-L2 positivity with a 50% cut-off value was positively correlated with tumor grade and the presence of sarcomatous overgrowth and lymphovascular invasion (LVI) (p = 0.025, p = 0.025, and p = 0.025, respectively). Nine of 11 high-grade adenosarcomas and none of the low-grade adenosarcomas showed mutant type p53 expression (p = 0.000). However, PD-L1 expression and tumor-infiltrating immune cells did not correlate with clinicopathological parameters. The CPS PD-L2 positivity with a 50% cut-off value was also positively correlated with mutant type p53 expression (p = 0.024) and tumor-associated macrophages density (p = 0.024). The CPS PD-L2 positivity with a 50% cut-off value and mutant type p53 expression were associated with shorter disease-free survival and shorter overall survival. The high density of tumor-associated macrophages and low density of tumor-infiltrating lymphocytes were also associated with shorter disease-free survival and overall survival (p < 0.05).These results suggested that the CPS PD-L2 positivity with a 50% cut-off value, p53 mutation and tumor microenvironment played an essential role in the progression of uterine adenosarcomas.

Association between focal adhesion kinase and matrix metalloproteinase-9 expression in prostate adenocarcinoma and their influence on the progression of prostatic adenocarcinoma.

Focal adhesion kinase (FAK), a member of the non-receptor cytoplasmic tyrosine kinase family, is associated with the development and progression of cancer. Matrix metalloproteinase-9 (MMP-9) is directly involved in the degradation of the extracellular matrix, and basement membrane components promote cancer cell migration and invasion. There is a functional interaction among FAK, MMP-9 and vascular endothelial growth factor (VEGF), which leads to enhanced cancer angiogenesis, cancer cell invasion and progression of malignancy. FAK, MMP-9, VEGF and CD34-positive microvessel density (MVD) were examined in 100 patients with prostate adenocarcinoma using immunohistochemistry. The relationship among these proteins and their impact on angiogenesis and clinicopathological parameters were also evaluated. The FAK expression was found to be positively correlated with the Gleason score, WHO grade group, tumour stage, extracapsular extension and perineural invasion. The MMP-9 expression was positively correlated with the WHO grade group, tumour stage, extracapsular extension, positive surgical margin and lymphovascular and perineural invasion. The FAK expression was also positively correlated with MMP-9 expression and MVD. However, no correlation between FAK and VEGF expression was identified. The MMP-9 expression was positively correlated with FAK expression and MVD. Strong MMP-9 expression was associated with shorter disease-free survival. These results suggest that strong MMP-9 and FAK expressions play an essential role in the progression of prostate adenocarcinoma. Further investigations should be conducted to determine the importance of these proteins as therapeutic targets for patients with prostate adenocarcinomas.

De Novo Thrombotic Microangiopathy in Renal Transplant Patients.

OBJECTIVES: Thrombotic microangiopathy is a form of renal capillary injury possibly associated with calcineurin inhibitor toxicity, acute humoral rejection, infections, and recurrent diseases. Here, we examined its incidence in patients diagnosed with acute and chronic active humoral rejection, polyomavirus nephropathy, acute cellular rejection, and immunoglobulin A recurrence. MATERIALS AND METHODS: In total, 272 renal allograft recipients who met the inclusion criteria were reevaluated for presence of renal thrombotic microangiopathy. Thrombotic microangiopathy diagnosis was established by clinical, laboratory, and histologic features. C4d expression in peritubular capillaries was determined. Clinical data were collected from medical records. RESULTS: Of 272 patients (mean age of 42.8 ± 12.7 years), only 74 patients (27.2%) had de novo thrombotic microangiopathy, which was found in 30/90 patients (33.3%) with acute humoral rejection, 9/51 (17.6%) with acute cellular rejection, 22/53 (41.5%) with chronic active humoral rejection, 10/55 (18.2%) with polyomavirus nephropathy, and 3/23 (13%) with immunoglobulin A nephropathy. Significant differences were shown between therapy type and thrombotic microangiopathy development (P = .02). Patients who received cyclosporine (38.5%) tended to show higher incidence of thrombotic microangiopathy than patients who received tacrolimus (20.7%) or sirolimus (7.7%). Patients with C4d-positive acute humoral (97.6% vs 2.4%) and chronic active humoral rejection (68.2% vs 31.8%) had greater incidence of thrombotic microangiopathy versus those who were C4d-negative. Graft loss was significantly higher in C4d-positive than in C4d-negative thrombotic microangiopathy groups (P < .001). Overall 1-, 3-, and 5-year graft survival was 94%, 85%, and 85% versus 83%, 51%, and 51% in thrombotic microangiopathy-negative versus thrombotic microangiopathy-positive patients (P < .001). CONCLUSIONS: Acute humoral rejection and chronic active humoral rejection were the most common and therefore most important causes of de novo thrombotic microangiopathy in renal transplant patients. Its presence in the renal allograft biopsy should arouse suspicion for underlying acute or chronic active humoral rejection.

Effects of Hyaluronic Acid and Hydroxyapatite/Beta-tricalcium Phosphate in Combination on Bone Regeneration of a Critical-size Defect in an Experimental Model.

Hyaluronic acid (HyA) is an outstanding new product in the field of oral and maxillofacial surgery. The aim of this study was to evaluate the effects of HyA on bone regeneration in critical-size calvarial defects. Twenty-four female Sprague-Dawley rats were used in the present study. In each rat, 4 critical-size defects received different treatments: no treatment (control); HyA; Graft; and HyA + Graft combination. New bone formation, defect closure, inflammation, vascular proliferation, immature bone formation, mature bone formation, and bone marrow existence were investigated based on histological findings. The healing parameters related to bone formation (new bone formation, defect closure, immature bone formation) were significantly higher in the HyA group compared with the control group. However, HyA alone was unable to induce sufficient bone regeneration compared with treatments involving graft materials (Graft and HyA + Graft). In the Graft and HyA + Graft groups, prominent enhancement of all healing parameters was noted. The present results demonstrate that HyA alone did not adequately enhance bone regeneration in critical-size defects. Moreover, addition of HyA to a biphasic alloplastic graft material did not result in improved regeneration compared with the graft material alone.

Doppler Ultrasonography Findings During Recovery Period of Transplanted Kidney After Infarction and Necrosis Due to Renal Vein Thrombosis: A Case Report.

A 47-year-old male patient underwent living-related renal transplant. On day 3 posttransplant, without evidence of associated clinical symptoms, the patient's serum creatinine levels had increased. The patient was given immunosuppressive medication, and a followup Doppler ultrasonography revealed hypoechoic areas in the inferior pole of the renal parenchyma. Eventually, on day 25, there was no perfusion in the superior and inferior poles of the transplanted kidney. No venous flow was shown in the middle segment, and only arterial vascularization with a high resistive index and negative diastolic phase was observed. Renal biopsy showed acute humoral rejection. This was interpreted as venous thrombosis secondary to acute humoral rejection. Tissue plasminogen activator infusion, plasmapheresis, and hemodialysis were administered. After 1.5 months, arterial flow returned to its normal pattern and the renal allograft recovered by gaining back its full vascularity at the end of month 8.

Pretransplant Thyroid Findings in Patients With End-Stage Renal Disease.

OBJECTIVES: Patients with end-stage renal diseases can display abnormal thyroid gland function due to altered hormone excretion and transport. In this study, we aimed to evaluate the incidence of thyroid diseases by fine-needle aspiration cytology in kidney transplant candidates and to estimate the outcomes of these patients. MATERIALS AND METHODS: We reevaluated thyroid fineneedle aspiration biopsies, which were performed between January 2000 and December 2015, of 181 candidates for kidney transplant. Patient demographics and thyroid ultrasonography and biopsy findings were recorded. RESULTS: The fine-needle aspiration biopsy findings of 181 patients were as follows: 162 were benign 5 were thyroiditis, 9 were atypia of undetermined significance/follicular lesion of undetermined significance, and 5 were malignant. Only 13 patients (7.1%) underwent thyroid operation after fine-needle aspiration, with 5 of these patients receiving a benign diagnosis, 3 receiving diagnosis of atypia of undetermined significance/follicular lesion of undetermined significance, and 5 patients showing malignancy. In the 5 patients with benign cytology, histopathologic findings were also benign. In the 3 patients with atypia of undetermined significance/follicular lesion of undetermined significance, the final diagnosis was adenomatous hyperplasia. Finally, in the 5 patients (2.8%) showing malignancy, results after fine-needle aspiration showed papillary thyroid carcinoma. In the 5 patients with papillary thyroid carcinoma, 4 underwent renal transplant. Survival of these 4 patients was 92 ± 42 months without tumor recurrence. CONCLUSIONS: Fine-needle aspiration is a useful diagnostic modality in evaluation of thyroid nodules in kidney transplant candidates. Early detection and treatment of thyroid nodules are essential to decrease the morbidity and mortality of these patients.

De Novo Malignant Neoplasms in Renal Transplant Patients.

OBJECTIVES: The aim of this study was to evaluate the incidence of posttransplant malignancy in kidney transplant patients and investigate the clinical and histopathologic features of these patients. MATERIALS AND METHODS: We retrospectively reviewed information on donor and recipient characteristics, patient and graft survival, and cancer incidence after transplant for 867 kidney transplant patients. Patients with neoplasms prior to transplant were excluded. A follow-up study estimated cancer incidence after transplant. RESULTS: Neoplasms were diagnosed in 59 patients (6.8%), 41 men and 18 women; 22 (37.3%) had skin tumors, 19 (32.2%) had solid tumors, 10 (16.9%) had posttransplant lymphoproliferative disorders, and 8 (13.6%) had Kaposi sarcoma. The mean age at the time of malignant tumor diagnosis was 42.7 ± 13.6 years, and statistically significant differences were found between tumor groups (P < .01). The average latency period between transplant and diagnosis of malignant tumors was 99.8 ± 56.9 months for solid tumors, 78.4 ± 52 months for skin tumors, 64.5 ± 48.8 months for posttransplant lymphoproliferative disorders, and 13.5 ± 8.8 months for Kaposi sarcoma, with significant difference found between tumor groups (P < .01). Ten patients (16.9%) had more than 1 malignant tumor. Eighteen patients died, with a mean time to death of 31.5 ± 22.8 months after tumor diagnosis. A significant positive association was found between survival and the number of tumors (P = .001); 5-year survival after tumor diagnosis was 81% and 40% for patients with 1 malignant tumor and patients with more than 1 malignant tumor, respectively. CONCLUSIONS: Malignancy is a common cause of death after renal transplant. Early detection and treatment of posttransplant malignancies is an important challenge. Screening these patients for malignancies posttransplant is crucial, and efforts should be directed to define effective immunosuppressive protocols that are associated with a lower incidence of malignancy.

Histologic Changes in Bone Marrow Biopsies From Liver Transplant Patients.

OBJECTIVES: Liver transplant may complicated by various hematologic conditions, resulting in indication for bone marrow biopsy. Immunosuppressive therapies, specific infections, and secondary neoplasms affect bone marrow. In the present study, we evaluated the histologic spectrum of bone marrow findings in liver allograft recipients. MATERIALS AND METHODS: Of 338 patients who received liver transplants and were followed at the Baskent University, Faculty of Medicine, 44 patients underwent bone marrow biopsy. The medical and pathologic information about these patients were evaluated, including age at liver transplant, age at bone marrow biopsy, sex, primary disease, bone marrow histology, and indication for bone marrow biopsy. RESULTS: Of 44 patients who required bone marrow sampling, 30 were male (68.2%), and 14 were female (31.8%). Fifteen patients (34.1%) were in pediatric age group at the time of transplant. The most common cause of liver insufficiency leading to liver transplant was viral hepatitis in 11 patients (25%), followed by cryptogenic cirrhosis in 10 patients (22.8%). The source of the graft liver was a living donor in 40 patients (90.9%). The average age at transplant was 28.8 years, and the mean age at bone marrow sampling was 29.9 years. Nineteen patients (43.2%) required bone marrow sampling within the first year after transplant. The most common histologic findings were hypocellular, and normocellular bone marrow, observed in 18 patients (40.9%) each. Six patients (13.6%) had bone marrow biopsies for staging of posttransplant lymphoproliferative disorder. Only 1 patient of the 6 with this disease (16.7%) had malignant infiltration of the bone marrow, which was a case of Burkitt lymphoma developed as posttransplant lymphoproliferative disorder, and this was the only malignant infiltration in this patient group (2.3%). Neither specific infections nor granulomatous inflammation was detected. CONCLUSIONS: Bone marrow morphology has a major role in the follow-up of liver transplant patients, who may present with peripheral blood cytopenias. The present study represents the first systematic evaluation of bone marrow findings in liver allograft recipients.

Splenic Peliosis Resulting in Spontaneous Splenic Rupture in a Concomitant Hepatic and Renal Allograft Recipient.

Splenic peliosis is an exceedingly rare complication following liver and kidney transplant, with few previously reported cases. A 24-year-old man with chronic renal and hepatic failure due to primary oxalosis underwent concomitant renal and hepatic transplant. On the eighth day of successful transplant, he showed signs and symptoms of hypovolemia with suspicion of intra-abdominal bleeding. Diagnostic laparotomy was performed, yielding splenic rupture, and a splenectomy was performed. Macroscopically, the spleen was ruptured, and the cut surface displayed multiple parenchymal blood-filled cysts. Microscopically, the splenic microarchitecture was distorted by numerous irregular hemorrhagic lacunes partially lined by sinusoidal endothelium. Splenic peliosis was diagnosed. The patient recovered with splenectomy. Peliosis is a condition characterized by multiple bloodfilled cavities in parenchymatous organs, and it most frequently affects the liver. It is thought to be related to many conditions, including hematologic malignancies, acquired immuno deficiency syndrome, chronic alcoholism, use of oral contraceptives, and posttransplant immunodeficiency state. However, peliosis of the spleen, compared with the liver, is relatively rare, and it may cause spontaneous splenic rupture. Although rare, splenic peliosis and secondary splenic rupture is a significant posttransplant complications leading to unexplained hypovolemia.

Lung Biopsy Findings of Patients Who Have Undergone a Liver and Kidney Transplant.

OBJECTIVES: Our objective was to analyze the incidence of pulmonary disorders in solid-organ transplant recipients and report on outcomes in these patients. MATERIALS AND METHODS: Seventy liver and kidney transplant patients, who underwent lung biopsy because of pulmonary symptoms between January 2000 and December 2015, were enrolled in the study. We examined and evaluated histopathologic findings of these patients based on clinical data recorded in patients' files. RESULTS: Patients' mean age was 44.5 ± 16.4 years. Of 70 patients, 25 underwent liver transplant and 45 patients underwent kidney transplant. Forty-six patients received organs from living donors and 24 from deceased donors. Biopsy results of all patients included nonspecific findings (28), organized pneumonia (2), tuberculosis (6), fungal infections (11), tumors (5), amyloidosis (1), diffuse alveolar damage (4), mixed bacterial infection (1), and bronchopneumonia (12). Forty-two patients (60%) died within 54.1 ± 53.3 months after transplant and 24.6 ± 41.9 months after lung biopsy. Autopsies were performed on 14 patients. The causes of fatal lung diseases included fungal infections (8), malignant tumors (4), amyloidosis (1), diffuse alveolar damage (4), and mixed bacterial infection (1). Aspergillosis was the most frequently implicated lung infection, occurring in 54.5% of patients with fungal infections. CONCLUSIONS: Pulmonary diseases remain an important cause of morbidity and mortality in solid-organ transplant recipients. Fungal infection, especially aspergillosis, was the leading cause of early death in these patients.

Bone marrow involvement by lymphoproliferative disorders after solid-organ transplant.

OBJECTIVES: Posttransplant lymphoproliferative disorders are classified as monomorphic, polymorphic, early lesions, or Hodgkin lymphoma. Bone marrow staging examination is recommended in posttransplant lymphoproliferative disorder patients. However, information about bone marrow involvement in these disorders is scarce. We evaluated 19 transplant patients with posttransplant lymphoproliferative disorder to investigate incidence of bone marrow involvement, associated morphologic changes, and prognosis. MATERIALS AND METHODS: We retrospectively assessed bone marrow findings of 19 transplant patients with posttransplant lymphoproliferative disorder who underwent bone marrow staging at Baskent University from 1985 to 2013. Clinical and pathologic data were reviewed from the medical records. Follow-up information was obtained from medical records or communication with patients or families. Data collected including age, sex, Epstein-Barr virus status, immunosuppressive therapy, elapsed time from transplant to diagnosis of posttransplant lymphoproliferative disorder, B symptoms, number of extranodal sites, involvement of different organs, Ann Arbor clinical staging, hematologic parameters, and serum lactate dehydrogenase levels. RESULTS: There were 5 of 19 patients (26.3%) who had bone marrow involvement with posttransplant lymphoproliferative disorder, including 2 patients diagnosed with posttransplant lymphoproliferative disorder by lymph node biopsy and 1 patient each diagnosed by native liver biopsy, nasopharyngeal biopsy, or allograft liver biopsy. In 4 patients, there was monomorphic posttransplant lymphoproliferative disorder subtype and 1 patient had early lesion posttransplant lymphoproliferative disorder subtype. In 10 of 19 patients (52.6%), Epstein-Barr virus was detected with in situ hybridization, including 3 patients with bone marrow involvement who were diagnosed with Burkitt lymphoma (n = 1), diffuse large B-cell lymphoma (n = 1), or early lesion (n = 1). CONCLUSIONS: Patients with posttransplant lymphoproliferative disorder have high incidence of bone marrow involvement and high mortality rates. Therefore, bone marrow examination may be important in the diagnosis and staging evaluation of posttransplant lymphoproliferative disorder.

Invasive fungal infections in liver transplant recipients.

OBJECTIVES: We sought to assess the incidence of invasive fungal infections and identify the risk factors and outcome of invasive fungal infections in liver transplant recipient. MATERIALS AND METHODS: A retrospective analysis was made of 408 patients who received a liver transplant between January 1990 to December 2012 at Baskent University in Ankara, Turkey. Only 305 of 408 patients were included. Demographic and clinical findings were reviewed, and these findings were compared between patients with or without invasive fungal infections. RESULTS: Ten of 408 liver transplant patients (2.5%) developed invasive fungal infections. Aspergillus was the most common cause of invasive fungal infections (n=8), followed by Candida (n=1), and Cryptococcus neoformans (n=1). Pulmonary involvement was dominant in all patients (n=10), and only 1 patient had disseminated fungal infection (cryptococcosis). The mean time from transplant to invasive fungal infection diagnosis was 32 ± 19.2 days. Most patients with invasive fungal infection (9/10) died. Mean survival time between diagnosis of fungal infection and death was 24.2 ± 27.3 days in all 10 patients. Fungal infections occurred significantly more frequently in patients with older transplant age, diabetes mellitus, cytomegalovirus infection, renal insufficiency. In addition, other risk factors included long stays in the surgical intensive care unit, the overall length of stay in hospital, and having preoperative high creatinine level. CONCLUSIONS: Invasive fungal infections were associated with increased morbidity and mortality among liver transplant recipients, with Aspergillus spp. being the most common pathogen in our series. Because of its high mortality rate, it is important to follow up transplant patients for the development of invasive fungal infections.

A case of cerebral tuberculosis after liver transplant and literature review.

The risk of active tuberculosis is high in solid-organ recipients. We evaluated the clinical presentation of tuberculosis. Pulmonary locations were the most frequent, and extrapulmonary locations were rarely seen. Among extrapulmonary sites, intracranial tuberculosis is rare, with a few case reports reported in the literature. We report a case of 27-year-old man, who received deceased-donor liver transplant due to hepatitis B virus-related chronic liver failure. One month after the liver transplant, neurologic symptoms developed, then he had attacks of tonic-clonic convulsions. Cerebral stereotactic needle biopsy of left temporal lobe was performed. Histopathologically gliosis, rare lymphocyte infiltration, and epithelioid histiocytes were seen. Histochemical staining by Ziehl-Neelsen stain noted acid-fast resistant bacillus. The case was diagnosed as granulomatous inflammation which led to tuberculosis. In addition to antituberculosis therapy, he was given antiviral therapy for prophylaxis. During therapy, reactivation of hepatitis B virus was noted, and the recurrent diseases of hepatitis B virus-related viral hepatitis was diagnosed on serial biopsies. Ten months after transplant, he died from liver failure. Tuberculosis is a serious opportunistic infection in transplant recipients. The incidence of Mycobacterium tuberculosis infection in organ transplant recipients worldwide ranges from 0.35% to 15%. In nonrenal transplant, rejection within 6 months before the onset of tuberculosis and type of primary immunosuppressive regimen were predictors of tuberculosis infection occurring 12 months after transplant. The diagnosis and effective management of tuberculosis after transplant warnings recognition of the epidemiologic and clinical characteristics of tuberculosis in transplant recipients.

T-cell acute lymphoblastic leukemia after liver transplant.

T-cell posttransplant lymphoproliferative disorders after solid-organ transplant are rare and may be clinically aggressive. A 3-year-old boy had liver transplant from his grandfather because of hepatoblastoma. The immunosuppressive regimen was based on tacrolimus and prednisolone. At 22 months after transplant (age, 5 years), the patient presented to the hospital because of severe cough. Computed tomography scan of the chest showed a large left mediastinal mass (9 × 7.2 × 7 cm) and left pleural effusion. A Tru-Cut biopsy of the mediastinal mass showed diffuse infiltration with blast cells, and the diagnosis of T-cell acute lymphoblastic leukemia was made. Immunohistochemical examination of blasts showed strong and diffuse terminal deoxynucleotidyl transferase and CD3 antibody expression; Ki-67 proliferation index was > 95%, and tumor cells were negative for Epstein-Barr virus. Tacrolimus was stopped, sirolimus was started, and chemotherapy was given, but he died 2 months after diagnosis because of chemotherapy-induced sepsis. Monomorphic T-cell posttransplant lymphoproliferative disorder with features of acute lymphoblastic leukemia and lymphoblastic lymphoma is rare after liver transplant.