Rebound Thymic Hyperplasia After Chemotherapy in Children

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ORIGINAL ARTICLE Rebound Thymic Hyperplasia after Chemotherapy in Children with Lymphoma Chih-Ho Chen a, Chih-Chen Hsiao a, Yu-Chieh Chen a, Sheung-Fat Ko b, Shu-Hua Huang c, Shun-Chen Huang d, Kai-Sheng Hsieh a, Jiunn-Ming Sheen a,*

a Department of Pediatrics, Chang Gung Memorial HospitaldKaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan b Department of Radiology, Chang Gung Memorial HospitaldKaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan c Department of Nuclear Medicine, Chang Gung Memorial HospitaldKaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan d Department of Pathology, Chang Gung Memorial HospitaldKaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan

Received Sep 24, 2015; received in revised form Nov 30, 2015; accepted Feb 5, 2016 Available online ---

Key Words Background: Development of mediastinal masses after completion of chemotherapy in pediat- lymphoma; ric patients with malignant lymphoma is worrisome and challenging to clinicians. prognosis; Methods: We performed a retrospective review of 67 patients with lymphoma treated at our rebound thymic hospital from January 1, 2001 to June 1, 2013. Patients who received at least two chest hyperplasia; computed tomography (CT) examinations after complete remission (CR) was achieved were recurrence further analyzed. Gallium-67 scans and positron emission tomography (PET) were recorded and compared between these patients. Results: 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 3 years to 18 years (median 10 years). 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 (5 years). Relapse was statistically signiﬁcantly different (p Z 0.001) between patients with and without RTH.

* Corresponding author. Chang Gung Memorial HospitaldKaohsiung Medical Center, 123 Ta-Pei Road, Niao Sung, Kaohsiung, 833, Taiwan. E-mail address: [email protected] (J.-M. Sheen).

http://dx.doi.org/10.1016/j.pedneo.2016.02.007 1875-9572/Copyright ª 2016, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY- NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Conclusion: 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. Copyright ª 2016, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).

1. Introduction IL, USA). We used the chi-square or Fisher exact tests to compare the categorical variables. The chi-square test was Development of anterior mediastinal mass after the used initially in our study. However, if there was a quadrant < completion of chemotherapy in children with malignant with expected frequencies 5, the Fisher exact test was e lymphoma is worrisome. Although rebound thymic hyper- used instead. The Mann Whitney U test was used to plasia (RTH) is not uncommon in patients after chemo- compare the continuous variables. Additionally, Cox pro- therapy,1 concern regarding lymphoma relapse may lead to portional hazards models were ﬁtted with covariates further unnecessary diagnostic procedures and chemo- selected using a backward stepwise approach. For time- therapy. Differentiation of RTH from lymphoma relapse is dependent analysis, cases that did not experience relapse essential for clinicians. Furthermore, the relationship be- were right-censored at the end of the follow-up period to tween RTH and the prognosis of lymphoma is not very clear. control for potential differences in the duration of follow < Therefore, we wish to establish possible answers based on the up. A two-tailed p value 0.05 was considered statistically review of cases treated at our facility over the past 13 years. signiﬁcant.

3. Results 2. Methods Sixty-two of 67 patients reached CR after chemotherapy. We performed a retrospective review of 67 patients diag- The follow-up period ranged from 13 months to 13 years. nosed with non-Hodgkin’s lymphoma (NHL) or Hodgkin’s Thirty-one patients (23 NHL, 8 HL; 22 male, 9 female) had lymphoma (HL) in a single tertiary medical center in atleasttwochestCTstudiesafterCR(Figures 1 and 2). southern Taiwan from January 1, 2001 to December 31, All but two patients had initial chest CT studies at the 2013, with follow up to their clinical course until May 30, time of lymphoma diagnosis. Of 29 patients with initial 2015. The responses were evaluated according to the In- chest CT studies, 20 patients (64.5%) had initial thoracic ternational Working Group response criteria.2 Complete disease at the time of diagnosis. Twenty-one patients remission (CR) was defined as complete disappearance of (67.7%) developed RTH (Table 1). Among the patients with all detectable clinical evidence of disease and disease- RTH, 14 patients (60.9%) were diagnosed with NHL and related symptoms if present before therapy.2,3 The defini- seven patients (87.5%) with HL. RTH was supported by tion of relapse was as follows: (1) appearance of a new evidence that there was a lack of uptake in other sites, lesion(s) > 1.5 cm in any axis; (2) 50% increase in the sum and by resolution of an enlarged thymus later. Ages of the product of the diameters of more than one lesion ranged from 3 years to 18 years, with a median age of from the nadir; and (3) 50% increase in the longest 10 years. Thymus enlargement resolved gradually to diameter of a previously identified lesion > 1 cm in short normal size within the time period of 3 months to 5 years. axis from the nadir.2,3 Thymic craniocaudal extent, Seven of 21 cases had RTH that persisted for more than maximum anteroposterior, and transverse dimensions were 2 years. No lymphoma relapse was noted in any patients measured using computed tomography (CT) scans. An in- with RTH at follow up. crease in thymus size was considered when all of the cra- Some patients with chest CT-confirmed RTH also niocaudal, anteroposterior, and transverse dimensions received gallium-67 and PET scans. Twenty of 21 patients increased. RTH was defined as an increase in thymus size with RTH received gallium scan studies. Increased gallium- relative to the previous CT scan when patients achieved CR 67-avid radioactivities in the anterior mediastinum (1 after chemotherapy. We also reviewed the results of representative is shown in Figure 3A) were noted at the gallium-67 and positron emission tomography (PET) scans. time of development of RTH in nine of 20 patients (45%). We attempted to analyze the associated risk factors for Negative findings in the chest were noted in the other 11 RTH. This study was approved by the institutional review patients. Fluorodeoxyglucose (FDG) PET/CT scans were board of the Chang Gung Memorial Hospital, Kaohsiung, studied in six of 21 patients with RTH and four patients Taiwan. (66.7%) had increased FDG-avid uptake in the anterior mediastinum at the time of development of RTH. PET 2.1. Statistical analysis revealed a well-defined concave mass in the upper anterior mediastinum with visually detectable FDG activity higher All statistical analyses were performed using SPSS statistic than that of the adjacent aortic arch (1 representative is software, version 19.0 for Windows (IBM Company, Chicago, shown in Figure 3B with an early maximum standardized

Figure 1 Assessment algorithm for patients with non-Hodgkin’s lymphoma (NHL). CT Z computed tomography.

uptake value (SUVmax) of 3.5 and a delayed SUVmax of thymus at the time of development of RTH. This patient 4.2). The early SUVmax of the other 3 patients was 3.33, had no relapse at follow up. Two of 28 patients had relapse 3.30, and 2.97, respectively. The delayed SUVmax was at follow up. One patient had relapse in the abdomen and 3.13, 3.30, and 3.19, respectively. There were negative bone. The PET scan showed increased FDG uptake in the chest PET scans ﬁndings in the other 2 patients. abdominal paraaortic and right common iliac lymph nodes, Twenty-eight patients who did not undergo CT scan right fourth rib, left pubis, bilateral femora, and right studies at least twice were excluded from the study humerus. The other patient had relapse which was limited initially. All 28 patients underwent gallium scan studies. to the abdomen. The PET scan was not done while the Increased radioactivity in the thymus only was noted at gallium scan showed increased radioactivities in the right the time of development of RTH in eight of 28 patients retroperitoneal region. (29%). No relapse was noted in these eight patients at One patient had biopsy-documented RTH. She had an follow up. PET scans were performed on three of these enlarged thymus after completion of chemotherapy for patients that did not have at least two CT studies, and one lymphoma. The pathology of lymphoma is shown in patient (33%) had increased FDG-avid uptake in the Figure 4A. Chest CT showed progressive enlargement of the

Figure 2 Assessment algorithm for patients with Hodgkin’s lymphoma (HL). CT Z computed tomography.

Table 1 Clinical data for 21 patients with rebound thymic hyperplasia. Case Age (y) Sex Histology Primary tumor sites Stage Follow-up period 1 9 Female DLBCL Oropharynx II 7 y 2 12 Male ALCL Axilla, bones IV 8 y 3 5 Male T-LBL Neck, inguinal, BM IV 1 y 5 m 4 9 Female T-LBL Anterior mediastinum, pericardium, pleura IV 1 y 7 m 5 18 Male Pre-T-LBL Mediastinum, pleura IV 7 y 6 6 Male Pre-B-LBL Clavicle I 2 y 7 16 Female LBCL Anterior mediastinum III 3 y 8 5 Male ALCL Axilla I 2 y 9 3 Female Burkitt Axilla, skull IV 13 y 10 10 Male T-LBL Anterior mediastinum, pleura III 3 y 11 17 Male ALCL Anterior mediastinum III 7 y 12 3 Female T-LBL Anterior mediastinum III 11 y 13 8 Male ALCL Neck, mediastinum, BM IV 9 y 14 16 Male B-lineage Kidney, lung, BM IV 2 y 15 14 Male NS Neck, BM IV 5 y 16 11 Female NS Neck, mediastinum, lung III 2 y 17 9 Male HLa Neck, sacrococcyx III 7 y 18 17 Female NS Neck, bones IV 4 y 19 14 Male Nodular lymphocytic Submandibular I 1 y 1 m 20 8 Male Mixed Neck I 11 y 21 11 Male NS Neck, axilla, bilateral lungs IV 1 y 3 m ALCL Z anaplastic large cell lymphoma; BM Z bone marrow; DLBCL Z diffuse large B-cell lymphoma; LBCL Z large B-cell lymphoma; NS Z nodular sclerotic; Pre-B-LBL Z precursor B-cell lymphoblastic lymphoma; Pre-T-LBL Z precursor T-cell lymphoblastic lymphoma; T-LBL Z T-cell lymphoblastic lymphoma. a The pathologic specimen was too small to categorize Hodgkin’s lymphoma (HL).

thymus 16 months after completion of chemotherapy. A significantly different (p Z 0.004) between patients with PET scan study 2 months later still revealed increased FDG- and without RTH. In Cox proportional hazards models, the avid uptake in the thymus with moderate intensity. Due to hazard ratio of RTH to non-RTH associated with relapse is concerns that lymphoma relapse could not be excluded, a 0.008 (95% confidence interval, 0.000e16.540; p Z 0.217). thymectomy was eventually performed. Pathology If analyzed in patients with NHL only, the hazard ratio of confirmed thymic hyperplasia (Figure 4B). RTH to non-RTH associated with relapse is 0.014 (95% con- In regard to the 10/31 patients without RTH according fidence interval, 0.000e17.075; p Z 0.240). to the chest CT studies, increased radioactivity in the thymus was noted in three of 10 patients by gallium scan. One of the 10 patients underwent a PET scan study, which 4. Discussion showed increased FDG-avid uptake in the thymus. Inter- estingly, five of 10 patients without RTH had relapse in RTH is defined as an increase in thymus size relative to several lymph nodes at follow up (Figures 1 and 2). These previous CT scans when patients achieved CR after five patients were diagnosed with NHL and all had relapse chemotherapy. Physicians must be aware of this phenom- in neck lymph nodes. Other sites of relapse involved enon in order to treat patients appropriately. Mis- supraclavicular, mediastinal, thymus, axillary, inguinal, interpretations may cause prolongation of chemotherapy or mesenteric, retroperitoneal lymph nodes, lung, bone unnecessary radiation therapy, biopsy, needle aspiration, marrow, and central nervous system (CNS) (Table 2). or thymectomy.4e6 However, thymus size did not increase in the patients with The development of thymic enlargement is not only thymus involvement at the time of relapse. No patient present in patients with lymphoma after chemotherapy, presented with enlargement of the thymus at the time of but also in patients with other malignancy or conditions.7 relapse. All patients with thymus involvement at the time RTH has been reported in patients with osteosarcoma, of relapse also had other locations involved. nasopharyngeal carcinoma, germ cell tumor, synovial sar- We compared the characteristics between patients with coma, breast cancer, colon cancer, lung cancer, and Wilms’ and without RTH. There were no differences in age, sex, tumor after chemotherapy.7e9 RTH has also been described diagnosis, stage, NHL subtypes, and chemotherapy regi- after recovery from stress such as pneumonia, operation, mens. No patient (0/21) with RTH had relapse. However, after administration of steroids, and bone marrow 50% (5/10) of patients without RTH had relapse. Differences transplantation.7,10,11 Z in relapse were statistically significant (p 0.001) between Very few studies reported the incidence of RTH. The patients with and without RTH (Table 3). If analyzed in majority of previous studies present a case report or case patients with NHL only, relapse was still statistically series with diverse diagnoses.5,7 Kissin et al12 reported that

Figure 3 Gallium and positron emission tomography (PET) scans. (A) Increased gallium-67-avid radioactivities in the Figure 4 Microscopic findings. (A) Thymic lymphoma: the anterior mediastinum in gallium scan. (B) Increased fluo- section shows neoplastic lymphoid cells and skeletal rodeoxyglucose (FDG)-avid uptake mass in the anterior medi- muscle(40x). The immunohistochemical study was suggestive astinum in PET scan (maximum standardized uptake value of a precursor T cell lymphoblastic lymphoma. Higher magni- (SUVmax) early: 3.5, delayed: 4.2). fication (400Â) picture located in the upper right corner. (B) Rebound thymic hyperplasia (RTH): RTH developed after chemotherapy in the same patient 2 years later. The section thymic enlargement occurred in 14/120 adult patients shows thymic tissue with Hassall’s corpuscles and micro- (11.6%) with testicular teratomas after chemotherapy. Jeon 13 calcification (40x). No significant pathologic change was seen. et al reported that overall incidence of RTH after radio- Higher magnification (400Â) picture located in the upper right active iodine ablation therapy for thyroid cancer was corner. 1.49%. In our study, because the primary sites of lymphoma did not include the chest in some patients, not all patients pain and dyspnea after termination of immunosuppression had received chest CT assessment during their treatment following renal transplant removal. CT demonstrated a course. We excluded those patients who did not have at blood-containing mediastinal tumor and a hemothorax. least two chest CT studies. By comparing chest CT studies Histology confirmed RTH with secondary intrathymic after CR, RTH was noted in 21/31 (68%) patients who un- bleeding. derwent at least two chest CT studies. Since CT was not Some reports discussed the differentiation of RTH from performed at regular intervals for ongoing follow up, the lymphoma relapse through chest CT morphology. Yarom exact incidence of RTH in patients with lymphoma after et al7 stated that features like arrowhead-shaped triangular chemotherapy may be higher. The exact incidence of RTH structure and bilobulated configuration with convex bor- of various tumors needs further study. ders, being located in the normal site of the thymus, and The interval from the cessation of chemotherapy to the homogeneous soft tissue density favored RTH. Gallium scan identification of RTH ranged from 1 month to 17 months in is often used as a follow-up tool. However, increased our study. In addition, the thymic hyperplasia persisted radioactivity in the anterior mediastinum in a gallium-67 from 3 months to 5 years and gradually faded. These are scan cannot differentiate RTH from lymphoma relapse. similar to previous reports.7,8,12 All 21 patients with RTH in Mediastinal uptake of gallium-67 after chemotherapy in our study were asymptomatic. However, Gerhardt et al14 children with NHL was noted.15 If chest CT is used as the reported that one patient presented with acute chest standard for diagnosing RTH, the sensitivity and specificity

Table 2 Relapsed patients and their involved sites. Table 3 Clinical characteristics of the patients with or Case Age Sex Histology Initial Locations Intervala without rebound thymic hyperplasia. (y) stage Characteristics No RTH RTH p Z Z 1 5 M T-LBL III Neck, 11 m n 10 n 21 supraclavicular, Age (y) 12.2 (3e17) 10.3 (3e18) 0.35 mediastinal LNs, Sex (no.) (M:F) 8:2 14:7 0.31 lung, paraspinal, Diagnosis 0.22 BM, CNS NHL 9 14 2 12 M T-LBL III Neck, clavicular 1y4m HL 1 7 LNs, BM Stage 1.00 3 13 M LBCL II Neck, 2y6m IeII 2 5 supraclavicular, IIIeIV 8 16 anterior Relapse 5 0 0.001 mediastinal, HL Z Hodgkin’s lymphoma; NHL Z non-Hodgkin’s lymphoma; axilla, inguinal, RTH Z rebound thymic hyperplasia. retroperitoneal, mesenteric LNs, BM chemical-shift MRI to facilitate differentiating benign from 21 4 16 M T-LBL III Neck, axilla, 6y malignant conditions. back, No patient had relapse of lymphoma among those pa- paratracheal, tients with RTH in our study. Paradoxically, five patients anterior had relapse of lymphoma among those patients without mediastinal LNs, RTH. The hazard ratio of RTH to non-RTH associated with left pleural relapse was 0.008. Although there was no statistical sig- effusion nificance, it was possible that the enrolled number was too 22 5 11 M Burkitt I Neck 7 y small so the statistical power was too low. Heron et al 6 b 12 F NS III Hepatoduodenal, 7y reported that thymic hyperplasia at the time of relapse in celiac, retrocaval, patients with HL was never the only finding. HL relapse with paraaortic, thymus enlargement was accompanied by lymph nodes 15 retroperitoneal disease in the mediastinum. Peylan-Ramu et al found that LNs, bone all patients with mediastinal uptake of gallium-67 after 7 b 4 M Mixed III Retroperitoneal 16 y completion of chemotherapy were disease-free with a LNs mean follow up of 52.5 months. In our study, there were several regions of lymph node involvement in most patients BM Z bone marrow; CNS Z central nervous system; with relapse. Thymic enlargement without other regions of LBCL Z large B-cell lymphoma; LNs Z lymph nodes; NS Z nodular sclerotic; T-LBL Z T-cell lymphoblastic lymph node involvement can be highly suspected as RTH lymphoma. and may be associated with a good feature for relapse-free a The interval between the disease onset and relapse. status in patients with lymphoma. Thymic hyperplasia b Patients 6 and 7 were initially excluded because they could represent a restoration of the host immune system, received fewer than two chest computed tomography (CT) particularly cell-mediated immunity, an immunologic examinations after achieving complete remission. rebounding phenomenon, and it could reflect a stronger immune surveillance for children with lymphoma and favor successful control of lymphoma.23,24 of a gallium-67 scan to detect RTH are 45% (9/20) and 70% We did not find any risk factors which were associated (7/10), respectively, in our study. In the past decade, the with RTH. The average age in patients with RTH seemed to PET scan emerged as a novel lymphoma staging and follow- be lower than that of patients without RTH, but this was not up tool. However, PET does not differentiate thymic hy- statistically significant. Female patients seemed to be more perplasia from thymic neoplasia.16 No patients with likely to develop RTH than male patients, but this was not increased FDG-avid uptake in the anterior mediastinum in statistically significant. Because the case number is too PET scan (4 patients with RTH, 1 patient without RTH) small, larger studies may be needed to further clarify these showed relapse in our study. Thallium-201 scan was once associations. Jeon et al13 found a significantly decreased reported to have accumulation in the anterior mediastinum incidence of RTH from the 2nd to the 5th decade of age after in thymic rebound.17,18 Inaoka et al19 and Priola et al20 radioactive iodine ablation therapy for thyroid cancer. In reported that chemical-shift magnetic resonance image each age-related subgroup, the radioactive iodine dose was (MRI) was a useful tool to differentiate thymic hyperplasia significantly higher in the RTH than the non-RTH group. from thymic tumors. Mean chemical shift ratios in the Female predominance was also noted in RTH after radio- thymic hyperplasia were lower than those in the tumor active iodine ablation therapy for thyroid cancer. group.19 Both signal intensity index and chemical-shift ratio Our findings suggest that when clinicians discover patients on chemical-shift MRI have high accuracy to distinguish had mediastinal widening at follow up of lymphoma, the thymic hyperplasia from tumors.20 Diffusion-weighted MRI history taking and physical examinations are important to may also be helpful in cases of nonsuppressing RTH on uncover abnormal clinical manifestations. Chest CT scans

Please cite this article in press as: Chen C-H, et al., Rebound Thymic Hyperplasia after Chemotherapy in Children with Lymphoma, Pediatrics and Neonatology (2016), http://dx.doi.org/10.1016/j.pedneo.2016.02.007 + MODEL Rebound thymic hyperplasia 7 may be arranged to evaluate whether any nodal diseases 7. Yarom N, Zissin R, Apter S, Hertz M, Rahimi-Levene N, Gayer G. exist or not. If there are any new enlarged lymph nodes, Rebound thymic enlargement on CT in adults. Int J Clin Pract diagnostic biopsy may be arranged to rule out lymphoma 2007;61:562e8. relapse. If there is only thymic enlargement without other 8. Chertoff J, Barth RA, Dickerman JD. Rebound thymic hyper- abnormalities, RTH is most likely. In this situation, we pro- plasia five years after chemotherapy for Wilms’ tumor. Pediatr Radiol 1991;21:596e7. pose that only a close follow up is needed. However, there 9. Priola AM, Priola SM. Chemical-shift MRI of rebound thymic were some limitations in our study. This was a retrospective hyperplasia with unusual appearance and intense (18)F-FDG study and the case number enrolled was relatively small. A uptake in adulthood: report of two cases. Clin Imaging 2014; larger prospective cohort study is needed to elucidate the 38:739e42. association between RTH and relapse. 10. Miniero R, Busca A, Leonardo E, Mossetti C, Machado D, In conclusion, RTH developed in 67.7% of pediatric pa- Vassallo E, et al. Rebound thymic hyperplasia following high tients with lymphoma achieving CR after chemotherapy. If dose chemotherapy and allogeneic BMT. Bone Marrow Trans- there is only thymic enlargement without other nodal dis- plant 1993;11:67e70. eases at follow up, RTH may be considered. Otherwise, RTH 11. Hofmann WJ, Mo¨ller P, Otto HF. Thymic hyperplasia. I. True will be misclassified as thymic relapse according to the thymic hyperplasia. Review of the literature. Klin Wochenschr 1987;65:49e52. revised response criteria.2 Therefore, isolated thymic 12. 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