Hodgkin's lymphoma: the pathologist's viewpoint

Abstract

Despite its well known histological and clinical features, Hodgkin's lymphoma (HL) has recently been the object of intense research activity, leading to a better understanding of its phenotype, molecular characteristics, histogenesis, and possible mechanisms of lymphomagenesis. There is complete consensus on the B cell derivation of the tumour in most cases, and on the relevance of Epstein-Barr virus infection and defective cytokinesis in at least a proportion of patients. The REAL/WHO classification recognises a basic distinction between lymphocyte predominance HL (LP-HL) and classic HL (CHL), reflecting the differences in clinical presentation and behaviour, morphology, phenotype, and molecular features. CHL has been classified into four subtypes: lymphocyte rich, nodular sclerosing, with mixed cellularity, and lymphocyte depleted. The borders between CHL and anaplastic large cell lymphoma have become sharper, whereas those between LP-HL and T cell rich B cell lymphoma remain ill defined. Treatments adjusted to the pathobiological characteristics of the tumour in at risk patients have been proposed and are on the way to being applied.

Figure 1

(A) A typical diagnostic Reed-Sternberg (RS) cell within a composite inflammatory milieu (haematoxylin and eosin; original magnification, ×500). (B) Nodular lymphocyte predominant Hodgkin's lymphoma (LP-HL): at low power, a neoplastic nodule can be seen as a densely packed cellular area with a high content of small lymphocytes (Giemsa; original magnification, ×40). (C) Nodular LP-HL: at higher magnification, some popcorn cells and one Reed-Sternberg-like element are detected among small lymphocytes (Giemsa; original magnification, ×450). (D) Nodular LP-HL: at low magnification, a progressively transformed germinal centre looks like a nodule of LP-HL; however, among small lymphocytes there are some centroblasts and centrocytes, but no popcorn cells (Giemsa; original magnification, ×40). (E) Nodular LP-HL: a popcorn cell and most small lymphocytes within a nodule express the B cell marker CD79a (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×500). (F) Nodular LP-HL: popcorn cells are surrounded by rosettes of CD3⁺ T cells (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×250). (G) Nodular LP-HL: rosetting T cells largely express CD57 (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×250). (H) Nodular LP-HL: popcorn cells express epithelial membrane antigen (EMA) (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×250). (I) Nodular LP-HL: popcorn cells (circled) express the bcl-6 gene product (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×250). (J) Nodular LP-HL: positivity of neoplastic elements for the Oct2 gene product (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×300). (K) Nodular LP-HL: popcorn cells strongly express CD40 (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×300). (L) Nodular LP-HL: neoplastic elements are found within a delicate meshwork of CD21⁺ follicular dendritic cells (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×300). (M) Common Hodgkin's lymphoma (CHL): Hodgkin and Reed-Sternberg (H&RS) cells express the CD30 molecule both at the cytoplasmic membrane and in the Golgi area (dot-like positivity) (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×350). (N) CD30 membrane bound positivity in an example of embryonal carcinoma (immunoperoxidase, SABC technique; Gill's haematoxylin counterstain; original magnification, ×200). (O) CHL: neoplastic cells show membrane bound and dot-like CD15 positivity (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×350). (P) CHL: H&RS cells display variable degrees of CD20 staining (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×200). (Q) CHL: staining for IRF4/MUM1 gene product (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×350). (R) CHL: most neoplastic cells express the Ki-67 molecule as revealed by the Mib-1 monoclonal antibody; some small lymphocytes are also in the cell cycle (immunoperoxidase, SABC technique; Gill's haematoxylin counterstain; original magnification, ×500). (S) CHL: moderate Bcl-2 protein expression by H&RS cells and a ratio of small lymphocytes (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×300). (T) CHL: most neoplastic cells show p53 overexpression (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×300). (U) CHL: H & RS show genomic Epstein-Barr virus integration by in situ hybridisation with fluorescein labelled EBER1/2 probes (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×300).

Figure 1

(A) A typical diagnostic Reed-Sternberg (RS) cell within a composite inflammatory milieu (haematoxylin and eosin; original magnification, ×500). (B) Nodular lymphocyte predominant Hodgkin's lymphoma (LP-HL): at low power, a neoplastic nodule can be seen as a densely packed cellular area with a high content of small lymphocytes (Giemsa; original magnification, ×40). (C) Nodular LP-HL: at higher magnification, some popcorn cells and one Reed-Sternberg-like element are detected among small lymphocytes (Giemsa; original magnification, ×450). (D) Nodular LP-HL: at low magnification, a progressively transformed germinal centre looks like a nodule of LP-HL; however, among small lymphocytes there are some centroblasts and centrocytes, but no popcorn cells (Giemsa; original magnification, ×40). (E) Nodular LP-HL: a popcorn cell and most small lymphocytes within a nodule express the B cell marker CD79a (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×500). (F) Nodular LP-HL: popcorn cells are surrounded by rosettes of CD3⁺ T cells (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×250). (G) Nodular LP-HL: rosetting T cells largely express CD57 (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×250). (H) Nodular LP-HL: popcorn cells express epithelial membrane antigen (EMA) (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×250). (I) Nodular LP-HL: popcorn cells (circled) express the bcl-6 gene product (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×250). (J) Nodular LP-HL: positivity of neoplastic elements for the Oct2 gene product (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×300). (K) Nodular LP-HL: popcorn cells strongly express CD40 (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×300). (L) Nodular LP-HL: neoplastic elements are found within a delicate meshwork of CD21⁺ follicular dendritic cells (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×300). (M) Common Hodgkin's lymphoma (CHL): Hodgkin and Reed-Sternberg (H&RS) cells express the CD30 molecule both at the cytoplasmic membrane and in the Golgi area (dot-like positivity) (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×350). (N) CD30 membrane bound positivity in an example of embryonal carcinoma (immunoperoxidase, SABC technique; Gill's haematoxylin counterstain; original magnification, ×200). (O) CHL: neoplastic cells show membrane bound and dot-like CD15 positivity (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×350). (P) CHL: H&RS cells display variable degrees of CD20 staining (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×200). (Q) CHL: staining for IRF4/MUM1 gene product (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×350). (R) CHL: most neoplastic cells express the Ki-67 molecule as revealed by the Mib-1 monoclonal antibody; some small lymphocytes are also in the cell cycle (immunoperoxidase, SABC technique; Gill's haematoxylin counterstain; original magnification, ×500). (S) CHL: moderate Bcl-2 protein expression by H&RS cells and a ratio of small lymphocytes (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×300). (T) CHL: most neoplastic cells show p53 overexpression (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×300). (U) CHL: H & RS show genomic Epstein-Barr virus integration by in situ hybridisation with fluorescein labelled EBER1/2 probes (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×300).

Figure 2

(A) Nodular sclerosing common Hodgkin's lymphoma (NS-CHL): the normal lymph node structure is largely effaced because of a nodular growth; the nodule is surrounded by thick collagen bands originating from the capsule (haematoxylin and eosin; original magnification, ×40). Inset: birefringence of collagen bands (polarised light microscopy; original magnification, ×20). (B) NS-CHL: scattered lacunar cells can easily be seen within one nodule (haematoxylin and eosin; original magnification, ×300). Inset: cytological details of a lacunar cell (Giemsa; original magnification, ×800). (C) NS-CHL: so called cellular phase; note the nodularity of the growth (haematoxylin and eosin; original magnification, ×80). (D) NS-CHL: so called syncytial variant; note the cohesive growth pattern of neoplastic cells (haematoxylin and eosin; original magnification, ×400). (E) NS-CHL: an example of grade II tumour; note the content of neoplastic cells within the nodule, which covers more than 25% of the examined area (haematoxylin and eosin; original magnification, ×300). (F) An example of anaplastic large cell lymphoma of the Hodgkin-like type (ALCL-HL): the tumour consists of nodules partly surrounded by collagen bands (haematoxylin and eosin, original magnification, ×20).(G) ALCL-HL: at higher magnification it can be seen that the collagen bands are almost exclusively formed by neoplastic cells (Giemsa; original magnification, ×300). (H) ALCL-HL: typical intrasinusoidal diffusion of neoplastic cells as shown by CD30 staining (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×200). (I) ALCL-HL: ALK protein expression by neoplastic cells (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×400). (J) Primary mediastinal large B cell lymphoma (PMLBCL): neoplastic cells sometimes have multiple nuclei, show a wide rim of clear, fragile cytoplasm, and elicit a stromal reaction with compartmentalisation (Giemsa; original magnification, ×300). (K) PMLBCL: neoplastic cells express the CD30 molecule (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×300). (L) Mixed cellularity common Hodgkin's lymphoma (MC-CHL): Hodgkin and Reed-Sternberg (H&RS) cells are easily identified; they are found with a cellular milieu consisting of small lymphocytes, some plasma cells, histiocytes, and granulocytes (haematoxylin and eosin; original magnification, ×350). (M) MC-CHL: an example of a mummified cell (arrow) (haematoxylin and eosin; original magnification, ×350). (N) MC-CHL: the tumour has a patent interfollicular location; a spared follicle with Castleman-like features can be seen (haematoxylin and eosin; original magnification, ×150). (O) MC-CHL: the tumour contains reactive epithelioid cells (haematoxylin and eosin; original magnification, ×300). (P) Peripheral T cell lymphoma not otherwise specified with a high content of epithelioid cells (so called Lennert's lymphoma): lymphoid elements show variation in size and shape (haematoxylin and eosin; original magnification, ×400). (Q) T cell rich, histiocyte rich large B cell lymphoma (TCRBCL): neoplastic cells strongly express the CD79a molecule (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×300). (R) TCRBCL: reactive T cells and histiocytes are stained by the anti-CD3 antibody (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×150). (S) TCRBCL: reactive T cells and histiocytes are stained by the anti-CD68 antibody (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×150). (T) Lymphocyte depleted common Hodgkin's lymphoma (LD-CHL), fibrotic variant: rare neoplastic cells are surrounded by thick collagen bands with a haphazard organisation, some histiocytes and scanty lymphocytes (haematoxylin and eosin; original magnification, ×400). (U) LD-CHL, sarcomatous variant: H&RS cells are quite numerous; there is a certain degree of fibrotic reaction; small lymphocytes are exceedingly rare (haematoxylin and eosin; original magnification, ×350). (V) Lymphocyte rich common Hodgkin's lymphoma (LR-CHL): mononuclear and diagnostic neoplastic elements are found within a cellular milieu mostly consisting of small lymphocytes (haematoxylin and eosin; original magnification, ×350). (W) LR-CHL: neoplastic cells express CD15 (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×300). (X) CHL: typical example of bone marrow involvement; note the fibrotic reaction, and the presence of H&RS cells (haematoxylin and eosin; original magnification, ×300).

Figure 2

(A) Nodular sclerosing common Hodgkin's lymphoma (NS-CHL): the normal lymph node structure is largely effaced because of a nodular growth; the nodule is surrounded by thick collagen bands originating from the capsule (haematoxylin and eosin; original magnification, ×40). Inset: birefringence of collagen bands (polarised light microscopy; original magnification, ×20). (B) NS-CHL: scattered lacunar cells can easily be seen within one nodule (haematoxylin and eosin; original magnification, ×300). Inset: cytological details of a lacunar cell (Giemsa; original magnification, ×800). (C) NS-CHL: so called cellular phase; note the nodularity of the growth (haematoxylin and eosin; original magnification, ×80). (D) NS-CHL: so called syncytial variant; note the cohesive growth pattern of neoplastic cells (haematoxylin and eosin; original magnification, ×400). (E) NS-CHL: an example of grade II tumour; note the content of neoplastic cells within the nodule, which covers more than 25% of the examined area (haematoxylin and eosin; original magnification, ×300). (F) An example of anaplastic large cell lymphoma of the Hodgkin-like type (ALCL-HL): the tumour consists of nodules partly surrounded by collagen bands (haematoxylin and eosin, original magnification, ×20).(G) ALCL-HL: at higher magnification it can be seen that the collagen bands are almost exclusively formed by neoplastic cells (Giemsa; original magnification, ×300). (H) ALCL-HL: typical intrasinusoidal diffusion of neoplastic cells as shown by CD30 staining (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×200). (I) ALCL-HL: ALK protein expression by neoplastic cells (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×400). (J) Primary mediastinal large B cell lymphoma (PMLBCL): neoplastic cells sometimes have multiple nuclei, show a wide rim of clear, fragile cytoplasm, and elicit a stromal reaction with compartmentalisation (Giemsa; original magnification, ×300). (K) PMLBCL: neoplastic cells express the CD30 molecule (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×300). (L) Mixed cellularity common Hodgkin's lymphoma (MC-CHL): Hodgkin and Reed-Sternberg (H&RS) cells are easily identified; they are found with a cellular milieu consisting of small lymphocytes, some plasma cells, histiocytes, and granulocytes (haematoxylin and eosin; original magnification, ×350). (M) MC-CHL: an example of a mummified cell (arrow) (haematoxylin and eosin; original magnification, ×350). (N) MC-CHL: the tumour has a patent interfollicular location; a spared follicle with Castleman-like features can be seen (haematoxylin and eosin; original magnification, ×150). (O) MC-CHL: the tumour contains reactive epithelioid cells (haematoxylin and eosin; original magnification, ×300). (P) Peripheral T cell lymphoma not otherwise specified with a high content of epithelioid cells (so called Lennert's lymphoma): lymphoid elements show variation in size and shape (haematoxylin and eosin; original magnification, ×400). (Q) T cell rich, histiocyte rich large B cell lymphoma (TCRBCL): neoplastic cells strongly express the CD79a molecule (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×300). (R) TCRBCL: reactive T cells and histiocytes are stained by the anti-CD3 antibody (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×150). (S) TCRBCL: reactive T cells and histiocytes are stained by the anti-CD68 antibody (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×150). (T) Lymphocyte depleted common Hodgkin's lymphoma (LD-CHL), fibrotic variant: rare neoplastic cells are surrounded by thick collagen bands with a haphazard organisation, some histiocytes and scanty lymphocytes (haematoxylin and eosin; original magnification, ×400). (U) LD-CHL, sarcomatous variant: H&RS cells are quite numerous; there is a certain degree of fibrotic reaction; small lymphocytes are exceedingly rare (haematoxylin and eosin; original magnification, ×350). (V) Lymphocyte rich common Hodgkin's lymphoma (LR-CHL): mononuclear and diagnostic neoplastic elements are found within a cellular milieu mostly consisting of small lymphocytes (haematoxylin and eosin; original magnification, ×350). (W) LR-CHL: neoplastic cells express CD15 (APAAP technique, Gill's haematoxylin counterstain; original magnification, ×300). (X) CHL: typical example of bone marrow involvement; note the fibrotic reaction, and the presence of H&RS cells (haematoxylin and eosin; original magnification, ×300).