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Peripheral T-cell Lymphoma, Not Otherwise Specified
C H A P T E R
54 Peripheral T-cell Lymphoma, Not Otherwise Specified Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) includes all the T-cell lymphomas that are not included in the well-defined clinicopathologic entities previously described in this book. PTCL, NOS is predominantly nodal and represents the most common T-cell lymphoma in Western countries. • PTCL, NOS constitutes approximately 30% of all noncutaneous peripheral T-cell lymphomas. It occurs in middle-aged to elderly patients, with a median age of 54 years and a male to female ratio of about 1–2:1. Most patients are in advanced stages (stage III/IV) at diagnosis. Extranodal disease, B symptoms, and elevated LDH are frequent findings and are associated with unfavorable prognosis. Other risk factors include age >60 years and a decline in performance status. The most frequently involved extranodal sites are bone marrow, spleen, liver, Waldeyer ring, and skin (Table 54.1). • Molecular and immunophenotypic studies have demonstrated that p53 mutation and overexpression of p53 protein correlate with treatment failure and unfavorable prognosis. In general, PTCL, NOS is an aggressive disease with a poor response to therapy and frequent relapses.
54.1 MORPHOLOGY • The normal nodal architecture is often effaced with a diffuse infiltration of neoplastic lymphoid cells. The neoplastic lymphocytes display a wide spectrum of cytologic features, with most cases contain medium to large atypical lymphocytes containing irregular to pleomorphic nuclei, vesicular chromatin, and prominent nucleoli. Large neoplastic lymphocytes with clear cytoplasm or ones resembling Hodgkin–Reed–Sternberg cells may be present. The infiltrating neoplastic cells are often mixed with inflammatory cells, such as small lymphocytes, eosinophils, and histiocytes. Vascular proliferation is frequently noted. • Three morphologic variants have been described: (1) lymphoepithelioid type, (2) follicular type, and (3) T-zone type. • The lymphoepithelioid variant (Lennert lymphoma) is characterized by predominantly diffuse proliferation of small neoplastic lymphocytes, admixed with numerous scattered and/or small aggregates of epithelioid histiocytes (Fig. 54.1). Scattered larger atypical lymphocytes with clear cytoplasm may be present. Rarely, interfollicular growth pattern may be appreciated. Vascular proliferation and presence of inflammatory cells are common features. • The follicular variant is characterized by neoplastic clear cells in interfollicular aggregates, small nodule aggregates associated with background PTGC, and/or perifollicular/nodular aggregates surrounding hyperplastic follicles, mimicking follicular lymphoma, nodular lymphocyte predominant Hodgkin lymphoma, and marginal zone lymphoma, respectively. • The T-zone variant is characterized by perifollicular infiltration by predominantly small- to medium-sized lymphocytes with minimal atypia (Fig. 54.2). Clusters of atypical lymphocytes with clear cytoplasm are often present and scattered Reed–Sternberg-like cells may be present. Background lymphoid follicles are usually well preserved or even hyperplastic.
Atlas of Hematopathology. http://dx.doi.org/10.1016/B978-0-12-809843-1.00054-1 Copyright © 2018 Elsevier Inc. All rights reserved.
771
772
54. Peripheral T-cell Lymphoma, Not Otherwise Specified
TABLE 54.1 Differential Diagnosis of Peripheral T-cell Lymphoma, Not Otherwise Specified (PTCL, NOS) Entity
T-cells
Large HRS-like cells
Epithelioid histiocytes
Molecular/cytogenetic
PTCL, NOS
Atypical, pleomorphic
May be present, express pan-T markers
Often present, prominent in Lennert type
Rearranged TCR
Classical HL
Small, no atypia
CD15+, CD30+, CD45−, EBV±
Variable
IGH rearrangement not routinely detected
NLPHL
Small, no atypia, interfollicular CD57+
CD15−, CD30−, CD45+, CD20+, EMA+
Variable
IGH rearrangement not routinely detected
THR-LBCL
Small, no atypia
CD15−, CD30−, CD45+, CD20+
Abundant
Rearranged IGH
AITL
Atypical, some with clear cytoplasm and CD10+
Mostly reactive B-cells, CD30+, EBV+
Variable
Rearranged TCR
ALCL
Atypical, pleomorphic
T-cells, CD30+, ALK±
Variable
Rearranged ALK, TCR
Reactive nodes
Small and large
Mostly reactive B-cells, CD30+, EBV±
Variable
No TCR or IGH rearrangement
AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large cell lymphoma; HL, Hodgkin lymphoma; HRS, Hodgkin and Reed–Sternberg; NLPHL, nodular lymphocyte predominant HL; THR-LBCL, T-cell/histiocyte rich large B-cell lymphoma.
FIGURE 54.1 Peripheral T-cell lymphoma, lymphoepithelioid cell variant (Lennert lymphoma). Epithelioid histiocytes are mixed with infiltrating lymphocytes in small (A) or large (B and C) clusters.
54.2 Immunophenotype
773
• Bone marrow involvement shows focal or diffuse infiltration of bone marrow by neoplastic lymphocytes. Focal infiltrates are usually non-paratrabecular. The infiltrates are highly vascular, are admixed with inflammatory cells, and may show increased reticulin fibers. • Splenic infiltrates are often patchy and may primarily involve the periarterial T-cell zones or extend to the red pulp. • Cutaneous involvement is frequent and may appear as diffuse or nodular patterns with or without epidermotropism.
54.2 IMMUNOPHENOTYPE Immunophenotypic features include (Fig. 54.3): • • • • • • •
Pan-T-cell aberrancies with variable loss of CD5 and/or CD7; Expression of TCR-β; Common CD4 phenotype; but CD8 phenotype, or double positive, or double negative in some cases; Expression of CD56 and/or cytotoxic markers in some cases; Positivity of CD30 in some cases, but rare expression of CD15; Occasional aberrant expression of B-cell-associated markers CD20 or CD79a; Lack of follicular T-helper (FTH)-associated markers in cases other than PTCL, NOS, FTH type.
FIGURE 54.2 Peripheral T-cell lymphoma, T-zone variant. This demonstrates a mixture of small to large lymphocytes (A and B) and the presence of lymphoid cells with clear cytoplasm (C).
774
54. Peripheral T-cell Lymphoma, Not Otherwise Specified
FIGURE 54.3 Flow cytometric findings of peripheral T-cell lymphoma. Lymphoid-enriched gate of a neck lymph node reveals predominantly abnormal T-cells, which are double positive (circled) for CD4 (dim) and CD8 (heterogeneous). In addition, the neoplastic T-cells are positive for CD2, CD3, CD5 (bright), CD25 (heterogeneous), and TCR alpha/beta. They demonstrate complete loss of CD7 expression, and are negative for CD1a.
54.3 MOLECULAR AND CYTOGENETIC STUDIES • Approximately 90% of patients with PTCL, NOS show clonally rearranged TCR genes, and 70%–90% demonstrate cytogenetic aberrations. • A novel t(5;9)(q33;q22), that creates a fusion gene between ITK and SYK genes, has been reported in 17% of PTCL, NOS. • Complex karyotypes consistent with clonal evolution are a frequent finding. Breaks involving the TCR loci are common. The chromosomes most frequently altered in structural aberrations are 1, 6, 2, 4, 11, 14, and 17. Additionally, trisomies of 3 or 5 and an extra X chromosome are also common. • CGH studies have found recurrent losses on chromosomes 5q, 6q, 9p, 10q, 12q, and 13q (Fig. 54.4). Recurrent gains were found on chromosome 7q. • High-level amplifications of 12p13 have been observed in a few PTCL cases with cytotoxic phenotype. These results suggest that certain genetic alterations may indeed exist in PTCL, NOS, but definitive clinicopathologic subgroups have not yet been identified and, thus far, a variety of molecular and cytogenetic findings do not allow for a consistent model for pathogenesis to be constructed.
54.4 DIFFERENTIAL DIAGNOSIS The differential diagnosis includes a variety of reactive lymphadenopathies, ALCL, AITL, and Hodgkin lymphoma (Table 54.1). Presence of clusters of epithelioid histiocytes in the lymphoepithelioid cell (Lennert) variant may simulate toxoplasmosis, sarcoidosis, or other types of granulomatous lymphadenitis. The follicular variant may mimic follicular lymphoma or nodular lymphocyte predominant Hodgkin lymphoma. The interfollicular expansion and the presence of inflammatory cells in the T-zone variant may mimic T-zone hyperplasia. Cases with the presence of anaplastic large cells or the presence of Reed–Sternberg-like cells may resemble T-cell/histiocyte-rich large B-cell lymphoma, ALCL. Vascular proliferation and polymorphous infiltrate are among the overlapping features between PTCL, NOS and AITL.
54.4 Differential diagnosis
775
FIGURE 54.4 Deletion of 5q in a patient with peripheral T-cell lymphoma: (A) karyotype and (B) FISH analysis.
Additional Resources Bellei, M., et al., 2016. Pitfalls and major issues in the histologic diagnosis of peripheral T-cell lymphomas: results of the central review of 573 cases from the T-Cell Project, an international, cooperative study. Hematol Oncol 34, 2028–2036. De Leval, L., Gaulard, P., 2011. Pathology and biology of peripheral T-cell lymphomas. Histopathology 58, 49–68. Foss, F.M., Zinzani, P.L., Vose, J.M., 2011. Peripheral T-cell lymphoma. Blood 117, 6756–6767. Gaulard, P., de Leval, L., 2014. Pathology of peripheral T-cell lymphomas: where do we stand? Semin Hematol 51, 5–16. Gooptu, M., Rhoades, R., Pro, B., 2015. Current management of peripheral T-cell lymphomas. Cancer Treat Res 165, 289–303. Jaffe, E.S., et al., 2016. Hematopathology. eBook, Elsevier, second ed. Piccaluga, P.P., Agostinelli, C., Tripodo, C., 2011. European T-cell lymphoma study group peripheral T-cell lymphoma classification: the matter of cellular derivation. Expert Rev Hematol 4, 415–425. Ondrejka, S.L., Hsi, E.D., 2016. T-cell lymphomas: updates in biology and diagnosis. Surg Pathol Clin 9, 131–141. Savage, K.J., Ferreri, A.J., Zinzani, P.L., 2011. Peripheral T-cell lymphoma–not otherwise specified. Crit Rev Oncol Hematol 79, 321–329. Savage, K.J., 2011. Update: peripheral T-cell lymphomas. Curr Hematol Malig Rep 6, 222–230. Sekiguchi, Y., et al., 2015. Peripheral T cell lymphoma, not otherwise specified with myelofibrosis: report of a case with review of the literature. Int J Clin Exp Pathol 8, 4186–4203. Swerdlow, S.H., et al., 2008. WHO classification of tumours of haematopoietic and lymphoid tissues. International Agency for Research on Cancer, Lyon. Zhang, Y., et al., 2016. Therapeutic options in peripheral T cell lymphoma. J Hematol Oncol 9, 37–46.
54 Peripheral T-cell Lymphoma, Not Otherwise Specified Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) includes all the T-cell lymphomas that are not included in the well-defined clinicopathologic entities previously described in this book. PTCL, NOS is predominantly nodal and represents the most common T-cell lymphoma in Western countries. • PTCL, NOS constitutes approximately 30% of all noncutaneous peripheral T-cell lymphomas. It occurs in middle-aged to elderly patients, with a median age of 54 years and a male to female ratio of about 1–2:1. Most patients are in advanced stages (stage III/IV) at diagnosis. Extranodal disease, B symptoms, and elevated LDH are frequent findings and are associated with unfavorable prognosis. Other risk factors include age >60 years and a decline in performance status. The most frequently involved extranodal sites are bone marrow, spleen, liver, Waldeyer ring, and skin (Table 54.1). • Molecular and immunophenotypic studies have demonstrated that p53 mutation and overexpression of p53 protein correlate with treatment failure and unfavorable prognosis. In general, PTCL, NOS is an aggressive disease with a poor response to therapy and frequent relapses.
54.1 MORPHOLOGY • The normal nodal architecture is often effaced with a diffuse infiltration of neoplastic lymphoid cells. The neoplastic lymphocytes display a wide spectrum of cytologic features, with most cases contain medium to large atypical lymphocytes containing irregular to pleomorphic nuclei, vesicular chromatin, and prominent nucleoli. Large neoplastic lymphocytes with clear cytoplasm or ones resembling Hodgkin–Reed–Sternberg cells may be present. The infiltrating neoplastic cells are often mixed with inflammatory cells, such as small lymphocytes, eosinophils, and histiocytes. Vascular proliferation is frequently noted. • Three morphologic variants have been described: (1) lymphoepithelioid type, (2) follicular type, and (3) T-zone type. • The lymphoepithelioid variant (Lennert lymphoma) is characterized by predominantly diffuse proliferation of small neoplastic lymphocytes, admixed with numerous scattered and/or small aggregates of epithelioid histiocytes (Fig. 54.1). Scattered larger atypical lymphocytes with clear cytoplasm may be present. Rarely, interfollicular growth pattern may be appreciated. Vascular proliferation and presence of inflammatory cells are common features. • The follicular variant is characterized by neoplastic clear cells in interfollicular aggregates, small nodule aggregates associated with background PTGC, and/or perifollicular/nodular aggregates surrounding hyperplastic follicles, mimicking follicular lymphoma, nodular lymphocyte predominant Hodgkin lymphoma, and marginal zone lymphoma, respectively. • The T-zone variant is characterized by perifollicular infiltration by predominantly small- to medium-sized lymphocytes with minimal atypia (Fig. 54.2). Clusters of atypical lymphocytes with clear cytoplasm are often present and scattered Reed–Sternberg-like cells may be present. Background lymphoid follicles are usually well preserved or even hyperplastic.
Atlas of Hematopathology. http://dx.doi.org/10.1016/B978-0-12-809843-1.00054-1 Copyright © 2018 Elsevier Inc. All rights reserved.
771
772
54. Peripheral T-cell Lymphoma, Not Otherwise Specified
TABLE 54.1 Differential Diagnosis of Peripheral T-cell Lymphoma, Not Otherwise Specified (PTCL, NOS) Entity
T-cells
Large HRS-like cells
Epithelioid histiocytes
Molecular/cytogenetic
PTCL, NOS
Atypical, pleomorphic
May be present, express pan-T markers
Often present, prominent in Lennert type
Rearranged TCR
Classical HL
Small, no atypia
CD15+, CD30+, CD45−, EBV±
Variable
IGH rearrangement not routinely detected
NLPHL
Small, no atypia, interfollicular CD57+
CD15−, CD30−, CD45+, CD20+, EMA+
Variable
IGH rearrangement not routinely detected
THR-LBCL
Small, no atypia
CD15−, CD30−, CD45+, CD20+
Abundant
Rearranged IGH
AITL
Atypical, some with clear cytoplasm and CD10+
Mostly reactive B-cells, CD30+, EBV+
Variable
Rearranged TCR
ALCL
Atypical, pleomorphic
T-cells, CD30+, ALK±
Variable
Rearranged ALK, TCR
Reactive nodes
Small and large
Mostly reactive B-cells, CD30+, EBV±
Variable
No TCR or IGH rearrangement
AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large cell lymphoma; HL, Hodgkin lymphoma; HRS, Hodgkin and Reed–Sternberg; NLPHL, nodular lymphocyte predominant HL; THR-LBCL, T-cell/histiocyte rich large B-cell lymphoma.
FIGURE 54.1 Peripheral T-cell lymphoma, lymphoepithelioid cell variant (Lennert lymphoma). Epithelioid histiocytes are mixed with infiltrating lymphocytes in small (A) or large (B and C) clusters.
54.2 Immunophenotype
773
• Bone marrow involvement shows focal or diffuse infiltration of bone marrow by neoplastic lymphocytes. Focal infiltrates are usually non-paratrabecular. The infiltrates are highly vascular, are admixed with inflammatory cells, and may show increased reticulin fibers. • Splenic infiltrates are often patchy and may primarily involve the periarterial T-cell zones or extend to the red pulp. • Cutaneous involvement is frequent and may appear as diffuse or nodular patterns with or without epidermotropism.
54.2 IMMUNOPHENOTYPE Immunophenotypic features include (Fig. 54.3): • • • • • • •
Pan-T-cell aberrancies with variable loss of CD5 and/or CD7; Expression of TCR-β; Common CD4 phenotype; but CD8 phenotype, or double positive, or double negative in some cases; Expression of CD56 and/or cytotoxic markers in some cases; Positivity of CD30 in some cases, but rare expression of CD15; Occasional aberrant expression of B-cell-associated markers CD20 or CD79a; Lack of follicular T-helper (FTH)-associated markers in cases other than PTCL, NOS, FTH type.
FIGURE 54.2 Peripheral T-cell lymphoma, T-zone variant. This demonstrates a mixture of small to large lymphocytes (A and B) and the presence of lymphoid cells with clear cytoplasm (C).
774
54. Peripheral T-cell Lymphoma, Not Otherwise Specified
FIGURE 54.3 Flow cytometric findings of peripheral T-cell lymphoma. Lymphoid-enriched gate of a neck lymph node reveals predominantly abnormal T-cells, which are double positive (circled) for CD4 (dim) and CD8 (heterogeneous). In addition, the neoplastic T-cells are positive for CD2, CD3, CD5 (bright), CD25 (heterogeneous), and TCR alpha/beta. They demonstrate complete loss of CD7 expression, and are negative for CD1a.
54.3 MOLECULAR AND CYTOGENETIC STUDIES • Approximately 90% of patients with PTCL, NOS show clonally rearranged TCR genes, and 70%–90% demonstrate cytogenetic aberrations. • A novel t(5;9)(q33;q22), that creates a fusion gene between ITK and SYK genes, has been reported in 17% of PTCL, NOS. • Complex karyotypes consistent with clonal evolution are a frequent finding. Breaks involving the TCR loci are common. The chromosomes most frequently altered in structural aberrations are 1, 6, 2, 4, 11, 14, and 17. Additionally, trisomies of 3 or 5 and an extra X chromosome are also common. • CGH studies have found recurrent losses on chromosomes 5q, 6q, 9p, 10q, 12q, and 13q (Fig. 54.4). Recurrent gains were found on chromosome 7q. • High-level amplifications of 12p13 have been observed in a few PTCL cases with cytotoxic phenotype. These results suggest that certain genetic alterations may indeed exist in PTCL, NOS, but definitive clinicopathologic subgroups have not yet been identified and, thus far, a variety of molecular and cytogenetic findings do not allow for a consistent model for pathogenesis to be constructed.
54.4 DIFFERENTIAL DIAGNOSIS The differential diagnosis includes a variety of reactive lymphadenopathies, ALCL, AITL, and Hodgkin lymphoma (Table 54.1). Presence of clusters of epithelioid histiocytes in the lymphoepithelioid cell (Lennert) variant may simulate toxoplasmosis, sarcoidosis, or other types of granulomatous lymphadenitis. The follicular variant may mimic follicular lymphoma or nodular lymphocyte predominant Hodgkin lymphoma. The interfollicular expansion and the presence of inflammatory cells in the T-zone variant may mimic T-zone hyperplasia. Cases with the presence of anaplastic large cells or the presence of Reed–Sternberg-like cells may resemble T-cell/histiocyte-rich large B-cell lymphoma, ALCL. Vascular proliferation and polymorphous infiltrate are among the overlapping features between PTCL, NOS and AITL.
54.4 Differential diagnosis
775
FIGURE 54.4 Deletion of 5q in a patient with peripheral T-cell lymphoma: (A) karyotype and (B) FISH analysis.
Additional Resources Bellei, M., et al., 2016. Pitfalls and major issues in the histologic diagnosis of peripheral T-cell lymphomas: results of the central review of 573 cases from the T-Cell Project, an international, cooperative study. Hematol Oncol 34, 2028–2036. De Leval, L., Gaulard, P., 2011. Pathology and biology of peripheral T-cell lymphomas. Histopathology 58, 49–68. Foss, F.M., Zinzani, P.L., Vose, J.M., 2011. Peripheral T-cell lymphoma. Blood 117, 6756–6767. Gaulard, P., de Leval, L., 2014. Pathology of peripheral T-cell lymphomas: where do we stand? Semin Hematol 51, 5–16. Gooptu, M., Rhoades, R., Pro, B., 2015. Current management of peripheral T-cell lymphomas. Cancer Treat Res 165, 289–303. Jaffe, E.S., et al., 2016. Hematopathology. eBook, Elsevier, second ed. Piccaluga, P.P., Agostinelli, C., Tripodo, C., 2011. European T-cell lymphoma study group peripheral T-cell lymphoma classification: the matter of cellular derivation. Expert Rev Hematol 4, 415–425. Ondrejka, S.L., Hsi, E.D., 2016. T-cell lymphomas: updates in biology and diagnosis. Surg Pathol Clin 9, 131–141. Savage, K.J., Ferreri, A.J., Zinzani, P.L., 2011. Peripheral T-cell lymphoma–not otherwise specified. Crit Rev Oncol Hematol 79, 321–329. Savage, K.J., 2011. Update: peripheral T-cell lymphomas. Curr Hematol Malig Rep 6, 222–230. Sekiguchi, Y., et al., 2015. Peripheral T cell lymphoma, not otherwise specified with myelofibrosis: report of a case with review of the literature. Int J Clin Exp Pathol 8, 4186–4203. Swerdlow, S.H., et al., 2008. WHO classification of tumours of haematopoietic and lymphoid tissues. International Agency for Research on Cancer, Lyon. Zhang, Y., et al., 2016. Therapeutic options in peripheral T cell lymphoma. J Hematol Oncol 9, 37–46.