Residency · Residency · Pathology

Hodgkin Lymphoma and T-Cell Lymphomas

Overview

Hodgkin lymphoma (HL) is defined by the presence of rare neoplastic cells, known as Reed-Sternberg cells and their variants, embedded within a reactive inflammatory background. T-cell lymphomas comprise a heterogeneous group of neoplasms arising from mature (post-thymic) T-cells and NK cells, accounting for approximately 10 to 15 percent of all non-Hodgkin lymphomas in Western countries. Despite their relative rarity, these entities require precise classification because treatment strategies vary enormously.

Classic Hodgkin Lymphoma (CHL)

General Features

Classic Hodgkin lymphoma follows a bimodal age distribution, with peaks in young adults aged 15 to 35 and in older adults over 55. The neoplastic cells are the Hodgkin and Reed-Sternberg (HRS) cells, which are large binucleated or multinucleated cells with prominent eosinophilic nucleoli that produce the characteristic "owl-eye" appearance. Remarkably, HRS cells constitute less than 1 to 2 percent of the total tumor mass; the vast majority of cells are a reactive background of lymphocytes, eosinophils, histiocytes, plasma cells, and fibrosis. Epstein-Barr virus (EBV) is associated with approximately 30 to 40 percent of cases, with higher rates in the mixed cellularity and lymphocyte-depleted subtypes.

Immunophenotype of HRS Cells

The defining immunophenotype of HRS cells includes strong CD30 positivity in a membranous and Golgi pattern, CD15 positivity in approximately 75 to 85 percent of cases, and characteristically weak or dim PAX5 expression (a B-cell transcription factor). CD20 is negative or only weakly positive in a minority of cases (20 to 30 percent). Critically, CD45 (LCA) is negative, which is the key feature distinguishing CHL from DLBCL. The B-cell transcription factors BOB.1 and Oct-2 are negative or reduced, while MUM1/IRF4 is positive. EBER (EBV-encoded RNA) is positive in 30 to 40 percent.

Subtypes of Classic Hodgkin Lymphoma

Nodular Sclerosis (NSHL)

Nodular sclerosis is the most common subtype, comprising 60 to 70 percent of cases, and typically presents in young adults with a mediastinal mass. Broad bands of collagen divide the tumor into nodules, and the HRS cell variant seen here is the lacunar cell, which has retracted cytoplasm in formalin-fixed tissue. Grading into Grade 1 (rare HRS cells) versus Grade 2 (numerous HRS cells or HRS cell-rich areas) exists, though its clinical significance remains debated.

Mixed Cellularity (MCHL)

The second most common subtype at 20 to 25 percent, mixed cellularity tends to occur in older adults and frequently shows EBV positivity. The background is a mixed inflammatory infiltrate without the sclerotic bands seen in nodular sclerosis. Classic binucleated Reed-Sternberg cells are readily identified.

Lymphocyte-Rich (LRHL)

This rare subtype (approximately 5 percent) has either a nodular or diffuse growth pattern with abundant small lymphocytes and few HRS cells. It carries an excellent prognosis but must be carefully distinguished from nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL).

Lymphocyte-Depleted (LDHL)

The rarest subtype at 1 to 2 percent, lymphocyte-depleted HL occurs in older adults and is associated with HIV infection and EBV. It shows a paucity of background lymphocytes with numerous HRS cells or a sarcomatous growth pattern. DLBCL (anaplastic variant) with CD30 expression must be excluded.

Staging and Prognosis

Staging follows the Ann Arbor/Lugano system (Stages I through IV) based on the number of involved regions and extranodal extension. B symptoms include fever, night sweats, and weight loss exceeding 10 percent of body weight. PET/CT is the standard imaging modality given the FDG-avid nature of the disease. CHL is curable in more than 85 percent of cases with chemotherapy (ABVD) with or without radiation.

Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL)

Reclassification in WHO 5th Edition

In the WHO 5th edition, this entity has been renamed nodular lymphocyte-predominant B-cell lymphoma (NLPBL) and reclassified as a B-cell lymphoma rather than a subtype of Hodgkin lymphoma. This change reflects its true B-cell nature and clinical behavior.

Morphology

The neoplastic cells are lymphocyte-predominant (LP) cells, formerly called "popcorn cells" or L&H cells. These are large cells with multilobated vesicular nuclei, fine chromatin, and small nucleoli. They reside within a nodular background of small lymphocytes, epithelioid histiocytes, and follicular dendritic cell meshworks. The LP cells characteristically sit within expanded follicular dendritic cell meshworks, which is distinct from CHL.

Immunophenotype of LP Cells

LP cells are strongly CD20-positive, which is the key difference from CHL. They also express CD45, BCL6, Oct-2, and BOB.1. In contrast to CHL, CD30 is negative or very weak, and CD15 is negative. EMA is variably positive. EBV is negative. A characteristic finding is rosettes of CD3-positive/CD57-positive T-cells surrounding the LP cells.

Clinical Features

NLPBL follows an indolent course with localized disease in most cases. Treatment options include observation, limited radiation, or rituximab (given CD20 positivity). Late relapses are common but generally treatable. There is a risk of transformation to T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL).

Peripheral T-Cell Lymphomas

Anaplastic Large Cell Lymphoma (ALCL)

ALK-Positive ALCL

This entity primarily affects young adults and children, often presenting with advanced stage disease. Morphologically, it consists of large pleomorphic cells with horseshoe or kidney-shaped nuclei termed "hallmark cells," growing in a sinusoidal pattern within lymph nodes. The immunophenotype shows strong uniform CD30 positivity and ALK positivity, with the staining pattern of ALK indicating the fusion partner: nuclear plus cytoplasmic staining indicates NPM1-ALK, while restricted cytoplasmic staining indicates variant translocation partners. The cells are typically CD3-negative, variably CD4-positive, and EMA-positive. The defining translocation is t(2;5)(p23;q35) producing the NPM1-ALK fusion. Prognosis is favorable with a 5-year overall survival of approximately 80 percent.

ALK-Negative ALCL

This variant occurs in older adults and has similar morphology to ALK-positive ALCL but lacks ALK protein expression. CD30 positivity is required for diagnosis. It must be distinguished from CD30-positive DLBCL and CHL. DUSP22 rearrangement confers a favorable prognosis similar to ALK-positive disease, while TP63 rearrangement carries a very adverse prognosis. Overall, the intermediate prognosis yields a 5-year overall survival of approximately 50 percent.

Breast Implant-Associated ALCL (BIA-ALCL)

This entity arises exclusively around textured breast implants, presenting as a periprosthetic seroma or mass. It is CD30-positive and ALK-negative. When disease is confined to the seroma, prognosis is excellent with implant removal and capsulectomy alone. Mass-forming disease requires systemic therapy and carries a worse outcome.

Angioimmunoblastic T-Cell Lymphoma (AITL) / Nodal TFH Lymphoma

Morphology

AITL effaces the lymph node architecture with a polymorphous infiltrate. The hallmark features are prominent arborizing high endothelial venules with perivascular clear cells (the neoplastic T-follicular helper cells), expanded follicular dendritic cell meshworks (highlighted by CD21/CD23), and a mixed background of eosinophils, plasma cells, epithelioid histiocytes, and B-immunoblasts that are often EBV-positive.

Immunophenotype

The neoplastic cells express T-follicular helper (TFH) markers including CD10, BCL6, PD-1, CXCL13, and ICOS. They are CD4-positive with variable CD3 expression. At least two to three TFH markers must be expressed for diagnosis. Importantly, the EBV-positive B-immunoblasts in the background represent a reactive component, not the neoplastic clone.

Molecular

Characteristic mutations include TET2, DNMT3A, IDH2 R172, and RHOA G17V. The IDH2 R172 mutation is relatively specific for AITL and TFH lymphomas. A secondary EBV-positive B-cell lymphoma (DLBCL) may develop from the expanded B-immunoblast population.

Clinical

Patients present with systemic symptoms, generalized lymphadenopathy, hepatosplenomegaly, hypergammaglobulinemia, and autoimmune phenomena such as hemolytic anemia and a positive Coombs test. The course is aggressive with a median survival of 3 to 5 years.

Peripheral T-Cell Lymphoma, Not Otherwise Specified (PTCL-NOS)

This is a heterogeneous group that serves as a diagnosis of exclusion after ruling out all specific T-cell lymphoma entities. Morphology is variable, ranging from small to medium to large cells with paracortical involvement. The cells are CD3-positive, CD4 or CD8-positive, and often show loss of one or more T-cell antigens (CD5, CD7). No defining molecular or morphologic feature exists. It follows an aggressive course with a 5-year overall survival of approximately 30 percent.

Mycosis Fungoides (MF) and Sezary Syndrome

Mycosis Fungoides

Mycosis fungoides is the most common cutaneous T-cell lymphoma, progressing through clinical stages of patches, plaques, tumors, and erythroderma. Histologically, it shows an epidermotropic infiltrate of atypical lymphocytes with cerebriform nuclei. Pautrier microabscesses, which are intraepidermal collections of atypical T-cells, are a characteristic but not always present finding. The dermis shows a band-like (lichenoid) infiltrate of small to medium atypical lymphocytes. Immunophenotypically, the cells are CD3-positive, CD4-positive, and usually CD8-negative, with common loss of CD7. Early-stage disease is indolent, while tumor-stage and advanced disease behaves aggressively.

Sezary Syndrome

Sezary syndrome is the leukemic variant of cutaneous T-cell lymphoma, defined by the triad of erythroderma, generalized lymphadenopathy, and circulating Sezary cells (cerebriform lymphocytes exceeding 1000 per microliter). It is aggressive with a median survival of 2 to 4 years.

Adult T-Cell Leukemia/Lymphoma (ATLL)

ATLL is caused by HTLV-1 infection and is endemic in Japan, the Caribbean, and parts of Africa. The characteristic "flower cells" in the blood have multilobated or cloverleaf nuclei. The immunophenotype is CD4-positive, CD25 (IL-2R)-positive, CD3-positive, and FoxP3-positive. Four clinical subtypes exist: acute, lymphomatous, chronic, and smoldering, with the acute and lymphomatous forms being aggressive. Hypercalcemia is common, resulting from PTHrP secretion or osteolytic lesions.

Hepatosplenic T-Cell Lymphoma

This rare entity affects primarily young males, presenting with splenomegaly and hepatomegaly without lymphadenopathy. The neoplastic cells show sinusoidal infiltration of the liver, spleen, and bone marrow. They are CD3-positive, CD56-positive, usually express gamma-delta T-cell receptor, and are CD4-negative/CD8-negative. Isochromosome 7q is the characteristic cytogenetic finding. The prognosis is very poor.

<image>A medical illustration comparing the morphologic and immunophenotypic features of Classic Hodgkin Lymphoma (CHL) and Nodular Lymphocyte-Predominant B-cell Lymphoma (NLPBL). Left panel (CHL): A Reed-Sternberg cell with bilobed nucleus, prominent eosinophilic nucleoli resembling owl eyes, and a mixed inflammatory background of lymphocytes, eosinophils, and histiocytes. IHC insets show CD30 strong membranous/Golgi positivity, CD15 positive, PAX5 weak/dim, and CD20 negative. Right panel (NLPBL): A lymphocyte-predominant (LP/popcorn) cell with multilobated nucleus, vesicular chromatin, and small nucleoli, surrounded by a rosette of small lymphocytes within a nodular FDC meshwork. IHC insets show CD20 strong positive, CD30 negative, CD15 negative, and CD3/CD57 highlighting the rosetting T-cells. A comparison table below lists the key immunophenotypic differences.</image>

<image>A medical illustration showing the histologic features of three major peripheral T-cell lymphoma subtypes. Panel A (ALCL, ALK-positive): Large pleomorphic hallmark cells with horseshoe-shaped nuclei in a sinusoidal distribution within a lymph node, with an inset showing ALK IHC with nuclear and cytoplasmic staining pattern (NPM1-ALK fusion). Panel B (AITL): Polymorphous infiltrate with prominent arborizing high endothelial venules (PAS stain inset), perivascular clear cells (neoplastic TFH cells), expanded CD21+ follicular dendritic cell meshworks (CD21 IHC inset), and scattered EBV+ B-immunoblasts (EBER ISH inset). Panel C (Mycosis fungoides): Skin biopsy showing epidermotropism with atypical lymphocytes lining the basal layer and forming Pautrier microabscesses in the epidermis, with cerebriform nuclear morphology visible on high power.</image>

Clinical Pearls

CD30 positivity alone does not establish a diagnosis of Hodgkin lymphoma. CD30 is also expressed in ALCL, a subset of DLBCL, embryonal carcinoma, and even reactive immunoblasts, so correlation with CD15, CD45, PAX5, ALK, and morphology is essential. The most critical distinction in Hodgkin lymphoma workup is CHL versus NLPBL (formerly NLPHL): NLPBL is CD20-positive/CD30-negative/CD15-negative while CHL is CD20-negative/CD30-positive/CD15-positive, and this distinction determines whether the patient receives rituximab or ABVD.

In AITL/TFH lymphoma, the EBV-positive cells are reactive B-immunoblasts rather than the neoplastic population. Recognizing this prevents the critical error of misdiagnosing the case as EBV-positive DLBCL. Loss of pan-T-cell antigens (CD5, CD7, CD2) on an abnormal T-cell population is a major clue to T-cell lymphoma, as no reactive condition causes loss of multiple T-cell markers simultaneously.

The ALK immunohistochemistry staining pattern predicts the fusion partner: nuclear plus cytoplasmic staining indicates NPM1-ALK, while restricted cytoplasmic staining suggests non-NPM1 partners such as TPM3 or ATIC. Breast implant-associated ALCL is exclusively linked to textured implants, and capsulectomy with implant removal is curative for seroma-confined disease. Mycosis fungoides in the early patch/plaque stage may be histologically subtle, and multiple biopsies over time may be needed before diagnostic features emerge.

References

• Alaggio R, et al. The 5th edition of the WHO Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia. 2022;36(7):1720-1748.
• Swerdlow SH, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th ed. IARC; 2017.
• Eichenauer DA, et al. Hodgkin lymphoma: ESMO Clinical Practice Guidelines. Ann Oncol. 2018;29(suppl_4):iv19-iv29.
• Vose J, et al. International peripheral T-cell and natural killer/T-cell lymphoma study: Pathology findings and clinical outcomes. J Clin Oncol. 2008;26(25):4124-4130.
• Clemens MW, et al. Complete Surgical Excision Is Essential for the Management of Patients With Breast Implant-Associated Anaplastic Large-Cell Lymphoma. J Clin Oncol. 2016;34(2):160-168.

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