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Case Presentation - Summer, 2015

Hodgkin's Lymphoma

Written by: Marianna Zhorova, student, Cleveland Clinic School of Cytotechnology, Cleveland, Ohio

Patient Age: Male, age 45

Patient History: History of Stage II nodular sclerosing Hodgkin’s disease diagnosed 10 years prior, status post chemotherapy and radiation therapy. The patient had complications of osteonecrosis of the sternum. Recurrence to left axillary lymph node 6 years ago, status post autologous stem cell transplant. The patient presented 4 years ago with a 3.2 cm right axillary node. Biopsy of the node was consistent with recurrent Hodgkin’s disease, nodular sclerosing type. Immunohistochemistry in the Reed Sternberg cells showed CD30+, Fascin +, CD20 -. Flow cytometry was negative.

Specimen type: FNA of the Right Axillary Lymph Node, ThinPrep® Non-Gyn cytology

Cytologic Diagnosis: Positive for malignant cells, consistent with Hodgkin’s Lymphoma

Case provided by: Milstead Pathology, Conyers, Georgia

Hodgkin’s Lymphoma

Hodgkin Lymphoma (HL) is a malignant disorder of lymphoreticular origin, characterized histologically by the presence of predominantly binucleated giant cells (Reed-Sternberg cells) usually originating from B lymphocytes in the germinal centers of lymphoid tissue. It was first microscopically described by Thomas Hodgkin in 1832. In 1898 and 1902, Carl Sternberg and Dorothy Reed independently described the cells.

HL is rare, comprising less than 1 % of all de novo neoplasms occurring every year worldwide and representing approximately 30 % of all lymphomas. In the United States, there are 7000-7500 new cases diagnosed and about 1410 deaths annually5. According to the WHO 2008 classification, there are two histological types: the “classic” Hodgkin Lymphoma (cHL), which comprises 95% of all cases, with the remaining 5% of cases being nodular lymphocyte predominant Hodgkin Lymphoma (NLPHL) type. The “classic” type includes four subtypes: nodular sclerosis (the most common, with 75%-80%), mixed cellularity, lymphocyte-depletion, and lymphocyte-rich. In developed world countries, the most common variant is nodular sclerosis, but in developing nations, the most common is mixed cellularity. In industrialized countries cHL has a bimodal curve in age-incidence with one peak at 15 to 35 years and the second peak with advancing age. In developing countries, there is a third peak in childhood.

Etiology:
HL has a strong association with Epstein-Barr virus (EBV).The EBV genome has been detected in 1/3 to 1/2 of patients with HL. It is expressed as latent membrane proteins (LMP-1 and LMP-2), EBV encoded RNAs, or as an EBV nuclear antigen-1 (EBNA). It is also well-established that HIV infections elevate the risk of HL due to deregulated immunity. Data collected from large linkages of US population-based AIDS and cancer registries shows that the risk of HL in HIV-infected populations is estimated at 11.5-fold higher than in the general population.4

Genetic factors are also an important cause of HL. HLA-A*01 (Human Leukocyte Antigen) is one of these factors.5 Supporting the genetic importance is a known fact that first-degree relatives of patients with HL have about a threefold increased risk.

Some autoimmune diseases and chronic inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, sarcoidosis and inflammatory bowel disease, may also increase the risk of HL. A large Scandinavian database linking disease registries showed that the risk of HL was increased two-fold for systematic autoimmune disease overall.4

Several occupational exposures have been associated with HL such as wood, herbicides, tobacco, and other chemicals. It has been reported that there is a near doubling of HL risk with cigarette smoking. Tobacco may impact HL pathogenesis through its associated immunosuppression especially by permitting reactivation of latent EBV infection. Moreover, in the medical literature, a connection of HL with tonsillectomy and tuberculosis has been mentioned.5

Clinical Features:
Most patients with cHL are males with superficial lymph node enlargement (lymphadenopathy). There are often no associated symptoms in these patients. The lymph node enlargement is usually painless, rubbery, and discrete. The most common location is the neck (75%) and supraclavicular areas. Routine chest x-ray can show enlargement of mediastinal and para-aortic lymph nodes. Sub-diaphragmatic lymphadenopathy is less common, and involved abdominal lymph nodes can be seen in older patients. Bone marrow, liver, and spleen can be involved, too. Interestingly, the number of nodules of splenic involvement can have prognostic significance for recurrence following initial treatment (more than 5 nodules in spleen associated with high risk for recurrence of HL).8 In addition, sarcoid- type granulomas can be encountered in any tissue sample obtained from patients with Hodgkin lymphoma. Fever, night sweats, weight loss, and pruritus are systemic symptoms of advanced or aggressive HL. Moderate amounts of alcohol can trigger pain in one of the anatomic deep sites involved by the disease. Other clinical presentations such as superior vena cava syndrome, acute spinal cord compression, CNS solitary lesions, testicular masses, Waldeyer’s ring involvement, and intestinal occlusion can be seen less commonly.

The nodular lymphocyte predominant Hodgkin Lymphoma (NLPHL) presents with more localized peripheral adenopathy with slow progression that may transform to diffuse large B-cell or other aggressive lymphomas.

Treatment and Prognosis:
HL is a highly curable malignancy. The 5-year survival rate among early-stage HL patients with favorable clinical prognostic indicators is 95%. A combination of polychemotherapy (Adriamycin, Bleomycin, Vinblastine, Dacarbazine) and immunotherapy (monoclonal antibodies) followed by involved-field irradiation is the standard treatment. Treatment is based on the stage of HL, the sub-type of tumor, and the overall health and age of the patient. One of the new approaches in the treatment of lymphomas is targeted therapy such as anti-CD30 (Brentuximab), a new drug for neoplasms that express this marker, including HL.

The adverse prognostic factors are age over 45 years old, male sex, stage IV, serum albumin < 4mgldL, hemoglobin < 10.5 mg/dL, white blood cell count > 15000 x/L, lymphocyte count< 600 x/L and an association with a reduction in 7-8% tumor control at five years.

Cytology:
The hallmark of the “classic” Hodgkin Lymphoma (cHL) is the presence of large mononuclear Hodgkin cells (H) or binucleated or multinucleated Reed-Sternberg cells (RS) cells which have prominent basophilic nucleoli and moderately abundant cytoplasm. Together, they are referred to as HRS cells. They are scattered amongst the background of small lymphocytes, mixed with other inflammatory cells, including eosinophils. In the backgrounds of nodular sclerosis and lymphocyte-depletion types, there is necrotic cellular debris, whereas, in lymphocyte-rich types, there are mostly small lymphocytes and very rarely R-S cells.

The nodular lymphocyte predominant Hodgkin Lymphoma (NLPHL is characterized by lymphocytic and/or histiocytic “L&H” R-S cell variants. They are known as “popcorn” cells, since they usually have one multilobated or extremely folded (like popcorn), big, irregular nucleus with vesicular chromatin. The cytoplasm is scant, and the nucleoli are multiple and basophilic but smaller than the nucleoli in cHL. The background cells are predominantly small lymphocytes, with an absence of neutrophils and eosinophils when compared with cHL.

Differential Diagnosis:
The differential diagnosis of HL includes reactive lymphoid hyperplasia, melanoma, infectious mononucleosis, T-cell rich large B-cell lymphoma (TCRLBL), anaplastic large cell lymphoma (ALCL), acute lymphadenitis, and nasopharyngeal carcinoma (NPC).

The key features for the diagnosis of cHL are a polymorphous background inflammation with CD 15+,CD 30+, CD 45-,ALK 1- HRS cells. The key features for NLPHL are CD 20+, CD 45+, L&H cells, CD 15-, and CD 30±. The following is a more detailed list of helpful criteria to distinguish cHL and NLPHL from the most common possible differential diagnoses.

  • Reactive lymphoid hyperplasia is also known as a chronic lymphadenitis is found in numerous conditions including autoimmune diseases, viral, TB, fungal infections, and post vaccination. Clinically, it presents as lymph node enlargement. In general, aspirates are cellular with cells of marked size variability and a predominant population of small lymphocytes. It can mimic HL because of the polymorphous pattern of cells, but the finding of L&H cells, R-S cells, or a specific immunophenotype is useful for the diagnosis of HL.
  • Infectious mononucleosis is a self–limited disease associated with Epstein-Barr virus. It affects young people and manifests as fever, pharyngitis, rash, and cervical adenopathy. The axillary and inguinal lymph nodes can be involved. This presentation can be confirmed by the heterophil antibody Monospot test. However, if patients have an unusual presentation of the disease, such as lymphadenopathy without associated symptoms, the diagnosis can be made using aspirations of lymph nodes. Aspirates contain a polymorphous population of lymphocytes, including binucleated immunoblasts. Immunoblasts can resemble RS cells, however they are smaller. Moreover, a spectrum of lymphoid proliferation is not characteristic of lymphoma. Clinical correlation, serological testing, and IHC wiil help to make the right diagnosis.
  • T-cell rich large B-cell lymphoma presents clinically as a rapidly enlarging neck or retroperitoneal mass. Cytologic features of this lymphoma are predominantly large cells (2.5 to 5 times the size of lymphocytes), irregular nuclei with protrusions, lymphoglandular bodies, and variable numbers of tingible-body macrophages. It mimics HL in the abundance of small lymphocytes. IHC helps with the differentiation. TCRLBL neoplastic cells are CD20+, CD30-, and CD15-, which excludes cHL. Cytologic differentiation from NLPHL is impossible and requires nodal excision with histologic examination.
  • Patients with anaplastic large cell lymphoma may not only have nodal disease but also cutaneous involvement with aspirates containing large cells with pleomorphic, hyperchromatic nuclei and abundant cytoplasm. Nuclei usually lack the inclusion-like micro-nucleoli. The amount of malignant cells in smears of ALCL is greater HL. IHC is helpful because EMA is positive in ALCL (HL, EMA-). Also, ALCL cells are CD 15- and BSAP -, unlike cHL. Gene rearrangement can be useful.
  • Acute lymphadenitis clinically appears as a red, hot, tender area. It is most commonly caused by bacteria. Early in this process, lymph node aspirates contain an admixture of neutrophils and lymphocytes. Later, aspirates contain a purulent material comprised of neutrophils and cell debris. Ultimately, there are neutrophils, plasma cells, and large macrophages containing fragments of phagocytized material, known as tingible-body macrophages. Acute lymphadenitis does not have any R-S cells.
  • Nasopharyngeal carcinoma is a common tumor in Asians, especially men. Cervical lymphadenopathy may be the first manifestation. The undifferentiated lymphoepitelioma subtype can mimic lymphoma. Aspirates show epithelial tumor cells arranged in dense clusters or single cells with hyperchromatic, spindle shaped nuclei with irregular nuclear borders and prominent nucleoli. There are variable numbers of lymphocytes in the background. Metastatic nasopharyngeal carcinoma will be positive for keratin immunostains, a feature not characteristics of HL.
  • Lymph node aspirates of patients with malignant melanoma can be similar to lymphoma because of the dispersed cell population. Melanoma cells have pleomorphic shapes with eccentric nuclei, and are occasionally binucleated. Intranuclear cytoplasmic inclusions are often observed. The presence of melanin pigment is a helpful feature but not always seen. IHC reveals the neoplastic cells to be S-100+, HMB45+, MelanA+, MART-1+.

References:

  1. Gobbi PG, Ferreri AJ et al. Hodgkin Lymphoma .Oncology/Hematology February 2013Volume 85, Issue 2, Pages 216–237 http://www.croh-online.com/article/S1040-8428(12)00138-2/fulltext
  2. Cibas ES, Ducatman BS. Cytology: Diagnostic Principles and Clinical Correlation4 ed.Philadelphia, PA: Elsevier Saunders 2014pgs.184, 348,369
  3. Bibbo M., Wilbur DC. Comprehensive Cytopathology 4 ed. London, New York, Oxford,Philadelphia: Elsevier Saunders 2015pgs. 559-576
  4. Hodgkin lymphoma [electronic resource] : a comprehensive update on diagnostics and clinics /Andreas Engert, Sandra J. Horning, editors Publish Info Heidelberg ; New York : Springer-Verlag, c2011
  5. Hoppe RT, Mauch PT, Armitage JO, Volker Diehl, Weiss LM.Hodgkin lymphoma 2 ed., Philadelphia, PA: Lippincott Williams & Wilkins 2007 pgs.7, 12, 19,205
  6. Zhang X, Aguilera N. New immunohistochemistry for B-Cell Lymphoma and Hodgkin Lymphoma. Archives of Pathology & Laboratory Medicine: December 2014, Vol. 138 No. 12, pp.1666-1672
  7. KossLeonard, Melamed M R. Koss’ Diagnostic cytology and its histopathologic bases, Volume II, 5 ed., Philadelphia, PA: Lippincott Williams & Wilkins 2006 pgs. 1189, 1215-1217
  8. Greer JP, Daniel AA et al.Wintrobe’s Clinical Hematology 13 ed., Philadelphia, PA: Lippincott Williams & Wilkins 2013 pgs. 1793-1798