Diagnosis of Hodgkin lymphoma in the modern era

Abstract

The Hodgkin lymphomas are a family of unique lymphoma subtypes, in which the nature of the neoplastic cell was enigmatic for many years. Much of the mystery has been solved, with all forms now considered to be of B-cell origin, in most cases of germinal centre derivation. Today we recognize Hodgkin lymphoma as an eponym that encompasses multiple entities. One of the unifying themes is the major contribution from the tumour microenvironment. Both the character of the neoplastic cells and the nature of the immune environment are critical to accurate diagnosis. Moreover, an understanding of the molecular alterations that characterize both the neoplastic cells and their microenvironment have led to therapeutic advances, targeting both neoplastic and reactive components. Other conditions may foster a similar inflammatory milieu and lead to lymphoproliferations that mimic the Hodgkin lymphomas. In this review we provide an update on the diagnostic features of the various subtypes and include additional information relevant for prognostic evaluation and investigation of potential therapeutic targets. Additionally, we also discuss those conditions that often cause confusion in diagnosis and need to be distinguished from the Hodgkin lymphomas.

Keywords: Epstein Barr virus; T-cell/histiocyte-rich large B-cell lymphoma; classical Hodgkin lymphoma; grey zone lymphoma; nodular lymphocyte predominant Hodgkin lymphoma.

Fig 1.

Histological and immunophenotypic features of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). (A) Haematoxylin and eosin stain at low magnification (x40) shows vaguely nodular architecture of NLPHL. (B) Scattered lymphocyte-predominant (LP) cells with polylobated (popcorn-like) nuclei are present in a background rich in small lymphocytes (x600). Also note the absence of other inflammatory cells. (C) Immunohistochemical (IHC) stain for OCT2 highlights the LP cells, usually with stronger expression than the background small B cells (x600). Also note the nuclear irregularity highlighted by OCT2 nuclear staining. (D) IHC for PD-1 shows small T cells forming tight rosettes surrounding the LP cells (x600).

Fig 2.

Patterns of PD-L1 in classical Hodgkin lymphoma. (A) Haematoxylin and eosin (H&E) stain shows a case of nodular sclerosis classical Hodgkin lymphoma (NSCHL) with clusters of Hodgkin/Reed-Sternberg (HRS) cells (x600). (B) Immunohistochemistry (IHC) highlights strong and uniform expression of PD-L1 in the HRS cells (x600). (C) H&E stain showing a different case of NSCHL with scattered HRS cells (arrows) (x600). (D) IHC demonstrating the expression of PD-L1 by stromal cells, while the HRS cells are negative (x600). The lace-like pattern surrounds the HRS cells.

Fig 3.

Mediastinal Grey zone lymphoma (GZL). (A-B) Low and high magnification haematoxylin and eosin stains demonstrate cohesive sheets of large atypical neoplastic cells with variation in size and morphology (A: x400; B: x600). A subset of cells exhibits Hodgkin/Reed-Sternberg cell-like features with irregular nuclei and prominent nucleoli. (C-F) Immunohistochemical studies (x400) show typical immunophenotype of classical Hodgkin lymphoma in the atypical cells with expression of CD30 (C) and CD15 (D), but the atypical cells retain strong expression of B-cell markers CD20 (E) and OCT2 (F). Also note marked nuclear variability and range in cell size and shape.

Fig 4.

Epstein–Barr virus (EBV)-positive mucocutaneous ulcer, skin biopsy (x20). (A) Haematoxylin and eosin stain demonstrates a dense dermal infiltrate extending to subcutis. (B) Immunohistochemistry (IHC) for CD30 highlights the atypical cells, showing a localized distribution confined to the subcutis (x20). (C-E) IHC studies at higher magnification (x400) showing that the atypical cells express CD30 (C), CD15 (D) and CD20 (E). (F) In-situ hybridization for EBV-encoded RNAs (EBER, at x400) shows that the atypical cells are uniformly positive for EBV. Note the variation in size of the EBV-positive cells, which is characteristic of EBV-associated B-cell lymphoproliferative disorders.

Fig 5.

Peripheral T-cell lymphomas with “Hodgkin-like” cells. (A) Haematoxylin and eosin stain (x400) demonstrates an atypical lymphoid infiltrate composed of small-to-medium-sized lymphoid cells and scattered large “Hodgkin-like” cells (arrows and inset). (B) Immunohistochemistry (IHC) shows expression of CD3 in the small-to-medium-sized atypical T cells, also highlighting the cytological atypia (x400). (C-F) IHC and in situ hybridization studies (x400) showing that the large “Hodgkin-like” cells are positive for CD30 (C), CD15 (D), PAX5 (E) and EBV (F).