Rebound Thymic Hyperplasia Research Articles

P.277: The relationship between rebound thymic hyperplasia and the risk of rejection in renal transplantation patients.

P.277: The relationship between rebound thymic hyperplasia and the risk of rejection in renal transplantation patients.

Divergent Immediate and Delayed Effects of Juvenile Exposure to Doxorubicin on the Thymus in C57BL/6 Mice.

The understanding of alterations within the immune system following doxorubicin (DOX) chemotherapy, and subsequent restoration, in childhood cancer survivors remains limited. This investigation endeavors to elucidate the immediate and delayed changes in thymic immune cell populations and their phenotypes in response to clinically relevant low doses of DOX in a juvenile mouse model. Male mice underwent a regimen of repeated low-dose DOX intraperitoneal injections at 4 mg/kg/week for three consecutive weeks. One week after the last dose of DOX, a subset of mice was euthanized to assess the immediate effects of DOX administration. A second subset of mice was euthanized five weeks after the last DOX dose to evaluate the delayed effects. Thymic samples were collected for multiparameter flow cytometry analysis to evaluate alterations in immune cell composition and phenotype. Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) was employed to measure gene expression of- cytokines and senescence markers. One week following DOX administration, DOX treatment resulted in significant decline in thymus weight, with notable alterations in immune cell subpopulations. Reduced frequencies of mature CD3+CD4+ and CD3+CD8+ T cells were observed, along with changes in proliferation and exhaustion markers. Gene expression analysis revealed upregulation of Foxn, Pax1, Ifnγ, and Il7 alongside decreased Il6 and Il17 expression. Furthermore, Cdkn1a (p21Cip1) expression was elevated, suggesting immunosenescence. Five weeks following DOX administration, delayed effects of DOX treatment manifested in rebound increase in thymus weight and altered frequencies of CD4+ and CD8+ T cell subsets, with distinct patterns of proliferation and exhaustion observed. Notably, central memory CD4+ T cells exhibited significant decrease in frequency, while naive and effector memory CD4+ T cells showed reduced proliferation (Ki67+) and PD1 expression. Similar trends were observed in CD8+ T cell subsets, indicating selective effects of DOX on T cell differentiation and function. Although expression of thymus-related genes was normalized, p21Cip1 gene expression remained elevated. DOX treatment elicits a multifaceted influence on immune cell subsets and thymic weight. Immediate effects included thymic atrophy and reductions in mature T cell populations, while delayed effects showed rebound thymic hyperplasia and selective changes in CD4+ and CD8+ T cell subsets. Notably, both central memory and effector memory T cells exhibited reduced proliferation and exhaustion, suggesting unique impacts of DOX on immune cell function. The enduring elevation in p21Cip1 gene expression 5 weeks after DOX treatment suggests an immunosenescent phenotype. These observations collectively illuminate the formidable task of preserving immune competence and overall well-being in childhood cancer survivors subjected to DOX therapy.

FRI042 Worsening Shortness Of Breath After A Mild Case Of Covid-19

Abstract Disclosure: K. Qureshi: None. T.S. Krause: None. K. Vidlock: None. This case demonstrates a complication of COVID 19 that may be more common than we know and overlooked. A 34-year-old female presents to the Emergency Department with worsening shortness of breath and tachycardia for 3 days. Her symptoms are worse with ambulation. She feels dizzy and lightheaded. The patient had COVID-19 about two weeks ago and received monoclonal antibodies. The patient has a history of “drenching” night sweats and unintentional weight loss. She denies fever and cough. The patient is eating and drinking normally with no abdominal pain, nausea, or rash. No changes in bowel movements. The patient’s past medical history consists of ADHD, Anxiety, Neuropathy, and Insomnia. The patient takes Adderall, amitriptyline (ELAVIL), fluocinonide (LIDEX). The patient’s family history consists of an aunt who has autoimmune disease and a maternal grandfather who has Non-Hodgkin's Lymphoma. She works as a medical assistant in a family medicine clinic. Patient underwent a CTA which displayed a new anterior mediastinal mass measuring 4.6 x 2.6 x 3.2 cm which was not shown on a previous CT scan 11 months prior. She was referred to a thoracic surgeon for mediastinoscopy, which couldn’t be performed due to location not adjacent to trachea. A PET scan showed mildly FDG-avid soft tissue density in the anterior mediastinum. Four months later, the patient had a CT scan which showed a modest decrease in size measuring 2.1 x 2.5 cm. The thymus is important in maturation of T cells and is replaced with fat through aging. The thymus plays an important immunological role in defending against pathogens and cancer by maturing and releasing T cells. Thymic hyperplasia is a response that has been displayed in autoimmune diseases such as Myasthenia Gravis. Thymic rebound hyperplasia is seen more often in children, typically after chemotherapy treatment but not seen in adults. Rebound hyperplasia occurs less often with viral illness. There have been a limited number of cases seen with COVID-19. An observational study of 87 participants suggested that rebound thymic hyperplasia may be a positive predictive factor due to the benefit of T-cell lymphocyte production. The presence of thymic hyperplasia on CT scan in COVID patients correlated with a better prognosis in a retrospective study of 325 COVID patients that had a CT scan. This patient will require repeated imaging and follow up. The long-term consequences of this finding are unknown and this patient has a history of night sweats which preceded the COVID course. Presentation: Friday, June 16, 2023

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

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. 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. 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. 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.

Novel Presentation of a Mosaic STAT5B Gain-of-Function Variant

Somatic gain-of-function (GOF) variants in STAT5B have been described in leukemias and lymphomas, and more recently in three patients presenting with nonclonal eosinophilia, atopic dermatitis, diarrhea, and urticaria. Here, we describe a 7-year-old middle-Eastern female presenting with autoimmune adrenal insufficiency and lower extremity weakness. Diagnostic studies revealed CNS demyelination and demyelinating polyneuropathy of the motor nerves. CBC was notable for leukocytosis with eosinophilia, with peak AEC at 3100 cells/cumm. Immunophenotyping demonstrated normal IgG and subclasses and IgA, elevated IgM (233.1 mg/dL), and mildly elevated IgE (135 IU/ml). T cell lymphocytosis was noted on flow cytometry. Extensive infectious and autoantibody testing was unremarkable, and flow cytometry and cytology from CSF, blood, and bone marrow were not concerning for malignancy. She was treated with IV methylprednisolone and steroid taper, followed by rituximab and IVIG. Additional imaging demonstrated an enlarged thymus thought to represent rebound thymic hyperplasia, and splenomegaly. Trio whole exome sequencing performed on a buccal sample was notable for a de novo STAT5B c.1883C>G (p.Thr628Ser) variant present in 13/111 (–12%) of sequencing reads. This STAT5B variant has been reported in T cell prolymphocytic leukemia and studies have shown this variant confers GOF. Clinical evaluation for the STAT5B variant detected mosaicism in buccal swab DNA and near 50% variant allele frequency (VAF) in blood and bone marrow. We then assessed the VAF in various cells on a research basis. The VAF in buccal DNA was 7–9%, 46–48% in whole blood, and 48% in the bone marrow. Cell sorting for CD4+ and CD8+ T cells revealed a VAF of 46–48%. A similar VAF was observed in CD56+ cells (48%) and CD14+ cells (–50%). A fibroblast line was generated from a skin punch biopsy, and the variant allele was absent, suggesting somatic origin. Preliminary data from peripheral blood flow cytometric analysis demonstrated a slight increase in Treg cells, and Th2 skewing of Tregs as implied by cell surface markers. Assessment of pSTAT5 at baseline and after cytokine stimulation suggest increased responsiveness. The patient was started on tofacitinib, a JAK inhibitor primarily targeting JAK1/JAK3. She improved clinically, weaned on steroids, and is being evaluated for HSCT.

Rebound Thymic Hyperplasia Secondary to Surgical Therapy of Parotid Tumor

Rebound Thymic Hyperplasia Secondary to Surgical Therapy of Parotid Tumor

Thymic Hyperplasia Developing After Treatment of Cushing’s Syndrome, Management and Literature Review

Thymic Hyperplasia Developing After Treatment of Cushing’s Syndrome, Management and Literature Review Introduction/ Background: Rebound thymic hyperplasia (RTH) has been described after the resolution of hypercortisolism from multiple conditions. It can potentially lead to a variety of diagnostic dilemmas. We describe a case where thymic enlargement was seen after unilateral adrenalectomy for adrenal Cushing’s syndrome. Thymic hyperplasia developing after treatment of adrenal Cushing’s syndrome has been very rarely reported. Clinical Case: 43 year old female with type 2 diabetes, hypertension, morbid obesity, depression underwent left adrenalectomy for management of Cushing’s syndrome. Two years after adenoma resection, the patient underwent a CT angiogram of the chest as part of a work up for chest pain which revealed a new anterior mediastinal soft tissue attenuation mass (30–40 Hounsfield units) measuring 6.5cm x2.5cm x 3.7cm. It was found to be abutting the inferior margin of the left brachiocephalic vein and anterior margin of the aortic arch. MRI chest demonstarated mild homogeneous postcontrast enhancement and loss of signal on the opposed phase T1 sequence indicating microscopic fat, deemed to be consistent with thymic hyperplasia. Patient had a detailed discussion of risks versus benefits of biopsy/surgery/conservative management with thoracic surgeon and opted to be managed conservatively. MRI Chest done at 3 month follow up showed a decrease in the size of the mass to 5.8 x 2.4 x 5.cm. She has been on chronic hydrocortisone therapy since adrenalectomy and multiple attempts to wean her off of steroids have been unsuccessful. She continues to be followed closely in the outpatient setting for presumed RTH. Clinical Lesson/ Conclusion: This case highlights the importance of recognizing RTH in patients treated for Cushing’s syndrome. Rapid enlargement of the thymus post adrenalectomy can often lead to unnecessary biopsies and surgeries. The underlying mechanism though unclear has been attributed to depletion of thymic lymphocytes caused by high cortisol concentrations of the plasma leading to RTH when the cortisol level declines. Keywords: Thymic Hypertrophy, Cushing’s syndrome, Thymic hyperplasia

Effect of Rebound Thymic Hyperplasia on Survival in Chemotherapy-Treated Lung Cancer.

Thymus is a lymphoepithelial system in which cells responsible for the immune system are produced and directed. The aim of this study is to determine the overall survival effect of rebound thymic hyperplasia (RTH) in patients with non-small cell lung cancer (NSCLC) treated with systemic chemotherapy (CT). The study was designed as retrospective case series. One hundred and thirty patients who met the inclusion criteria were evaluated. Demographic data, type of tumor, and treatments administered were recorded. The frequency of RTH development and the relationship between RTH development and survival was investigated. The median age of the patients was 59, and nine of 13 patients (69.4%) with RTH were iden-tified as stable disease, two patients had a partial response (15.3%), and two were evaluated as progres-sive disease (15.3%). Of the remaining 117 patients, 78 (66.6%) had stable disease, 11 (9.4%) had com-plete response, 21 (17.9%) had partial response, and seven patients were evaluated as having progressive disease (5.9%). The patients were categorized into two groups: Group 1 - without RTH and group 2 - with RTH. Thirteen (10%) of 130 patients developed RTH (group 2), while the remaining 117 (90%) patients did not have RTH (group 1). There was no difference between the two groups (59.1 years) in terms of age (p = 0.933). The RTH developed after a median time of 4.5 months (2-7 months) after CT had been administered. Overall survival was longer in patients with RTH than in patients without RTH (20.04 months) (95% CI, 4.79-35.29) vs. 10.05 months (95% CI, 8.74-11.36; p=0.049). The developing of RTH during systemic CT may be a prognostic marker in stage 4 non-small cell lung cancer.

Effect of rebound thymic hyperplasia on survival in chemotherapy treated lung cancer

Effect of rebound thymic hyperplasia on survival in chemotherapy treated lung cancer

Rebound (reactive) thymic hyperplasia after chemotherapy in children with lymphoma

IntroductionThymic 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 methodsWe 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. ResultsRebound 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 months). ConclusionRTH 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.

THYMIC HYPERPLASIA AS A CASE OF FALSE-POSITIVE PET CT IN A FEMALE WITH LYNCH SYNDROME

SESSION TITLE: Disorders of the Mediastinum 1 SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 pm - 02:15 pm INTRODUCTION: Lynch syndrome is an autosomal dominant genetic condition of defective DNA mismatch repair predisposing for malignancies. Here we present a case of Lynch syndrome with endometrial cancer and a hypermetabolic superior mediastinal lymph node on positron emission tomography-computed tomography (PET- CT). CASE PRESENTATION: An Asymptomatic 59-year old female tested positive for Lynch syndrome (PMS2 mutation) during family screening prompted by the death of her son by colon cancer after being diagnosed with Lynch syndrome. She underwent a prophylactic hysterectomy and was found to have well-differentiated adenocarcinoma of the endometrium, pT1b NxM0. Screening mammogram, colonoscopy, and upper endoscopy were negative. CT chest/abdomen/pelvis showed several lung nodules, some of which were calcified suggesting granulomas. PET-CT showed an isolated nodule (1.6 x 1.1 cm) in the upper left paratracheal area with standardized uptake values (SUV) of 11.1. She underwent ultrasound-guided biopsy of the nodule. Histopathology demonstrated scant lymphoid tissue. Flow cytometry was negative for lymphoma. Due to her Lynch syndrome and high activity on PET-CT, she underwent a second ultrasound-guided biopsy the result was suggestive of benign thymic tissue. There was no evidence of metastatic carcinoma. Repeat PET CT showed persistent hypermetabolic activity. She was referred to a thoracic surgeon for mediastinoscopy. She chose conservative observation strategy and is being followed closely. DISCUSSION: Superior mediastinal masses range from benign thymic hyperplasia to malignant etiologies such as lymphoma. Patients with Lynch syndrome are at increased risk for colorectal, endometrial, ovarian, gastric, brain, and skin cancers. However, they are not associated with chest or mediastinal malignancies.The thymus is a lymphoid organ that is active in the early years of life and atrophies in adults. Thymic hyperplasia is the proliferation of cells and increase in activity and size with normal histology seen on biopsy and is seen in young adults. Rebound thymic hyperplasia has been described in young patients treated for malignancy. (1) Increased FDG uptake was previously reported, however, the SUV ranged from 1.1 to 2.2 (2). Sakasi et al (3) reported the mean SUV to be 7.2 ± 2.9 in patients with thymic cancer. Thymic hyperplasia with SUV of 11.1 has not been reported before.Our patient had two negative core biopsies for malignancy despite having a very high SUV on PET-CT, thereby confirming a false positive scan. Our patient also did not have any obvious reasons for hyperplasia and was never treated with chemotherapy, adding to the uniqueness of the case. CONCLUSIONS: Thymic malignancies are typically associated with highly elevated SUVs on PET-CT however, on occasion, hyperplasia can cause mild elevations of an SUV. Our patient had a strongly positive PET CT but benign thymic tissue on biopsy. Reference #1: Sarji A. Physiological uptake in FDG PET simulating disease. Biomed Imaging Interv J. 2006 Oct-Dec; 2(4): e59. Reference #2: Wittram C, Fischman A, Mark E, et al. Thymic Enlargement and FDG Uptake in Three Patients: CT and FDG Positron Emission Tomography Correlated with Pathology. American Journal of Roentgenology. 2003; 180: 519-522. Reference #3: Sasaki M, Kuwabara Y, Ichiya Y, et al. Differential diagnosis of thymic tumors using a combination of 11C-methionine PET and FDG PET. J Nucl Med 1999; 40:1595-1601. DISCLOSURES: No relevant relationships by Amit Diwakar, source=Web Response No relevant relationships by Ahmad JABRI, source=Web Response no disclosure on file for Jason Lane; No relevant relationships by Colin McLaughlin, source=Web Response

RETROSPECTIVE STUDY OF THE RADIOLOGICAL FINDINGS OF THE MEDIASTINUM AFTER END-OF-TREATMENT FOR A MEDIASTINAL LYMPHOMATOUS MASS IN PEDIATRIC ONCOLOGY

Abstract BACKGROUND Reactive thymic hyperplasia, or rebound thymus, is a well-known phenomenon following chemotherapy. While rebound thymus has been described after treatment for many different malignancy, it has been more often noted after treatment for lymphomas. In children and adolescents in which the primary lymphoma was located in the mediastinum, a mediastinal mass, such as a reactive thymic hyperplasia, can be misdiagnosed as a tumor relapse. It can be difficult for the clinician to differentiate between a tumor relapse and a reactive thymic hyperplasia, which may cause unnecessary additional imaging and invasive diagnostic procedures as well as anxiety for the patient and his family. OBJECTIVES The main objective was to measure the incidence of reactive thymic hyperplasia following treatment for a paediatric mediastinal lymphoma. The secondary objectives were to describe the radiologic findings which may help differentiate thymic hyperplasia and tumor relapse and to analyse if the finding of a mediastinal mass changed the clinical management. DESIGN/METHODS We conducted a retrospective cohort study. The consent for reviewing medical files was obtained from the institutional ethics board. We obtained data from the archives at the Centre mère-enfant Soleil, CHU de Québec. The medical and radiologic files of 72 paediatric patients which completed two years of follow-up after the treatment for mediastinal lymphoma were reviewed. The radiologic imaging reports were analysed and the patients were classified depending if they developed a mediastinal mass during follow-up or not. If a mass was developed, its characteristics were described to differentiate between a tumor relapse and a thymic hyperplasia. Statistical analyses were performed using SAS 9.4 Statistical Software (Institute SAS, Cary, NC, USA). Descriptive analysis includes mean ± standard deviation, range and median, interquartile range for continuous variables, and frequency and percentage for categorical. Bivariate tests were used to compare the rebound thymic hyperplasia group with the group without this problem. RESULTS The patients were followed for a mean of 27.7 ± 28.0 months (95% CI 21.1–34.2) and a median of 12.6 months. Of seventy-two patients reviewed, thirty-nine (54.2%) developed a mediastinal mass at follow-up. Of them, three had a mediastinal relapse of their tumor. One patient had a lymphoma relapse located elsewhere than the mediastinum and a benign rebound mediastinal mass. Thirty-five out of the 72 patients (48.6%, 95% CI 37.3%-60%) developed a benign mediastinal mass and were diagnosed with having rebound thymic hyperplasia. Of those thirty-five patients, twelve were investigated with additional imaging, and one had a mediastinal biopsy showing true thymic hyperplasia. The other twenty-three were followed-up according to the clinician, with no modification to their follow-up because of the mediastinal mass. These results are shown in Table 2. The majority of the rebound thymic hyperplasia were a mass of triangular shape, with well-defined margins and homogenous density. It remained unchanged or minimized at follow-up, but it was noted that three patients had an augmentation of the hyperplasia at follow-up, while remaining disease-free. The age <14 years old was a risk factor in our population (Hazard Ratio (HR) 1.95, p=.0491). CONCLUSION Reactive thymic hyperplasia is a common phenomenon showed in half of our cohort of patients. Some radiological findings, including triangular shape, well defined margins and mild homogenous enhancement, oriented towards a rebound thymic hyperplasia. Additional imaging study should be limited to patients whose rebound mass or symptoms make the clinician suspect a tumor relapse. A prospective cohort study with standardized care should be conducted to better characterize the rebound thymic hyperplasia and help the clinician approach a mediastinal mass at follow-up.

Rebound thymic hyperplasia after bone marrow transplantation in children with haemato-oncological diseases.

Aim of the studyTo evaluate prevalence of rebound thymic hyperplasia (RTH) after bone marrow transplantation (BMT) in paediatric patients with haemato-oncological diseases.Material and methodsBetween February 2013 and December 2017, BMT was performed in 189 paediatric patients with haemato-oncological diseases in our institution. Fifty-six patients who underwent at least two chest computed tomography (CT) exams performed before and after BMT were included in the study. Maximum transverse and anterior-posterior (AP) diameters and CT attenuation of the thymus were measured on axial images. Thymic enlargement was considered when both transverse and AP diameters increased. RTH was defined as the presence of thymic enlargement on CT after BMT relative to the CT taken before.ResultsTwenty of 56 patients (36%) demonstrated RTH (12 boys, 8 girls; age range = 4-18 years; median age = 9.8 years). In 20 patients with RTH, seven patients (35%) were diagnosed with ALL, five patients (25%) with thalassemia, two patients (10%) with AML, and one patient (5%) with various diseases. Mean follow-up period between pre-BMT CT and BMT was 46 days, which was 239 days between BMT and post-BMT CT. Mean thymic transverse and AP diameters were 9 mm and 16 mm, respectively, before BMT, which were 17 mm and 33 mm after BMT. Mean HU was 57 on contrast enhanced and 35 on unenhanced images before BMT, which were 59 and 36, respectively, after BMT.ConclusionsRTH is common finding after BMT in children with various haemato-oncological diseases and should be taken under consideration in paediatric patients after BMT.

Investigating Factors Associated with Thymic Regeneration after Chemotherapy in Patients with Lymphoma.

The factors involved in thymus regeneration after chemotherapy has not been sufficiently explored. This study was aimed to identify the clinical characteristics and single-nucleotide polymorphisms in the gene (IL7R) encoding IL-7Rα associated with thymus renewal after chemotherapy in Chinese Han individuals with lymphoma. The dynamics of thymic activity in 134 adults with Hodgkin lymphoma (HL) and B cell lymphoma from baseline to 12 months post-chemotherapy were analyzed by assessing thymic structural changes using serial computed tomography scans and correlating these with measurements of thymic output by concurrent analysis of single-joint T-cell receptor excision circles (sjTREC) and CD31+ recent thymic emigrants (RTE) in peripheral blood. The association of clinical variables and IL7R polymorphisms with the occurrence of rebound thymic hyperplasia (TH) and the recovery of thymic output following chemotherapy were evaluated. Thymic regeneration was observed, with the evidence that TH occurred in 38/134 (28.4%) cases, and thymic output, assessed by CD31+ RTE numbers and sjTREC content, recovered to baseline levels within 1 year after the end of therapy. The frequencies of the T allele and TT + GT genotype of rs7718919 located in the promoter of IL7R were significantly higher in patients with TH compared with those without TH (P = 0.031 and 0.027, respectively). In contrast, no significant difference was found between two groups with respect to the distribution of allele and genotype frequencies of rs6897932. By general linear models repeated-measure analysis, rs7718919 and rs6897932 were determined to exert no significant effects on the recovery of thymic output after therapy. Univariate analysis revealed host age under 30, the diagnosis of HL, baseline thymic index and CD31+ RTE counts, and rs7718919 genotype as potential predictors for TH after chemotherapy (P < 0.05); after multivariate adjustment, only host age was independently associated with the occurrence of TH (odds ratios = 4.710, 95% confidence intervals: 1.727–12.845, P = 0.002). These findings indicate that patient age is an independent predictor for thymic regrowth after chemotherapy, which should promote awareness among physicians to make a timely diagnosis of TH in young adults and help physicians to prioritize intervention strategies for thymus rejuvenation in this population.

Rebound Thymic Hyperplasia after Chemotherapy in Children with Lymphoma

Development of mediastinal masses after completion of chemotherapy in pediatric patients with malignant lymphoma is worrisome and challenging to clinicians. We performed a retrospective review of 67 patients with lymphoma treated at our hospital from January 1, 2001 to June 1, 2013. Patients who received at least two chest computed tomography (CT) examinations after complete remission (CR) was achieved were further analyzed. Gallium-67 scans and positron emission tomography (PET) were recorded and compared between these patients. Sixty-two of 67 patients reached CR, of whom 31 (22 male, 9 female) were patients that received at least two chest CT examinations after CR. Rebound thymic hyperplasia (RTH) was diagnosed in 21/31 patients (67.7%), including 14/23 (60.9%) and seven out of eight (87.5%) with non-Hodgkin's lymphoma and Hodgkin's lymphoma, respectively. Ages ranged from 3years to 18years (median 10years). Increased radioactivity uptake of the anterior mediastinum in gallium scans was found in nine out of 20 patients (45%) with thymic rebound. PET was performed in six out of 21 patients. Increased fluorodeoxyglucose (FDG)-avid uptake in the anterior mediastinum was observed in four of six patients (66.7%) by PET. One patient received thymectomy. No patients with RTH had lymphoma relapse within the median follow-up period (5years). Relapse was statistically significantly different (p=0.001) between patients with and without RTH. RTH developed in 67.7% of pediatric patients with lymphoma in CR after chemotherapy. The association of RTH development and lowered relapse rates has yet to be determined. Awareness of this phenomenon is important in the prevention of unnecessary surgical intervention or chemotherapy.

Thymic hyperplasia after chemotherapy in adults with mature B cell lymphoma and its influence on thymic output and CD4+ T cells repopulation

ABSTRACTTo investigate the thymic regenerative potential in adults accepting chemotherapy for lymphoma. The dynamics of thymic activity in 54 adults from baseline to 12 mo post-chemotherapy was analyzed by assessing thymic structural changes with serial computed tomography (CT) scans, and correlating these with measurements of thymic output by concurrent analysis of single-joint (sj) T-cell receptor excision circles (sjTREC) and CD31+ recent thymic emigrants (RTE) in peripheral blood. Furthermore, the consequence of thymic renewal on peripheral CD4+ T cell recovery after chemotherapy was evaluated. Time-dependent changes of thymic size and thymic output assessed by both sjTREC levels and CD31+ RTE counts in peripheral blood were observed during and after chemotherapy. Enlargement of thymus over baseline following chemotherapy regarded as rebound thymic hyperplasia (TH) was identified in 20 patients aged 18−53 y (median 33 y). By general linear models repeated measure analysis, it was found that, patients with TH (n = 20) had a faster recovery of sjTREC levels and CD31+ RTE counts after chemotherapy than patients with comparable age, gender, diagnosis, disease stage, thymic volume and output function at baseline but without TH (n = 18) (p = 0.035, 0.047); besides, patients with TH had a faster repopulation of both naïve CD4+ T cell and natural regulatory CD4+ T cell subsets than those without TH (p = 0.042, 0.038). These data suggested that adult thymus retains the capacity of regeneration after chemotherapy, especially in young adults. The presence of TH could contribute to the renewal of thymopoiesis and the replenishment of peripheral CD4+ T cell pool following chemotherapy in adults.

Thymic 18F-FDG PET/CT Findings in Pediatric Malignant Lymphoma after Chemotherapy: Differentiation of Long-Lasting Thymic Hyperplasia from Lymphoma Recurrence

BackgroundThymic FDG uptake due to rebound thymic hyperplasia after chemotherapy for cancers including malignant lymphoma (ML) is relatively widely-recognized phenomenon, especially in children. However, its occurrence rate based on ages and intensity of chemotherapy for various cancers has not really investigated. Therefore, to make clear distinction between thymic hyperplasia and lymphoma recurrence would be often difficult. To avoid misdiagnosis or unnecessary biopsies, recent report emphasized the importance to be aware of the possibility of thymic hyperplasia after chemotherapy. Another group suggested that SUV alone could be sufficient for differential diagnosis. However the duration showing rebound thymic hyperplasia after chemotherapy has never been studied so far, and there are no reports about the difference between rebound thymic hyperplasia and malignancy from the aspect of the morphological thymic uptake pattern. In this study, we investigated: 1) how long rebound thymic hyperplasia could last and 2) whether SUV alone would be sufficient or using additional findings such as the pattern of uptake (diffuse or nodular) would become much easier to distinguish them.MethodFrom 2010 to 2014, eleven pediatric patients with ML were enrolled (ALCL 3, T-LBL 3, B-LBL 1, Burkitt lymphoma 2, DLBCL 2). PET/CT findings before and after completion of chemotherapy or autologous/allogeneic hematopoietic stem cell transplantation (HSCT) were reviewed retrospectively.ResultsDiffuse thymic FDG uptake before chemotherapy was seen in 3 patients with T-LBL (mean SUV 7.9, range 5.5-12.5). Seven cases showed diffuse uptake in thymus after completion of therapy with relatively low SUV (mean SUV 3.4, range 2.2-5.2). We eventually considered all of them as rebound thymic hyperplasia and they are alive. On the other hand, one patient with nodular uptake in thymus (SUV 6.4) accompanied with high sIL-2R was finally diagnosed lymphoma recurrence by biopsy. The timing appearing thymic uptake after chemotherapy alone and high-dose chemotherapy with autologous HSCT were 2.8 months (range 1-7 months) and 8.0 months (range 6-10 months), respectively. In contrast, two patients receiving allogeneic HSCT did not show thymic hyperplasia anymore. Interestingly rebound thymic hyperplasia was persistently observed once it occurred and even in some cases the SUV increased slowly during follow period. The longest case in our cohort is 4.5 years at present time.ConclusionDiffuse thymic uptake with low SUV after chemotherapy could be rebound thymic hyperplasia unless relapse was suspected by any symptoms or abnormal laboratory findings. Rebound hyperplasia was frequently observed in pediatric patients, and once it occurs, it could last at least couple of years. More importantly, in case of nodular uptake, thymic recurrence should be strongly considered especially when accompanied with high SUV. DisclosuresNo relevant conflicts of interest to declare.

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

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. 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. 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. 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.

Chemotherapy Definitions and Policies for Thymic Malignancies

Thymic malignancies are rare epithelial tumors that may be aggressive and difficult to treat.1 Thymomas are usually localized to the anterior mediastinum and are frequently eligible for upfront surgical resection, which is the mainstay of the curative-intent treatment.1 However, approximately 30% of patients present with an advanced tumor at the time of diagnosis, with invasion of neighboring organs, dissemination to the pleura, the pericardium, or less frequently extrathoracic organs. In such cases, chemotherapy has been used both to reduce the tumor burden—possibly allowing subsequent surgery or radiotherapy—and to achieve prolonged disease control. Recurrence after resection may be similarly treated with chemotherapy. Thymic carcinomas, although rare, are usually already advanced at the time of presentation, and systemic therapy is important for almost all of these patients. Knowledge regarding chemotherapy for thymic tumors has mainly been based on retrospective series,2–9 although several prospective trials have also been conducted.10–21 These studies have clearly demonstrated the chemosensitivity of thymoma, and to a lesser extent thymic carcinoma, to various cytotoxic agents and combinations. However, details of patient selection are often lacking (either disease extent or general condition), and the intent of the treatment sequence is often vague. Adoption of a common language and definition of terms is crucial for the International Thymic Malignancies Interest Group (ITMIG) effort to develop a international prospective database of thymic tumors. The article by Huang et al.22 provides definitions for survival and endpoints for recurrences assessment and discusses how to measure response to treatment. Herein, we discuss additional points with regard to chemotherapy, including treatment sequence, general modalities, and impact of corticosteroids.

Technetium-99m depreotide imaging by single photon emission tomography/low resolution computed tomography in malignant lymphomas: comparison with gallium-67 citrate

Previous studies have demonstrated the feasibility of targeting lymphoma lesions with somatostatin receptor binding agents, mainly with In-111-pentetreotide. In the present work another somatostatin analog, Tc-99m depreotide, is investigated. One-hundred and six patients, 47 with Hodgkin's (HL) and 59 with various types of non-Hodgkin's lymphoma (NHL), were imaged with both Tc-99m depreotide and Ga-67 citrate. Planar whole-body and single photon emission tomography/low resolution computerized tomography (SPECT/CT) images were obtained. A total of 142 examinations were undertaken at different phases of the disease. Depreotide and gallium findings were compared visually and semi-quantitatively, with reference to the results of conventional work-up and the patients' follow-up data. In most HL, intermediate- and low-grade B-cell, as well as in T-cell NHL, depreotide depicted more lesions than Ga-67 and/or exhibited higher tumor uptake. The opposite was true in aggressive B-cell NHL. However, there were notable exceptions in all lymphoma subtypes. During initial staging, 93.3% of affected lymph nodes above the diaphragm, 100% of inguinal nodes and all cases with splenic infiltration were detected by depreotide. On the basis of depreotide findings, 32% of patients with early-stage HL were upstaged. However, advanced HL and NHL cases were frequently downstaged, due to low sensitivity for abdominal lymph node (22.7%), liver (45.5%) and bone marrow involvement (36.4%). Post-therapy, depreotide detected 94.7% of cases with refractory disease or recurrence. Its overall specificity was moderate (57.1%). Rebound thymic hyperplasia, various inflammatory processes and sites of unspecific uptake were the commonest causes of false positive findings. The combination of depreotide and gallium enhanced sensitivity (100%), while various false positive results of either agent could be avoided. Except perhaps for early-stage HL, Tc-99m depreotide as a stand-alone imaging modality has limited value for the initial staging of lymphomas. Post-therapy, however, depreotide scintigraphy seems useful in the evaluation of certain anatomic areas, particularly in non-aggressive lymphoma types. The combination with Ga-67 potentially enhances sensitivity and specificity. If fluorodeoxyglucose positron emission tomography is not available or in case of certain indolent lymphoma types, Tc-99m depreotide may have a role as an adjunct to conventional imaging procedures.