A 26-year-old man presents with a six-month history of unintentional weight loss, persistent fever, and night sweats. Upon physical examination, splenomegaly without lymphadenopathy is noted. A subsequent positron emission tomography-computed tomography (PET-CT) demonstrates a solitary splenic mass measuring 12.0 cm in greatest diameter, with no extrasplenic extension or involvement. A splenectomy is performed. Macroscopically, the mass is gray-white and firm. The patient remains disease free 12 months after the splenectomy. On H&E sections, there are scattered cells with large nucleoli that are CD30, CD15, MUM1, PAX5, and EBER positive, but are negative for CD45rb and cytokeratin AE1/3.

Master List of Diagnoses

  • ALK(+) anaplastic large cell lymphoma
  • Classical Hodgkin lymphoma, mixed cellularity subtype
  • Hepatosplenic T-cell lymphoma
  • Metastatic carcinoma
  • Peripheral T-cell lymphoma, not otherwise specified
  • Splenic diffuse red pulp small B-cell lymphoma
  • T-cell/histiocyte-rich large B-cell lymphoma
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This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2017, Case 23, and is Classical Hodgkin lymphoma, mixed cellularity subtype of the spleen.

Criteria for Diagnosis and Comments

Sections demonstrate the spleen with an intact capsule seen on some of the slides. The white pulp is involved by several nodules showing an atypical hematopoietic infiltrate. Some of the nodules consist of clusters of small lymphocytes, but other nodules have a more mixed hematopoietic infiltrate with scattered large atypical cells. On some of the slides, a subset of the large atypical cells are binucleate with prominent nucleoli consistent with Reed-Sternberg cells. Some of the large atypical cells are mononucleate with vesicular chromatin and one or more distinct nucleoli. The mixed background infiltrate shows many small lymphocytes; scattered histiocytes; and rare neutrophils, eosinophils, and plasma cells. The white pulp is mostly unremarkable and no extramedullary hematopoiesis is identified. These morphologic findings, in conjunction with the phenotype described as large atypical cells positive for CD30, CD15, MUM1, PAX5, and EBER, are interpreted as classical Hodgkin lymphoma (CHL). There are wisps of fibrosis but there are no large bands of fibrosis compartmentalizing hematopoietic areas as would be seen in nodular sclerosis classical Hodgkin lymphoma (NSCHL). Given the lack of compartmentalizing fibrosis and the mixed background infiltrate, this is considered the (MCCHL). 

Hodgkin lymphoma represents approximately 10% of all lymphoma seen in the United States. Most of these patients present with early stage disease and demonstrate a bimodal incidence in young adults and patients greater than 55 years of age. The 2017 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues categorizes Hodgkin lymphoma into nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and CHL. The characteristic cell of CHL is the Reed-Sternberg cell, a large, polynucleated cell with one or more prominent nucleoli. Mononuclear variants of Reed-Sternberg cells are predominant in this case and include Hodgkin cells and lacunar cells, which are often seen in NSCHL. In lacunar cells, retraction of the cytoplasm gives the appearance of the cells sitting in a lacuna, hence the name.

MCCHL comprises approximately 20% - 25% of CHL. Histologically, there are scattered Reed-Sternberg cells within a diffuse or vaguely nodular mixed inflammatory background without the thick collagen bands typical of NSCHL. Like all CHL subtypes, the malignant cells of MCCHL are strongly positive with CD30 by immunohistochemical stains with a membranous and Golgi staining pattern. CD15 is sometimes, but not always, positive. CD20 can be detected in up to 30% - 40% of CHL, but is often weakly expressed. PAX5 and MUM1 are also usually positive. OCT2, BOB.1, and CD45 are usually negative, unlike the cells of NLPHL. Epstein-Barr latent membrane protein is present in approximately 75% of cases and is more frequent than in NSCHL and lymphocyte-rich CHL.  

Most patients with CHL present with supra-diaphragmatic lymphadenopathy, with or without constitutional symptoms. CHL usually spreads contiguously within the lymphatic network, with late extension to adjacent and distant viscera. The standard staging system for Hodgkin lymphoma was proposed at the Ann Arbor Conference in 1971 and modified at the Cotswold Meeting in 1988. This modified Ann Arbor staging system is based on the location and extent of lymphadenopathy, extranodal disease, and constitutional symptoms. This staging system also suggests prognostic information. Stage I is involvement of one lymph node group. Stage II is involvement of two or more lymph node groups on the same side of the diaphragm. Stage III is involvement of lymph nodes on both sides of the diaphragm and/or spleen involvement. Stage IV is involvement of one or more nonsplenic organs. Hodgkin lymphoma is further categorized based on the patient’s symptoms. Category A patients have no constitutional symptoms, whereas Category B patients have constitutional symptoms.

While mediastinal involvement is often present in CHL, splenic involvement is seen in a minority of cases and is usually simultaneous with hepatic involvement. Splenic involvement may be characterized by homogenous splenomegaly, diffuse infiltration with miliary lesions, focal nodular lesions, or a large solitary mass. In one large study by Colby et al, 358 patients with NSCHL underwent staging laparotomies with splenectomies. In the study, 122 of 358 cases (34%) showed at least microscopic focus of disease involvement. The average spleen weight was 195 g, but ranged from 40-2000 grams. Primary splenic Hodgkin lymphoma is an even rarer entity, with only nine cases reported. Patients with primary splenic Hodgkin lymphoma confined to the spleen appear to be cured after simple splenectomy.

Patients are treated according to prognostic risk factors. Patients are divided into early-stage (stages I and II) or advanced (stages III and IV) Hodgkin lymphoma. The early-stage group is further subdivided into the two categories of “favorable” and “unfavorable.” One or more of the following unfavorable prognostic features is needed to shift the category of “favorable” to that of “unfavorable” in the early stage: bulky mediastinal mass, equal to or greater than 50 years of age, erythrocyte sedimentation rate (ESR) equal to or greater than 50 without B symptoms or equal to or greater than 30 with B symptoms, and/or nodal areas equal to or greater than 4. Bulky disease is defined as a single nodal mass of 10.0 cm or greater than one-third of the transthoracic diameter at any level of the thoracic vertebrae as determined by computed tomography (CT). The International Prognostic Factors Project on Advanced Hodgkin’s Disease identifies seven variables for patients with advanced disease (equal to or greater than 45 years of age, male sex, stage IV, serum albumin less than 4 mg/dL, hemoglobin less than 10.5 mg/dL, white blood cell count equal to or greater than 15000 x/L, and lymphocytes count less than 600 x/L).  Advances in treatment have substantially decreased the mortality of Hodgkin lymphoma. The prognosis for patients with Hodgkin lymphoma has been steadily increasing over the last 40 years. In the 1970s the five-year relative survival rate was 72%. This has steadily increased to 88% from 2005-2011.

The differential diagnosis of MCCHL would include other CD30(+) neoplasms such as ALK(+) anaplastic large cell lymphoma (ALCL) and other lymphomas which may involve the spleen such as and splenic diffuse red pulp small B-cell lymphoma, hepatosplenic T-cell lymphoma (HSTCL), THRLBCL, peripheral T-cell lymphoma (PTCL), not otherwise specified, and metastatic carcinoma.

ALK(+)ALCL is a CD30(+) lymphoma of T- or null cell lineage with chromosomal abnormalities involving the ALK gene at 2p23. The tumor cells are typically seen in sheets and clusters unlike the scattered tumor cells of CHL. ALK gene mutations are not typically detected in CHL. The immunophenotype can distinguish CHL from ALCL, since PAX5, CD20, CD15, MUM1, and EBER are not frequently positive in ALCL and CD45rb is positive in ALCL.

Although splenic diffuse red pulp small B-cell lymphoma (SDRPSBCL) is a B-cell lymphoma like CHL, its histology differs. SDRPSBCL is a mature B-cell neoplasm that involves peripheral blood, bone marrow, and spleen. The patients often present with massive splenomegaly and stage IV Hodgkin lymphoma, although the disease is clinically indolent. Histologically, large atypical cells and Reed-Sternberg cells are not typically identified. Instead, the B-cells are monomorphic, round, small to intermediate-sized lymphocytes that diffusely infiltrate red pulp cords and sinuses and efface white pulp. Blood and bone marrow smears show lymphocytes with small cytoplasmic projections that are broad based and unevenly distributed around the cells. The B-cells are CD45rb positive unlike CHL and CD30, CD15, and EBER would not typically be positive.

HSTCL would also need to be distinguished from CHL. HSTCL has a fairly unique anatomic distribution since it is typically located in the spleen, liver, and bone marrow, and usually in the sinusoids of each organ. This distribution would not be expected in CHL. The phenotype would also differ as HSTCL is a T-cell lymphoma—CD3(+), CD4(-)/CD8(-/+), CD56(+), TCR-γδ(+)—unlike CHL. Molecular changes including T-cell receptor gene rearrangement and isochromosome 7q would also not be expected in CHL.

THRLBCL may be very difficult to differentiate from CHL. Like CHL, THRLBCL shows scattered large malignant cells. These large atypical cells often do not have a Reed-Sternberg-like appearance and the background infiltrate lacks acute inflammation such as eosinophils or neutrophils. The phenotype differs since the tumor cells are usually CD45/LCA(+), but CD15(-). Also, there are a larger number of cytotoxic T cells than in CHL. Flow cytometry or molecular studies may show monoclonal B-cells or IGH gene rearrangements.

PTCL, like CHL, can have highly atypical large cells with Reed-Sternberg-like features in a mixed inflammatory background. However, the phenotype of PTCL differs. The large cells express T-cell antigens such as CD3 and are CD45/LCA(+), but they are CD15(-). Furthermore, flow cytometry often shows aberrant T-cell immunophenotype and TRB and TRG gene rearrangement studies will show evidence of T-cell clonality.

Metastatic carcinoma is excluded in this case, as the tumor cells are negative for cytokeratin AE1/3, and express Hodgkin markers, CD30, CD15, MUM1, PAX5, and EBER.

  1. A 67-year-old patient presents with classical Hodgkin’s lymphoma (CHL) of the spleen. Which of the following would be expected in this entity?

    1. CHL does not involve the spleen.
    2. Hodgkin lymphoma represents approximately 50% of all lymphoma seen in the United States.
    3. Primary splenic lymphoma is more common than splenic lymphoma which is secondarily involving the spleen.
    4. Splenic involvement is seen in the majority of cases of patients with CHL.
    5. The liver is often involved if the spleen is involved.
  2. A man presents with fevers, night sweats, and weight loss. An excisional biopsy demonstrates nodular sclerosis classical Hodgkin lymphoma. Subsequently, a staging PET-CT demonstrates involvement of two supradiaphragmatic right-sided lymph nodes and spleen. What is his stage?

    1. IA
    2. IIB
    3. IIIA
    4. IIIB
    5. IVB
  3. Which of the following panels of immunohistochemical stains is most consistent with CHL?

    1. CD15-, CD20-, CD30-, CD45-, BOB1-
    2. CD15-, CD20+, CD30-, CD45+, BOB1+
    3. CD15+, CD20-, CD30+, CD45-, BOB1-
    4. CD15+, CD20-, CD30+, CD45-, BOB1+
    5. CD15+, CD20-, CD30+, CD45+, BOB1-

References

  1. Ansell SM. Hodgkin Lymphoma: Diagnosis and Treatment. Mayo Clin Proc. 2015;90(11):1574-1583.
  2. Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the Committee on Hodgkin’s Disease Staging Classification. Canc Res. 1971;31(11):1860-1861.
  3. Colby TV, Hoppe RT, Warnke RA. Hodgkin’s disease: a clinicopathologic study of 659 cases. Cancer. 1982:49(9):1848-1858.
  4. Cosset JM, Henry-Amar M, Meerwaldt JH, et al. The EORTC trials for limited stage Hodgkin’s disease. The EORTC Lymphoma Cooperative Group. Eur J Cancer. 1992;28A(11):1847-1850.
  5. Gobbi PG, Ferreri AJ, Ponzoni M, Levis A. Hodgkin lymphoma. Crit Rev Oncol Hematol. 2013;85(2):216-237.
  6. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med. 1998;339(21):1506-1514.
  7. Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds Meeting. J Clin Oncol. 1989;7(11):1630-1636.
  8. Martinazzi M, Palatini M. A casual finding of primary splenic Hodgkin’s disease in a case of traumatic rupture of the spleen. Tumori. 1978;64(6):639-643.
  9. Parekh V, Peker D. EBV-related primary splenic lymphocyte-depleted classical Hodgkin lymphoma. J Clin Pathol. 2015;68(11):947-950.
  10. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30.
  11. Swerdlow SH, Campo E, Pileri SA, et al. World Health Organization Classification of Tumours of Hematopoietic and Lymphoid Tissue, Revised 4th ed; IARC Press, 2017.
  12. Zellers RA, Thibodeau, SN, Banks PM. Primary splenic lymphocyte-depletion Hodgkin’s disease. Am J Clin Pathol. 1990;94(4):453-457.

Authors

Emily Heckendorn, DO
Pathology Resident
Walter Reed National Medical Military Center
Bethesda, MD

Aaron Auerbach, MD, MPH
Staff Hematopathologist
Joint Pathology Center
Silver Spring, MD


Answer Key

  1. The liver is often involved if the spleen is involved. (e)
  2. IIIB (d)
  3. CD15+, CD20-, CD30+, CD45-, BOB1- (c)