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Characterization of genetic subgroups of anaplastic large cell lymphoma, ALK negative by fish technique in Brazilian cases

Grant number: 16/09180-0
Support Opportunities:Scholarships abroad - Research
Effective date (Start): November 07, 2016
Effective date (End): November 06, 2017
Field of knowledge:Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
Principal Investigator:Cristiane Rúbia Ferreira
Grantee:Cristiane Rúbia Ferreira
Host Investigator: Yasodha Natkunam
Host Institution: Hospital Universitário (HU). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: Stanford University, United States  


Anaplastic large-cell lymphoma ALK-negative (ALCL, ALK-) is classified as a provisional entity in the last World Health Organization (WHO) classification and is defined as a CD30+ T-cell neoplasm that is not reproducibly distinguishable on morphological grounds from ALK-positive ALCL, but lacks anaplastic large cell lymphoma kinase (ALK) protein. Cases with cutaneous involvement must be distinguished from primary cutaneous ALCL (pcALCL). There is a question whether the ALCL, ALK- would be better classified as an anaplastic variant of peripheral T-cell lymphoma not otherwise specified (PTCL, NOS), since there is no specific biomarker for ALCL, ALK- or PTCL, NOS, and the differential diagnosis between them is basically based on histological aspects. There may be a morphological overlap between ALCL, ALK- and PTCL, NOS, since PTCL, NOS show great morphological diversity, with variable tumor cell morphology, ranging from small cells with minimal atypia to large cells, sometimes with anaplastic features. Even by immunohistochemical study the positivity of immunohistochemical markers is not uniform and some can be shared by both entities, usually a broad panel of antibodies is used. The differential diagnosis is much more difficult between cases of PTCL, NOS with positivity for CD30, 4.5% to 18.39% of cases can present more than 75%-80% of tumor cells positivity. However differences in clinical course and prognosis justify placing ALCL, ALK- in a separate entity from PTCL, NOS (OS of 49% x 32%). Molecular genetic studies suggest that molecular subclassification may be clinically relevant in ALCL, ALK-. Two new recurrent translocations were described in ALCL, ALK-, the first was t(6;7)(p25.3;q32.3), the DUSP22-IRF4 (DUSP22 rearrangements), which have been identified in approximately 30% of cases. These rearrangements also can be seen in pcALCL (28%) and lymphomatoid papulosis cases. Another rearrangement involves the TP63 gene locus on 3q28, and has been identified in approximately 8% of ALCL, ALK- cases. The remaining ALCL, ALK- lacking DUSP22 and TP63 (and also ALK) rearrangements, which were mutually exclusive, have been designed as triple negative. At last, ectopic coexpression of ERBB4 and COL29A1 genes was detected in 24% of ALCL, ALK- patients, but not present in PTCL-NOS and ALCL, ALK+. ERBB4 deregulation was characterized by the expression of two truncated transcripts with oncogenic potentials. However, it is not defined whether ERBB4-expressing ALCL overlaps with the other genetic subsets of ALCL, ALK- described above. Interestingly, these genetic subsets of ALCL, ALK- have different morphologic features, immunophenotype and prognostic. DUSP22-rearranged ALCL have favorable outcomes with a 5-year OS rate of 90%. Morphologically, they showed monotonous appearance, with sheet-like growth of hallmark cells with a tendency to have the appearance of doughnut cells, without large pleomorphic cells, such as wreath-like and Reed-Stenberg-like cells. By immunohistochemistry, DUSP22-rearranged ALCL generally were negative for cytotoxic markers. TP63-rearranged ALCL have very poor outcomes with a 5-year OS rate of 17%. Although TP63-rearranged ALCL are rare, morphologically, they did not tend to have large pleomorphic cells, which were observed almost exclusively in triple-negative ALCL and ALCL, ALK+. The marker p63 was expressed in all cases by immunohistochemistry. ERBB4-positive ALCL patients had OS rates similar from patients with ALCL, ALK-. Of interest, these cases showed a Hodgkin-like morphology and were highly correlated to MMP9 protein expression by immunohistochemistry, which could be a tool to recognize them. So these advances in molecular studies have shown that ALCL, ALK- has multiple genetic subgroups. In this sense, we propose a cooperative study with the Pathology Department of Stanford University to study, set up FISH assay and validating the test for clinical use on these uncommon cases. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FERREIRA, CRISTIANE R.; MANOHAR, VIDHYA; ZHAO, SHUCHUN; BANGS, CHARLES D.; CHERRY, ATHENA; AZEVEDO, RAYMUNDO SOARES; LAGE, LUIS A. P. C.; PEREIRA, JULIANA; ZERBINI, MARIA C. N.; GRATZINGER, DITA; et al. Genetic Subtypes of Systemic Anaplastic Large Cell Lymphoma Show Distinct Differences in PD-L1 Expression and Regulatory and Cytotoxic T Cells in the Tumor Microenvironment. APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY, v. 28, n. 1, p. 10-16, . (16/09180-0)
FERREIRA, CRISTIANE R.; ZHAO, SHUCHUN; SAHOO, MALAYA K.; PINSKY, BENJAMIN; WEBER, JENNA; LAGE, LUIS A. P. C.; PEREIRA, JULIANA; ZERBINI, MARIA C. N.; NATKUNAM, YASODHA. FOXP3-positive T-cell lymphomas in non-HTLV1 carriers include ALK-negative anaplastic large cell lymphoma: expanding the spectrum of T-cell lymphomas with regulatory phenotype. HUMAN PATHOLOGY, v. 80, p. 138-144, . (16/09180-0)
FERREIRA, CRISTIANE RUBIA; ZHAO, SHUCHUN; SANCHES, JOSE ANTONIO; MIYASHIRO, DENIS; CURY-MARTINS, JADE; AZEVEDO, RAYMUNDO SOARES; ZERBINI, MARIA C. N.; NATKUNAM, YASODHA; GRATZINGER, DITA. Clinicopathologic and microenvironmental analysis of primary cutaneous CD30-positive lymphoproliferative disorders: a 26 year experience from an academic medical center in Brazil. DIAGNOSTIC PATHOLOGY, v. 14, n. 1, . (16/09180-0)

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