Differentiation between rebound thymic hyperplasia and thymic relapse after chemotherapy in pediatric Hodgkin lymphoma.

BACKGROUND: Rebound thymic hyperplasia (RTH) is a common phenomenon caused by stress factors such as chemotherapy (CTX) or radiotherapy, with an incidence between 44% and 67.7% in pediatric lymphoma. Misinterpretation of RTH and thymic lymphoma relapse (LR) may lead to unnecessary diagnostic procedures including invasive biopsies or treatment intensification. The aim of this study was to identify parameters that differentiate between RTH and thymic LR in the anterior mediastinum. METHODS: After completion of CTX, we analyzed computed tomographies (CTs) and magnetic resonance images (MRIs) of 291 patients with classical Hodgkin lymphoma (CHL) and adequate imaging available from the European Network for Pediatric Hodgkin lymphoma C1 trial. In all patients with biopsy-proven LR, an additional fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT was assessed. Structure and morphologic configuration in addition to calcifications and presence of multiple masses in the thymic region and signs of extrathymic LR were evaluated. RESULTS: After CTX, a significant volume increase of new or growing masses in the thymic space occurred in 133 of 291 patients. Without biopsy, only 98 patients could be identified as RTH or LR. No single finding related to thymic regrowth allowed differentiation between RTH and LR. However, the vast majority of cases with thymic LR presented with additional increasing tumor masses (33/34). All RTH patients (64/64) presented with isolated thymic growth. CONCLUSION: Isolated thymic LR is very uncommon. CHL relapse should be suspected when increasing tumor masses are present in distant sites outside of the thymic area. Conversely, if regrowth of lymphoma in other sites can be excluded, isolated thymic mass after CTX likely represents RTH.

[Rebound (reactive) thymic hyperplasia after chemotherapy in children with lymphoma]. / Hiperplasia tímica de rebote posquimioterapia en niños con linfoma.

INTRODUCTION: Thymic regrowth after chemotherapy treatment has been reported in children with lymphoma, and in order to avoid misdiagnosing these cases as relapses, physicians should become familiar with rebound (reactive) thymic hyperplasia (RTH) and remain aware of its possible occurrence. We aimed to estimate the prevalence of RTH in children with lymphoma after completion of chemotherapy and to evaluate the clinical characteristics, outcomes, and the findings of computed tomography (CT) and gallium-67 (GA-67) scans in these patients. PATIENTS AND METHODS: We conducted a retrospective cross-sectional study by reviewing the health records of children with a lymphoma diagnosis managed at an outpatient paediatric oncology clinic in Jeddah, Saudi Arabia. RESULTS: Rebound thymic hyperplasia was detected in 51.9% of the lymphoma patients (14/27). It developed a median of 2.5 months after completion of chemotherapy (range, 2.0-4.25 months). Patients with RTH had significantly shorter treatment durations, and we found no significant differences between patients with and without RTH in sex, age at diagnosis, type of lymphoma or type of treatment received. All patients with RTH were asymptomatic, and routine laboratory tests did not detect any abnormalities in them. The findings of CT and GA-67 scans were highly suggestive of RTH. None of the patients with RTH had a recurrence, and RTH resolved spontaneously within a median of 6 months (range, 4.0-11.0). CONCLUSION: RTH was detected in ∼50% of children with lymphoma after completion of chemotherapy. A clinical evaluation and laboratory tests combined with imaging by CT and GA-67 can help identify RTH and rule out other lesions elsewhere.

A tri-modal distribution of age-of-onset in female patients with myasthenia gravis is associated with the gender-related clinical differences.

BACKGROUND: A tri-modal distribution of age-at-onset emerged among females patients with myasthenia gravis (MG) in our database. This finding may be indicative of different gender-based disease mechanisms. METHODS: We retrospectively reviewed the files of 127 MG patients for the clinical, serology and thymus pathology according to their age at disease onset: ≤40 years (early-onset, EOMG), 40-70 years (intermediate-onset, IOMG) and >70 years (late-onset, LOMG). RESULTS: EOMG was more common among females, and IOMG was more common among males. Ocular MG was more common among the male MG patients with an IOMG. Patients with EOMG had lower rates of positive anti-acetylcholine receptor (anti-AChR). IOMG females, but not IOMG males, had lower rates of positive anti-AChR. IOMG and EOMG females had high rates of thymic hyperplasia, while EOMG males had high rates of thymoma. Comorbidity with autoimmune diseases was common among females with IOMG and LOMG. CONCLUSIONS: The prevalence of IOMG was the reason for the trend reversal of MG prevalence between genders. The clinical features of patients with IOMG differed between genders in the rates of positive anti-AChR, follicular hyperplasia of the thymus and comorbidity with autoimmune diseases. This may suggest a different gender-based mechanism of immune intolerance towards AChR and other antigens.

Predictors for reactive thymic hyperplasia and its prognostic value in children and adolescents with lymphoma.

BACKGROUND: Reactive thymic hyperplasia (RTH) is seen in children and adolescents receiving chemotherapy for various malignancies. However, it is not clear why this occurs only in some patients. The aim of this study was to identify the predictors for RTH in children and adolescents receiving chemotherapy for lymphoma and to determine the effect of RTH on prognosis. METHODS: We reviewed the medical records of 126 lymphoma patients (October 2007-October 2012). The patients were divided into two groups according to different criteria, i.e., age at initial diagnosis (2-12 years vs. 13-18 years); presence of thymic infiltration at baseline (yes vs. no); and receipt of mediastinal radiotherapy (yes vs. no). The Kaplan-Meier method and multivariate Cox regression model analysis were used to analyze predictors for RTH. Further, patients were divided into two groups according to the occurrence of RTH during follow-up, and Kaplan-Meier survival analysis was used to analyze the prognostic value of RTH. RESULTS: The 2-12-year-old group had a shorter duration from the end of therapy to RTH than the 13-18-year-old group (median: 3 months vs. 16 months) and a higher rate of RTH (97.1% vs. 60.3%, P < 0.001). The lymphoma thymic non-infiltration group had a shorter duration from the end of therapy to RTH than the lymphoma infiltration group (median: 4 months vs. 22 months), and a higher rate of RTH (88.2% vs. 57.6%, P < 0.001). The non-mediastinal radiotherapy group had higher rate of RTH than the mediastinal radiotherapy group (84.7% vs. 12.5%, P < 0.001). Low age, absence of thymic infiltration by lymphoma at baseline, and absence of mediastinal radiation were predictors for RTH by multivariate Cox regression analysis (P < 0.05). The RTH group had a lower recurrence rate than the non-RTH group (13.9% vs. 40%), and a longer duration from the end of therapy to recurrence (median: 10 months vs. 5 months, P < 0.001). CONCLUSIONS: Younger age, absence of thymic infiltration by lymphoma at baseline and absence of mediastinal radiotherapy are predictors for RTH in children and adolescents. RTH may be a positive prognostic factor.

[An enlarged thymus associated with Graves' disease]. / Een vergrote thymus bij ziekte van Graves.

BACKGROUND: Thyrotoxicosis and orbitopathy are the best-known expressions of Graves' disease. There are also rarer and less-known phenomena, such as thymic hyperplasia. Identification of these is important in order to avoid potentially unnecessary invasive interventions. CASE DESCRIPTION: In the case of two young women with lung embolisms, CT pulmonary angiography also revealed an enlarged thymus. This turned out to be caused by as of yet unknown Graves' disease. Since pathological examination of a thymus-biopsy sample was unable to rule out thymoma, thymectomy was performed on the first patient. Pathological examination of the entire thymus revealed hyperplasia. Additional FDG-PET/CT scan of the second patient revealed diffuse hyperactivity in the diffusely enlarged thymus. In this case, we opted for expectant treatment. A follow-up FDG-PET/CT scan 1 year later, revealed a non-abnormal thymus. CONCLUSION: An enlarged thymus caused by thymic hyperplasia is a less well-known manifestation of Graves' disease. In case additional abnormalities develop in patients with Graves' disease, it is important to consider that these might be related to the disease before diagnosing an additional new condition.

Modified unilateral video-assisted thoracoscopic extended thymectomy for myasthenia gravis using 5-mm incisions: A case report.

RATIONALE: Myasthenia gravis (MG) is the most common cause of acquired neuromuscular junction disorder. Thymectomy has been established as an effective therapy for MG, as it attenuates the natural course of the disease and may result in complete remission. PATIENT CONCERNS: We report the case of a 22-year-old female with a 6-year history of MG presented with bilateral ptosis, diplopia, and intermittent dysphagia. She denied shortness of breath, dysarthria, and fatigue. DIAGNOSES: She had been diagnosed with MG 6 years previously at the Neurology Department of our hospital. A computed tomography (CT) scan revealed thymic hyperplasia INTERVENTIONS:: She was treated with modified unilateral VATET that minimized incision size. OUTCOMES: Unilateral VATET was performed using two 5-mm incisions to minimize pressure on intercostal soft tissues/nerves and reduce postoperative pain. LESSONS: The lesson learnt from this case report is that this modified VATET method could be a useful approach to the management of non-thymomatous MG. The ability to achieve complete dissection with good cosmetic results may lead to wider acceptance of this technique by patients with MG and their neurologists for earlier thymectomy and improved outcomes. Additional studies are needed to determine the superiority of this approach to established methods.

Rebound thymic hyperplasia after adrenalectomy in a patient with Cushing syndrome caused by adrenocortical adenoma: A case report.

RATIONALE: The development of rebound thymic hyperplasia (RTH) has been reported in patients who have recovered from stressful conditions such as surgery and steroid therapy. We report a case of RTH following the resolution of hypercortisolism after adrenalectomy for the treatment of adrenocortical adenoma in a patient with Cushing syndrome. PATIENT CONCERNS: A 5-month-old female infant with a history of overeating, hirsutism, and excessive weight gain for the previous 2 months was referred to the hospital. The laboratory results revealed elevated 24-hour urinary free cortisol levels. An overnight dexamethasone suppression test showed no response. Abdominal imaging revealed a right-sided suprarenal mass measuring 4_3cm. Histology showed an adrenocortical adenoma. Thus, she underwent a right adrenalectomy. DIAGNOSES: The patient showed clinical improvement with weight loss and normal cortisol levels over the next 4 months. Six months after the operation, a chest computed tomography showed enlargement of the left thymic lobe, which was previously nonexistent. INTERVENTIONS: A fine needle aspiration biopsy was performed, and histological examination revealed diffuse thymic hyperplasia. OUTCOMES: At the 1-year follow-up, the chest imaging studies showed resolution of the RTH. LESSIONS: An understanding of RTH after adrenalectomy as a treatment for cortisol-producing adrenocortical tumors is important for the prevention of unnecessary surgical intervention and therapy.

miR-548k regulates CXCL13 expression in myasthenia gravis patients with thymic hyperplasia and in Jurkat cells.

Myasthenia gravis (MG) is a B cell-mediated and T cell-dependent autoimmune disease. Thymic hyperplasia has great significance for MG pathogenesis and treatment. MicroRNAs (miRNAs) are a newly recognized type of gene expression regulatory factor that regulate gene expression at the post-transcriptional level. Additionally, miRNAs are involved in immune regulation of the thymus and the occurrence and development of autoimmune diseases. In this study, we found 33 miRNAs that were significantly dysregulated in thymic tissues from MG patients with thymus hyperplasia (MGH) compared with thymic tissues from normal controls using a miRNA microarray chip. We found a negative correlation between the miR-548k and CXCL13 mRNA levels in a large set of samples using quantitative real-time polymerase chain reaction (qRT-PCR). We found that the CXCL13 3'-untranslated region (UTR) was a target of miR-548k using bioinformatics analysis. Next, we obtained direct evidence that CXCL13 is a target of miR-548k using a luciferase reporter assay. Finally, we demonstrated negative regulation between mir-548k and CXCL13 in Jurkat cells. Thus, miR-548k regulates the mRNA expression of its target gene CXCL13 in the thymus of MGH patients and plays an important role in MGH pathogenesis.

The thymidylate synthase enhancer region (TSER) polymorphism increases the risk of thymic lymphoid hyperplasia in patients with Myasthenia Gravis.

BACKGROUND: Myasthenia Gravis (MG) is caused, in approximately 80% of the patients, by autoantibodies against the nicotinic acetylcholine receptor (AChR). The disease is often associated with pathological changes of the thymus: thymic epithelial tumours are present in about 10-20% of the patients, while up to 80% of the patients with early disease onset have thymic hyperplasia. Folate metabolism is required for the production of DNA precursors and for proper DNA methylation reactions, and impaired folate metabolism has been often associated with cellular growth and cancer. METHODS: We investigated if major polymorphisms of folate-related genes, namely MTHFR c.677C>T, MTR c.2756A>G, MTRR c.66A>G and TYMS TSER (a 28-bp tandem repeat in the 5' promoter enhancer region of TYMS) increase the risk of pathological changes of the thymus in AChR+ MG patients. A total of 526 AChR+ MG patients, including 132 patients with normal (involuted) thymus, 146 patients with thymic hyperplasia, and 248 patients with a thymoma were included in the study. Allele and genotype comparisons were performed among the three study groups, after correcting for multiple testing. RESULTS: The frequency of the TYMS TSER 3R allele was significantly higher in MG patients with thymic hyperplasia (P=0.004), and the TYMS TSER 3R3R genotype was significantly associated with increased risk of thymic hyperplasia [OR 2.71 (95% CI: 1.34-5.47)]. CONCLUSIONS: The 3R allele in the thymidylate synthase promoter enhancer region results in increased protein production, required for the synthesis of DNA precursors. The present study suggests that the TYMS TSER 3R allele increases the risk of thymic lymphoid hyperplasia in AChR+ MG patients.

[VATS THYMECTOMY IN MYASTHENIA GRAVIS TREATMENT--A CASE REPORT]. / VATS TIMEKTOMIJA U LIJECENJU MIASTENIJE GRAVIS--PRIKAZ BOLESNICE.

Myasthenia gravis (MG) is a chronic autoimmune disease characterized by weakness of skeletal muscles, specifically ocular. Relationship between the thymus gland and MG is not fully understood yet. Thymectomy is recommended for individuals with thymoma, but should be considered in all patients under 60 years of age with generalized MG in cases with no thymomatous tissue. We report a 27-year-old female patient with ocular type myasthenia gravis and radiological findings of anterior mediastinal mass, treated by VATS thymectomy. The intervention was carried out by 3-portal right-sided thoracoscopic approach. Single-lung ventilation and carbon-dioxide insufflation provided working space, and harmonic scalpel was used for the dissection and ligation. The patient's postoperative course was uncomplicated and the patient was discharged on the third postoperative day. The aim of our case report is to stress the importance of VATS technique in faster recovery and better cosmetic effect than in sternotomy procedures.

Thymic lymphoid hyperplasia with multilocular thymic cysts diagnosed before the Sjögren syndrome diagnosis.

BACKGROUND: Thymic lymphoid hyperplasia is often present with myasthenia gravis as well as other autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Of the 4 cases of thymic lymphoid hyperplasia associated with Sjögren syndrome that have been reported, no case with a thymic lesion diagnosis that led to the diagnosis of Sjögren syndrome has been reported. We herein report a case of thymic lymphoid hyperplasia with multilocular thymic cysts, diagnosed before Sjögren syndrome. CASE PRESENTATION: A 37-year-old Japanese woman had an approximate 5-cm anterior mediastinal mass detected by chest imaging. The resected lesion revealed multilocular thymic cysts that were filled with colloid-like material. Histology showed lymph follicular hyperplasia with many epithelial cysts. The epithelium consisted of thymic medullary epithelium, and no epithelial proliferation was seen in the lymphoid tissue. Lymphocytes were composed of an organized mixed population of mature T and B cells without significant atypia. The infiltrated B cells did not reveal light chain restriction or immunoglobulin heavy chain gene rearrangement. After the pathological diagnosis of thymic lesion, tests for the presence of autoantibodies were positive for antinuclear antibodies, rheumatic factor, and anti-SSA/Ro antibodies. The Schirmer's, chewing gum, and Saxon tests showed decreased salivary and lacrimal secretion. Lip biopsy showed focal lymphocytic sialadenitis. The signs and symptoms of Sjögren syndrome had not resolved, without aggravation, 1 year after the thymectomy. CONCLUSION: When a case with thymic lymphoid hyperplasia without myasthenia gravis is encountered, it is essential to consider the presence of another autoimmune disease including Sjögren syndrome.

Thymic hyperplasia following chemotherapy in adults with lymphoma: (18)F-fluorodeoxyglucose positron emission tomography/computed tomography findings and correlation with T cell repopulation.

Thymic hyperplasia (TH) after chemotherapy is an infrequent phenomenon in adults. This study analyzed the incidence and metabolic activity of TH on 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in this population. By reviewing 471 PET/CT recordings of 211 adults with lymphoma, increased FDG uptake within an enlarged thymus regarded as TH was observed in 27 patients aged 18-53 years. FDG uptake in hyperplastic thymus was mild and diffuse, with a maximum standard uptake value (SUVmax) of 2.6±0.9. Its intensity varied with different occurrence times following chemotherapy. In addition, by comparing the recovery of T cell subsets in patients with TH (n=20) and without TH (n=28), no impact of the presence of TH was found on the repopulation of total CD4+and CD8+T cells within the first year after treatment. These data may be helpful to avoid misinterpretation of increased thymic uptake in adults.

Thymic uptake after high-dose I-131 treatment in patients with differentiated thyroid carcinoma: a brief review of possible causes and management.

PURPOSE: To report five cases of patients diagnosed with differentiated thyroid carcinoma (DTC) with uptake in the thymic area after high-dose treatment with I-131 and to evaluate the potential causes and therapeutic management. METHODS: Five cases of young female patients with a mean age of 36.6 years (24-43) who had been treated with a mean dose of 106 mCi of I-131 (100-150 mCi) showing tracer uptake in the thymic area are reported. An I-131 whole-body scan (131I-WBS) was performed 7 days after therapeutic dose administration to each patient. Anterior and posterior planar images, followed by SPECT/CT of the head, neck and superior mediastinum were acquired in all patients. Thyroglobulin levels were measured with and without hormone replacement therapy in all cases. Samples taken from the superior mediastinum were sent to pathology for analysis, which confirmed the presence of thymic tissue. RESULTS: Two patients underwent elective total thymectomy due to the gross characteristics of the gland, local 131-I uptake, and high thyroglobulin levels. The remaining three patients had already undergone thymectomy as part of neck dissection during initial surgery, and no further invasive interventions were therefore performed. Pathological examination revealed no metastases in these five patients. CONCLUSIONS: Thymus visualization in young patients after administration of therapeutic doses of I-131 seems to be a more common finding than usually thought. Absence of metastasis in the thymus despite high thyroglobulin levels was confirmed in all cases. Based on these results, we suggest that a more expectant and less aggressive therapeutic approach could be used. We also suggest that I-131 therapy for DTC should be considered in classification of the potential causes of true thymic hyperplasia in the subgroup of patients recovering from a stressor.

Rebound thymic hyperplasia detected by 18F-FDG PET/CT after radioactive iodine ablation therapy for thyroid cancer.

BACKGROUND: Rebound thymic hyperplasia (RTHP) is not an uncommon finding after radiation or chemotherapy in patients with various malignancies. However, there are limited case reports of this phenomenon after radioactive iodine ablation therapy (RIAT) in differentiated thyroid cancer (DTC). The goal of this study was to evaluate the incidence, patterns, and factors affecting RTHP after RIAT using (18)F-FDG PET/CT. METHODS: The study design was a retrospective review of 2550 patients (568 men, 1982 women; age 13-79 years) who underwent FDG PET/CT imaging after total thyroidectomy and RIAT from June 2009 through June 2012. Patients were divided into four age-related subgroups. Overall incidence, age-related incidences, and sex distribution were evaluated in patients with thymic FDG uptake on PET/CT (RTHP+). The correlation between incidence of RTHP and age was assessed using the Cochran-Armitage trend test. The Wilcoxon rank-sum test and multiple regression were applied to investigate the effect of applied dose of radioactive iodine (RAI) and age on the incidence of RTHP. Correlations of standardized uptake value (SUV) and thymic volume with age and morphologic type were also evaluated. RESULTS: Overall incidence of RTHP after RIAT was 1.49%, and all of the RTHP+ patients except one were female. The Cochran-Armitage trend test revealed significantly decreased incidence from the second to fifth decade (8.84%, 1.74%, 0.98%, and 0.39% respectively; p<0.001). In each age-related subgroup, the RAI dose was significantly higher in the RTHP+ than RTHP- group (p<0.001), while there was no difference in RAI dose in RTHP+ patients among age-related subgroups (p=0.838). SUVmean and SUVmax of RTHP revealed no meaningful correlation with RAI dose or age. There were no differences among morphologic patterns of RTHP in age distribution and ablation dose. CONCLUSIONS: RTHP after RIAT showed a strong female predominance, despite the higher administration dose of RAI in male patients. Although the decreased incidence of RTHP after RIAT with age is similar to the pattern of RTHP induced by other causes, the fact that older patients, even sixth decade patients, can present with RTHP after RIAT is noteworthy in the management of DTC.

Bone loss in surgically ovariectomized premenopausal women is associated with T lymphocyte activation and thymic hypertrophy.

Postmenopausal osteoporosis is associated with estrogen deficiency and rapid bone loss. The mechanism by which estrogen deficiency results in bone loss has not been fully explained. Studies in mice rendered acutely estrogen deficient by ovariectomy have suggested that estrogen deficiency results in an activated T-lymphocyte phenotype and increased production of pro-osteoclastic cytokines. The aim of this study was to translate these findings from mouse models that suggest that the T lymphocyte plays an important role in the etiology of postmenopausal osteoporosis. We recruited premenopausal women who underwent ovariectomy for benign gynecologic conditions or for prophylaxis against ovarian cancer and a group of matched control women without ovariectomy (OVX). Subjects provided blood samples to characterize T-lymphocyte phenotype by flow cytometry and for T-lymphocyte culture and collection of conditioned media. Bone mineral density at the lumbar spine and left femoral neck was performed annually for 2 years, and volumetric measurements by computed tomography (CT) of the thymus were obtained during the first 6 months. We enrolled 6 patients who underwent OVX and 13 control women. The OVX subjects had a significant loss of bone mineral density at the lumbar spine and left femoral neck. The volumetric thymus measurements suggested an increase in thymus size in the OVX subjects but did not reach statistical significance owing to the small sample size. The T-lymphocyte phenotype in the OVX subjects demonstrated increased T-lymphocyte activation by flow cytometry compared to the control subjects. Our findings support the hypothesis that estrogen deficiency leads to an activated T-lymphocyte phenotype, which may contribute to the bone loss seen in estrogen deficiency. Larger clinical studies are necessary to confirm these findings.