Journal of Pathology and Translational Medicine

Review

Molecular Testing of Lymphoproliferative Disorders: Current Status and Perspectives: Yoon Kyung Jeon, Sun Och Yoon, Jin Ho Paik, Young A Kim, Bong Kyung Shin, Hyun-Jung Kim, Hee Jeong Cha, Ji Eun Kim, Jooryung Huh, Young-Hyeh Ko; J Pathol Transl Med. 2017;51(3):224-241. Published online May 10, 2017; DOI: https://doi.org/10.4132/jptm.2017.04.09

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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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Original Articles

EBV-Positive T/NK-Cell Lymphoproliferative Disease of Childhood: Mineui Hong, Young Hyeh Ko, Keon Hee Yoo, Hong Hoe Koo, Seok Jin Kim, Won Seog Kim, Heejung Park; Korean J Pathol. 2013;47(2):137-147. Published online April 24, 2013; DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.2.137

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Abstract PDF

Background

Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH), EBV-positive systemic T-cell lymphoproliferative disease (STLPD) of childhood, and chronic active EBV (CAEBV) infection may develop after primary EBV infection. This study reviewed the clinicopathological spectrum of EBV-associated T- and natural killer (NK)-cell LPD, including STLPD and CAEBV infection, with an analysis of T-cell clonality.

Methods

Clinicopathological features of seven patients with EBV-associated HLH or STLPD and 12 patients with CAEBV infection were reviewed. Immunohistochemical staining and a T-cell receptor (TCR) gene rearrangement study were performed.

Results

STLPD and EBV-positive HLH showed significantly overlapping clinicopathological findings. One patient with STLPD and one patient with EBV-positive HLH demonstrated moderate to severe atypia of the infiltrating lymphocytes, whereas the remaining patients lacked significant atypia. Twelve patients had CAEBV infection, four of whom suffered mosquito-bite hypersensitivity, five showed NK lymphocytosis, and one suffered hydroa vacciniforme. Infiltrating lymphocytes were predominantly small and devoid of atypia. Hemophagocytic histiocytosis was found in seven of 11 patients. Monoclonality was detected in three (50%) of the six patients with successful TCR gene analysis.

Conclusions

EBV-positive HLH and STLPD share similar clinicopathological findings and may constitute a continuous spectrum of acute EBV-associated T- or NK-cell proliferative disorders. The distinction of EBV-positive T-cell LPD from EBV-positive HLH may be difficult during routine diagnoses because of the technical limitations of clonality assessment.

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Detection Limit of Monoclonal B-Cells Using Multiplex PCR and Laser-Induced Fluorescence Capillary Electrophoresis.: Sung Hak Lee, Yeonsook Moon, Byunghoo Song, Hyung Nam Lee, Ahwon Lee, Eun Sun Jung, Yeong Jin Choi, Kyo Young Lee, Chang Suk Kang, Gyeongsin Park; Korean J Pathol. 2011;45(6):582-588.; DOI: https://doi.org/10.4132/KoreanJPathol.2011.45.6.582

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Abstract PDF

BACKGROUND
The identification of monoclonality has been widely used for making diagnoses of lymphoproliferative lesions. Awareness of the sensitivity and detection limit of the technique used would be important for the data to be convincing.
METHODS
We investigated the minimum requirement of cells and sensitivity of gel electrophoresis (GE) and laser-induced fluorescence capillary electrophoresis (LFCE) for identifying IgH gene rearrangement using BIOMED-2 protocols. DNA extracted from Raji cells were diluted serially with peripheral blood mononuclear cells (PBMNCs) DNA. DNA from mixtures of diffuse large B-cell lymphoma (DLBCL) and reactive lymph nodes were also serially diluted.
RESULTS
For Raji cells, the detection limit was 62 and 16 cell-equivalents for GE and LFCE, respectively. In the condition with PBMNCs mixture, 2.5% and 1.25% of clonal cells was the minimum requirement for GE and LFCE, respectively. In 23% of DLBCL cells in tissue section, the detection limit was 120 and 12 cell-equivalents for GE and LFCE, respectively. In 3.2% of DLBCL cells, that was 1,200 and 120 cell-equivalents for GE and LFCE, respectively.
CONCLUSIONS
These results show that LFCE method is more sensitive than GE and the sensitivity of clonality detection can be influenced by the amount of admixed normal lymphoid cells.

Citations

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Molecular pathology diagnosis of diffuse large B cell lymphoma using BIOMED-2 clonal gene rearrangements
Saeid Ghorbian
Annals of Diagnostic Pathology.2017; 29: 28. CrossRef

Non-Radioactive Detection of Clonality in Malignant Lymphoid Neoplasms using the Polymerase Chain Reaction.: Chan Kum Park, Chul Woo Kim; Korean J Pathol. 1996;30(4):311-317.

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Abstract PDF: The polymerase chain reaction(PCR) was performed to detect clonal rearrangements of the immunoglobulin heavy chain gene(IgH) or T-cell receptor(TCR) genes in 57 lymphoproliferative diseases including 26 B-cell lymphomas and 23 peripheral T-cell lymphomas(PTCL). Using the IgH primers, monoclonality was detected in 19 out of 22(86.4%) cases of diffuse lymphomas and 2 out of 4(50%) follicular lymphomas, respectively, but not in the 23 PTCL cases. Using the V and J regions of the TCRgamma chain primers, monoclonality was detected in 14 out of the 23(60.9%) PTCL cases. TCR beta chain gene rearrangements were observed in 7 out of the 9 cases which did not show TCRgamma chain gene rearrangements. One non-T non-B acute lymphoblastic leukemia was found to have TCR beta chain gene rearrangements. In conclusion, analysis of Ig and TCR gene rearrangements by using the PCR technique can be used as a useful diagnostic adjunct to establish the clonality of various lymphoproliferative diseases.

Clonality of Large Regenerative Nodule Accompanied by Hepatocellular Carcinoma.: Zhe Piao, Bong Kyun Chun, Woo Jung Lee, Young Nyun Park, Ho guen Kim, Chanil Park; Korean J Pathol. 1997;31(9):884-890.

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Abstract PDF: In order to clarify the preneoplastic nature of large regenerative nodules without dysplastic change, we analysed the clonality of hepatocellular carcinomas (HCCs) and large nodules, diameter > or =0.5 cm, of cirrhotic liver by X-linked human androgen receptor (HUMARA) gene assay, using the principle of random X chromosome methylation and inactivation in female. Ten cases of HCC and 5 cases of large nodules without dysplasia from 9 female patients were selected. All the tumors, large nodules and paired normal control cells were selectively microdissected from deparaffinized hematoxylin and eosin stained slides. Genomic DNA was isolated and digested with HhaI. Polymerase chain reaction(PCR) amplication of the HUMARA locus was performed using 32P-a-dCTP containing PCR mixtures. The PCR amplified products were separated by gel electrophoresis and analysed by autoradiography. Nine HCCs from 8 patients were monoclonal and 1 case was polyclonal and the remaining 1 case was not polymorphic at the HUMARA locus. The HCC case which showed polyclonality contained many inflammatory cells. All the large nodules were polyclonal by HUMARA assay. These results suggest that all or most of the cells composing the large regenerative nodules without dysplasia are polyclonal. This assay may be informative for the differentiation between regenerative and preneoplastic nodules in cirrhotic liver and the size of nodule may be not important in hepatocarcinogenesis.

Detection of Minimal Lesion and Identification of Clonality in Malignant Lymphoma.: Young Shin Kim, Chang Suk Kang, Kyun gja Han, Kyo Young Lee, Yong Goo Kim, Won Il Kim, Sang In Shim; Korean J Pathol. 1998;32(4):298-308.

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Abstract PDF: 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.

Assay of Proliferative Activity, Clonality and Immortality of.: Hyung Seok Kim, Young Jik Lee, Mee Sook Kim, Hyang Mi Ko, Sang Woo Juhng; Korean J Pathol. 1999;33(9):652-661.

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Abstract PDF: Among the precancerous lesions, dysplasia of the uterine cervix and adenoma of the colon have been widely studied in terms of genetic alterations. However, little has been performed regarding phenotypic alterations of the precancerous lesions. We investigated the relationship among cellular proliferation, clonality, immortality and histopathologic grading of the squamous epithelial lesions of the uterine cervix. Proliferation index (PI) was calculated based on the ratio of the epithelial cells positive for proliferating cell nuclear antigen to the total epithelial cells. Clonality was assayed by X-linked HUMARA polymorphism. For immortality assay, PCR-based TRAP (telomeric repeat amplification protocol) was done and telomerase processivity was calculated by comparison with the positive control. PI increased gradually as the lesions advanced from dysplasia to invasive carcinoma. Among informative case, all of the carcinoma in situ showed monoclonal pattern (7 of 7). Among invasive squamous cell carcinoma, 6 cases showed monoclonal pattern and 2 cases polyclonal pattern. TRAP reaction was positive in 92.6% (25 of 27) of dysplasia (high grade: 14 of 15; low grade: 11 of 12), 95.0% (19 of 20) of carcinoma in situ, 100% (9 of 9) of microinvasive carcinoma, and 92.9% (13 of 14) of invasive carcinoma. It was also positive in 12 of 12 samples of chronic cervicitis or squamous metaplasia near the lesions of dysplasia. There was no difference in TRAP positivity among the dysplasia, carcinoma in situ and invasive carcinoma, whereas telomerase processivity showed significant correlation. These results suggest that proliferative activity and telomerase processivity may be progressive events in oncogenesis, although telomerase activation may be an early event.

Clonal Analysis of Neurofibroma by PCR Amplification of HUMARA Gene.: Jae Hyuk Lee, Seung Sang Han, Hyun Sik Oh, Yoo Duk Choi, Hyun Joong Kim, Kyung Hwa Lee, Jong Hee Nam, Chan Choi, Sang Woo Juhng; Korean J Pathol. 2003;37(6):421-428.

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Abstract PDF: BACKGROUND
While neurofibromas have generally been regarded as polyclonal hyperplastic lesions, it remains unclear whether the tumor is a true neoplasm or a hyperplastic lesion.
METHODS
Determination of clonality by X chromosome inactivation pattern was investigated in twenty-one cases of neurofibroma employing enzyme digestion and PCR of the HUMARA gene. The histological, immunohistochemical, and ultrastructural characteristics of the tumors were also examined.
RESULTS
Immunohistochemically, most of the tumor cells showed vimentin and S-100 protein positivity. Axons were demonstrated by neurofilament protein positivity and were seen mainly at the periphery and rarely in the central portion of the tumor. Ultrastructurally, the tumors were composed of a variety of cell types: perineurial cells, Schwann cells, fibroblasts, and axons. X chromosome inactivation analysis was completed on thirteen out of fifteen cases in which DNA was successfully extracted. Of thirteen neurofibromas that were heterozygous at the HUMARA loci, eleven showed a polyclonal pattern. The remaining two cases were considered as indeterminate for clonality because of unequal band intensity and failure to obtain the normal control DNA.
CONCLUSION
The results from this study suggest that neurofibromas are polyclonal in origin and might be a neoplastic lesion comprising non-neoplastic cells among constituent components.

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