Hodgkin Lymphoma and its Differential Diagnosis

Question 1

Variants of Reed-Sternberg cell in CHL

Answer 1

Question 2

In what type of Hodgkin lymphoma is this cell usually found?

Answer 2

Lacunar Reed-Sternberg cell

Often found in nodular sclerosing-type Hodgkin

Question 3

In what type of Hodgkin lymphoma is this cell usually found?

Answer 3

Popcorn Reed-Sternberg cell
Often found in nodular lymphocyte-predominant-type Hodgkin

Question 4

Classic Reed-Sternberg cell IHC markers

Answer 4

CD30 membranous
CD15 membranous and intense Golgi
MUM1+
PAX5+, but weaker than background B cells
Usually either OCT2 or BOB1 negative
CD20 weak to negative
CD45 weak to negative

Question 5

CD3

Answer 5

“Rosettes” of T cells surrounding Reed-Sternberg/Popcorn cells, classic for nodular lymphocyte-predominant-type Hodgkin.

Question 6

Interpretation of EBV positivity in large Reed-Sternberg-like cells

Answer 6

EBV positivity is frequently seen in classical Hodgkin lymphoma.

EBV negativity suggests EBV positive reactive lymphadneopathy in mononucleosis, nodular lymphocyte-predominant type lymphoma, primary mediastinal large B cell lymphoma, or mediastinal gray zone lymphoma.

Question 7

Answer 7

Infectious mononucleosis

Note that while there is marked distortion of the nodal architecture due to expansion of the interfollicular zone by a polymorphous infiltrate including immunoblasts, the architecture is still recognizable in the background.

Scattered mitoses, occasional apoptoses, and occasional foci of necrosis are present.

Some immunoblasts may display Hodgkinoid features, such as irregular multilobated nuclei, but not the classic morphology. However, nodular fibrosis and and classic Reed-Sternberg cells are absent.

In a lymph node affected by mononucleosis, there are almost always some areas with patent sinuses and reactive-appearing follicles.

Question 8

IHC to help distinguish between Hodgkin lymphoma and mononucleosis

Answer 8

Mononucleosis: CD20+ immunoblasts, co-express CD30 and MUM1 but lack CD15. OCT2/BOB1 double positive.

Hodgkin’s: CD30+/MUM1+ RS cells that are CD15+ but lack CD20 or are very weak for CD20. Either OCT2 or BOB1 will be lost.

Both may be EBV positive or negative, so this is not really helpful (you can have mononucleosis syndrome secondary to toxoplasma or acute HIV).

Question 9

Answer 9

EBV-positive mucocutaneous ulcer

An EBV-associated LPD that dvelops in the setting of immunodeficiency. Typically presents as a sharply demarcated, well-circumscribed focus or foci within the oral mucosa or GI tract (all highly unusual locations for Hodgkin lymphoma).

Inflammatory infiltrate is mixed, composed of scattered large lymphoid cells among small lymphocytes and granulocytes. CD8-predominant T cells often reside at the periphery of the lesion, creating a halo.

Some larger immunoblasts may be reminiscent of Reed-Sternberg cells. Their immunophenotype is CD45+, CD30+, MUM1+, CD20+, PAX5+, BOB1+, OCT2+, EBER ISH +. 50% are CD15+.

Question 10

Answer 10

Primary mediastinal large B cell lymphoma

A large B cell lymphoma arising from the mediastinum, which bears distinct clinical features that warrant its differentiation from DLBCL.

There is a female-predominance with a median age of 35 years at presentation. Typically presents as a bulky mediastinal mass with invasion of surrounding structures. However, marrow and nonmediastinal nodal involvement is uncommon. Extranodal disease may be seen at the time of relapse, most commonly involving the brain, kidneys, adrenals, liver, or gonads.

Morphologically composed of large, atypical cellls with abundant pale cytoplasm and irregular, sometimes multilobulated nuclei. Surrounded by thin bands of compartmentalizing fibrosis. Some larger cells may display features reminscent of Reed-Sternberg cells.

On IHC, large atypical cells are CD45+, CD19+, CD20+, PAX5+, CD79a+, OCT2+, BOB1+. They show a non-GC phenotype with MUM1+ and CD10 neg. Many cases are CD23+ and CD30+.

Question 11

Relationship between Hodgkin lymphoma and Primary Mediastinal Large B Cell lymphoma

Answer 11

They share a genetic transcription profile with NFkB activation and JAK-STAT activation.

This is reflected by nuclear TRAF1 and cREL positivity in >80% of CHL and >50% of PMLBCLs.

Both often involve 9q24 amplification and PDL1/PDL2 upregualtion.

Mutations in PTPN1 may occur in both.

Question 12

Mediastinal Gray-Zone Lymphoma

Answer 12

A rare group of lymphomas with intermediate featuers between PMLBCL and Hodgkin lymphoma.

Characterized by more numerous large cells than classical Hodgkin lymphoma present in clusters or sheets in an inflammatory background. Fibrous bands and lacunar cells may be present.

Demographically, more common in younger individuals and affects men more than women. It is clinically more aggressive than either CHL or PLMBCL.

Should really be considered in two scenarios:
1. Morphology is large cell lymphoma-like with sheets of large cells, but the immunophenotype is that of CHL with loss of CD20, dominished staining for other pan-B-cell antigens, and expression of classical RS cell markers CD30 and/or CD15.
2. Morphology is more CHL-like with scattered large atypical cells, but there is greater retention of the B-cell program with expression of multiple B-cell antigens, including strong CD20, retention of both OCT2 and BOB1, and expression of CD19 and/or CD79a.

Question 13

Answer 13

Nodular lymphocyte-predominant type Hodgkin lymphoma

Debated as to whether or not to call this a Hodgkin lymphoma anymore.

Characterized by a mixed inflammatory infiltrate with intermixed large “popcorn” cells. Unlike RS cells in a classical Hodgkin lymphoma, the popcorn cells in NLPHL express the full B cell program (CD20+, OCT2+, BOB1+, PAX5+). PAX5 is expressed at a similar level to background B cells. These cells are also CD30 and CD15 negative.

CD21 staining highlights expanded FDC meshworks in the background.

Question 14

NLPHL transformation to DLBCL

Answer 14

Rarely, NPLHL has been known to undergo transformation to a diffuse large B cell lymphoma.

The risk of transformation is 7% at 10y and 30% at 20y, and occurs more frequently when the spleen is a site of initial involvement.

Transformation is associated with copy number gains in REL and mutations in epigentic regulators such as TET2, CREBBP, and EP300.

Question 15

Genetics of NLPHL

Answer 15

Mutations in MAPK genes, such as CARD11,
JUNB, BCL10, NFKBIA, and TNFAIP3.

Mutations in PI3K genes, especially SGK1.

Question 16

NPLHL transformation to T-cell and histiocyte-rich LBCL

Answer 16

One pattern of NPLHL can look very similar to THRLBLC, but is distinguished by the presence of at least a focal B-cell-rich or nodular component.

Identification of a pure THRLBCL-like pattern in a patient with a history of NPLHL is diagnostic of transformation.

Question 17

Answer 17

T-cell and histiocyte-rich large B cell lymphoma

Hodgkinoid lymphoma with a mixed inflammatory background containing T cells and histiocytes as well as large neoplastic B cells that may have a popcorn cell or RS cell-like morphology, or may resemble conventional centroblasts or immunoblasts. The immunophenotype of these cells is similar to NLPHL popcorn cells: CD20+, PAX5+, BCL6+, CD30 neg, CD15 neg, EBV neg.

The original term of “T-cell-rich B-cell lymphoma” was
introduced to describe a variety of B-cell lymphomas with
a prominent T-cell reaction mimicking T-cell lymphoma.

Molecularly, shares X chromosome gains and short arm 17 losses with NLPHL.

Question 18

Answer 18

Progressive transformation of germinal centers

Form of reactive nodal hyperplasia that may be mistaken for a Hodgkinoid lymphoma.

Often coexists with reactive follicular hyperplasia, and some areas of a true Hodgkin lymphoma may contain areas of PTGC.

Characterized by involution of mantle zone B cells with infiltration and disruption of the germinal center and expansion of the B-cell follicle, which may be marked. The end product is the replacement of the germinal center by mantle cells. Creates a nodular architecture.

This infiltration of the GC by mantle cells is similar to what may be seen in mantle cell neoplasia in situ. You can rule this out with a CyclinD1 stain, showing that the cells are negative for cyclin D1 (caveat: cyclin D2 or D3 may substitute more rarely).

Question 19

Nodal T-follicular helper cell lymphomas

Answer 19

Divided into 3 subcategories:
- Angioimmunoblastic type (formerly AITCL)
- Follicular type
- NOS

In these lymphomas, localized lack of T-cell immunosurveillance can lead to teh proliferation of variable numbers of large, atypical B cells with features of centroblasts or immunoblasts. These may resemble RS cells or popcorn cells, and are PAX5+, CD30+, CD15+, variably CD20+, and may be EBV+.

Clues favoring a diagnosis of a nodal T-follicular helper cell lymphoma over a Hodgkin lymphoma are T cell cytologic atypia, such as nuclear irregularities, clumped or dispersed chromatin, and moderate amounts of pale or clear cytoplasm. Eosinophilia can be helpful in suggesting a nodal T cell lymphoma over lymphocyte-rich or lymphocyte-predominant Hodgkin lymphoma.

The predominant atypical T cell population is CD4+ and coexpresses at least two follicular helper cell markers (CXCL13, ICOS, PD-1, BCL-6, CD10). These cells are often dim or negative for surface CD3 by flow.

Question 20

One sure-fire way to differentiate neoplastic B cells vs non-neoplastic immunoblasts with reactive atypia

Answer 20

Kappa and lambda ISH

Never forget, you can always use ISH to rule out neoplasia in B cells, as long as you can identify your target population from the background.

Question 21

Answer 21

Nodal T-follicular helper cell lymphoma, angioimmunoblastic type

Note that the large, atypical, Hodgkinoid B cells here are actually just reactive immunoblasts! The real neoplastic cells are the T cells in the background.

Also note the prominent, slightly hyalinized vessels.