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Agnes Stephanie Harahap,1– 3 Imam Subekti,4 Sonar Soni Panigoro,5 Asmarinah,6 Lisnawati,1 Retno Asti Werdhani,7 Hasrayati Agustina,8 Dina Khoirunnisa,1 Mutiah Mutmainnah,1 Salinah,1 Alvita Dewi Siswoyo,9 Maria Francisca Ham1,2 1Department of Anatomical Pathology, Faculty of Medicine Universitas Indonesia/Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia; 2Human Cancer Research Center-Indonesian Medical Education and Research Institute, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia; 3Doctoral Program in Medical Sciences, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia; 4Department of Internal Medicine, Faculty of Medicine Universitas Indonesia/Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia; 5Department of Surgery, Faculty of Medicine Universitas Indonesia/Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia; 6Department of Medical Biology, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia; 7Department of Community Medicine, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia; 8Department of Anatomical Pathology, Faculty of Medicine Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung, Indonesia; 9Department of Radiology, Faculty of Medicine Universitas Indonesia/Dr. Cipto Mangunkusumo Hospital, Jakarta, IndonesiaCorrespondence: Agnes Stephanie Harahap, Department of Anatomical Pathology, Faculty of Medicine Universitas Indonesia, Jl. Salemba Raya No. 6, Jakarta, 14320, Indonesia, Tel +62818765563, Email agnes.stephanie01@ui.ac.idIntroduction: BRAFV600E and RAS mutations are the most common gene mutations in papillary thyroid carcinoma (PTC) that may be correlated with its biological behavior. There are still limited data about BRAFV600E and RAS mutations in Indonesia. This study aims to determine the prevalence of BRAFV600E and RAS mutations, and their association with clinicopathologic characteristics.Methods: Patients who had total thyroidectomy from 2019 to 2021 and those who met our study criteria underwent PCR and DNA sequencing analysis for BRAFV600E, BRAFK601E, exon 2 and 3 of NRAS, HRAS, and KRAS. Analyses were performed to determine the associations of BRAFV600E and RAS mutations with clinicopathologic characteristics.Results: Of 172 PTC patients, BRAFV600E mutation was observed in 37.8% of the patients and RAS mutations were found in 21.5%. One patient harbored BRAFK601E mutation. There was a significant association of BRAFV600E with a high-stage (p = 0.033, OR: 3.279; 95% CI: 1.048– 10.259), tall-cell variants (p ≤ 0.001, OR: 41.143; 95% CI: 11.979– 141.308), non-encapsulated (p = 0.001, OR: 4.176; 95% CI: 2.008– 8.685), lymphovascular invasion (p = 0.043, OR: 1.912; 95% CI: 1.018– 3.592), extrathyroidal extension (p = < 0.001, OR: 3.983; 95% CI: 1.970– 8.054), and lymph node metastasis (p = 0.009, OR: 2.301; 95% CI: 1.224– 4.326). Follicular variant (p = 0.001, OR: 7.011; 95% CI: 2.690– 18.268), encapsulated (p = 0.017, OR: 2.433; 95% CI: 1.161– 5.100), and absent of extrathyroidal extension (p = 0.033, OR: 2.890; 95% CI: 1.052– 7.940) were associated with RAS mutations.Conclusion: A significant association between BRAFV600E mutation and high clinical stage, tall-cell variants, non-encapsulated morphology, lymphovascular invasion, extrathyroidal extension, and lymph node metastasis in PTC was observed. RAS mutations were associated with the follicular variant, encapsulated tumor, and no extrathyroidal extension. HRAS-mutated PTC frequently exhibited tumor multifocality.Keywords: papillary thyroid carcinoma, BRAFV600E, BRAFK601E, RAS, clinicopathological characteristics

Agnes Stephanie Harahap,1,2 Fanny Kamarudy Lay,1 Ria Kodariah,1 Fresia Juwitasari Wongkar,1 Maria Francisca Ham1,2 1Department of Anatomical Pathology, Faculty of Medicine Universitas Indonesia/Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia; 2Human Cancer Research Center - Indonesian Medical Education and Research Institute, Faculty of Medicine Universitas Indonesia, Jakarta, IndonesiaCorrespondence: Maria Francisca Ham, Email mariafranciscaham@gmail.comIntroduction: Immunohistochemical expression of programmed death-ligand 1 (PD-L1) has become a biomarker to predict the usefulness of cancer immunotherapy using PD-1/PD-L1 blockade in a variety of advanced-stage tumours. This emerging biomarker may serve to generate novel therapies for aggressive thyroid carcinoma (TC), which has not shown optimal results with existing treatments.Methods: The present study investigated the relevance of PD-L1 expression in aggressive histological types of TC compared with that found in less aggressive types. Surgically resected specimens were investigated, including 52 cases of TC consisting of 26 cases of aggressive histological types and 26 cases of less aggressive histological types. Immunohistochemical examinations were carried out on paraffin blocks of both groups using a mouse monoclonal primary antibody against PD-L1 (clone 22C3). PD-L1 expression was evaluated by calculating the tumour proportion score (TPS) in both groups.Results: The results revealed a significant difference in the median TPS value of PD-L1 expression between the two groups. The TPS values were found to be higher in the group of aggressive histological types of TC compared with those in the group of less aggressive histological types. A significant difference in TPS value was also found for the extrathyroidal extension variable.Discussion: In conclusion, the present study found a significant association between PD-L1 expression and the aggressive histological type of TC. In addition, a potential association between PD-L1 expression and the presence of extrathyroidal extension of TC was observed. These findings provide novel approaches for immunotherapy as a potential new treatment modality in patients with aggressive histological types of TC.Keywords: thyroid carcinoma, histological type, aggressive, programmed death-ligand 1

Wulyo Rajabto,1,2 Vitya Chandika,1 Agnes Stephanie Harahap,3 Maria Francisca Ham3 1Division of Hematology-Medical Oncology, Department of Internal Medicine, Dr. Cipto Mangunkusumo General Hospital/ Faculty of Medicine Universitas Indonesia, Central Jakarta, Indonesia; 2Department of Internal Medicine, Metropolitan Medical Centre Hospital, South Jakarta, Indonesia; 3Department of Anatomical Pathology, Dr. Cipto Mangunkusumo General Hospital/ Faculty of Medicine Universitas Indonesia, Central Jakarta, IndonesiaCorrespondence: Vitya Chandika, Division of Hematology-Medical Oncology, Department of Internal Medicine, Dr. Cipto Mangunkusumo General Hospital/ Faculty of Medicine Universitas Indonesia, Jalan Pangeran Diponegoro No. 71, Central Jakarta, 10430, Indonesia, Email vityachandika@gmail.comBackground: Salvage conventional chemotherapy followed by high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) is the treatment of choice for most patients with refractory classical Hodgkin lymphoma (cHL). In the era of pandemic COVID-19, there are obstacles to administering salvage chemotherapy followed by HDT and ASCT due to side effects and toxicities which make the patient more susceptible to COVID-19 infection. The toxicities and side effects of BV are different from salvage chemotherapy, but it has clear efficacy as monotherapy.Case Presentation: A 46-year-old female with a history of cHL nodular sclerosis subtype was presented with right cervical lymph node enlargement, after 3 cycles of first-line chemotherapy ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) 3 months ago. She was afraid to undergo second-line chemotherapy in the era of pandemic COVID-19 because of the side effects and toxicities; therefore, she was given 8 cycles of BV as monotherapy. The response of the treatment was complete remission.Conclusion: In this particular case of patient, BV as monotherapy can be an option during the pandemic COVID-19 for refractory cHL ineligible for second-line chemotherapy followed by HDT and ASCT.Keywords: brentuximab vedotin, COVID-19, monotherapy, refractory Hodgkin’s lymphoma

Cosphiadi Irawan,1 Martha Iskandar,1 Agnes Stephanie Harahap,2 Cleopas Martin Rumende,3 Maria Francisca Ham2 1Hematology and Medical Oncology Division, Internal Medicine Department, Dr. Cipto Mangunkusumo Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, 10430, Indonesia; 2Anatomical Pathology Department, Dr. Cipto Mangunkusumo Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, 10430, Indonesia; 3Internal Medicine Department, Dr. Cipto Mangunkusumo Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, 10430, IndonesiaCorrespondence: Martha Iskandar, Tel +628161924095, Email marthaiskandar@gmail.comBackground: Treatment response in diffuse large B-cell lymphoma (DLBCL) is heterogenous. The Hans algorithm (using 30% cut-offs for CD10, BCL6, and MUM1 protein expression) has been the most favored method to categorize DLBCL into germinal center B-cell (GCB) and non-GCB subtypes in order to predict prognosis. However, the algorithm’s ability to prognosticate is not always consistent.Methods: This retrospective cohort study was conducted on DLBCL patients receiving R-CHOP therapy at Dr. Cipto Mangunkusumo Hospital, Jakarta from 2014 to 2017. We aimed to compare the prognostic value of Hans algorithm as well as the protein levels of CD10, BCL6, MUM1, and Ki67 at different cut-offs. Ninety-two patients were classified based on Hans algorithm and various proteins at different cut-off values were analyzed with regard to event-free survival at 24 months using survival analysis. The cut-off values were then compared using receiver operating characteristic curves.Results: A significant survival difference was observed with MUM1 expression cut-off of 50% or more (log rank p = 0.035). CD10, BCL6, Ki67, and Hans algorithm showed AUCs below or near 0.5 (0.405, 0.436, 0.498, and 0.413, respectively), whereas MUM1 showed an AUC of 0.835, in predicting events within 24 months. MUM-1 cut-off of 70.5% yielded an optimal trade-off for sensitivity and specificity.Conclusion: MUM1 expression of 50% or more can help predict prognosis in DLBCL patients receiving R-CHOP therapy and can be considered as for use as a single marker to predict prognosis.Keywords: DLBCL, RCHOP, MUM1, Hans algorithm, prognosisMeSH Terms: lymphoma, large B-cell, dIffuse, MUM1 nucleosome-binding protein, human, antineoplastic combined chemotherapy protocols/adverse effects, rituximab/therapeutic use, retrospective studies, prognosis

Introduction: The incidence of anaplastic transformation of thyroid cancer from Papillary Thyroid Carcinoma (PTC) is a rare tumor event, which ranges from 1 to 2 % of all cases of thyroid malignancy. Anaplastic transformation is often reported in primary lesions, but is rarely found in metastatic lesions from Differentiated Thyroid Carcinoma (DTC)., Presentation of Case: This case report reports a unique tumor process where a 70-year-old woman had a metastatic lesion in the Mandible from PTC which transformed into ATC with histological features resembling squamous cell carcinoma-type. Immunohistochemical examination was able to prove that the lesion in the Mandible is a type of undifferentiated Thyroid carcinoma (anaplastic) with a squamous pattern originating from PTC., Discussion: This type of tumor with histological variant images that resemble other types of tumors is a challenge for diagnosis and appropriate management, so understanding the variants of this type of ATC is important for better management., Conclusion: Although rare, anaplastic transformation can occur in metastatic sites of PTC. This necessitates the need for early accurate diagnosis through IHC assessment and somatic mutation testing so that appropriate treatment can be delivered., Competing Interests: Conflict of interest statement The authors declare no conflict of interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The diagnosis of thyroid neoplasms necessitates the identification of distinct histological features. Various education/hospital centers located in cities across Indonesia likely result in discordances among pathologists when diagnosing thyroid neoplasms., Methods: This study examined the concordance among Indonesian pathologists in assessing nuclear features and capsular and vascular invasion of thyroid tumors. Fifteen pathologists from different centers independently assessed the same 14 digital slides of thyroid tumor specimens. All the specimens were thyroid neoplasms with known BRAFV600E and RAS mutational status, from a single center. We evaluated the pre- and post-training agreement using the Fleiss kappa. The significance of the training was evaluated using a paired T-test., Results: Baseline agreement on nuclear features was slight to fair based on a 3-point scoring system (k = 0.14 to 0.28) and poor to fair based on an eight-point system (k = -0.02 to 0.24). Agreements on vascular (κ = 0.35) and capsular invasion (κ = 0.27) were fair, whereas the estimated molecular type showed substantial agreement (κ = 0.74). Following the training, agreement using the eight-point system significantly improved (p = 0.001)., Conclusions: The level of concordance among Indonesian pathologists in diagnosing thyroid neoplasm was relatively poor. Consensus in pathology assessment requires ongoing collaboration and education to refine diagnostic criteria.

Purpose: The global burden of lymphoma is substantial because of the increase in its incidence in recent decades. However, disease characteristics vary across different geographical locations. Numerous immunohistochemistry markers and molecular studies are essential to determine lymphoma diagnosis and prognosis. This poses significant challenges in developing countries with limited health care resources. This large-scale study assesses the frequency of non-Hodgkin lymphoma (NHL) in Indonesia over the past 15 years, analyses its clinicopathologic features, and predicts future trends., Methods: This retrospective study collected lymphoma patients diagnosed at the Department of Anatomical Pathology Dr. Cipto Mangunkusumo National Central General Hospital, Indonesia, from 2009 until 2023. All lymphoma diagnoses were confirmed by using ancillary tools classified as an enhanced lymphoma panel according to a resource-stratified guideline. We analyzed the clinicopathologic features of each NHL type and further applied the Autoregressive Integrated Moving Average model to predict future incidence trends., Results: The study consisted of 7,368 NHL patients. Among these, B-cell lymphomas accounted for 90.6%, with diffuse large B-cell lymphoma being the most prevalent subtype (68.8%), followed by follicular lymphoma (8.8%) and marginal zone lymphoma (5.8%). Extranodal natural killer/T-cell lymphoma, nasal type, is the most common T-cell lymphoma found (26.3%). All types of lymphoma were found to be more common in males (57.7%). Extranodal involvement, particularly in the tonsil and upper respiratory tract, was frequently observed. Projection analysis indicates a steady increase in lymphoma patients in the future., Conclusion: This study highlights the distribution and burden of NHL in Indonesia over 15 years. The overall epidemiologic pattern of NHL in this study aligns with the results observed in other Asian countries. The rising incidence of lymphoma requires improved health care infrastructure and prevention strategies.

Objective: Twenty percent of all classical Hodgkin lymphoma (CHL) cases relapse and recur, especially in advanced stages with a high International Prognostic Score (IPS). Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a regulatory molecule that can inhibit the immune response and is related to tumor aggressiveness. This study aimed to determine the relationship between CTLA-4 expression in advanced-stage CHL and IPS, identifying it as a potential therapy target., Results: In advanced-stage CHL, the group with a high IPS exhibited significantly higher mean CTLA-4 expression compared to the group with a low IPS (p = 0.003).The group with Hb level < 10.5 g/dl, leukocyte count > 15,000/µL, lymphocyte count < 8%, albumin level < 4 g/dl, and stage 4 exhibited higher CTLA-4 expression than the other group, although only leukocyte count and stage showed statistical significance (p = 0.004 and p = 0.020). Mean CTLA-4 expression was 239.84 ± 76.36 for nodular sclerosis, 293.95 ± 147.94 for mixed cellularity, 271.4 ± 23.56 for lymphocyte depleted, and 225.2 for lymphocyte-rich subtypes. The results suggest that CTLA-4 expression is associated with adverse prognostic factors in the IPS for advanced-stage CHL, supporting the notion that immune checkpoints play a role in cancer progression., (© 2024. The Author(s).)

A 44-year-old female presented with a distended abdomen and fatigue. On physical examination, prominent splenomegaly was found. The laboratory investigations revealed pancytopenia and decreased albumin-globulin ratio. The abdominal ultrasonography revealed splenomegaly, cholelithiasis, and cystitis, and the bone survey showed osteopenia. Differential diagnoses included leukemia, multiple myeloma, and myelofibrosis therefore bone marrow puncture was performed. However, histopathologic examination found Gaucher-like cells in the bone marrow aspiration. The finding of CD68 positivity in Gaucher-like cells by using the immunohistochemistry staining supporting Gaucher disease. To confirm the diagnosis, an examination of glucocerebroside substrate from the patient's blood plasma was performed. Glucosylsphingosine, a deacylated form of glucosylceramide, was markedly elevated. Therefore, the diagnosis of Gaucher disease was confirmed. This is the first reported adult Gaucher case diagnosed in Indonesia.

The Cancer Genome Atlas (TCGA) has classified papillary thyroid carcinoma (PTC) into indolent RAS-like and aggressive BRAF-like based on its distinct driver gene mutations. This retrospective study aimed to assess clinicopathology and pERK1/2 expression variations between BRAF-like and RAS-like PTCs and establish predictive models for BRAF V600E and RAS -mutated PTCs. A total of 222 PTCs underwent immunohistochemistry staining to assess pERK1/2 expression and Sanger sequencing to analyze the BRAF and RAS genes. Multivariate logistic regression was employed to develop prediction models. Independent predictors of the BRAF V600E mutation include a nuclear score of 3, the absence of capsules, an aggressive histology subtype, and pERK1/2 levels exceeding 10% (X 2 = 0.128, p > 0.05, AUC = 0.734, p < 0.001). The RAS mutation predictive model includes follicular histology subtype and pERK1/2 expression > 10% (X 2 = 0.174, p > 0.05, AUC = 0.8, p < 0.001). We propose using the prediction model concurrently with four potential combination group outcomes. PTC cases included in a combination of the low- BRAF V600E-scoring group and high- RAS -scoring group are categorized as RAS-like (adjOR = 4.857, p = 0.01, 95% CI = 1.470-16.049). PTCs included in a combination of the high- BRAF V600E-scoring group and low- RAS -scoring group are categorized as BRAF-like PTCs (adjOR = 3.091, p = 0.001, 95% CI = 1.594-5.995). The different prediction models indicate variations in biological behavior between BRAF-like and RAS-like PTCs.

Introduction: BRAF V600E and RAS mutations are the most common gene mutations in papillary thyroid carcinoma (PTC) that may be correlated with its biological behavior. There are still limited data about BRAF V600E and RAS mutations in Indonesia. This study aims to determine the prevalence of BRAF V600E and RAS mutations, and their association with clinicopathologic characteristics., Methods: Patients who had total thyroidectomy from 2019 to 2021 and those who met our study criteria underwent PCR and DNA sequencing analysis for BRAF V600E, BRAF K601E, exon 2 and 3 of NRAS, HRAS , and KRAS . Analyses were performed to determine the associations of BRAF V600E and RAS mutations with clinicopathologic characteristics., Results: Of 172 PTC patients, BRAF V600E mutation was observed in 37.8% of the patients and RAS mutations were found in 21.5%. One patient harbored BRAF K601E mutation. There was a significant association of BRAF V600E with a high-stage (p = 0.033, OR: 3.279; 95% CI: 1.048-10.259), tall-cell variants (p ≤0.001, OR: 41.143; 95% CI: 11.979-141.308), non-encapsulated (p = 0.001, OR: 4.176; 95% CI: 2.008-8.685), lymphovascular invasion (p = 0.043, OR: 1.912; 95% CI: 1.018-3.592), extrathyroidal extension (p = <0.001, OR: 3.983; 95% CI: 1.970-8.054), and lymph node metastasis (p = 0.009, OR: 2.301; 95% CI: 1.224-4.326). Follicular variant (p = 0.001, OR: 7.011; 95% CI: 2.690-18.268), encapsulated (p = 0.017, OR: 2.433; 95% CI: 1.161-5.100), and absent of extrathyroidal extension (p = 0.033, OR: 2.890; 95% CI: 1.052-7.940) were associated with RAS mutations., Conclusion: A significant association between BRAF V600E mutation and high clinical stage, tall-cell variants, non-encapsulated morphology, lymphovascular invasion, extrathyroidal extension, and lymph node metastasis in PTC was observed. RAS mutations were associated with the follicular variant, encapsulated tumor, and no extrathyroidal extension. HRAS -mutated PTC frequently exhibited tumor multifocality., Competing Interests: The authors declare no conflict of interest., (© 2023 Harahap et al.)

Background: Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of peripheral T-cell lymphoma. Patients usually present with splenomegaly and pancytopenia but without lymphadenopathy. Immunohistochemistry (IHC) staining of bone marrow biopsy shows intra-sinusoidal infiltration of CD3 and CD56 T-lymphocytes. Current treatment strategy of HSTCL includes a CHOP regimen (cyclophosphamide, adriamycine, vincristine, prednisone) followed by autologous transplantation., Case: A 28-year-old male presented with abdominal fullness, weight loss, and massive splenomegaly. Laboratory findings revealed pancytopenia. A CT scan of the abdomen displayed hepatomegaly and massive splenomegaly. The bone marrow pathology examination showed monotonous medium-sized lymphocytes with some cluster of atypical lymphocytes with loosely condensed chromatin and pale cytoplasm. The intra-sinusoidal location was more prominent after using IHC staining of CD3 and CD56, which are characteristics of HSTCL. We administered CHOP-based regiment every 3 weeks for 3 cycles; however, the response was a stable disease. Since the splenomegaly was still massive and compromised the patient, the multidisciplinary team decided to perform splenectomy. Unfortunately, the patient did not survive the surgery., Conclusion: Hepatosplenic T-cell lymphoma is a rare aggressive disease, which is part of peripheral T-cell lymphoma. CHOP-based chemotherapy appeared to be ineffective, and we need further studies to find the optimal treatment of HSTCL.

Introduction and Importance: Cancer of unknown primary site (CUP) is metastatic cancer without primary tumor found from comprehensive medical history, physical examination, and regular laboratory examination. Eighty percent of CUP include unfavorable groups with 3 to 6 months of median survival despite chemotherapy treatment., Case Presentation: A 52-year-old male was presented with a chief complaint of a recurrent lump in the neck and axilla. After comprehensive examinations over three years, the primary site of the metastatic tumor could not be found. Therefore, this patient was diagnosed with cancer of an unknown primary site., Clinical Discussion: In patient with CUP, more precise therapy can only begin when the exact form of cancer is identified. However, the delay in diagnosis would worsen the patient's condition, as treatment measures cannot be implemented., Conclusion: Trimodal modalities including surgery, chemotherapy, and radiotherapy are suitable for CUP with squamous cell carcinoma proven in immunohistochemistry evaluation., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma worldwide. However, there is still limited information on the expression of programmed cell death ligand-1 (PD-L1), a type 1 transmembrane protein of immunoglobulin B7/CD28 in the DLBCL subtypes. The present study aimed to identify the expression of PD-L1 in germinal center B-cell-like (GCB) subtype and non-germinal center B-cell-like (non-GCB) subtype of DLBCL. A total of 40 patient samples (formalin-fixed paraffin-embedded tissues) consisting of 20 cases of GCB subtype and 20 cases of non-GCB subtype of DLBCL were examined. The PD-L1 protein expressions were evaluated by using immunohistochemical staining in the tumor cells. The results showed a statistically significant difference (P=0.003) between the expression of PD-L1 in the GCB subtype and the non-GCB subtype of DLBCL. PD-L1 expression in the tumor cells were observed in 13 cases (65%) of non-GCB subtype and in three cases (15%) of the GCB subtype of DLBCL. In conclusion, it was found that the expression of PD-L1 protein in the tumor cells of the non-GCB subtype of DLBCL was significantly higher as compared with the tumor cells of the GCB subtype of DLBCL., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020, Spandidos Publications.)

Introduction: Thyroid cancer is the third most common cancer that occurs in children and adolescents. Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy. Although the mortality rate of thyroid malignancy in children is usually low, the disease recurrence is higher in children with more severe clinical presentation than in adults. This study aimed to determine the demographic and clinicopathological characteristics and outcome of pediatric and adolescent patients with thyroid malignancy in Indonesia., Methods: The retrospective study included all patients diagnosed with thyroid carcinoma aged <20 years, from January 1, 2015, to December 31, 2019. Twenty-nine subjects fulfilled the inclusion and exclusion criteria. We retrieved baseline characteristics, pathology features, TSH and fT4 status, radioactive iodine therapy data, and patients' outcomes. Then, data were analyzed using the chi-square or Fisher's exact method., Results: We identified 29 eligible subjects, including 3 boys and 26 girls. The most common type of thyroid carcinoma was PTC (96.5%), and follicular type (31%) was the predominant variant of PTC. Lymph node involvement occurred in 24% of patients, while distant metastasis occurred in 17.2% of patients with PTC. Twenty-four (82.7%) patients had stage 1 disease. Disease recurrence was recorded in 31% of patients during the study period with a median follow-up time of 24 months., Conclusion: PTC is the most frequent type of thyroid carcinoma among children and adolescents. This malignancy has a low mortality rate, but the recurrence rate remains high among younger patients than adults even during a short-term follow-up analysis. Distant metastasis and lymph node involvement are commonly found in this age group., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Agnes Stephanie Harahap et al.)

Introduction and Importance: Thyroid hemiagenesis (TH) is a rare congenital anomaly where one lobe fails to develop, especially more frequently occurs on the left lobe. The exact mechanisms for thyroid morphogenesis remain unclear. In this paper, we report a rare case of right lobe TH associated with Hurthle cell carcinoma., Case Presentation: A 59 years old woman was admitted with a neck lump increasing in size in the last 20 years. There were no symptoms of hyperthyroidism and hypothyroidism. There was a palpable, painless 5 cm mass in the middle of the neck. Initial thyroid ultrasonography (USG) revealed an enlarged left lobe, with hypoechoic lesion with cystic component and calcification (TIRADS 4). However, the right lobe was non-visualized. Fine needle aspiration biopsy result tendency was a malignancy. Hence, isthmolobectomy was conducted. Pathology result was Hurthle cell carcinoma. On the ninth month, USG revealed fibrotic tissue in the right thyroid bed and bilateral lymphadenopathy. Due to discrepancy, the patient was planned for a neck exploration surgery and a right lobe incision. Intraoperatively, the right thyroid was absent. Intraoperative USG also confirmed no right thyroid lobe., Discussion: Thyroid hemiagenesis can be visualized by using USG due to its practicality and cost effectiveness reasons. Follow up evaluations consisted of systematic monitoring of thyroid morphology and hormonal functions should follow the diagnosis of TH. Neck exploration surgery might need to be performed to clarify any discrepancy and confirm the diagnosis., Conclusion: TH can be recognized through supporting examination; however, discrepancy may occur., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Primary breast lymphoma is a rare disease and accounts for 0.4-0.5% of malignant breast neoplasms and 1.7-2.2% of extra-nodal lymphomas, with diffuse large B-cell lymphoma (DLBCL) as the most common histologic subtype., Case: A 47-year-old female with beta thalassemia presented with a lump of the left breast, redness, pain, and swelling of her left breast. Physical examination showed tender, red, swollen left breast. Laboratory findings show mild anemia and normal level of lactate dehydrogenase 329 U/L (normal range: 240-480 U/L). PET scan showed hypermetabolic mass with irregular margins covering the whole left breast quadrants with the size of 11.25 x 5.17cm with left pectoralis major, left parasternal, and left axillary hypermetabolic nodules. Histopathology and immunohistochemistry staining showed a non-germinal center B-cell-like subtype of DLBCL CD20+. We administered the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednison) every 3 weeks for 6 cycles. The response was complete remission. The patient tolerated the chemotherapy well and achieved long term complete remission., Conclusion: Primary breast lymphoma is a rare disease with the most common subtype is diffuse large B-cell lymphoma. Systemic chemother-apy R-CHOP is the treatment option for primary breast diffuse large B-cell lymphoma.

RUNX3, runt-domain transcription factor, is a master regulator of gene expression in major developmental pathways. It acts as a tumor suppressor in many cancers but is oncogenic in certain tumors. We observed upregulation of RUNX3 mRNA and protein expression in nasal-type extranodal natural killer (NK)/T-cell lymphoma (NKTL) patient samples and NKTL cell lines compared to normal NK cells. RUNX3 silenced NKTL cells showed increased apoptosis and reduced cell proliferation. Potential binding sites for MYC were identified in the RUNX3 enhancer region. Chromatin immunoprecipitation-quantitative PCR revealed binding activity between MYC and RUNX3. Co-transfection of the MYC expression vector with RUNX3 enhancer reporter plasmid resulted in activation of RUNX3 enhancer indicating that MYC positively regulates RUNX3 transcription in NKTL cell lines. Treatment with a small-molecule MYC inhibitor (JQ1) caused significant downregulation of MYC and RUNX3, leading to apoptosis in NKTL cells. The growth inhibition resulting from depletion of MYC by JQ1 was rescued by ectopic MYC expression. In summary, our study identified RUNX3 overexpression in NKTL with functional oncogenic properties. We further delineate that MYC may be an important upstream driver of RUNX3 upregulation and since MYC is upregulated in NKTL, further study on the employment of MYC inhibition as a therapeutic strategy is warranted.

Natural killer (NK) cell neoplasm is a heterogeneous disease group. In the latest World Health Organization (WHO) classification of tumours of hematopoietic and lymphoid tissues (2008), disease entities considered as NK-cell derivation include NK-lymphoblastic leukemia/lymphoma, chronic lymphoproliferative disorders of NK cells, aggressive NK-cell leukemia, and extranodal NK-cell lymphoma, nasal-type. Despite recent advances in NK-cell research, which have expanded our understanding of the biology of NK-cell neoplasm, it cannot yet be sharply delineated from myeloid neoplasms and T-cell neoplasms even in some "well-known" entity, such as extranodal NK/T-cell lymphoma. This review describes current knowledge of the biology of NK cells and pathology of NK neoplasms as classified in the 2008 WHO classification of tumours of hematopoietic and lymphoid tissues.

The present study examines clinicopathologic findings and their association with the Epstein-Barr virus (EBV) in Waldeyer's ring lymphomas (WRLs) from Indonesia (91 cases), P.R. China (31 cases), Korea (101 cases) and Japan (61 cases). Waldeyer's ring (WR) was categorized into upper and lower parts comprising the pharyngeal and tubal tonsils (upper WR) or palatine and lingual tonsils (lower WR), respectively. Diffuse large B-cell lymphoma (DLBCL) pre-dominated in the lower WR in all countries at a frequency of 78.9-100%. Natural killer/T-cell lymphoma (NKTCL) was predominant in the upper WR in China, Korea and Japan at a frequency of 50-62.5%, while in Indonesia it occcurred at a frequency of less than 10%. On the whole, patients with NKTCL were significantly younger (median 43 years) than those with DLBCL (57 years). Patients with DLBCL in the lower WR were significantly younger in Indonesia (median 50 years) than in China (63 years) or Japan (69 years). The percentage of EBV-positive cases was much higher in NKTCL (78.6-100%) than in DLBCL (2.2-6%). This study evaluates the differences between East and Southeast Asian countries in terms of histologic type and age distribution in WRLs categorized by the location of the lesions in WR.

Transfer of genetic information during mitosis is accurately conducted by proper condensation and segregation of chromosomes, for which condensins play a central role. Both condensin I and II have common structural maintenance of chromosomes subunits, named hCAP-C and hCAP-E. Pyothorax-associated lymphoma (PAL) is a non-Hodgkin's lymphoma developing in the pleural cavity of patients with long-standing pyothorax. Mutations of hCAP-C and hCAP-E were investigated in 24 leukemia-lymphoma cell lines including eight PAL cell lines, and their influences in chromosome morphology were evaluated. Heterozygous point mutations within hCAP-C were found in two PAL cell lines and corresponding tumor samples (OPL-3 and OPL-7). Deletion of exon 24 within hCAP-E and a point mutation at the donor splice site of intron 24 were detected in OPL-5 and original tumor samples. OPL-5 showed an extensive reduction in expression of not only hCAP-E but also hCAP-C proteins. OPL-5 occasionally showed the chromosome bridge in anaphase and telophase, indicating that segregation is not accurate. OPL-7 showed reduced hCAP-C protein expression, abnormality in chromosome length and width, and abnormal aggregates of hCAP-C protein. These findings indicated that condensin gene alteration might play a role in genome instability, which accelerates the accumulation of other gene alterations in PAL.

Previous studies have indicated that genome instability is involved in the lymphomagenesis of pyothorax-associated lymphoma (PAL), which develops in patients with a long-standing history of pyothorax. One of the well-known causes of genome instability is telomere dysfunction. In the present study, the condition of telomeres was analyzed in the cell lines and clinical samples from PAL. Telomere length (TL) in PAL cell lines was extremely short (<4.5 kbp). TL in tumor samples was broad in range, and shorter than that in the peripheral blood leukocytes from the matched patients. Three of five PAL cell lines showed frequent loss of telomere signals (telomere erosion); however, telomerase activity in PAL cell lines was similar to that in Burkitt lymphoma cell lines. Rb expression was detected in three PAL cell lines and four of 15 clinical samples, respectively. Rb protein expressed in three PAL cell lines was heavily phosphorylated, indicating that function of Rb protein was suppressed. p16(INK4a) expression was not detected in either cell lines or clinical samples. The promoter region in p16(INK4a) was heavily methylated in all cell lines as well as the clinical samples. Inactivation of the p16(INK4a)/Rb pathway may allow continuous cell division and critical telomere shortening, which induce genome instability, finally leading to malignant transformation. Taken together, telomere dysfunction and inactivation of the p16(INK4a)/Rb pathway might play a role for PAL development.

Pyothorax-associated lymphoma (PAL) is a non-Hodgkin's lymphoma, which develops in the pleural cavity of patients who have had pyothorax for over 20 years, and is strongly associated with Epstein-Barr virus (EBV) infection. The expression of latent genes, especially EBV nuclear antigen-2 (EBNA-2), influences the growth characteristics and malignant features of EBV-infected cells. Here, the effect of EBNA-2 expression on clinical features was examined in 13 cases of PAL. The EBNA-2 transcript was detected in 8 cases but was absent in 5. There was a significant difference in survival between patients with the transcripts and those without: the 1-year survival rate was 87.5 and 0%, respectively (p < 0.01). There was a discrepancy between EBNA-2 expression and EBNA promoter usage in 6 cases. The Cp/Wp promoter was used in 3 EBNA-2-negative cases, whereas the Qp promoter or multiple promoters were used in 3 EBNA-2-positive cases. Analysis of PAL cell lines provided a clue as to the mechanism underlying the discrepancy between EBNA-2 expression and EBNA promoter usage. Loss of EBNA-2 expression, irrespective of the latency pattern, is correlated with a poor prognosis, suggesting that down-regulation of the EBNA-2 expression could be selection pressure for the progression of PAL.

Sinonasal lymphomas comprise NK/T-cell (NKTCL) type and B-cell type with unique geographical development. In this study, mutations of p53, K-ras, c-kit, beta-catenin, and bak gene were analyzed using polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) followed by direct sequencing in 41 sinonasal lymphomas (27 NKTCL and 14 B-cell type) from Indonesia. In situ hybridization study with EBER-1 probe revealed that 85% of NKTCL cases were EBV positive, but none of B-cell type was EBV positive. Frequency of mutations in p53, K-ras, c-kit, beta-catenin, and bak gene was 62.9%, 0%, 11.1%, 18.5%, and 25.9%, respectively, in NKTCL, and 71.4%, 0%, 23.1%, 21.4%, and 57.1%, respectively, in B-cell cases, showing that mutation frequency in all genes was higher in B-cell than in NKTCL cases. These findings suggest that gene mutations might be the driving-force for B-cell lymphoma, whereas combined EBV infection and gene mutations contribute to NKTCL development in Indonesia.

Mutations of DNA double-strand breaks (DSB) repair genes, ATM, MRE11, RAD50, NBS1 and ATR, are postulated to play a role in the development of gastrointestinal malignancies with an impaired mismatch repair (MMR) function. In the present study, mutations of these genes together with the presence of microsatellite instability (MSI) were examined in 50 leukemia-lymphoma cell lines. MSI was detected in 13 (26%) lines. Mutations of intronic mononucleotide repeats in ATM and MRE11 were found in nine and six lines, respectively, whereas mutations of mononucleotide repeats of RAD50 were found in only one line, and none were found in either NBS1 or ATR. Frequencies of ATM and MRE11 mutations were significantly higher in MSI-positive than MSI-negative lines. These mutations generated aberrant splicing in both genes. The intensity of the aberrant transcript of ATM (497del22) was stronger in five lines harboring mononucleotide mutations of 2 bp or more than in the lines without or with a 1-bp mutation. The intensity of the aberrant transcript of MRE11 (315del88) was stronger in four lines with mononucleotide mutations than in lines without. The expression levels of ATM and MRE11 transcripts in MSI-positive lines were significantly higher than those in MSI-negative lines. MSI-positive cell lines showed delay or abrogation of DSB repair. The present study suggests that impairment of the MMR system causes aberrant transcripts in the DSB repair genes ATM and MRE11. This might result in inactivation of the DSB repair system, thus inducing an acceleration of genome instability and accumulation of genetic damage.

IB4 is a lymphoblastoid cell line frequently used for the functional analysis of the latent genes of EBV. Previous study indicated that EBV whole genome is integrated tandemly as the linear viral genome into host genome of IB4, although sites of integration have not been determined. Through cloning of the junctional regions between EBV and host genomes, one of the integration sites was identified on the BamHI-C fragments around oriP sequences and another on the EcoRI-I fragment. Both of the integration sites were located on the clone RP11-119H12 of chromosome 4q25 and separated approximately 6.5 kbp from each other. The integration sites identified were apart from the genes of the host genome, indicating that both host gene and EBV latent genes are not altered by the integration event.

Pyothorax-associated lymphoma (PAL) is non-Hodgkin's lymphoma that develops from chronic inflammation. Free radicals and oxidative stress generated in the inflammatory lesions could cause DNA damage and thus provide a basis for lymphomagenesis. Ataxia-telangiectasia mutated (ATM) and ATM and Rad3-related (ATR) genes are responsive genes for DNA damage, therefore potential involvement of these genes in PAL lymphomagenesis was examined in eight PAL cell lines and clinical samples from five cases. ATM mutations were detected in five of eight PAL lines. All but one of these mutations affected the phosphatidylinositol 3-kinase domain, indicating the loss-of-function mutation of ATM gene. Heterozygous mutations of ATR were found in two of eight lines; one a missense and the other a truncation mutation. ATR mutations were also detected in two of five cases in clinical samples from PAL. PAL cells with ATR mutation showed a delay or abrogation in repair for ionizing radiation (IR)-induced DNA double-strand breaks (DSBs) or ultraviolet (UV)-induced DNA single-strand breaks (SSBs), and exhibited a defect in p53 accumulation and failure in cell cycle checkpoint at G1-S phase. These findings showed that mutations of ATR gene result in failure for DNA DSB and SSB repair, suggesting the role of ATM and ATR gene mutations in PAL lymphomagenesis.

Epstein-Barr virus (EBV) initially isolated from the cultured Burkitt lymphoma (BL) cells, is one of the well-known oncogenic virus. The NAB-2 line, which was established from a North American Burkitt's tumor, was indicated to contain one copy of EBV DNA as the integrated form into chromosome 2p13 of the host genome. To demonstrate the integration site of EBV directly, and to clarify the relation between the integration sites and the oncogenes, fragments containing the nucleotide sequence of NAB-2 integration sites were cloned. EBV was integrated via the terminal repeats (TR), and integration sites located in the clone RP11-440P5 on chromosome 2, between two oncogenes, REL and BCL11A, which is apart from approximately 350 kbp from each other. Expression level of REL in NAB-2 was increased. The flanking region of chromosome 2 at the bilateral junction sites showed no homology to the junction sites of EBV. The integration site 2p13 overlaps with common fragile site, FRA2E. NAB-2 cells expressed almost all latent genes but LMP-2A that flanks the TR, indicating the type III of latent infection of EBV. Integration event in NAB-2 might alter the regulation of the oncogenes and provide advantage for continuous cell proliferation.

Aims: Excessive alcohol consumption is a common problem in society and medical practice. There is a need for a diagnostic tool with both high sensitivity and specificity for the detection of excessive alcohol consumption in unselected medical populations. Therefore, we evaluated the diagnostic accuracy of carbohydrate-deficient transferrin (CDT) in the detection of excessive alcohol consumption., Methods: Computerised literature searches in Medline, Embase and Current Contents databases (01/1966-06/2003) and reference checking. Articles on the detection of excessive alcohol consumption reporting CDT levels and self-reported alcohol consumption as a reference test were selected (n = 101). Studies concerning treatment, relapse detection and traffic offenders were excluded. Quality assessment and data-extraction was done by two reviewers independently. Only studies scoring positive on core validity criteria by Lijmer were eligible for quantitative analysis (n = 29)., Results: Only two CDT-assays (CDTect and CDTriTIA) were evaluated in more than two high validity studies fulfilling the criteria for inclusion in the statistical analysis. Sensitivity of CDTect (14 data points) ranged from 20 to 85%, whereas specificity ranged from 77 to 95%. A summary ROC curve was computed for CDTect. Sensitivity of CDTTriTIA (4 data points) ranged from 10 to 67%, and specificity ranged from 90 to 100%. No summary measure could be computed for CDTTriTIA. The heterogeneity of results could not be explained clinically., Conclusions: The validity of CDT as a diagnostic tool is still questionable. If the higher values for sensitivity that some studies report can be confirmed by others it is a useful diagnostic tool in unselected populations. However, more methodologically sound, comparable studies need to be performed before firm conclusions can be drawn.

Epstein-Barr virus (EBV) initially isolated from cultured Burkitt lymphoma (BL) cells, is a well-known oncogenic virus. The Raji cell line was established from BL tissue and used for research worldwide. Previous study showed that each Raji cell contains an average of 50-60 EBV genome equivalents, and a significant proportion of the EBV genome is linearly integrated into host genome through BamHI-W close to the BamHI-Y fragment. However, a definitive EBV integration site in the chromosome has not been identified as yet. In this study, direct evidence that EBV DNA is integrated into the host genome was provided through cloning of the fragments containing nucleotide sequence of Raji integration sites. Integrated EBV DNA consisted of the BamHI-W fragment at one end and BamHI-D fragment at another end. Both junction sites were highly guanine/cytosine-rich. The BamHI-W fragment and the adjacent part of chromosome 6 showed 70% homology, while no homology was found between the BamHI-D and adjacent host sequences. EBV was present at intron 1 of the BACH2 gene located on chromosome 6q15. BACH2 was not expressed in the Raji cell line. Because BACH2 is a putative tumor suppressor gene, loss of its expression through EBV integration might contribute to lymphomagenesis.

Malignant lymphoma frequently develops in the pleural cavity of patients with over 20 years' history of pyothorax. The term pyothorax-associated lymphoma (PAL) has been proposed for this type of tumor. We established four novel lymphoma cell lines (OPL-3, -4, -5, and -7) from four patients with PAL. Characteristics of the four cell lines are as follows: B-cell nature with defective expression of B-cell and T-cell surface antigens, monoclonal pattern of Epstein-Barr virus (EBV) infection in lymphoma cells (thus indicating an etiological role of EBV for lymphomagenesis), complicated chromosomal abnormalities with numerous structural and numerical abnormalities, and occasional but distinct genome instability. These abnormalities in cell character might be caused by the specific circumstances of PAL lymphomagenesis, i.e., chronic inflammation. Thus, PAL cell lines could be useful in analysis of molecular mechanisms leading to malignancy in chronic inflammation.

Recently we reported the different frequencies of p53 and c-kit gene mutations among sinonasal NK/T cell lymphoma (NKTCL) in Korea, north China (Beijing), and Japan, suggesting some racial, environmental, or life-style differences as a possible cause of nasal tumorigenesis. In this study, gene mutations in p53, c-kit, K-ras, and beta-catenin gene were analyzed by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) followed by direct sequencing in 20 cases of sinonasal NKTCL from northeast China (Shen Yang). Age of patients ranged from 5 to 63 (median, 40.0) years. p53 gene mutations were found in eight of 20 cases (40%), with exon 4 involvement in 10% of cases. The majority was missense mutations and G:C to A:T transition was predominant. The frequency of the c-kit and K-ras gene mutations was low (5%), while that of the beta-catenin gene was six of 20 cases (30%). From these findings, it is concluded that nasal NKTCL in northeast China shared common features with that in Korea in the younger onset of disease compared to that in Japan and lower frequency of p53 gene mutations with infrequent exon 4 involvement compared to that in Japan and north China. These differences might be caused by migration of susceptible populations or some environmental confounding factors.