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Nodular lymphocyte predominant Hodgkin lymphoma diagnostic pearls and pitfalls.

The category of Hodgkin lymphoma includes classical Hodgkin lymphoma (CHL) and the less common nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). Both CHL and NLPHL are characterized by large, neoplastic cells derived from germinal center B cells, in an inflammatory background.

Clinically, NLPHL differs from CHL. In NLPHL, the classic scenario is a male patient with a single site of lymphadenopathy that has been slowly enlarging for months or years. Many patients present with very large solitary masses and no other signs or symptoms of lymphoma. Nodular lymphocyte predominant Hodgkin lymphoma has a male predominance and typically presents in middle age. The most common sites of involvement are peripheral lymph nodes, including cervical, axillary, and inguinal. Mediastinal and retroperitoneal involvement is rare; a diagnosis of NLPHL in these locations should be made with caution. Bone marrow involvement is very uncommon, (4) but when stage IV disease is present, the prognosis is poor. (1) Nodular lymphocyte predominant Hodgkin lymphoma is clinically indolent but has a higher recurrence rate than CHL; consequently, many patients die from therapy-related complications rather than from lymphoma. (2) As a result, the approach to therapy has changed. Classical Hodgkin lymphoma is treated aggressively and NLPHL may be treated more conservatively, making accurate subclassification of Hodgkin lymphoma essential.

GROSS AND MICROSCOPIC FEATURES

On gross examination, the involved lymph node is typically nodular and firm with a homogeneous, pale appearance (Figure 1). Microscopically, on low magnification, the lymph node architecture is effaced by large, often interlocking nodules. A rim of normal compressed lymph node is often present (Figure 2, A through C). Unlike classical Hodgkin lymphoma, sclerosis between nodules is rare, but can occur in older lesions. The large nodules that are typically present may not be evident in the other less common histologic subtypes including occasional cases with smaller nodules, less circumscribed nodules, a serpiginous pattern, or older lesions that have been infiltrated by T cells. (3)

On higher magnification, the nodules in NLPHL are typically composed of small B lymphocytes and variable numbers of larger atypical cells. Admixed epithelioid histiocytes may be present. The large cells have lobulated nuclei (Figure 2, E) but may occasionally resemble classic Reed-Sternberg (R-S) cells. The neoplastic cells in NLPHL were historically known as lymphocytic and histiocytic (L&H) cells, since they were believed to be histiocytes, although they are now known to be B cells. Owing to the uncanny resemblance to a kernel of popped corn, they have also often been termed popcorn cells. More recently, the preferred terminology is lymphocyte-predominant cells or LP cells. (4)

IMMUNOPHENOTYPE

While the classic morphologic features are essential in diagnosing NLPHL, immunohistochemistry is very helpful in confirming the initial histopathologic impression. The most cost-effective panel of immunohistochemical stains includes CD3, CD20, CD15, CD30, and CD45. In the classic case, CD20 should highlight the large nodules on low magnification (Figure 2, C). This finding effectively excludes nodular sclerosis Hodgkin lymphoma. On higher magnification, CD20 and CD45 mark the LP cells (Figure 2, D). The LP cells are generally negative for CD30, although a small subset may be positive since CD30 is an activation marker. CD15 is not expressed on LP cells. CD3-positive T cells typically surround the LP cells, forming what are commonly referred to as T-cell rosettes (Figure 2, F).

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DIFFERENTIAL DIAGNOSIS

Follicular Hyperplasia With Progressive Transformation of Germinal Centers

Progressive transformation of germinal centers (PTGC) can mimic NLPHL clinically and histologically. It is a reactive phenomenon that is more common in children. While PTGC was once believed to be a precursor of NLPHL, many patients with PTGC show no evidence of NLPHL later in life. (5) However, PTGC may be present in the same lymph node as NLPHL; thus, liberal sampling is recommended to exclude malignancy in large lymph nodes containing PTGC. (6)

On low magnification, progressively transformed follicles are similar to NLPHL nodules in that they are composed of nonneoplastic mantle cells. However, interspersed hyperplastic follicles are typically present, which would be highly unusual in NLPHL (Figure 3). Occasionally, NLPHL can show admixed regressively transformed germinal centers, but this is a rare finding. In addition, on higher magnification, the nodules should not contain LP cells. In regards to immunohistochemical findings, PD-1 marks increased numbers of T cells in both the nodules and interfollicular areas in PTGC; however, T-cell rosettes should be absent. (7)

Follicular Lymphoma, Floral Variant

Nodular lymphocyte predominant Hodgkin lymphoma can also resemble an uncommon morphologic variant of follicular lymphoma. Occasionally, the neoplastic follicles in follicular lymphoma may be infiltrated by mantle cells causing a lysed appearance. The pattern resembles a flower; thus, this phenomenon has been termed the floral variant. (8) While this histologic pattern has no prognostic or therapeutic consequences, it may be difficult to recognize and mimics other processes. On low-power magnification, it may closely resemble NLPHL or PTGC (Figure 4). Importantly, LP cells should not be present. Immunostains are helpful, as the centrocytes and centroblasts of the neoplastic follicles in follicular lymphoma are typically CD10, BCL-6, and BCL-2 positive.

Lymphocyte-Rich Classical Hodgkin Lymphoma

Classical Hodgkin lymphoma includes the subtypes of nodular sclerosis (nodular sclerosis Hodgkin lymphoma), mixed cellularity, lymphocyte rich, and lymphocyte depleted. Of these subtypes, lymphocyte-rich classical Hodgkin lymphoma (LRCHL) is the most difficult subtype to differentiate from NLPHL and misclassification has frequently been found in retrospective studies. (9) This occurs because, unlike most subtypes of CHL, LRCHL contains a predominance of small B cells rather than small T cells. Histologically, important distinguishing features exist. In typical cases of LRCHL, the nodules contain germinal centers and the neoplastic R-S cells are found predominantly within the expanded mantle zones of the follicles (Figure 5, A). As mentioned previously, NLPHL typically does not show evidence of residual germinal centers. Whereas NLPHL often contains large nodules, LRCHL more commonly contains smaller, more irregular nodules, which may have a "moth-eaten" appearance (Figure 5, B). Reed-Sternberg cells in LRCHL can resemble LP cells morphologically. Of utmost importance in difficult cases is the immunophenotypic profile. Reed-Sternberg cells in LRCHL are positive for CD30 (Figure 5, D) and often express CD15 (Figure 5, C). CD20 can be expressed but is typically weaker and less uniform than CD30 expression. Additional immunostains can be added to distinguish CHL from NLPHL in more difficult cases (Table 1). The distinction is essential owing to therapeutic and prognostic differences.

T-Cell/Histiocyte-Rich Large B-Cell Lymphoma

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is an aggressive non-Hodgkin lymphoma with a male predominance. It typically presents with high-stage disease and systemic symptoms. As the treatment and prognosis of this lymphoma differ markedly from NLPHL, appropriate classification is essential.

Nodular lymphocyte predominant Hodgkin lymphoma may mimic THRLBCL in the subset of cases in which T cells rather than B cells predominate. This typically occurs in older lesions in which T cells have infiltrated the nodules of B cells and disrupted the nodular architecture. In excisional biopsies, these T-cell-rich areas often coexist with nodular areas and can be recognized and appropriately classified as NLPHL (Figure 6, A and B). This finding was previously termed nodular lymphocyte predominant Hodgkin lymphoma with diffuse areas; the current preferred term is nodular lymphocyte predominant Hodgkin lymphoma, THRLBCL-like. (4) This lesion should not be called THRLBCL as it has not been associated with aggressive clinical behavior. (10)

In small biopsies, including core biopsies, the distinction between NLPHL and THRLBCL can be treacherous. A small biopsy specimen of NLPHL in a diffuse area may show primarily an infiltrate of small T lymphocytes with occasional large cells. In NLPHL, CD20 marks large LP cells with variable numbers of admixed small B cells (Figure 6, C). A large number of background small B cells would be unusual in THRLBCL. CD21 may show wisps of residual follicular dendritic-cell meshwork, the remnants of the prior nodules of NLPHL (Figure 6, D). An expanded panel of immunostains, including analysis of the T-cell subsets, may be helpful in differentiating between THRLBCL and NLPHL (Table 2). (10) In general, since none of these features are absolutely definitive, diagnoses of THRLBCL on core biopsies may be ill advised. Whenever NLPHL is a strong consideration, an excisional biopsy is prudent.

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Transformation

In a small minority of patients, the course of disease is complicated by transformation to a large B-cell lymphoma. Studies with longer follow-up intervals show rates of transformation as high as 14%. (11) Previously, both THRLBCL and diffuse large B-cell lymphoma were possible morphologic subtypes of transformation. Currently, the diagnosis of THRLBCL in a patient with a history of NLPHL is discouraged, as the more likely diagnosis in this clinical scenario is NLPHL with THRLBCL-like areas. (4) Transformation to diffuse large Bcell lymphoma does occur but should only be diagnosed if sheets of large cells are present. Such patients tend to require more aggressive chemotherapy. The prognosis has been reported as superior to de novo or transformed diffuse large B-cell lymphoma in some studies (11,12); however, others have shown a comparable or worse prognosis. (13,14)

CONCLUSION

Nodular lymphocyte predominant Hodgkin lymphoma is an uncommon subtype of Hodgkin lymphoma with disparate clinical, histologic, and immunophenotypic features. As this entity is rare, diagnostic difficulty can arise. A careful review of the morphology, particularly the histologic appearance at low magnification, is of paramount importance. Immunohistochemical stains and clinical information can be of great assistance in confirming the initial histologic impression and appropriately classifying this type of Hodgkin lymphoma.

The author wishes to thank Bertram Schnitzer, MD, for his mentorship in this area of interest and for his helpful comments on this manuscript.

References

(1.) Khoury JD, Jones D, Yared MA, et al. Bone marrow involvement in patients with nodular lymphocyte predominant Hodgkin lymphoma. Am J Surg Pathol. 2004;28(4):489-495.

(2.) Biasoli I, Stamatoullas A, Meignin V, et al. Nodular lymphocyte-predominant Hodgkin lymphoma: a long-term study and analysis of transformation to diffuse large B-cell lymphoma in a cohort of 164 patients from the Adult Lymphoma Study Group. Cancer. 2010;116(3):631-639.

(3.) Fan Z, Natkunam Y, Bair E, Tibshirani R, Warnke RA. Characterization of variant patterns of nodular lymphocyte predominant Hodgkin lymphoma with immunohistologic and clinical correlation. Am J Surg Pathol. 2003;27(10):1346-1356.

(4.) Poppema S, Delsol G, Pileri SA, et al. Nodular lymphocyte predominant Hodgkin lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al, eds. Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:323325. World Health Organization Classification of Tumours; vol 2.

(5.) Hansmann ML, Fellbaum C, Hui PK, Moubayed P. Progressive transformation of germinal centers with and without association to Hodgkin's disease. Am J Clin Pathol. 1990;93(2):219-226.

(6.) Burns BF, Colby TV, Dorfman RF. Differential diagnostic features of nodular L & H Hodgkin's disease, including progressive transformation of germinal centers. Am J Surg Pathol. 1984;8(4):253-261.

(7.) Krishnan C, Warnke RA, Arber DA, Natkunam Y. PD-1 expression in T-cell lymphomas and reactive lymphoid entities: potential overlap in staining patterns between lymphoma and viral lymphadenitis. Am J Surg Pathol. 2010:34(2):178 189.

(8.) Osbourne BM, Butler JJ. Follicular lymphoma mimicking progressive transformation of germinal centers. Am J Clin Pathol. 1987;88(3):264-269.

(9.) Diehl V, Sextro M, Franklin J, et al. Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin's disease and lymphocyte-rich classical Hodgkin's disease: report from the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin's Disease. J Clin Oncol. 1999:17(3):776-783.

(10.) Boudova L, Torlakovic E, Delabie J, et al. Nodular lymphocyte predominant Hodgkin lymphoma with nodules resembling T-cell/histiocyte-rich B-cell lymphoma: differential diagnosis between nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histocyte-rich B-cell lymphoma. Blood. 2003;102(10):3753-3758.

(11.) Al-Mansour M, Connors JM, Gascoyne RD, Skinnider B, Savage KL. Tranformation to aggressive lymphoma in nodular lymphocyte-predominant Hodgkin's lymphoma. J Clin Oncol. 2010;28(5)793-799.

(12.) Hansmann ML, Stein H, Fellbaum C, Hui PK, Parwaresch MR, Lennert K. Nodular paragranuloma can transform into high-grade malignantl ymphoma of B type. Hum Pathol. 1989;20(12):1169-1175.

(13.) Huang JZ, Weisenburger DD, Vose JM, et al. Diffuse large B-cell lymphoma arising in nodular lymphocyte predominant Hodgkin lymphoma: a report of 21 cases from the Nebraska Lymphoma Study Group. Leuk Lymphoma. 2004;45(8):1551-1557.

(14.) Rueffer U, Josting A, Franklin J, et al. Non-Hodgkin's lymphoma after primary Hodgkin's disease in the German Hodgkin's Lymphoma Study Group: incidence, treatment and prognosis. J Clin Oncol. 2001;19(7):2026-2032.

Lauren B. Smith, MD

Accepted for publication May 24, 2010.

From the Department of Pathology, Hematopathology Division, University of Michigan, Ann Arbor.

The author has no relevant financial interest in the products or companies described in this article.

Presented at New Frontiers in Pathology: An Update for Practicing Pathologists, University of Michigan, Ann Arbor, October 10, 2009.

Reprints: Lauren B. Smith, MD, Department of Pathology, Hematopathology Division, University of Michigan, 1301 Catherine St, Ann Arbor, Mi 48109 (e-mail: lbsmith@umich.edu).
Table 1. A Panel of Immunostains Useful in
Differentiating Between Classical Hodgkin Lymphoma
(CHL) and Nodular Lymphocyte Predominant Hodgkin

Lymphoma (NLPHL)

 CHL NLPHL
EMA -
OCT-2 /+ +
BOB.1 /+ +
PU.1 - +
EBER +/ -
CD79a /+ +
BCL-2 + -
IgD - +/
IRF4 + -
Fascin + -

Abbreviations: EBER, in situ hybridization for Epstein-Barr virus;EMA,
epithelial membrane antigen; IgD, immunoglobulin D; +, positive; -,
negative; +/-, usually positive, may be negative; -/+, usually negative,
may be positive.

Table 2. Immunostains Useful in Differentiating
T-Cell/Histiocyte-Rich Large B-Cell Lymphoma
(THRLBCL) From Nodular Lymphocyte Predominant
Hodgkin Lymphoma (NLPHL), THRLBCL-like

 THRLBCL NLPHL

PU.1+ large B cells - +
BCL-2+ large B cells + -
PD1+ T cells - +
CD4/[CD57.sup.+] T cells - +
[CD8.sup.+] T cells + -
Numerous small B cells - +
[CD21.sup.+] dendritic cell meshwork - +

Abbreviations: +, positive; -, negative.
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Author:Smith, Lauren B.
Publication:Archives of Pathology & Laboratory Medicine
Date:Oct 1, 2010
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