Hodgkin Disease Associated With T-Cell Non-Hodgkin Lymphomas Case Reports and Review of the Literature

Hematopathology / HODGKIN DISEASE AND T-CELL NHL Hodgkin Disease Associated With T-Cell Non-Hodgkin Lymphomas Case Reports and Review of the Literature Jennifer R. Brown, MD, PhD, 1,2,4 Andrew P. Weng, MD, PhD, 3,5 and Arnold S. Freedman, MD 1,2,4 Key Words: Hodgkin disease; Peripheral T-cell lymphoma; Anaplastic lymphoma Abstract Non-Hodgkin lymphoma (NHL) is more likely to develop in patients with Hodgkin disease (HD) than in the general population. Although reports of synchronous or metachronous HD and NHL are not uncommon in the literature, the biologic relationship of these 2 malignant neoplasms often is unclear. A largerthan-expected fraction of NHLs occurring in patients with HD are of the T-cell phenotype. We report 1 synchronous and 3 metachronous cases of HD and T- cell NHL. In 2 cases, the 2 tumors are unlikely to be related clonally. In the other 2 cases, however, T-cell receptor rearrangement studies demonstrated the presence of the same rearranged clone in both tumor specimens, suggesting that they share a common precursor or that one arose by transformation of the other. These observations imply that, similar to the observations in B-cell NHLs occurring with HD, a subset of synchronous and metachronous T-cell NHLs and HD may be related clonally. The occurrence of Hodgkin disease (HD) and non-hodgkin lymphoma (NHL) in the same patient at a higher-than-expected frequency has been noted for decades. The most common scenario is diffuse large B-cell lymphoma following previous nodular lymphocyte predominant HD, 1 but all types of NHL and HD have been observed, including T-cell NHLs in up to 33% of cases. 2-5 Initially such cases were considered to be induced by treatment, similar to therapy-related acute myelogenous leukemia. 1,6 However, patients also were identified who had simultaneous onset of HD and B- or T-cell NHL at different anatomic sites or even both histologic manifestations present within the same tissue specimen, commonly referred to as composite lymphomas. 7,8 These cases are extremely rare but suggest that a common underlying biologic mechanism may be driving the development of both lymphomas. We report 4 cases Table 1 that represent the range of possible associations between HD and T-cell NHL and discuss potential histogenetic causes based on a review of the literature. Materials and Methods Morphologic and Immunohistochemical Studies The morphologic features of the cases were assessed on H&E-stained sections of formalin- or B-5 fixed, paraffinembedded tissue specimens. Immunoperoxidase studies were performed on paraffin-embedded material by using a 3-step indirect immunoperoxidase technique after antigen retrieval by microwaving the slides in citrate buffer for 20 minutes or by pressure cooking the slides in a 1-mmol/L concentration of EDTA buffer (ph 8.0) for 5 minutes. 9 Downloaded from https://academic.oup.com/ajcp/article-abstract/121/5/701/1759346 Am J Clin Pathol 2004;121:701-708 701 701 701

Brown et al / HODGKIN DISEASE AND T-CELL NHL Table 1 Patient Data Case No./Sex/ Age (y) Date Biopsy Diagnosis Genes Therapy 1/M/32 September 22, 2000 Postcervical LN, R Classic HD NA ABVD October 22, 2002 Submandibular LN, L PTCL, unspecified TCRγ+; IgH NA 2/M/60 February 7, 2002 Bone marrow 20%-30% involved NA with PTCL February 10, 2002 L cervical LN Classic HD (NS) NA CHOP, relapsed with HD, autologous PBSCT February 10, 2002 L inguinal LN PTCL, unspecified TCRγ+; IgHµ 3/M/40 July 31, 1992 Inguinal LN Classic HD Weak (±) TCRβ band (Southern blot) August 12, 1992 Cervical LN Classic HD NA EVA May 31, 1994 Subcarinal LN ALCL TCRβ+, 2 strong bands; Died of sepsis during same weak (±) TCRβ band salvage chemotherapy 4/F/77 February 23, 1998 R cervical LN PTCL TCRβ+, 2 bands (Southern blot); CHOP IgH ; TCR V γ 1-V γ 8+ (PCR) May 8, 1998 Skin Necrotic T-cell NHL NA October 25, 2002 R cervical LN Classic HD Same TCR V γ 1-V γ 8+ (PCR) Radiation therapy February 20, 2003 Adenoids and Classic HD NA nasopharynx ABVD, doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine; ALCL, anaplastic large cell lymphoma; CHOP, cyclophosphamide, doxorubicin, vincristine (Oncovin), prednisone; EVA, etoposide, vinblastine, Adriamycin; HD, Hodgkin disease; IgH, immunoglobulin heavy chain; LN, lymph node; NA, not available; NHL, non-hodgkin lymphoma; NS, nodular sclerosis; PBSCT, peripheral blood stem cell transplant; PCR, polymerase chain reaction; PTCL, peripheral T-cell lymphoma; TCR, T-cell receptor; +, positive;, negative; ±, weakly positive. Molecular Studies Southern Blot Hybridization Genomic DNA was extracted from frozen tissue by using standard techniques and digested with the restriction enzymes BglII and HindIII. The digested DNA was separated by agarose gel electrophoresis, and Southern blot hybridization was performed with a probe specific for the J β 1 and J β 2 regions of the T-cell receptor (TCR)β locus. 10,11 Polymerase Chain Reaction Genomic DNA was prepared by using standard techniques from paraffin-embedded tissue sections 9 and used as template in a polymerase chain reaction (PCR) with GCclamped consensus primers for the TCR V γ 1 through TCR V γ 8 and J γ region gene segments. 12,13 The resulting PCR products then were resolved by using denaturing gradient gel electrophoresis as described. 12,13 Case Reports Case 1 A 32-year-old man was first examined in August 2000 for prolonged bronchitis and cervical lymphadenopathy. He underwent a biopsy of a right posterior cervical lymph node in September 2000, which revealed classic HD. Staging evaluation revealed stage IIIA disease, for which he received 6 cycles of ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine) chemotherapy, 14 completed in April 2001. He was well until the summer of 2002, when he noticed recurrent left submandibular lymphadenopathy, which doubled in size in 1 month. A biopsy was performed in October 2002, and unexpectedly revealed peripheral T-cell lymphoma (PTCL). He was advised to undergo salvage chemotherapy followed by autologous stem cell transplantation. Case 1 Results The initial biopsy revealed typical Reed-Sternberg (RS) cells that were immunohistochemically positive for CD30 and Epstein-Barr virus encoded RNAs and focally positive for CD15 and CD20. Surrounding T cells were normal morphologically and immunophenotypically by flow cytometric and immunohistochemical analyses. The second biopsy revealed lymph node effacement by an atypical lymphoid infiltrate positive for CD2, CD3, and CD4 and negative for CD5 and CD7, suggestive of PTCL. Rare, small, intermixed likely B cells stained positive for Epstein-Barr virus encoded RNAs. Flow cytometric analysis revealed an abnormal T-cell population, and PCR revealed a clonal TCRγ chain gene rearrangement. Case 2 A 60-year-old man was first examined in November 2001, because of low-grade fevers and cervical and supraclavicular lymphadenopathy. Worsening of the fevers and night sweats led to hospital admission in January 2002; during that stay he was treated for a perirectal abscess, and biopsies were performed of a left cervical lymph node, left 702 Am J Clin Pathol 2004;121:701-708 Downloaded 702 from https://academic.oup.com/ajcp/article-abstract/121/5/701/1759346

Hematopathology / ORIGINAL ARTICLE inguinal lymph node, and bone marrow. The left cervical lymph node biopsy revealed classic HD, nodular sclerosis type, whereas the left inguinal lymph node biopsy and the bone marrow biopsy both showed involvement by PTCL. The patient received 4 cycles of CHOP (cyclophosphamide, Adriamycin, vincristine [Oncovin], prednisone) 15 with initially good response, but the disease recurred with left axillary lymphadenopathy, proven by biopsy to be recurrent HD. He received 2 cycles of ESHAP (etoposide, methylprednisolone [Solumedrol], high-dose cytarabine [ara-c], cisplatin [Platinol-AQ]) salvage chemotherapy 16 and underwent high-dose chemotherapy and autologous stem cell transplantation. Case 2 Results The left cervical lymph node biopsy showed diagnostic RS cells positive for CD30 and CD15 and negative for CD3, CD20, CD43, CD45, and Epstein-Barr virus. In contrast, the left inguinal lymph node showed an atypical lymphoid infiltrate with negative immunohistochemical results for CD10, CD15, and CD30 but positive results for CD45, CD3, and CD5, while showing loss of CD7 and a CD4/CD8 ratio of 10:1. Flow cytometric analysis revealed an identical T-cell population, and PCR was positive for a clonal TCRγ chain gene rearrangement. Bone marrow biopsy revealed a mildly hypercellular marrow that was approximately 30% replaced by lymphoid aggregates, with no evidence of HD and consistent with involvement by a T- cell lymphoproliferative disorder. Case 3 A 40-year old man with sarcoidosis was first examined in July 1992, because of diffuse lymphadenopathy, polyarthralgias, and shortness of breath. Inguinal and cervical lymph node biopsies revealed classic HD. The staging evaluation showed stage IVB disease, on the basis of likely pulmonary parenchymal involvement, and he was treated with 6 cycles of EVA (etoposide, vinblastine, and Adriamycin), 17 completed in January 1993. He entered complete remission and did well until March 1994, when he was noted to have gallium avidity in the prevertebral area of the chest, without correlate on computed tomography scan. By May 1994, however, he clearly had a 3-cm gallium-avid subcarinal lymph node, with no other sites of disease. Because of his history of sarcoidosis, he underwent cervical mediastinoscopy, which revealed anaplastic large cell lymphoma (ALCL). Given these findings, salvage chemotherapy was started with a plan for autologous stem cell transplantation. During his second cycle of chemotherapy, septic shock and acute respiratory distress syndrome developed, likely due to pneumonia caused by Klebsiella pneumoniae, and the patient died. Case 3 Results The initial cervical and inguinal lymph node biopsy specimens had typical RS cells that were positive for CD30 and CD15, with some cells also positive for CD20. The inguinal lymph node biopsy specimen also showed evidence of a faint TCRβ chain gene rearrangement by Southern blot hybridization; although suggestive of a clonal T-cell process, no morphologic evidence supported this conclusion (see the Discussion section). Molecular studies were not performed on the cervical lymph node. The recurrent mediastinal disease revealed an atypical lymphoid infiltrate positive for CD2 and CD3, with extensive loss of CD5 and partial loss of CD7; results were negative for CD20 and CD15. The malignant cells were positive for CD30 and epithelial membrane antigen. The tumor had a complex karyotype, with 10 clonal abnormalities, but not t(2;5). Southern blot hybridization revealed the same faint TCRβ chain gene rearrangement as seen in the previous HD, along with 2 new strongly hybridizing bands, consistent with a T-cell lymphoproliferative disorder. Limited autopsy revealed extensive hepatic infiltration by T-cell lymphoma. Case 4 A 77-year-old woman was first examined in 1998 because of bilateral cervical lymphadenopathy. A lymph node biopsy was suggestive of early involvement by a T-cell lymphoproliferative disorder Image 1. Staging revealed no other sites of disease; the patient was treated with 6 cycles of CHOP and entered complete remission. During treatment, skin lesions developed, which biopsy revealed as suggestive of necrotic lymphoma. She was well until January 2002, when bilateral cervical lymphadenopathy again was noted on a computed tomography scan. These nodes remained stable and eventually were biopsied in October 2002. This lymph node was morphologically consistent with HD Image 2 but showed evidence of the same TCR gene rearrangement previously noted Image 3 (right panel). Staging revealed nasopharyngeal enhancement and thickening, which also was biopsied and revealed the same features as the cervical lymph node biopsy. Clinically, the patient s disease behaved most like HD and was treated as such. Case 4 Results The initial lymph node biopsy (Image 1) revealed an atypical lymphoid proliferation of small, polyclonal B cells with clusters of larger T cells that were positive for CD2, CD3, CD5, CD7, and CD4. The proliferation index was 50%. Gene rearrangement studies showed a strongly hybridizing nongermline band indicative of a clonal rearrangement of the TCRβ chain by Southern blot hybridization (Image 3, left panel), as well as a clonal rearrangement of the TCRγ chain by PCR (Image 3, right Downloaded from https://academic.oup.com/ajcp/article-abstract/121/5/701/1759346 Am J Clin Pathol 2004;121:701-708 703 703 703

Brown et al / HODGKIN DISEASE AND T-CELL NHL A B C Image 1 (Case 4) Cervical lymph node biopsy specimen from 1998. Nodal architecture was effaced by a diffuse, atypical T- cell proliferation. A diagnosis of peripheral T-cell lymphoma, unspecified, was given (A, H&E, 40; B, H&E, 200; C, H&E, 1,000). panel). Overall, these findings were consistent with a T-cell lymphoproliferative disorder. On recurrence, the lymph nodes had classic RS cells that were positive for CD15 and CD30 and negative for CD3 and CD20, in a background of small lymphocytes, eosinophils, and plasma cells, consistent with classic HD (Image 2). The T-cell population was not atypical and had a normal CD4/CD8 ratio. However, gene rearrangement studies using PCR demonstrated the same TCRγ gene rearrangement that was found in the 1998 lymph node, suggesting the presence of clonally related malignant T cells in both specimens (Image 3, right panel). Discussion We report 4 cases that illustrate the complexities of HD occurring together with T-cell lymphoproliferative disorders. Early reports noted that HD and NHL could occur simultaneously at diagnosis, at separate sites, or even within the same lymph node. 7,18 Our case 1 represents the situation of HD, treated and in remission, with subsequent development of PTCL. Several reports have focused on the apparently high incidence of NHL after treatment for HD, reported to be 4.4% at 10 years after diagnosis. 6,19,20 A recent populationbased study found a greater than 5-fold increased incidence of NHL in patients previously given a diagnosis of HD. 21 A surprising fraction of these lymphomas are T-cell lymphomas; in 3 large series that identified patients with both HD and NHL, 17 (33%) of 51 cases had T-cell NHL. 2-4 Even in lymphocyte predominant HD, which has clear features of a B-cell malignant neoplasm, the incidence of T- cell NHL occurring subsequently has been reported as 1.6%. 2 Although part of this high incidence of NHL might be attributed to complications of previous therapy, it is likely 704 Am J Clin Pathol 2004;121:701-708 Downloaded 704 from https://academic.oup.com/ajcp/article-abstract/121/5/701/1759346

Hematopathology / ORIGINAL ARTICLE A B C Image 2 (Case 4) Cervical lymph node biopsy specimen from 2002. Nodal architecture was effaced by a diffuse, vaguely nodular proliferation of small lymphocytes with occasional admixed plasma cells, eosinophils, and histiocytes and rare diagnostic Reed-Sternberg cells. A diagnosis of classic Hodgkin lymphoma was made based on histologic findings, while the presence of a T-cell clone identical to that identified in the previous biopsy specimen was detected by T-cell receptor γ polymerase chain reaction denaturing gradient gel electrophoresis (Image 3) (A, H&E, 40; B, H&E, 200; C, H&E, 1,000). that the immune system abnormalities associated with HD also contribute to this incidence, particularly given that the diagnoses sometimes are concurrent. 6,22-26 Much recent progress has led to understanding and documentation of the cell of origin and clonality of RS cells. A substantial fraction of RS cells express lymphoid antigens; approximately 15% to 38% express CD20, and 11% to 24% express CD3. 27-29 Although early studies detected clonal immunoglobulin heavy chain gene rearrangements in RS cells in only 50% of cases, 27-30 individual cell micromanipulation and PCR have permitted the identification of clonal immunoglobulin heavy chain gene rearrangements in 90% to 95% of HD cases, with evidence of somatic mutation suggestive of germinal center origin. 31-34 Because most cases of HD are presumed to arise from the B-cell lineage, it is not surprising that a high incidence of other B-cell lymphomas is seen. Of 6 cases in which singlecell molecular analysis of the RS cells was performed, 5 showed clonal identity between classic HD and NHL: 3 cases of follicular NHL occurring in the same patient as classic HD, 35-37 1 case of B-cell chronic lymphocytic leukemia and HD in the same lymph node, 37 and a T cell rich large B-cell lymphoma followed 3 years later by classic HD. 35 In a sixth case, no clonal relationship was found between an antecedent nodular sclerosis HD and a subsequent B-cell small noncleaved cell lymphoma. 38 In the clonally related cases, the somatic mutations of the immunoglobulin genes included some mutations present in both tumors and additional mutations unique to each tumor, suggesting that a common germinal center B-cell precursor developed additional mutations that dictated the development of 2 different but related lymphomas. 33 Nevertheless, as illustrated in the sixth case, some B-cell NHLs developing after HD are not clonally derived, but rather presumably are Downloaded from https://academic.oup.com/ajcp/article-abstract/121/5/701/1759346 Am J Clin Pathol 2004;121:701-708 705 705 705

Brown et al / HODGKIN DISEASE AND T-CELL NHL Bgl II HindIII C P C P Southern Reactive LN Water related to treatment or, perhaps, promoted by the persistent immune dysregulation associated with HD. 6,22-25 Parallel efforts to identify clonal TCR gene rearrangements in RS cells initially were unsuccessful. 39 Two recent studies focused on RS cells that express T-cell antigens and found that only 15% to 20% of these harbor clonal TCR gene rearrangements. 40,41 The remainder have clonal immunoglobulin heavy chain gene rearrangements and aberrantly express T-cell antigens. 40,41 These studies demonstrate that HD is rarely of T-cell lineage, probably fewer than 5% of all cases. 33 The simultaneous occurrence of PTCL and HD, as in our case 2, has been described but is rare and raises the question of whether the 2 malignant neoplasms are related clonally. Two reports have described molecular analysis of lymph node biopsy specimens from patients with PTCL and classic HD. 42,43 In one case, the tumors were believed to be of different clonal origin, based on cytogenetic results supported by in situ hybridization and molecular analysis performed on the entire lymph node biopsy specimen. 43 In the other case, involving a composite lymphoma followed by relapse with PTCL, the same TCR gene rearrangement was 2002 Biopsy 1998 PCR-DGGE Image 3 (Case 4) Left panel, T-cell receptor (TCR)β Southern blot hybridization of DNA from 1998 lymph node (LN) specimen. The presence of distinct, nongermline configuration bands in the patient sample indicates a T-cell clone. C, control germline configuration; P, patient specimen. Right panel, TCR V γ 1- V γ 8/J γ polymerase chain reaction denaturing gradient gel electrophoresis (PCR- DGGE) of DNA from 1998 and 2002 LN specimens. The identical banding patterns seen in the 1998 and 2002 samples are consistent with the presence of a common T- cell clone. Note the different banding pattern in the unrelated peripheral T-cell lymphoma (PTCL) sample and the polyclonal smear in the reactive LN sample Biopsy Unrelated PTCL present in both biopsy specimens, but the RS cells were Epstein-Barr virus infected and the T-cell lymphoma cells were not. 42 The diseases, therefore, were thought to be of different clonal origin, although single-cell molecular analysis was not performed. 42 In our case 2, although it is possible that the 2 tumors arose from the same clonal precursor, the immunophenotyping data and TCR gene rearrangement data suggest that the tumors were not related clonally, but rather developed simultaneously, perhaps fostered by the same immune microenvironment. 22-25,44 This immunodeficiency can promote the development of secondary lymphoma, as it does in HIV infection and organ transplantation. 1 Clonal identity between a T-cell lymphoma and HD has been described, however, suggesting that at least in some cases, clonal evolution from a common precursor might occur. The association between HD and cutaneous T-cell lymphoma or mycosis fungoides (MF) was first noted in 1963. 45-48 Lymphomatoid papulosis, a benign cutaneous eruption with large binucleate T cells that resemble RS cells, is associated with a 10% to 20% incidence of lymphoma, often cutaneous T-cell lymphoma, ALCL, or HD. 48 It has been proposed that a transformed clone of helper T cells can evolve from lymphomatoid papulosis to give rise to MF or HD. 48 A case has been reported in which lymphomatoid papulosis, HD, and cutaneous T-cell lymphoma, occurring during a period of 14 years, all were derived from the same clone, as determined by PCR on total biopsy tissue. 49 In addition, the same TCR rearrangement has been reported in 2 separate cases of HD occurring with cutaneous T-cell lymphoma. 50,51 In one of these studies, single-cell analysis of the HD CD30+ cells documented the same TCR rearrangement as found in the cutaneous T-cell lymphoma. 51 One additional study of 2 cases of HD and MF occurring in the same patient failed to demonstrate clonality based on PCR results from the total biopsy specimen. 46 Although single-cell analysis of RS cells in all cases would clarify this literature, at least one of the reported cases demonstrated clonality between the individual RS cells of HD and cutaneous T-cell lymphoma. It seems likely, therefore, that the relationship of HD and T-cell NHL is similar to that of HD and B-cell NHL in some cases the tumors derive from the same precursor and in other cases they do not. The lymphocyte activation that is evident in the HD microenvironment also might promote the development of other lymphoid neoplasms. For example, in our case 3, a faint TCR gene rearrangement was detected in the initial HD. This rearrangement might have arisen from the malignant RS cells, from an occult T-cell NHL, or from an oligoclonal population of reactive T cells. It is unlikely that this TCR rearrangement was derived from the RS cells, some of which were positive for CD20. An occult T-cell NHL is 706 Am J Clin Pathol 2004;121:701-708 Downloaded 706 from https://academic.oup.com/ajcp/article-abstract/121/5/701/1759346

Hematopathology / ORIGINAL ARTICLE possible but also unlikely, given that the faint TCR rearrangement persisted but did not expand in the subsequent biopsy specimen. This TCR rearrangement is most consistent with an initial and persistent oligoclonal T-cell expansion that permitted the emergence of the ALCL, with its 2 new, more definitive TCR rearrangements. Thus, the HD and ALCL likely are not related clonally, but the ALCL and possibly the HD developed as a result of a persistently abnormal immune microenvironment. Our case 4 is most difficult, with a previous T-cell lymphoproliferative disorder followed by HD, both with the same TCR gene rearrangement. This result possibly implies the presence of both classic HD and a T-cell lymphoproliferative disorder in the lymph node evaluated in 2002, although either one alone also is possible. Furthermore, although the TCR gene rearrangement seen in the previous PTCL was identified in the HD specimen, it is unclear whether it arose from the RS cells or from the surrounding T cells, which were normal by morphologic examination and immunophenotyping. Given the lack of evidence for a morphologically abnormal T-cell population, this case suggests that the RS cells might be related clonally to the previous T-cell lymphoproliferative disorder, although it is impossible to know without single-cell analysis. We report 4 cases of HD and T-cell lymphoproliferative disorders occurring in the same patient. Although rare, this combination occurs. Our case 1 represents the relatively common situation of a new NHL occurring following treated HD. Case 2 represents simultaneous onset but probably clonally unrelated HD and PTCL. Case 3 illustrates the development of both HD and ALCL from a microenvironment containing an expanded population of oligoclonal but presumably nonmalignant T cells. Case 4 raises the possibility of HD evolving from an underlying T-cell lymphoma. These cases illustrate the complex relationship between HD and T-cell NHL; a better understanding of this association likely will require new insights into lymphoma pathogenesis. From the Departments of 1 Medical Oncology, Dana-Farber Cancer Institute; 2 Medicine and 3 Pathology, Brigham and Women s Hospital; and 4 Medicine and 5 Pathology, Harvard Medical School, Boston, MA. Address reprint requests to Dr Freedman: Dept of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115. Dr Brown is supported in part by the Clinical Investigator Training Program: Harvard/MIT Health Sciences and Technology, Beth Israel Deaconess Medical Center, Boston, MA, in collaboration with Pfizer, New York, NY. Acknowledgments: We are indebted to the staff of the Dana- Farber Cancer Institute for their excellent care of the patients. 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