Intravascular lymphoma is characterized by an exclusively intravascular distribution of tumor cells. Intravascular natural killer/T-cell lymphoma (IVNKTL) is extremely rare, highly aggressive, commonly Epstein-Barr virus (EBV)–positive, and predominantly affects the skin and central nervous system. Here we report a case of IVNKTL diagnosed in a 67-year-old female, presenting with persistent intermittent fever and skin rashes throughout the body. Incisional biopsy of an erythematous lesion on the chest exhibited aggregation of medium to large-sized atypical lymphoid cells confined to the lumen of small vessels that were positive for CD3, granzyme B, and CD56 on immunohistochemistry and EBV-encoded RNA in situ hybridization. EBV DNA was also detected in serum after diagnosis. With a review of 26 cases of IVNKTL to date, we suggest that active biopsy based on EBV DNA detection may facilitate early diagnosis of IVNKTL.
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Cutaneous Intravascular Hematolymphoid Entities: A Review Emily Hatheway Marshall, Bethany Brumbaugh, Allison Holt, Steven T. Chen, Mai P. Hoang Diagnostics.2024; 14(7): 679. CrossRef
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Lymphocyte-rich effusions represent benign reactive process or neoplastic condition. Involvement of lymphoproliferative disease in body cavity is not uncommon, and it often causes diagnostic challenge. In this review, we suggest a practical diagnostic approach toward lymphocyte-rich effusions, share representative cases, and discuss the utility of ancillary tests. Cytomorphologic features favoring neoplastic condition include high cellularity, cellular atypia/pleomorphism, monomorphic cell population, and frequent apoptosis, whereas lack of atypia, polymorphic cell population, and predominance of small T cells usually represent benign reactive process. Involvement of non-hematolymphoid malignant cells in body fluid should be ruled out first, followed by categorization of the samples into either small/medium-sized cell dominant or large-sized cell dominant fluid. Small/medium-sized cell dominant effusions require ancillary tests when either cellular atypia or history/clinical suspicion of lymphoproliferative disease is present. Large-sized cell dominant effusions usually suggest neoplastic condition, however, in the settings of initial presentation or low overall cellularity, ancillary studies are helpful for more clarification. Ancillary tests including immunocytochemistry, in situ hybridization, clonality test, and next-generation sequencing can be performed using cytologic preparations. Throughout the diagnostic process, proper review of clinical history, cytomorphologic examination, and application of adequate ancillary tests are key elements for successful diagnosis.
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Background Primary adrenal (PA) diffuse large B cell lymphoma (DLBCL) was previously reported as an aggressive subset of DLBCL, but its genetic features were not sufficiently characterized. From our previous study of DLBCL with programmed death-ligand 1 (PD-L1) gene alterations, we focused on PD-L1 gene alterations in PA-DLBCL with clinicopathologic implications.
Methods We performed fluorescence in situ hybridization for PD-L1 gene translocation and amplification in PA-DLBCL (n = 18) and comparatively analyzed clinicopathologic characteristics with systemic non-adrenal (NA)-DLBCL (n = 90).
Results PA-DLBCL harbored distinctive features (vs. NADLBCL), including high international prognostic index score (3–5) (72% [13/18] vs. 38% [34/90], p = .007), poor Eastern Cooperative Oncology Group performance score (≥ 2) (47% [7/15] vs. 11% [10/90], p = .003), elevated serum lactate dehydrogenase (LDH) (78% [14/18] vs. 51% [44/87], p = .035) and MUM1 expression (87% [13/15] vs. 60% [54/90], p = .047). Moreover, PA-DLBCL showed frequent PD-L1 gene alterations (vs. NA-DLBCL) (39% [7/18] vs. 6% [5/86], p = .001), including translocation (22% [4/18] vs. 3% [3/87], p = .016) and amplification (17% [3/18] vs. 2% [2/87], p = .034). Within the PA-DLBCL group, PD-L1 gene–altered cases (vs. non-altered cases) tended to have B symptoms (p = .145) and elevated LDH (p = .119) but less frequent bulky disease (≥ 10 cm) (p = .119). In the survival analysis, PA-DLBCL had a poor prognosis for overall survival (OS) and progression-free survival (PFS) (vs. NA-DLBCL; p = .014 and p = .004). Within the PA-DLBCL group, PD-L1 translocation was associated with shorter OS and PFS (p < .001 and p = .012).
Conclusions PA-DLBCL is a clinically aggressive and distinct subset of DLBCL with frequent PD-L1 gene alterations. PD-L1 gene translocation was associated with poor prognosis in PA-DLBCL.
Follicular lymphoma (FL) with hyaline-vascular Castleman disease (FL-HVCD)-like features is a rare morphologic variant, with fewer than 20 cases in the literature. Herein, we report a case of FL-HVCD in a 37-year-old female who presented with isolated neck lymph node enlargement. The excised lymph node showed features reminiscent of HVCD, including regressed germinal centers (GCs) surrounded by onion skin-like mantle zones, lollipop lesions composed of hyalinized blood vessels penetrating into regressed GCs, and hyalinized interfollicular stroma. In addition, focal areas of abnormally conglomerated GCs composed of homogeneous, small centrocytes with strong BCL2, CD10, and BCL6 expression were observed, indicating partial involvement of the FL. Several other lymphoid follicles showed features of in situ follicular neoplasia. Based on the observations, a diagnosis of FL-HVCD was made. Although FLHVCD is very rare, the possibility of this variant should be considered in cases resembling CD. Identification of abnormal, neoplastic follicles and ancillary immunostaining are helpful for proper diagnosis.
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Molecular pathologic testing plays an important role for the diagnosis, prognostication and decision of treatment strategy in lymphoproliferative disease. Here, we briefly review the molecular tests currently used for lymphoproliferative disease and those which will be implicated in clinical practice in the near future. Specifically, this guideline addresses the clonality test for B- and T-cell proliferative lesions, molecular cytogenetic tests for malignant lymphoma, determination of cell-of-origin in diffuse large B-cell lymphoma, and molecular genetic alterations incorporated in the 2016 revision of the World Health Organization classification of lymphoid neoplasms. Finally, a new perspective on the next-generation sequencing for diagnostic, prognostic, and therapeutic purpose in malignant lymphoma will be summarized.
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Esophageal involvement by malignant lymphoma is extremely rare. A case of follicular lymphoma of the esophagus, misdiagnosed as focal lymphoid hyperplasia (pseudolymphoma) in a 72-year-old man is presented. The esophagogram revealed diffuse narrowing of the lumen in the middle and distal portion without ulceration. The resected esophagus showed mural thickening without any remarkable mucosal change.
Microscopically, the esophagus showed scattered follicular lymphoid aggregates in the submucosa, extending into periadventitial fat tissue. Most follicles were devoid of germinal center and consisted of loosely aggregated small cleaved cells without atypia. The surrounding stroma of the submucosa showed dense fibrosis entrapping the infiltrating small lymphocytes in a "indian-file" appearance. There were some reactive follicles with germinal center. In the lamina propria, many plasma cells and a few eosinophils were infiltrated. The gene rearrangement study showed rearranged band for Jk probe which confirmed monoclonal B-cell nature of infiltrated small lymphoid cells. The small cleaved lymphocytes arranged in follicles were positive for L26 and bcl-2 protein. This case demonstrated the necessity of immunophenotypic and gene rearrangement study in the diagnosis of pseudolymphoma in the digestive tract.
To evaluate the utility of gene rearrangement analysis, eight cases of malignant lymphoma, one case of Hodgkin's disease, two cases of angioiminunoblastic lymphadenopathy (AILD) and two cases of non-specific lymphadenitis were studied by immunohistochemical and genetic analysis.
Southern blot analysis was perfon-ned by a using vacuum transfer system and a biotin labelled probe. This method was faster, safer, and more convenient than conventional methods. Gene rearrangement study showed rearranged novel bands in five of six cases of B cell lymphoma, in all cases of T cell lymphoma, and in all cases of AILD. No rearrangement of the B cell receptor(BCR) or of the T cell receptor(TCR) was seen in Hodgkin's disease or in nonspecific lymphadenitis. These results suggest that gene rearrangement analysis of BCR and TCR is a recommended method for the diagnosis of clonality in lymphoproliferative disorders. It would allow pathologists to differentiate lymphoma from polyclonal lymphoid proliferation and to provide information for cell lineage.
Primary malignant lymphoma of the appendix is an unconnnon neoplasm although the gastrointestinal tract is the most common extranodal site of malignant lymphoma. We report a case of primary malignant lymphoma of the appendix in a 54-year-old male, who presented with pain in the right lower abdomen. An appendectomy was performed. The appendix measured 9.5 cm in length and 5.5 cm in diameter. Cut sections showed a solitary circumferential mass in the appendiceal lumen. Light microscopic features were compatible with malignant lymphoma of diffuse large cell type(Working Formulation) and the immunophenotype was B cell type.
The author examined the immunophenotype and expression of Epstem-Barr virus RNA (EBERs) used in the situ hybridization technique in 20 cases of conventional malignant lymphoma and 28 cases of polymorphic reticulosis and malignant lymphoma with features of polymorphic reticulosis occured in the upper aerodigestive tract including the upper digestive tract(palatine tonsil), and upper respiratory tract(nasal cavity, paranasal sinus, nasopharynx). The results obtained were summarized as followings; 1. The favorable site of malignant lymphoma that occured in the upper aerodigestive tract was in the palatine tonsil(11 out of 20 cases, 55%), those of polymorphic reticulosis and malignant lymphoma with features of polymorphic reticulosis were nasal cavity and nasopharynx(19 out of 28 cases, 78%). 2. The immunophentype of malignant lymphoma that occured in the upper aerodigestive tract was mostly B-cell phenotype (15 out of 20 cases, 75%), and that of polymorphic reticulosis and malignant lymphoma with features of polymorphic reticulosis was predominantly T-cell phenotype(22 out of 28 cases, 79%).
3. The EBERs positivity of malignant lymphoma that occured in the upper aerodigestive tract was 25%(5 out of 20 cases), but that of polymorphic reticulosis and malignant lymphoma with features of polymorphic reticulosis was 57%(16 out of 28 cases). 4. The positive cases for EBERs revealed angiocentricity with necrosis(16 out of 21 cases, 76%), predominantly T-cell phenotype(19 out of 21 cases, 90%), and favorably involved the nasal cavity and nasopharynx(16 out of 21 cases, 76%). Based on the above results, it was concluded that polymorphic reticulosis and malignant lymphoma with features of polymorphic reticulosis that occurred in the upper respiratory tract was an EBV-positive angiocentric T-cell lymphoma favorably involving the nasal cavity and nasopharynx.
Primary non-Hodgkin' lymphomas of the liver, an organ normally devoid of a native lymphoid tissue, are very rare.
We recently experienced a case of a primary low-grade hepatic B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type in a 36-year-old woman. The ultrasonography revealed a 5 cm sized mass in the right lobe of the liver. A right segmentectomy of the liver was done and showed a relatively well-circumscribed brownish yellow lobulated homogenous mass, measuring 5.5x4.5 cm in size. Histologic sections of liver mass revealed large lymphoid follicles with reactive germinal centers, follicular colonization by centrocyte-like cells (CCL cells), and lymphoepithelial lesions. The CCL cells were positive for B-cell (CD20), LCA (CD45RA), Bcl-2 oncoprotein, and lambda light chain.
The bone marrow biopsy is an integral part of the staging process in patients with malignant lymphomas. Bone marrow(BM) involvement indicates stage IV disease, but there are always a lot of cases in which clear separation is not possible when based on morphology alone. Additional difficulties are caused by morphologic discordance between the BM and the primary lymphoma. Immunohistochemical stain, mRNA in situ hybridization (ISH) for light chain restriction and polymerase chain reaction (PCR) for IgH CDR3 and TCRgamma were performed to find a minimal lesion and the clonality in formalin fixed paraffin embedded tissues of 39 primary lymphomas and corresponding BM biopsy specimens. As a result, nine morphologically negative bone marrows of 18 lymphomas were positive by PCR (Group I). Among the 6 lymphoma cases with morphologically suspicious BM involvement (Group II), one was confirmed to be positive for marrow involvement by both mRNA ISH and PCR and the other four by PCR alone. The positive bone marrows of Group I and II revealed gene rearrangement at the same site as the primary lesion, suggesting the same clonality. Thirteen of 15 lymphomas with morphologically positive BM (Group III) had the same clonality in the primary lymphomas and the BM lesion. Three cases among the Group III with morphologic discordance also revealed the same clonality by PCR. This study shows that a combination of mRNA ISH and PCR in addition to an immunohistochemical stain improves the diagnostic sensitivity in the detection of BM involvement and identification of clonality. Among the three different methods used, PCR is the most sensitive in detecting a minimal lesion.
The incidence of a primary central nervous system (CNS) lymphoma in western countries is about 1% of all the intracranial tumors and has increased 2.2% over the last decade. A similar pattern of increased frequency is observed in Korea. Although most CNS lymphomas in western countries are high grade tumors carrying poor prognosis, the clinicopathologic features of the Korean CNS lymphoma have not been well studied. We report clinicopathological features of 18 cases of histologically proven primary brain lymphoma. The mean age of the patients was 50 years and there was no sex difference. The clinical and radiological characteristics included multiple site of occurrence, infrequent extracranial spread, and frequent seeding via cerebrospinal fluid. No patients were immune-compromised host. Of 18 cases, 15 cases were of B-lineage and 2 cases were of T-lineage. According to REAL classification, there were 12 cases of diffuse large B cell lymphoma, two cases of B cell lymphomas of small lymphoid cell, and two cases of peripheral T cell lymphoma, unspecified. The remaining subtypes were not subclassified because of inadequate material. Pleomorphic cytologic features and necrosis of varying extent were frequent in the cases of diffuse large B-cell lymphoma. These results suggest that overall clinicopathologic features of primary malignant lymphomas of the central nervous system in Korea are similar to those of western countries.
Malignant lymphoma arising from mucosa-associated lymphoid tissue (MALT) represents distinct clinicopathologic features and remains localized for prolonged periods. We report a case of low grade B cell lymphoma of bronchus-associated lymphoid tissue (BALT). A 60-year-old female had a long-standing cough, sputum and intermittent fever for 10 years. In 1984, the chest radiography showed increased hazy density in both upper lungs. Although she had been treated by antituberculous medication under clinical diagnosis, there was no improvement. In 1995, open lung biopsy was carried out. Histologically, it showed massive nodular or diffuse infiltration of centrocyte-like cells in bronchus and parenchyme with pleural invasion. On immunohistochemical stain, they were positive for LN-2 and L26 and negative for UCHL-1, LN-1 and LN-3. In polymerase chain reaction (PCR), Ig heavy chain gene rearrangement was detected. The patient was well for 6 months after the biopsy.
There had been a continuous evolution of lymphoma classification and recently a Revised European-American Lymphoma Classification was proposed by the International Lymphoma Study Group. This new classification often requires information on immunophenotypic and molecular biologic markers in addition to the usual histologic findings. Recent advances in the production of commercially available monoclonal antibodies reactive on formalin-fixed paraffin-embedded tissues provide us a great help to classify the non-Hodgkin's lymphoma. We have analyzed 31 low grade B-cell lymphomas by the schemes proposed by the International Lymphoma Study Group using antibodies to CD3, CD5, CD20, CD23, CD43, cyclin D1, and bcl-2 protein, and have analyzed the immunophenotypic features. Among 31 low grade B-cell lymphomas, 8 small lymphocytic lymphomas, 5 mantle cell lymphomas, 7 follicle center lymphomas (2 grade I, 3 grade II, and 2 grade III), and 11 marginal zone B-cell lymphomas (all of which were extranodal) were identified.
Among 8 small lymphocytic lymphomas, 5 cases were positive for CD5; 6 cases were positive for CD23; 7 cases were positive for CD43; all 8 cases were negative for cyclin D1; and 7 cases were positive for bcl-2. Among 5 mantle cell lymphomas, 4 cases were positive for CD5 and CD43; all five cases were negative for CD23; 4 cases were positive for cyclin D1 and bcl-2. All 7 follicle center lymphomas were negative for CD5, CD43 and cyclin D1 and 2 cases were positive for CD23; and 6 cases were positive for bcl-2. All marginal zone B-cell lymphomas were negative for CD5, CD23 and cyclin D1; 3 cases were positive for CD43 and 9 cases were positive for bcl-2. Diagnostic utility for CD5 antigen detection on paraffin embedded tissue has a limitation due to weak antigen expression in tumor cells of B-cell lymphomas; however, still be useful in differentiating small lymphocytic lymphoma and mantle cell lymphoma from other B-cell lymphomas when applied in conjunction with CD43.
CD23, CD43, and cyclin D1 appear to be of great help in differentiating subgroups of low grade B-cell lymphomas.
Bcl-2, as known, is found to be useful to rule out reactive follicular hyperplasia.
The author classified 38 cases of malignant lymphoma involving the skin primarily or secondarily by the new WHO classification with minor modifications and carried out RNA in situ hybridization and/or polymerase chain reaction (PCR) to investigate the role of Epstein-Barr virus (EBV). A case was follicular lymphoma of B cell origin and 37 cases were malignant lymphomas of T cell origin, including 15 cases of Mycosis fungoides/Sezary syndrome, five cases of subcutaneous panniculitis-like T cell lymphomas, a case of anaplastic large cell lymphoma, and four cases of primary cutaneous CD30 T cell lymphoproliferative disorders. There were eight cases of unspecified peripheral T cell lymphomas, in which four cases were composed of medium-sized cells, three cases of large cells, and a case of lymphoepithelioid cells. Four cases of nasal and nasal type NK/T cell lymphomas and three cases of unspecified peripheral T cell lymphomas showed EBV genome. The nasal and nasal type NK/T cell lymphomas, especially those involving the nasal cavity, showed close association with the EBV infection.