Hodgkin Lymphoma Involving Waldeyer Ring A Clinicopathologic Study of 22 Cases

Transcription

1 Hematopathology / HODGKIN LYMPHOMA INVOLVING WALDEYER RING Hodgkin Lymphoma Involving Waldeyer Ring A Clinicopathologic Study of 22 Cases Maria del Pilar Quiñones-Avila, MD, Abel A. Gonzalez-Longoria, MD, Joan H. Admirand, MD, and L. Jeffrey Medeiros, MD Key Words: Hodgkin lymphoma; Waldeyer ring; Epstein-Barr virus Abstract We report 22 cases of Hodgkin lymphoma involving Waldeyer ring seen at our institution during a 31-year interval. There were 16 males (73%) and 6 females (27%) with a median age of 48 years (range, 5-81 years), and 15 (68%) patients had airway obstruction or tonsillar enlargement. For 19 patients, the clinical stage was as follows: I, 7 (32%); II, 11 (50%); and III, 1 (5%). The 3 patients (14%) whose disease was unstaged had concurrent or a history of non-hodgkin lymphoma. Histologically, the neoplasms were classified as follows: lymphocyte-rich classical, 8 (36%); nodular sclerosis, 7 (32%); mixed cellularity, 4 (18%); unclassified, 2 (9%); and lymphocyte depletion, 1 (5%). Of 7 stage I cases, 4 (57%) were the lymphocyte-rich classical type. Reed-Sternberg and Hodgkin cells were positive for CD15 and CD30 in 20 cases assessed. Epstein-Barr virus latent membrane protein type 1 was positive in 12 (67%) of 18 cases assessed. We conclude that Hodgkin lymphoma rarely involves Waldeyer ring, with the lymphocyte-rich classical type being common at this location. The term Waldeyer ring is used to encompass the lymphoid tissues of the faucial tonsils, nasopharynx, base of tongue, and oropharynx and, as defined by others, is an extranodal but not an extralymphatic site. 1 Waldeyer ring may be involved by a variety of neoplasms, and carcinomas, most often metastatic from nearby head and neck sites, are most common. Lymphomas involve Waldeyer ring much less often, 2 and most of these tumors are non-hodgkin lymphomas (NHLs). In published studies, approximately 90% of all lymphomas involving Waldeyer ring are types of NHL, 3 mostly extranodal natural killer/t-cell lymphoma of nasal type and diffuse large B-cell lymphoma, 4-6 with a lesser number of other types, including extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, mantle cell lymphoma, and peripheral T-cell lymphoma. Hodgkin lymphoma (HL) represents approximately 4% of all lymphomas of the head and neck, 7 and most of these neoplasms involve lymph nodes. Extranodal involvement by HL, including Waldeyer ring, is rare. 4,5 Previous studies of patients with HL have reported a low frequency of involvement of Waldeyer ring. For example, Todd and Michaels 8 reported a frequency of 1% for involvement of the nasopharynx and 1.5% for tonsil and oropharynx. Similarly, Kaplan and colleagues 9 reported that 5 (1.8%) of 285 consecutive patients with HL had involvement of Waldeyer ring. As a result, most previously published series of HL involving Waldeyer ring have been small groups of patients or case reports. In addition, most of the larger and better studies were performed before the advent of immunohistochemical analysis and, therefore, lack confirmatory immunophenotypic data. Most of these studies also used older lymphoma classification systems based on morphologic findings, without ancillary data. A study of a series of cases of HL involving Waldeyer ring, classified according Downloaded from Am J Clin Pathol 2005;123:

2 Quiñones-Avila et al / HODGKIN LYMPHOMA INVOLVING WALDEYER RING to the currently used World Health Organization (WHO) classification system, has not been published to date. We describe 22 cases of HL involving Waldeyer ring, including 7 stage I cases, classified according to the WHO classification. Carpinteria, CA, except CD15, which was purchased from BD Biosciences, San Jose, CA. All cases were classified using the criteria of the WHO classification system. 12 Although similar to earlier classifications of HL, the lymphocyte-rich classical type of HL now is recognized as an entity in the WHO classification. Materials and Methods We identified 22 cases of HL involving Waldeyer ring in the files of the Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, from January 1973 to December Eleven cases were treated at this institution and 11 cases were reviewed in consultation. Clinical information was obtained from data submitted at the time of consultation and the medical record. Clinical stage was determined using the Ann-Arbor staging system. We reviewed H&E-stained tissue sections of each case. We also reviewed all immunostains available, performed at the submitting institution or in our laboratory in the past. Immunohistochemical stains also were performed as part of this study, using fixed, paraffin-embedded tissue sections and an avidin-biotin complex method as previously described. 10,11 The panel of monoclonal antibodies used included reagents specific for CD15 (Leu M1), CD20 (L-26), CD30 (Ber H2), CD45 (LCA), CD45RO (UCHL-1), Epstein-Barr virus (EBV) latent membrane protein type 1 (LMP-1; CS1-4), and polyclonal CD3. Antibody dilutions varied during the interval of the study. All antibodies were obtained from DAKO, Results Clinical Findings Clinical data are summarized in Table 1. There were 16 males (73%) and 6 females (27%) with a median age of 48 years (range, 5-81 years). Only 1 patient (5%) was a child. Six patients (27%) were at least 60 years old. The disease was localized (stage I) to Waldeyer ring in 7 cases (32%), involved Waldeyer ring and cervical lymph nodes (stage II) in 11 cases (50%), and was associated with abdominal lymphadenopathy and spleen involvement (stage III) in 1 case (5%). Three patients had a history of NHL, and their disease was not staged. In this subgroup, 1 patient had follicular lymphoma with bone marrow involvement diagnosed in 1989 and was treated with chemotherapy and autologous bone marrow transplantation. The patient experienced a relapse in 1992 with bone marrow involvement by follicular lymphoma but was in clinical remission when HL developed in 1993 with involvement of the mediastinum and liver. Despite chemotherapy, HL involving the bone marrow and then tonsil developed in Two patients had chronic lymphocytic leukemia/small lymphocytic Table 1 Clinical Features in 22 Cases of Hodgkin Lymphoma in Waldeyer Ring Case No./Sex/ History of Age (y) Biopsy Site Symptoms and/or Signs Clinical Stage Lymphoma 1/M/45 Nasopharynx and LN Right-sided neck mass II 2/M/45 Nasopharynx and LN Nasal stuffiness II 3/F/47 Nasopharynx Nasopharyngeal mass I 4/M/49 Tonsil Tonsil enlargement II 5/M/39 Tonsil, cervical and celiac LNs, spleen Tonsil enlargement III 6/F/71 Nasopharynx Nasopharyngeal mass II 7/M/81 Tonsil Tonsil enlargement I 8/F/32 Adenoid and LN Right-sided neck mass II 9/M/69 Nasopharynx and LN Cervical adenopathy II 10/M/37 Adenoid Nasal congestion; LN enlargement II 11/M/32 Tonsil Throat pain I 12/M/53 Tonsil and LN Tonsil enlargement II 13/M/53 Nasopharynx Nasopharyngeal mass I 14/M/24 Nasopharynx Mass in sinuses (HIV+) I 15/M/57 Nasopharynx Nasopharyngeal mass I 16/F/67 Nasopharynx and LN Nasopharyngeal mass; LN enlarged II 17/M/5 Nasopharynx and LN Difficulty breathing II 18/M/41 Adenoids Obstructed airway I 19/M/48 Adenoids and cervical LN Nasal stuffiness II 20/F/57 Mediastinum and LN Mediastinal mass; painful throat + 21/M/70 Tongue and LN Exophytic lesion, base of tongue + 22/F/80 Palate, buccal gingiva Pain in the mouth; ulcers + LN, lymph node; +, positive;, negative. 652 Am J Clin Pathol 2005;123: Downloaded 652 from

3 Hematopathology / ORIGINAL ARTICLE lymphoma (CLL/SLL). One patient had fatigue and tenderness and pain in the mouth related to ulcers. Biopsies of the palate and buccal gingiva showed classical HL, and the patient underwent bone marrow aspiration and biopsy for staging. The bone marrow and flow cytometric immunophenotypic studies showed involvement by CLL/SLL without HL. The other patient had a 5-year history of CLL/SLL that was treated with chemotherapy. The patient was in clinical remission when an exophytic lesion at the base of the tongue and bilateral enlarged cervical lymph nodes developed. A biopsy of the tongue revealed classical HL and CLL/SLL Image 1E. Pathologic and Immunohistochemical Findings Pathologic and immunohistochemical data are summarized in Table 2. According to the WHO classification criteria, all 22 cases were classified as classical HL and 20 cases were further classified as follows: lymphocyte-rich classical Image 1A and Image 1B, 8 (36%); nodular sclerosis Image 1C, 7 (32%); mixed cellularity, 4 (18%); and lymphocyte depletion, 1 (5%). The remaining 2 cases (9%) arose in patients with CLL/SLL (Image 1E) and therefore were not further classifiable. The 7 stage I cases were classified as follows: lymphocyte-rich classical, 4 (57%); mixed cellularity, nodular sclerosis, and lymphocyte depletion, 1 (14%) each. In 20 cases, immunohistochemical studies were performed. (These studies were not performed in 2 cases of nodular sclerosis.) In all cases, the Reed-Sternberg and mononuclear variant cells were positive for CD15 and CD30 Image 1D. EBV LMP-1 was positive in 12 (67%) of 18 cases assessed, and CD20 was variably positive in 5 (28%) of 18 cases assessed. The neoplastic cells were negative for CD45 (n = 14), CD3 (n = 13), and CD45RO (n = 3) in all cases assessed. The 12 cases positive for EBV LMP-1 were classified as follows: lymphocyte-rich classical, 4 (33%); mixed cellularity, 3 (25%); nodular sclerosis, 2 (17%); lymphocyte depletion, 1 (8%); and not classified, 2 (17%) Image 1F. The patient with lymphocyte depletion HL was HIV+. The clinical stage of the neoplasms in these patients was as follows: I, 4; II, 4; III, 1; and not staged, 3. The 3 patients with unstaged disease had concurrent or a history of NHL. Discussion Although HL often involves the head and neck, these neoplasms usually arise in lymph nodes, most frequently in the cervical regions, and extranodal manifestation without nodal involvement is rare. 4,7 The frequency of HL involving extranodal sites of the head and neck is approximately 4%. 7 Among this group, HL involving Waldeyer ring, which encompasses the lymphoid tissues of the tonsils, nasopharynx, base of the tongue, and oropharynx wall, is even more rare. 3,6,13-21 For the present study, we identified 22 cases of HL involving Waldeyer ring obtained from the files of our institution during a 31-year period. Although previous studies of HL involving Waldeyer ring can be found in the literature, many of these studies did not include immunohistochemical data. For example, the largest series in the literature, by Cionini et al, 13 was a group of 28 cases Table 2 Pathologic and Immunophenotypic Findings in 22 Cases of Hodgkin Lymphoma in Waldeyer Ring Case No. Diagnosis CD3 CD15 CD20 CD30 CD45 CD45RO EBV LMP-1 1 MC ND + + ND 2 NS ND + + ND 3 LRC + ND + ND + 4 NS ND ND ND ND ND ND ND 5 MC ND + + ND ND + 6 MC ND + ND + ND + 7 NS ND ND ND ND ND ND ND 8 LRC + + ND + 9 LRC ND LRC + + ND + 11 MC ND ND + 12 NS + + ND 13 LRC + + ND ND + 14 LD ND + 15 LRC + + ND ND ND 16 NS + + ND ND ND 17 NS + + ND + 18 LRC ND 19 LRC + + ND 20 NS ND RS-HL ND ND + 22 RS-HL ND + EBV LMP-1, Epstein-Barr virus latent membrane protein type 1; LD, lymphocyte-depleted; LRC, lymphocyte-rich classical; MC, mixed cellularity; ND, not done; NS, nodular sclerosis; RS-HL, Richter syndrome, Hodgkin lymphoma type; +, positive;, negative. Downloaded from Am J Clin Pathol 2005;123:

4 Quiñones-Avila et al / HODGKIN LYMPHOMA INVOLVING WALDEYER RING A B C D Image 1 Hodgkin lymphoma involving Waldeyer ring. A, Lymphocyte-rich classical Hodgkin lymphoma involving adenoid tissue. Note the nodular growth pattern similar to that seen in nodular lymphocyte-predominant Hodgkin lymphoma (H&E, 50). B, Typical binucleated Reed-Sternberg cell in lymphocyte-rich classical Hodgkin lymphoma (H&E, 400). C, Nodular sclerosis Hodgkin lymphoma involving tonsil. Fibrous collagen bands divide the tissue into nodules (H&E, 100). D, Typical membranous and Golgi pattern of CD30 immunohistochemical staining in Hodgkin cells of nodular sclerosis Hodgkin lymphoma ( 400). without immunophenotypic workup. Because various types of NHL can resemble HL, such as T-cell/histiocyte-rich large B- cell lymphoma and peripheral T-cell lymphoma, immunohistochemical confirmation is needed to establish the diagnosis of most types of HL, with the possible exception of nodular sclerosis. Another drawback of many previous studies is that older lymphoma classification systems were used. Many of these older classification systems were based purely on morphologic findings and did not incorporate immunohistochemical and other ancillary data. As far as we are aware, this is the first study of a series of HL cases involving Waldeyer ring in which the neoplasms are classified according to the WHO classification. 12 Most reports in the literature suggest that mixed cellularity is the most common type of HL involving Waldeyer ring, 3,14-18 although the study by Cionini et al 13 found that lymphocyte predominant HL was most common. Our results are in disagreement with the literature because we had a predominance of the lymphocyte-rich classical (8/22 [36%]) and nodular sclerosis (7/22 [32%]) types of HL. In addition, more than half of localized (stage I) cases were the lymphocyte-rich classical type. This may be attributable, in large part, to the fact that the category of lymphocyte-rich classical HL was not recognized until it was first proposed as a provisional entity in the Revised European-American Lymphoma classification in 654 Am J Clin Pathol 2005;123: Downloaded 654 from

5 Hematopathology / ORIGINAL ARTICLE E F Image 1 E, Hodgkin lymphoma associated with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (Hodgkin-variant Richter syndrome); type II morphologic features with Hodgkin cells in a polymorphous inflammatory background. The small lymphocytes expressed CD20 and CD5, characteristic of CLL/SLL (H&E, 400). F, The Hodgkin cells in this case were positive for Epstein-Barr virus latent membrane protein-1( 200) Furthermore, lymphocyte-rich classical HL was refined into nodular and diffuse variants relatively recently, by the European Task Force on Lymphoma project. 23 Many cases classified in the past as mixed cellularity, nodular lymphocyte predominant, or unclassifiable HL might, in retrospect, be better considered the lymphocyte-rich classical type using current terminology and immunohistochemical analysis. 23 Extranodal HL frequently is related to immunodeficiency states, and in affected patients, a variety of anatomic sites can be involved by HL, including Waldeyer ring. 24,25 Thus, immunodeficiency is one possible explanation for involvement of Waldeyer ring by HL in the 4 patients with a history of lymphoma (n = 3) or HIV infection (n = 1). The HL in all 4 of these patients was positive for EBV, also consistent with immunodeficiency. However, 18 patients in this study had no clinical evidence of immunodeficiency, and 8 (57%) of 14 cases assessed in this apparently immunocompetent group also were positive for EBV. This frequency is higher than the frequency of EBV in most types of HL involving lymph nodes in immunocompetent patients. Previous studies have reported that EBV can be detected in approximately 20% to 60% of classical HL, depending on the histologic type, being lowest in nodular sclerosis and higher in mixed cellularity. 26 Because oropharyngeal epithelium is a lifetime reservoir for EBV and many malignant neoplasms arising at this site are positive for EBV, 2,3,14,17,18 it seems likely that anatomic location rather than histologic type explains the higher frequency of EBV in HL involving Waldeyer ring. O Grady and colleagues 27 made a similar suggestion based on the results of their study in which they showed a higher frequency of EBV in localized HL cases involving neck lymph nodes compared with HL cases involving nonneck body sites. Because EBV LMP is known to have oncogenic potential, 28 it seems possible that EBV has a role in pathogenesis rather than simply being a bystander. In agreement with the literature, in the present study, HL involving Waldeyer ring occurred most often in male patients (16/22 [73%]) with local symptoms, and 18 (95%) of 19 patients whose disease was staged had stage I or II disease. 3,14,16,20,21 Three patients had a history of NHL and were not staged; 2 cases in this group were unusual because they had concurrent evidence or a history of CLL/SLL. Thus, these cases can be considered examples of the Hodgkin variant of Richter syndrome. The term Richter syndrome is applied to the development of a secondary aggressive lymphoid malignancy in a patient with a history of CLL/SLL. 29 HL represents almost 15% of all cases of Richter syndrome and occurs in approximately 1% of patients with CLL. 30 Such cases have been referred to as Richter syndrome with HL features or the Hodgkin type or variant of Richter syndrome. The literature recognizes 2 types of the Hodgkin variant of Richter syndrome: type 1 is characterized by Reed-Sternberg and Hodgkin cells scattered in a background of CLL/SLL cells; in type 2, Reed-Sternberg and Hodgkin cells are present within a polymorphous inflammatory tissue. 31 Both cases in the present study were type 2. Richter syndrome has been associated with EBV infection. 32,33 Although we are not aware of other reported cases of Hodgkin-variant Richter syndrome involving Waldeyer ring, the high frequency of EBV at this anatomic site may contribute to onset of this type of Richter syndrome in these patients. Downloaded from Am J Clin Pathol 2005;123:

6 Quiñones-Avila et al / HODGKIN LYMPHOMA INVOLVING WALDEYER RING In summary, HL involving Waldeyer ring is rare; we identified only 22 cases during 31 years. At our institution, the lymphocyte-rich classical and nodular sclerosis types are most common at this anatomic site, with the lymphocyte-rich classical type also predominating (4/7 [57%]) in patients with stage I disease. We suggest that a subset of cases previously described in the literature as mixed cellularity, nodular lymphocyte predominant, and unclassified HL may, in fact, have been cases of lymphocyte-rich classical HL. From the Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston. Address reprint requests to Dr Medeiros: Dept of Hematopathology, Box 72, UT M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX References 1. Paryani S, Hoppe RT, Burke JS, et al. Extralymphatic involvement in diffuse non-hodgkin s lymphoma. J Clin Oncol. 1983;1: Rowley H, McRae RD, Cook JA, et al. Lymphoma presenting to a head and neck clinic. Clin Otolaryngol. 1995;20: Aloulou S, Farhat H, Bosq J, et al. Hodgkin s disease primarily involving the oropharynx: case report and review of the literature. Hematol J. 2002;3: Chan JKC, Ng CS, Lo STH. Immunohistochemical characterization of malignant lymphomas of the Waldeyer s ring other than the nasopharynx. Histopathology. 1987;11: Chan JKC, Ng CS, Lau WH, et al. Most nasal/nasopharyngeal lymphomas are peripheral T cell neoplasms. Am J Surg Pathol. 1987;11: Menarquez J, Mollejo M, Carrion R, et al. Waldeyer ring lymphomas: a clinicopathological study of 79 cases. Histopathology. 1994;24: Urquhart A, Berg R. Hodgkin s and non-hodgkin s lymphoma of the head and neck. Laryngoscope. 2001;111: Todd GB, Michaels L. Hodgkin s disease involving Waldeyer s lymphoid ring. Cancer. 1974;34: Kaplan HS, Dorfman RF, Nelsen TS, et al. Staging laparotomy and splenectomy in Hodgkin s disease: analysis of indications and patterns of involvement in 285 consecutive, unselected patients. Natl Cancer Inst Monogr. 1973;36: Lin P, Medeiros LJ, Wilder RB, et al. The activation profile of tumour-associated reactive T-cells differs in the nodular and diffuse patterns of lymphocyte predominant Hodgkin s disease. Histopathology. 2004;44: Park CK, Manning JT, Battifora H, et al. Follicle center lymphoma and Warthin tumor involving the same anatomic site: report of two cases and review of the literature. Am J Clin Pathol. 2000;113: Jaffe ES, Harris NL, Stein H, et al. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001: Cionini L, Bastiani P, Biti GP, et al. Waldeyer s ring (WR) involvement in Hodgkin s disease. Radiother Oncol. 1985;3: Kapadia SB, Roman LN, Kingma DW, et al. Hodgkin s disease of Waldeyer s ring; clinical and histoimmunophenotypic findings and association with Epstein-Barr virus in 16 cases. Am J Surg Pathol. 1995;19: Dunphy CH, Saravia O, Varvares MA. Hodgkin s disease primarily involving Waldeyer s ring: case report and review of the literature. Arch Pathol Lab Med. 1996;120: Sidhu JS, Rigotti R, Schotanus P. Primary adenoidal Hodgkin s disease: report of a case with unusual morphology and review of the literature. Int J Surg Pathol. 2000;8: Moghe GM, Borges AM, Soman CS, et al. Hodgkin s disease involving Waldeyer s ring: a study of four cases. Leuk Lymphoma. 2001;41: Abbes I, Mrad K, Sassi S, et al. Primary Hodgkin s disease of the nasopharynx: a rare but bona fide disease. Pathologica. 2002;94: Anselmo AP, Cavalieri E, Cardarelli L, et al. Hodgkin s disease of the nasopharynx: diagnostic and therapeutic approach with a review of the literature. Ann Hematol. 2002;81: O Reilly BJ, Kershaw JB. Hodgkin s disease of the nasopharynx. J Laryngol Otol. 1987;101: Molony NC, Stewart A, Ah-See K, et al. Hodgkin s lymphoma of the nasopharynx. J Laryngol Otol. 1998;112: Harris NL, Jaffe ES, Stein H, et al. A revised European- American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994;84: Anagnostopoulos I, Hansmann ML, Franssila K, et al. European Task Force on Lymphoma Project on lymphocyte predominance Hodgkin disease: histologic and immunohistologic analysis of submitted cases reveals 2 types of Hodgkin disease with a nodular growth pattern and abundant lymphocytes. Blood. 2000;96: Poluri A, Shah KG, Carew JF, et al. Hodgkin s disease of the head and neck in human immunodeficiency virus infected patients. Am J Otolaryngol. 2002;23: Ree HJ, Strauchen JA, Khan AA, et al. Human immunodeficiency virus associated Hodgkin s disease: clinicopathologic studies of 24 cases and preponderance of mixed cellularity type characterized by the occurrence of fibrohistiocytoid stromal cells. Cancer. 1991;67: Herling M, Rassidakis GZ, Medeiros LJ, et al. Expression of Epstein-Barr virus latent membrane protein-1 in Hodgkin and Reed-Sternberg cells of classical Hodgkin s lymphoma: associations with presenting features, serum interleukin 10 levels and clinical outcome. Clin Cancer Res. 2003;9: O Grady J, Stewart S, Elton RA, et al. Epstein-Barr virus in Hodgkin s disease and the site of origin of tumour. Lancet. 1994;343: Wang D, Liebowitz D, Kieff E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell. 1985;43: Nemets A, Ben Dor D, Barry T, et al. Variant Richter s syndrome: a rare case of classical Hodgkin s lymphoma developing in a patient with chronic lymphocytic leukemia treated with fludarabine. Leuk Lymphoma. 2003;44: Brecher M, Banks PM. Hodgkin s disease variant of Richter s syndrome: report of eight cases. Am J Clin Pathol. 1990;93: Robak T, Szmigielska-Kaplon A, Smolewski P, et al. Hodgkin s type of Richter s syndrome in familial chronic lymphocytic leukemia treated with cladribine and cyclophosphamide. Leuk Lymphoma. 2003;44: Rubin D, Hudnall SD, Aisenberg A, et al. Richter s transformation of chronic lymphocytic leukemia with Hodgkin s-like cells is associated with Epstein-Barr virus infection. Mod Pathol. 1994;7: Ansell SM, Li CY, Lloyd RV, et al. Epstein-Barr virus infection in Richter s transformation. Am J Hematol. 1999;60: Am J Clin Pathol 2005;123: Downloaded 656 from