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1.  A Case of Primary Gastric CD30-Positive Anaplastic Large-Cell Lymphoma 
Journal of Korean Medical Science  2005;20(6):1062-1065.
Gastric CD30-positive anaplastic large-cell lymphoma is a very rare disease. It is sometimes difficult to distinguish it from undifferentiated carcinoma, sarcoma and so on. We report here on a case of primary gastric anaplastic large-cell lymphoma. A 50-yr-old woman complained of epigastric pain and severe chest pain for 1 week. The gastroendoscopic examination revealed geographic mucosal irregularities with shallow ulceration at the antrum. She underwent a total gastrectomy. The gross finding of the resected stomach was an 8×4.5 cm sized ulceroinfiltrative lesion at the pyloric antrum along the lesser curvature. The microscopic examination revealed diffuse and solid proliferations of large atypical cells with pleomorphic nuclei. Immunohistochemically, the tumor cells were positive for CD30, vimentin and CD3, and this was a finding compatible with anaplastic large-cell lymphoma. To the best of our knowledge, this is the first such reported case in Korea.
PMCID: PMC2779310  PMID: 16361823
Antigens, CD30; Lymphoma Large-Cell, Ki-1; Stomach Neoplasms; Immunohistochemistry
2.  Expression of p63 in anaplastic large cell lymphoma but not in classical Hodgkin's lymphoma☆ 
Human pathology  2008;39(10):1505-1510.
Immunohistochemical determination of p63 protein is frequently used in the pathologic diagnosis of nonhematological solid tumors. In malignant hematological disease, p63 expression has been reported in 22% of follicular lymphoma, about 35% of diffuse large B-cell lymphoma, 23% of chronic lymphocytic leukemia, and in some cases of blast crisis of chronic myelogenous leukemia. Anaplastic large cell lymphoma is a rare disease that accounts for less than 5% of all cases of non-Hodgkin's lymphoma. There is little information concerning p63 expression in this specific type of lymphoma. In some cases, the morphological and phenotypic features between anaplastic large cell lymphoma and classical Hodgkin's lymphoma are similar, making this differential diagnosis challenging. We studied p63 expression using a tissue microarray approach in 154 cases of anaplastic large cell lymphoma, including 38% anaplastic large cell kinase positive and 62% anaplastic large cell kinase negative, and 58 Hodgkin's lymphoma cases. Sixty-eight cases of anaplastic large cell lymphoma (44%) showed p63 nuclear positivity (41% of anaplastic large cell kinase positive and 47% of anaplastic large cell kinase negative). Of 130 cases of systemic-anaplastic large cell lymphoma, 42% showed p63 positivity. The neoplastic cells expressed p63 in 38% of the cases of CD45-negative/anaplastic large cell kinase–negative null cell–type anaplastic large cell lymphoma, a subgroup that offers the most difficulties in the differential diagnosis with classical Hodgkin's lymphoma. In contrast, none of the cases of classical Hodgkin's lymphoma demonstrated any p63 expression. These results demonstrate that p63 protein expression is frequently expressed in a subset of anaplastic large cell lymphoma cases and may be used as a potential tool in the differential diagnosis between anaplastic large cell lymphoma and classical Hodgkin's lymphoma.
PMCID: PMC2744879  PMID: 18620733
p63; Anaplastic large cell lymphoma; Hodgkin's lymphoma; Immunohistochemistry; Tissue microarray
3.  PAX5-positive T-cell Anaplastic Large Cell Lymphomas Associated with Extra Copies of the PAX5 Gene Locus 
Cell lineage is the major criterion by which lymphomas are classified. Immunohistochemistry has greatly facilitated lymphoma diagnosis by detecting expression of lineage-associated antigens. However, loss or aberrant expression of these antigens may present diagnostic challenges. Anaplastic large cell lymphoma is a T-cell lymphoma that shows morphologic and phenotypic overlap with classical Hodgkin lymphoma, a tumor of B-cell derivation. Staining for the B-cell transcription factor, PAX5, has been suggested to be helpful in this differential, as it is positive in most classical Hodgkin lymphomas, but absent in anaplastic large cell lymphomas. Herein, we report four systemic T-cell anaplastic large cell lymphomas positive for PAX5 by immunohistochemistry, with weak staining intensity similar to that seen in classical Hodgkin lymphoma. All diagnoses were confirmed by a combination of morphologic, phenotypic, and molecular criteria. Three cases were ALK-negative and one was ALK-positive. PAX5 immunohistochemistry was negative in 198 additional peripheral T-cell lymphomas, including 66 anaplastic large cell lymphomas. Unexpectedly, though PAX5 translocations were absent, all evaluable PAX5-positive anaplastic large cell lymphomas showed extra copies of the PAX5 gene locus by fluorescence in situ hybridization. In contrast, only 4% of PAX5-negative peripheral T-cell lymphomas had extra copies of PAX5. We conclude that aberrant expression of PAX5 occurs rarely in T-cell anaplastic large cell lymphomas, and may be associated with extra copies of the PAX5 gene. PAX5-positive lymphomas with morphologic features overlapping different lymphoma types should be evaluated with an extensive immunohistochemical panel and/or molecular studies to avoid diagnostic errors that could lead to inappropriate treatment. Since PAX5 overexpression causes T-cell neoplasms in experimental models, PAX5 may have contributed to lymphomagenesis in our cases.
PMCID: PMC2848697  PMID: 20118907
Anaplastic large cell lymphoma; Hodgkin lymphoma; PAX5; CD30; T-cell receptor gene rearrangement; Immunohistochemistry; FISH
4.  Gastrointestinal malignant lymphoma: a pathologic study of 37 cases in a single Japanese institution 
The author reviewed pathologic features of 37 cases of malignant lymphoma in the gastrointestinal organs in the last 10 years in our pathology laboratory. The current WHO classification was adopted. The 37 cases consisted of 20 males and 17 female, and the age ranged from 46 to 89 years with a median of 69 years. Of the 37 cases, 25 cases (68%) were gastric lymphomas, 6 cases (16%) were small intestinal lymphomas, and 6 cases (16%) were colon lymphomas. Of the 37 cases, 35 cases (95%) were B-cell neoplasms and 2 cases (5%) were T-cell neoplasms. In the 25 gastric lymphomas (male:female=14:11, age range 46-84 years, median 70 years) 11 cases were diffuse large B-cell lymphomas, and 14 cases were extranodal marginal zone B-cell lymphomas (MALT lymphomas). The clinical endoscopic diagnosis was gastritis in 3, gastric ulcer in 3, gastric carcinoma in 7, carcinoid in 1, submucosal tumor in 1, malignant lymphoma in 2, and suspected MALT lymphoma in 8. In the 6 small intestinal lymphomas (male:female=2:4, age range 49-89 years, median 70 years), all cases were located in the ileum. Of the 6 cases, 4 were diffuse large B-cell lymphoma and 2 were peripheral T-cell lymphoma. One case showed multiple lymphomas, and one case was associated with rectal adenocarcinoma and one case with gastric MALT lymphoma. The clinical diagnosis was adenocarcinoma in 2, suspected lymphoma in 2, and ileal tumor in 2. In the 6 colon lymphomas (male:female=4:2, age range 69-86 years, median 74 years), 5 cases were diffuse large B-cell lymphomas and one case was follicular lymphoma. Clinical endoscopic diagnosis was GIST in 1, colon carcinoma in 4, and colon polyp in 1. Cases of Hodgkin’s disease, mantle cell lymphoma, Burkitt lymphoma were not recognized in the present series. In summary, the author reported pathologic features of 37 cases of gastrointestinal malignant lymphoma in our laboratory in the last 10 years.
PMCID: PMC3484413  PMID: 23119230
Malignant lymphoma; gastrointestinal organs
5.  Long term outcome of ocular adnexal lymphoma subtyped according to the REAL classification 
AIM—To classify ocular adnexal lymphomas according to the Revised European and American Lymphoma (REAL) classification and to determine any correlation between clinical features or histomorphological variables with the patients' outcome.
METHODS—Conventional and immunohistology were performed on representative sections of 53 specimens of 46 patients with ocular adnexal lymphoma. The antibodies used were CD20, BCL-2, CD21, CD23, CD43, CD3, CD5, p53, cyclin D1, pan-cytokeratin, kappa, lambda, IgD, and IgM. The growth fraction of the tumours was determined using the MIB-1 antibody directed against the Ki-67 antigen. Clinical follow up data regarding the outcome were obtained from the treating physicians and/or hospital files. The Student's t test and log rank test were used for statistical analysis.
RESULTS—The patient collective consisted of 29 females and 17 males with an age range of 32-89.7 years (average 63 years). Almost all specimens represented B cell non-Hodgkin's lymphomas: extranodal marginal zone lymphoma (EMZL) (n=38), diffuse large cell B cell lymphoma (n=8), lymphoplasmocytic lymphoma/immunocytoma (n=2), mantle cell lymphoma (n=2), follicle centre lymphoma (n=1), and plasmacytoma (n=1). One case of a secondary anaplastic large cell lymphoma of T cell type (T-ALCL) was diagnosed. The majority of the patients had stage I disease. A variety of therapeutic regimens was administered, the main form of treatment being radiotherapy. The average follow up time was 85 months. Complete remission was achieved in 24 patients (10 after excision alone, eight after radiotherapy alone, three after combined excision and radiotherapy, one after chemotherapy alone, and two after combined radiotherapy and chemotherapy). 12 patients died of causes related to lymphoma; in one patient the cause of death was unknown. Six patients had persistent tumour at final follow up and two patients were lost to follow up. The stage at presentation, as well as the lymphoma malignancy category, had a significant correlation with the final course of the disease (p=0.0001 and p=0.03, respectively). A significant correlation was also noted between the final outcome (p<0.05) and tumour cell expression for Ki-67 antigen and p53 protein.
CONCLUSION—67% of patients with ocular adnexal lymphoma had EMZL. The stage at presentation had a significant influence on the final outcome. MIB-1 and p53 expression by the tumour cells proved to be important immunohistochemical markers concerning the prognosis. It is suggested that, following thorough staging investigations, primary EMZL (stage I) (if accessible) should be treated with excisional biopsy and subsequent low dose radiotherapy. Primary diffuse large cell B cell lymphoma of the ocular adnexa requires at least similar therapeutic measures and regular intensive follow up.

PMCID: PMC1723704  PMID: 11133714
6.  Primary effusion lymphoma associated with Human Herpes Virus-8 and Epstein Barr virus in an HIV-infected woman from Kampala, Uganda: a case report 
Primary effusion lymphoma is a recently recognized entity of AIDS related non-Hodgkin lymphomas. Despite Africa being greatly affected by the HIV/AIDS pandemic, an extensive MEDLINE/PubMed search failed to find any report of primary effusion lymphoma in sub-Saharan Africa. To our knowledge this is the first report of primary effusion lymphoma in sub-Saharan Africa. We report the clinical, cytomorphologic and immunohistochemical findings of a patient with primary effusion lymphoma.
Case presentation
A 70-year-old newly diagnosed HIV-positive Ugandan African woman presented with a three-month history of cough, fever, weight loss and drenching night sweats. Three weeks prior to admission she developed right sided chest pain and difficulty in breathing. On examination she had bilateral pleural effusions.
Haematoxylin and eosin stained cytologic sections of the formalin-fixed paraffin-embedded cell block made from the pleural fluid were processed in the Department of Pathology, Makerere University, College of Health Sciences, Kampala, Uganda. Immunohistochemistry was done at the Institute of Haematology and Oncology "L and A Seragnoli", Bologna University School of Medicine, Bologna, Italy, using alkaline phosphatase anti-alkaline phosphatase method. In situ hybridization was used for detection of Epstein-Barr virus.
The tumor cells were CD45+, CD30+, CD38+, HHV-8 LANA-1+; but were negative for CD3-, CD20-, CD19-, and CD79a- and EBV RNA+ on in situ hybridization. CD138 and Ki-67 were not evaluable. Our patient tested HIV positive and her CD4 cell count was 127/μL.
A definitive diagnosis of primary effusion lymphoma rests on finding a proliferation of large immunoblastic, plasmacytoid and anaplastic cells; HHV-8 in the tumor cells, an immunophenotype that is CD45+, pan B-cell marker negative and lymphocyte activated marker positive. It is essential for clinicians and pathologists to have a high index of suspicion of primary effusion lymphoma when handling HIV positive patients who have effusions without palpable tumor masses. Basic immunohistochemistry is essential for definitive diagnosis.
PMCID: PMC3048476  PMID: 21320326
7.  Cytodiagnosis of epithelioid malignant melanoma (amelanotic) and diagnostic dilemmas 
Melanoma is an aggressive neoplasm, and early diagnosis can reduce mortality in such patients. Diagnosis may be delayed in amelanotic tumors. We present one such case, a 35-year-old lady with a rapidly growing mass over the right angle of mandible. Fine-needle aspiration cytology was done, and smears showed discretely arranged large epithelioid cells with high N:C ratio, prominent single to multiple nucleoli. Occasional binucleated and multinucleated tumor giant cells were also noted. Poorly differentiated carcinoma, high-grade non-Hodgkin lymphoma, amelanotic melanoma, and pleomorphic sarcoma were included as differential diagnoses. Immunocytochemistry (ICC) revealed Melan-A/MART-1 positivity in some cells and S-100 positivity in most tumor cells. Desmin, pancytokeratin, and leukocyte common antigen were negative. Based on cytomorphological features and ICC findings, a diagnosis of epithelioid variant of amelanotic melanoma was rendered. Later on, true cut biopsy and histologic examination of excised specimen and adjunct immunohistochemistry with positive Melan-A and S-100 confirmed the diagnosis.
PMCID: PMC4349013  PMID: 25745288
Amelanotic epithelioid melanoma; differential diagnoses; fine-needle aspiration cytology; immunocytochemistry
8.  A Primary Testicular Diffuse Large B-cell Lymphoma Belonging to the Germinal Center B-cell-like Group 
Testicular lymphoma was first reported by Malassez and Curling in 1866. Primary testicular lymphoma constitutes only 1 - 7% of all testicular neoplasms and less than 1% of all non Hodgkin lymphoma. The authors report a new case of primary testicular lymphoma and highlight its diagnostic and therapeutic challenge. We report the case of a 26-year old man without a particular past medical history, who presented with a painful right testicular swelling that he has noticed for several weeks. Radiological findings consisted in multiple hypoechoic masses that corresponded in histological examination to a diffuse intratubular lymphomatous infiltration situated away from the spermatic cord, the epididymis, ductuli efferentes and rete testis. Immunohistochemical study showed positivity for leukocytic common antigen (CD45), B-cell marker (CD20) and bcl 6. The patient underwent full staging for lymphoma showing no evidence of extra-testicular involvement by lymphoma and no lymph nodes. The diagnosis of stage I primary testicular large B-cell lymphoma of germinal center B-cell-like group was made. The patient is now treated by chemotherapy. Primary testicular lymphoma is a rare tumour whose diagnosis is based on histological findings. There are non consensual etiological or predisposing factors. Treatment modalities consist in surgical excision, chemotherapy and radiation therapy but the accurate procedures are not standardized. Factors that have been linked to more favorable outcomes include younger patient age, localized disease, presence of sclerosis at pathologic analysis, smaller tumour size, lower histological tumor grade and lack of epididymal or spermatic cord involvement.
Testicular lymphoma; Germinal center; B-cell
PMCID: PMC3299176  PMID: 22457702
9.  Analysis of clinical characteristics, diagnosis, treatment and prognosis of 46 patients with primary gastrointestinal non-Hodgkin lymphoma 
Molecular and Clinical Oncology  2013;2(2):259-264.
Primary gastrointestinal non-Hodgkin lymphoma (PGI NHL) is one of the most common types of extranodal lymphoma, accounting for ~30–50% of all extranodal lymphomas. The aim of the present study was to investigate the clinical characteristics, diagnosis, treatment and prognosis of patients with PGI NHL. A total of 46 patients with PGI NHL (mean age, 50 years) were enrolled in this study, with a male:female ratio of 1.3:1. The most common site of PGI NHL was the stomach (52.2%), followed by the colon (34.8%) and small intestine (8.7%). The most common symptoms of PGI NHL included abdominal pain or discomfort (91.3%), loss of appetite (65.2%) and weight loss (56.5%) and the most common pathological subtype of PGI NHL was diffuse large B-cell lymphoma (DLBCL) (78.3%). Lesions were identified in 95.7% of PGI NHL patients under preoperative endoscopic examination, whereas the diagnosis rate was only 21.7% during preoperative endoscopic biopsy. All 46 patients underwent surgical treatment and 36 also received postoperative chemotherapy or radiotherapy. The follow-up time was 6–70 months in 37 PGI NHL patients, with 1-, 3- and 5-year survival rates of 81.1, 62.16 and 50.0%, respectively. The 5-year survival rate differed significantly according to clinical stage (P=0.002) and tumor size (P=0.0017) among patients with PGI NHL. However, there was no statistically significant difference in the 5-year survival rate between patients who received surgery alone and those who received surgery plus postoperative chemotherapy or radiotherapy (P=0.1371). Furthermore, there were no statistically significant differences in gender (P=0.127), clinical stage (P=0.828), histological subtype (P=1.000) and surgical modality (P=0.509) between patients with primary gastric non-Hodgkin lymphoma (PG NHL) and those with primary intestinal non-Hodgkin lymphoma (PI NHL). In conclusion, PGI NHLs are a heterogeneous group of diseases, whereas clinical stage and tumor size were identified as adverse prognostic factors of PGI NHL. Further studies, including a larger number of patients treated with surgery alone, are required in order to elucidate the precise role of surgery combined with postoperative chemotherapy or radiotherapy in the prognosis of PGI NHL.
PMCID: PMC3917777  PMID: 24649343
non-Hodgkin lymphoma; gastrointestinal lymphoma; diagnosis; therapy; prognosis
10.  Aberrant expression of the dendritic cell marker TNFAIP2 by the malignant cells of Hodgkin lymphoma and primary mediastinal large B cell lymphoma distinguishes these tumor types from morphologically and phenotypically similar lymphomas 
TNFAIP2 is a protein upregulated in response to TNF signaling but its cellular expression and function in normal and neoplastic tissues remains largely unknown. Here we use standard immunohistochemical techniques to demonstrate that TNFAIP2 is normally expressed by follicular dendritic cells, interdigitating dendritic cells, and macrophages but not by lymphoid cells in secondary lymphoid tissues. Consistent with this expression pattern, we found strong TNFAIP2 staining of tumor cells in 4/4 cases (100%) of follicular dendritic cell sarcoma and in 3/3 cases (100%) of histiocytic sarcoma. Although TNFAIP2 is not expressed by the small and intermediate-size neoplastic B-cells comprising follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, or marginal zone lymphoma, we observed strong TNFAIP2 staining of the large, neoplastic cells, in 31/31 cases (100%) of classical Hodgkin lymphoma, 12/12 cases (100%) of nodular lymphocyte predominant Hodgkin lymphoma, and 27/31 cases (87%) of primary mediastinal (thymic) large B cell lymphoma. In contrast, TNFAIP2 was expressed by the malignant cells in only 2/45 cases (4%) of diffuse large B cell lymphoma, not otherwise specified, 2/18 cases (11%) of Burkitt lymphoma, and 1/19 cases (5%) of anaplastic large cell lymphoma. Further analysis indicates that TNFAIP2, as a single diagnostic marker, is more sensitive (sensitivity= 87%) and specific (specificity= 96%) than TRAF1, nuclear cRel, or CD23 for distinguishing the malignant B-cells of primary mediastinal (thymic) large B cell lymphoma from those of its morphologic and immunophenotypic mimic, diffuse large B cell lymphoma, not otherwise specified. Thus, TNFAIP2 may serve as a useful new marker of dendritic and histiocytic sarcomas whose aberrant expression in the malignant cells of classical Hodgkin lymphoma and primary mediastinal (thymic) large B cell lymphoma serves to distinguish these tumors from other large cell lymphomas in routine clinical practice.
PMCID: PMC3178718  PMID: 21921781
TNFAIP2; Hodgkin Lymphoma; primary mediastinal (thymic) large B cell lymphoma; immunohistochemistry
11.  Immunohistochemical (IHC) Analysis of Non-Hodgkin’s Lymphoma (NHL) Spectrum According to WHO/REAL Classification: A Single Centre Experience from Punjab, India 
Introduction: The distribution of the major subtypes of non-Hodgkin’s lymphoma (NHL) differs across geographic regions. This study, from the north Indian state of Punjab, has incorporated immunophenotypic findings while investigating the distribution of NHL subtypes based on World Health Organization (WHO)/ Revised European-American Classification of Lymphoid Neoplasms (REAL) system of classification.
Patients and methods: Over all seventy seven cases of lymphoma over a period of one year (between April 2012 and April 2013) were diagnosed in the Department of Pathology, Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar (Punjab). Of these 30 cases (39%) were of Hodgkin’s Lymphoma (HL) and 47 cases (61%) were of Non Hodgkins lymphoma NHL.
Of the total of cases of lympho-proliferative disorders, the diagnosis of NHL was done by light microscopy alone. All the cases diagnosed provisionally as NHL were taken up for immunophenotyping with Immunohistochemical (IHC) studies. There was 100 % concordance between the light microscopy and IHC studies.
The individual NHL cases were classified according to the WHO/REAL classification according to the positive or relevant negative immonophenotypic expression and tabulated to ascertain the morphological spectrum of NHL in this part of the country.
Results: B-cell lymphomas formed 89.3%, whereas T-cell lymphomas formed 10.7% of the NHLs. Diffuse Large B-Cell Lymphoma (DLBCL) was the most common subtype (46.8% of all NHLs). B-cell small lymphocytic lymphoma, Mantle-Cell Lymphoma (MCL), marginal zone B-cell lymphomas (including MALT lymphomas), Diffuse, mixed small cleaved cell and large-cell type and Follicular centre-cell lymphomas amounted to 17%, 12.8%, 2.1%, 2.1% and 4.3%, respectively. Among the T-cell lymphomas, T-cell lymphoblastic lymphoma, anaplastic large-cell lymphomas of T/null-cell type, and Angioimmunoblastic T-cell lymphoma (AITL) accounted for 6.4%, 2.1%, and 2.1% of all NHL cases, respectively.
Conclusions: The distribution of NHL subtypes in India shows disparity with those from the rest of the world. Follicular Lymphoma (FL) and MCL are less common in India compared to Europe and the USA. Peripheral T-cell lymphomas and T/NK-cell lymphomas of nasal and nasal types, which are common in many other Asian countries, are also less prevalent. T-cell lymphoblastic lymphoma and anaplastic large T/null cell lymphoma are more prevalent in India.
PMCID: PMC3939585  PMID: 24596721
Non Hodgkins lymphoma; WHO/REAL classification; Immunophenotyping; B-cell lymphomas; T-cell lymphomas
12.  Gastric Mucosa-Associated Lymphoid Tissue Lymphoma Followed by Primary Central Nervous System Lymphoma 
Mucosa-associated lymphoid tissue (MALT) lymphoma is one of the most common lymphomas and accounts for about 7% of all newly diagnosed non-Hodgkin's lymphoma (NHL). The clinical course of MALT lymphoma is relatively indolent and, in the majority of cases (50%), the lymphoma arises within the stomach. Primary central nervous system lymphoma (PCNSL), an uncommon variant of extranodal NHL, can affect any part of the neuraxis, including the eyes, brain, leptomeninges, or spinal cord. Herein, we present a rare case of PCNSL, which occurred one year after radiochemotherapy of gastric MALT lymphoma. A 62-year-old man presented with a 3-day history of left facial palsy. One year ago, he underwent antibiotic eradication therapy of Helicobacter pylori, local stomach fractional radiotherapy, and chemotherapy for gastric MALT lymphoma. Magnetic resonance imaging revealed a strong enhancing solid mass in the right frontal lobe. The tumor was completely removed, and the histological diagnosis of PCNSL developing from diffuse large B-cell lymphoma was made. Although elucidating the correlation between the first gastric MALT lymphoma and the second PCNSL seemed difficult, we have postulated and discussed some possible pathogeneses, together with a review of literature.
PMCID: PMC3424181  PMID: 22949970
MALT Lymphoma; Diffuse large B-Cell lymphoma
13.  Primary gastric mantle cell lymphoma 
Hematology Reports  2012;4(1):e1.
Mantle cell lymphoma represents 2.5–7% all of non Hodgkin's lymphomas. Stomach is the most common site of extranodal lymphoma. However, that is not the case with mantle cell lymphoma, which is extremely rare. We present a case of 71-year-old woman admitted to the Internal Clinic of the University Clinical Hospital Center Rijeka, because of stomach discomfort and melena. Endoscopy and computed tomography revealed a polyp in gastric antrum. Histopathologic, immunohistochemic and genetic methods were also performed and the results were consistent with primary gastric mantle cell lymphoma without periepigastric and/or local or distant abdominal lymph node involvement.
PMCID: PMC3343450  PMID: 22567215
primary gastric mantle cell lymphoma; diagnosis; therapy.
14.  Molecular markers (PECAM-1, ICAM-3, HLA-DR) determine prognosis in primary non-Hodgkin’s gastric lymphoma patients 
AIM: To investigate the prognostic significance of PECAM-1, ICAM-3 and HLA-DR antigens in patients with primary non-Hodgkin's gastric lymphoma.
METHODS: We immunohistochemically studied PECAM-1, ICAM-3 and HLA-DR antigen expression in 36 B-cell MALT-type primary gastric lymphoma patients. Ten non-malignant and ten healthy gastric tissue specimens were used as controls. Clinicopathological and survival data were correlated with the staining results.
RESULTS: HLA-DR antigen expression was detected in 33 gastric lymphoma patients (91.7%) and 6 non-malignant patients (54.5%). PECAM-1 stained tumor cells of 10 patients (27.8%), endothelial cells of 9 patients (25%) and inflammatory infiltrate of 4 patients (40%) with benign gastric disease. ICAM-3 expression was observed on the tumor cells of 17 patients (47.2%), while 5 non-malignant patients (50%) were stained positive as well. None of the healthy controls was stained for any of the genes studied. In the multivariate analysis, HLA-DR antigen and PECAM-1 were proved to be statistically significant independent prognostic factors associated with a favourable and an unfavourable prognosis respectively (P = 0.009 and P = 0.003). In the univariate analysis, PECAM-1(+)/ICAM-3(-) and HLA-DR(-)/ICAM-3(-) patients exhibited a significantly decreased overall survival compared to those with the exactly opposite gene expression patterns (P = 0.0041 and P = 0.0091, respectively). Those patients who were HLA-DR(+)/ICAM-3(+)/PECAM-1(-) (n = 8) had a significantly higher survival rate compared to the rest of the group (n = 24) (P = 0.0289).
CONCLUSION: PECAM-1, ICAM-3 and HLA-DR are representative markers of tumor expansion potential and host immune surveillance respectively. Their combined use may help us to identify high-risk patients who could benefit from more aggressive therapeutic protocols.
PMCID: PMC4087519  PMID: 16610000
PECAM-1; ICAM-3; HLA-DR; Non-Hodgkin's gastric lymphoma; Prognosis
15.  Epigenetic regulation of CD44 in Hodgkin and non-Hodgkin lymphoma 
BMC Cancer  2010;10:517.
Epigenetic inactivation of tumor suppressor genes (TSG) by promoter CpG island hypermethylation is a hallmark of cancer. To assay its extent in human lymphoma, methylation of 24 TSG was analyzed in lymphoma-derived cell lines as well as in patient samples.
We screened for TSG methylation using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in 40 lymphoma-derived cell lines representing anaplastic large cell lymphoma, Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Hodgkin lymphoma and mantle cell lymphoma (MCL) as well as in 50 primary lymphoma samples. The methylation status of differentially methylated CD44 was verified by methylation-specific PCR and bisulfite sequencing. Gene expression of CD44 and its reactivation by DNA demethylation was determined by quantitative real-time PCR and on the protein level by flow cytometry. Induction of apoptosis by anti-CD44 antibody was analyzed by annexin-V/PI staining and flow cytometry.
On average 8 ± 2.8 of 24 TSG were methylated per lymphoma cell line and 2.4 ± 2 of 24 TSG in primary lymphomas, whereas 0/24 TSG were methylated in tonsils and blood mononuclear cells from healthy donors. Notably, we identified that CD44 was hypermethylated and transcriptionally silenced in all BL and most FL and DLBCL cell lines, but was usually unmethylated and expressed in MCL cell lines. Concordant results were obtained from primary lymphoma material: CD44 was not methylated in MCL patients (0/11) whereas CD44 was frequently hypermethylated in BL patients (18/29). In cell lines with CD44 hypermethylation, expression was re-inducible at mRNA and protein levels by treatment with the DNA demethylating agent 5-Aza-2'-deoxycytidine, confirming epigenetic regulation of CD44. CD44 ligation assays with a monoclonal anti-CD44 antibody showed that CD44 can mediate apoptosis in CD44+ lymphoma cells. CD44 hypermethylated, CD44- lymphoma cell lines were consistently resistant towards anti-CD44 induced apoptosis.
Our data show that CD44 is epigenetically regulated in lymphoma and undergoes de novo methylation in distinct lymphoma subtypes like BL. Thus CD44 may be a promising new epigenetic marker for diagnosis and a potential therapeutic target for the treatment of specific lymphoma subtypes.
PMCID: PMC2955612  PMID: 20920234
16.  Primary gastric natural killer/T-cell lymphoma with diffuse CD30 expression and without CD56 expression: A case report 
Oncology Letters  2015;11(2):969-972.
The majority of natural killer (NK)/T-cell lymphomas occur in the nasal cavity and rarely involve the stomach. They possess a specific immunophenotype, with the expression of cluster of differentiation (CD)56, CD2 and CD3ε, but without CD3 expression. Few cases of NK/T-cell lymphoma have partial CD30 expression. The present study reveals a unique case of a 41-year-old female patient with gastric NK/T-cell lymphoma that did not express CD56 and diffusely expressed CD30. Immunohistochemical staining demonstrated that the tumor cells expressed CD3ε, CD43, CD30 and granzyme B and did not express CD2, CD4, CD5, CD7, CD8, CD56, anaplastic lymphoma kinase, CD20, paired box-5 or pan cytokeratin. Based on the immunostaining profile and morphological features, the initial diagnosis considered was gastric anaplastic large cell lymphoma. However, following a consultation with other pathologists, the Epstein-Barr virus (EBV) status of the patient was investigated to exclude a diagnosis of NK/T-cell lymphoma. Notably, the signal for EBV RNA was diffuse positive. Therefore, the final diagnosis was corrected to NK/T-cell lymphoma. To the best of our knowledge, the present study is the first to report NK/T-cell lymphoma in the stomach with a diffuse CD30-positive and CD56-negative phenotype.
PMCID: PMC4734030  PMID: 26893677
NK/T-cell lymphoma; stomach; CD56; CD30
17.  An atypical presentation of sporadic ovarian Burkitt’s lymphoma: case report and review of the literature 
Primary non-Hodgkin’s lymphoma of the ovary is a rare occurrence. An ovarian involvement by non-Hodgkin lymphoma (NHL) may include one of the four subtypes of lymphoma: diffuse large B-cell lymphoma, Burkitt’s lymphoma (BL), lymphoblastic lymphoma or anaplastic large cell lymphoma. Burkitt’s lymphoma is a rare entity with a specific poorly differentiated pattern.
Most women experience an ovarian BL with abdominal pelvic pain, abnormal vaginal bleeding, bowel obstruction, urinary frequency, incontinence and abdominal mass. Sometimes these warning signs may be absent, causing a late and more difficult diagnosis.
Here we report a case of a primary ovarian Burkitt’s lymphoma with bilateral involvement in a 57 year old patient. She firstly presented neurological symptoms in the upper limbs and she was treated with surgery and combined chemotherapy. The diagnosis of malignant lymphoma was established after bilateral adnexectomy and histological study of the excised tissue.
PMCID: PMC3710258  PMID: 23826666
Burkitt; Ovarian lymphoma; Hypoaesthesia; Oophorectomy; Chemotherapy
18.  Childhood non-Hodgkin lymphomas in the United Kingdom: findings from the UK Children's Cancer Study Group. 
Journal of Clinical Pathology  1997;50(2):128-134.
AIM: To review the presenting clinical features and the histology of cases of non-Hodgkin lymphoma (NHL) entered into the United Kingdom Children's Cancer Study Group NHL Trial. METHODS: Sections of biopsy specimens from all cases entered into the trial were stained with Giemsa and haematoxylin and eosin. All cases were stained immunohistochemically for CD45, CD3, CD45RO, CD20, and CD30. Sections were stained with either naphthol AS-D chloroacetate esterase or KP1 (CD68) to identify granulocytic tumours. In a minority of cases, additional immunohistochemical stains were performed when necessary to establish the diagnosis. The sections were reviewed by three pathologists. RESULTS: Of 308 cases analysed, 293 were categorised as NHL. There was only one case of low grade lymphoma in the series. Over 80% of the cases fell into the categories Burkitt lymphoma (42.2%), lymphoblastic lymphoma (27.2%) and anaplastic large cell lymphoma (15.1%). Cases of Burkitt lymphoma presented most often with abdominal tumours mainly of the ileocaecal region. Tumours of the oropharynx and nasopharynx were also common in this group. Of the 84 lymphoblastic lymphomas, 56 were of the T-cell phenotype, 12 of the B-cell phenotype and 16 of indeterminate lineage. Most of the T-lymphoblastic lymphomas showed mediastinal or pleural involvement. Infiltration of the skin and soft tissues was seen in 25% of lymphoblastic lymphoma of B or indeterminate phenotype. Forty six children were diagnosed as having anaplastic large cell lymphoma, the majority being of T or indeterminate lineage. Most patients presented with lymphadenopathy but involvement of the bones, soft tissues or skin was seen in seven patients and of the mediastinum and lungs in five. CONCLUSION: Childhood non-Hodgkin lymphomas are almost all high grade and frequently extranodal. They fall mainly into the categories Burkitt lymphoma, lymphoblastic lymphoma and anaplastic large cell lymphoma. The separation of these subcategories can be made on the basis of morphology and immunohistochemical features. The anatomical distribution of these different categories of non-Hodgkin lymphoma is distinctive.
PMCID: PMC499737  PMID: 9155693
19.  Primary Breast Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma Transformation to Diffuse Large B-cell Lymphoma: A Case Report 
Turkish Journal of Hematology  2012;29(3):274-277.
Primary non-Hodgkin’s lymphoma (NHL) of the breast constitutes 0.04%-0.53% of all malignancies and 2.2% of extra nodal lymphomas. In total, 7%-8% of all B-cell lymphomas are the mucosa-associated lymphoid tissue (MALT) type, of which up to 50% of primary gastric MALT lymphoma. Herein we present a patient with breast MALT lymphoma that transformed to diffuse large B-cell lymphoma (DLBCL). A 69-year-old female presented with a mass on her left breast. Physical examination showed a 3×3-cm mass located 1 cm from the areola on the upper lateral quadrant of the breast at the 1 o’clock position, which was fixed and firm. Excisional biopsy was performed and pathologic examination of the specimen showed MALT lymphoma transformation to DLBCL. The patient was staged as II-EA. The rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) protocol was scheduled as treatment. Following 6 courses of R-CHOP, 2 additional courses of rituximab were administered. Positron emission tomography (PET)-CT was done at the end of the treatment. PET showed that the patient was in complete remission. At the time this report was written, the patient was being followed-up at the outpatient clinic on a regular basis. Lymphoma of the breast is a rarity among malignant tumors of the breast. The most common type of lymphoma is DLBCL. Breast MALT lymphoma is extremely rare. Primary MALT lymphoma of the breast can transform from low grade to high grade and recurrence is possible; therefore, such patients should be monitored carefully for transformation.
PMCID: PMC3986754  PMID: 24744673
Primary breast mucosa-associated lymphoid tissue (MALT) lymphoma; Diffuse large B-cell lymphoma
20.  Rhabdomyosarcoma masquerading as lymphadenopathy in a patient with newly diagnosed Hodgkin’s lymphoma 
Hodgkin’s lymphoma (HL) is a rare malignancy which often presents with lymphadenopathy and classic “B symptoms” of weight loss, fever, and night sweats. Additional masses or nodes could easily be presumed to be a result of the initial diagnosis. On the other hand, adult rhabdomyosarcoma is a rare malignancy presenting with a new mass in a patient with previous diagnosis of Hodgkin’s lymphoma. In both cases, a tissue diagnosis should be obtained to appropriately confirm the diagnosis.
Case presentation
We present a case of a 64-year-old male who presents with right axillary lymphadenopathy, diagnosed as Hodgkin’s lymphoma. He subsequently developed left inguinal lymphadenopathy without the classic B symptoms of HL. Excisional biopsy revealed rhabdomyosarcoma. Stage III Hodgkin’s lymphoma (lymph node involvement on both sides of the diaphragm) is not commonly seen without typical B symptoms. Once the diagnosis of two primary malignancies is made, the dilemma becomes determining the treatment course. In the case of Hodgkin’s lymphoma and rhabdomyosarcoma, there is some overlap in the chemotherapeutic regimen and use of radiation.
This case illustrates the importance of careful examination of Hodgkin’s lymphoma patients and consideration of additional tissue diagnoses in atypical presentations of new masses or lymphadenopathy on the opposite side of the diaphragm.
PMCID: PMC4818867  PMID: 27038637
Hodgkin’s lymphoma; Nodular sclerosing type; Lymphadenopathic rhabdomyosarcoma; Alveolar type
21.  Poorly differentiated medullary carcinoma of the colon with an unusual phenotypic profile mimicking high grade large cell lymphoma – a unique case report and review of the literature 
Medullary carcinoma (MC) of the colon and rectum is a rare entity, accounting for less than 0.1% of colonic adenocarcinoma that poses a diagnostic challenge for the practicing pathologist. Poorly differentiated or undifferentiated MC with an unusual histological appearance and immunoprofile in addition to heavy lymphoid infiltrate could make it problematic when differentiating it from a high grade lymphoma, in particular anaplastic large B- or T-cell lymphoma, plasmablastic lymphoma, and other undifferentiated neoplasms. Here we reported a unique case of an 81 y/o woman presenting with a 7.0 cm colon mass detected by computed tomography (CT) scan. A partial transverse and ileum resection with appendectomy were performed. Microscopic examination revealed sheets of large, pleomorphic, mitotically-active cells with abundant eosinophilic cytoplasm and multiple prominent nucleoli, growing with a pushing border and poor glandular formation in a background of intratumoral lymphocytes. The neoplastic cells were only focally positive for keratins (<10%); diffusely and strongly positive for vimentin and CD10 with high proliferative index (Ki-67, 90%). The tumor cells were also aberrantly positive for CD30, CD79a and CD43 (diffusely or focally), resulting in a diagnostic dilemma between colonic MC and high grade lymphoma. Careful examination and additional immunohistochemical stains performed proved there was no evidence of T or B-cell lymphoma, melanoma, or other types of primary colon or metastatic carcinomas. This case highlights the difficulty in distinguishing a high grade lymphoma and poorly differentiated colonic MC, and, also the aberrant expression of CD10 and a significant loss of pancytokeratin could result in a diagnostic pitfall.
PMCID: PMC3925936  PMID: 24551312
Medullary carcinoma; colorectal; lymphoma; microsatellite instability
22.  Glioma Associated Oncogene Homologue 3 (GLI3), a Hedgehog Transcription Factor, is Highly Expressed in Hodgkin and Reed-Sternberg Cells of Classical Hodgkin Lymphoma 
Human pathology  2011;42(11):1643-1652.
The hedgehog signaling pathway has been shown to play a pathogenic role in diffuse large B-cell lymphoma and anaplastic large cell lymphoma, but has not been assessed in classical Hodgkin lymphoma. GLI1, GLI2, and GLI3 are transcriptional effectors of the hedgehog pathway. In this study, we first used real-time quantitative PCR to investigate expression of GLI1, GLI2, and GLI3 in 3 classical Hodgkin lymphoma cell lines. GLI1 and GLI2 were variably expressed, but GLI3 was highly expressed in all cell lines. We then used immunohistochemistry to assess GLI1, GLI2, and GLI3 in 39 classical Hodgkin lymphoma patient samples. GLI1 and GLI2 were weakly to variably expressed in a subset of classical Hodgkin lymphoma patient samples. In contrast, GLI3 showed strong, uniform nuclear expression in virtually all Hodgkin/Reed-Stenberg cells. We then performed an immunohistochemical survey of GLI3 expression in 13 cases of nodular lymphocyte predominant Hodgkin lymphoma and 218 non-Hodgkin lymphomas. Most other lymphoma types showed variable or no expression of GLI3, with a minor subset of cases of nodular lymphocyte predominant Hodgkin lymphoma, ALK-positive and ALK-negative anaplastic large cell lymphoma, and B-cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma showing a GLI3 staining pattern indistinguishable from classical Hodgkin lymphoma. Our data provide a rationale to further investigate the biological significance of GLI3 in classical Hodgkin lymphoma biology.
PMCID: PMC3165071  PMID: 21531006
GLI3; hedgehog signaling; classical Hodgkin lymphoma; immunohistochemistry
23.  Serum IgA to Epstein-Barr virus Early Antigen-Diffuse identifies Hodgkin's Lymphoma 
Journal of medical virology  2013;86(9):1621-1628.
Hodgkin's lymphoma is associated with immune dysregulation. Immune impairment often results in aberrant immune responses and lytic reactivation of ubiquitous Herpesviruses such as Epstein-Barr virus (EBV) in mucosal tissues. Accordingly, the specificity of IgA to EBV early-lytic antigens, which are important for reactivation, was evaluated to determine Hodgkin's lymphoma-specific sero-reactive patterns. Sera from 42 previously described patients with Hodgkin's lymphoma were compared to sera from 17 patients with infectious mononucleosis (IM), another EBV-related condition that often presents in a similar manner; and to sera from 15 healthy EBV-seropositive subjects. Flow cytometry analysis demonstrated that like IM sera, most Hodgkin's lymphoma sera contained IgA that labeled cells expressing EBV early-lytic antigens whereas healthy EBV-seropositive sera did not. Further evaluation to distinguish Hodgkin's lymphoma from IM showed that IgA in most Hodgkin's lymphoma, irrespective of the presence of EBV in primary tumors, detected only modified forms of EBV lytic Early Antigen-Diffuse (EA-D) while IM sera detected the un-modified form as well, further supporting the presence of immune dysregulation in Hodgkin's lymphoma patients. This IgA pattern distinguished Hodgkin's lymphoma from IM sera with a sensitivity of 92.9%, specificity 100%, positive predictive value 100%, and negative predictive value 85%. Our findings lay the groundwork for additional scientific and clinical investigation, particularly into the potential for developing Hodgkin's lymphoma -associated diagnostic and prognostic biomarkers.
PMCID: PMC3969873  PMID: 24122847
Hodgkin's lymphoma; Epstein-Barr virus; immune dysregulation; biomarker; lytic antigens
24.  Anorectal and gastric peripheral T-cell lymphoma, unspecified in a non-AIDS patient 
Anorectum is a rare location for malignant lymphoma. Involvement of is rare even for the lymphoma associated with acquired immune deficiency syndrome (AIDS), and AIDS has a relatively increased frequency of anorectal lymphoma. Most lymphomas in AIDS patients are of a B-cell origin, and T-cell lymphoma of the gastrointestinal tract is extremely rare. We report here on a case of anorectal and gastric peripheral T-cell lymphoma, unspecified (PTCLu) in a non-AIDS patient. A previously healthy 29-year-old man presented with hematochezia and tenesmus that he had suffered with for the previous 2 months. Sigmoidoscopy showed anal and rectal submucosal tumor. Multiple round-shaped, flat and elevated lesions were noted on the gastric antrum and body as well. He underwent excisional biopsy for the anal mass and the diagnosis was PTCLu. Biopsies of the gastric lesions gave the same diagnosis. There was no lymphoma involved in the bone marrow. At admission, no antibodies against human immunodeficiency virus were detected. He underwent systemic chemotherapy and upfront autologous stem cell transplantation.
PMCID: PMC3891034  PMID: 17249511
Rectum; Peripheral T-cell lymphoma unspecified; Non-AIDS
25.  A Case of Malignant T-Cell Lymphoma of Gastric Origin Accompanied by Pyothorax 
Case Reports in Gastroenterology  2009;3(2):162-168.
The patient was a 74-year-old man suffering from tuberculotic chronic pyothorax. He had hematemesis in January 2006. Hb was 6.1 g/dl. A type 2 tumor 3 cm in diameter was found in the vaulted region on the greater curvature side. It was diagnosed as a malignant lymphoma. WBC and differential count were normal, and the patient tested negative for HTVL-1 antibody. sIL2-R was elevated to 1,500 U/ml. The superficial lymph nodes were not palpable. CT examination was not remarkable for the liver and spleen. There was no generalized lymph node enlargement. Based on these findings, a diagnosis of malignant lymphoma of gastric origin was made. As the patient had respiratory disorders, too, wedge-shaped gastrectomy was performed to inhibit invasion. Pathological examination revealed CD3 positive large atypical lymphocytes diffusely, EBV positive, HP negative. As a result, a diagnosis of non-Hodgkin T-cell lymphoma was made. The tumor did not return for 1 year and 8 months after surgery, but the patient died of sudden aggravation of respiratory disorders in September 2007. Pathological anatomy was performed. The gastric remnant was left with lymphoma, and the bone marrow and systemic lymph nodes were negative for a malignant lymphoma. The possibility of stomach metastasis from the preoperative pyothorax-related malignant lymphoma was considered, but was ruled out because the lungs were devoid of a malignant lymphoma. We report a case of an extremely rare malignant T-cell lymphoma of gastric origin.
PMCID: PMC2988951  PMID: 21103269
Malignant T-cell lymphoma; Primary gastric; Pyothorax

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