Second malignancies in Hodgkin's disease: A review of the literature and report of a case with a secondary Lennert's lymphoma.

A small percentage of patients treated for Hodgkin's disease are at risk of developing a second malignancy. The appearance of secondary malignancies such as leukemia, carcinoma or non-Hodgkin's lymphomas may be attributed to the mutagenic effects of chemotherapy and/or radiotherapy. Most secondary non-Hodgkin's lymphomas are of the B-cell type, but isolated cases were reportedly of a T-cell lineage. A review of the literature pertaining to the development of secondary peripheral T-cell lymphomas is presented along with the description of an additional case. The latter developed in the tonsil and was diagnosed as a Lennert's lymphoma (lymphoepithelioid T cell lymphoma)on histological and immunological grounds. This report also reviews the development of a of peripheral T-cell lymphoma described in patients following chemotherapy and/or radiotherapy for Hodgkin's disease.

INTRODUCTION

Approximately 75% of patients with Hodgkin's disease (HD), regardless of the stage, may achieve long-term survival on modern treatment regimes,[1] but they are at an increased risk of developing a histologically unrelated second primary malignancy as a treatment complication.[2345678] Three types of second primary malignancy are recognized: Solid tumors, leukemia's and non-Hodgkins lymphoma (NHL), of which solid tumors of visceral organs constitute up to three quarters of all cases of second primary malignancy.[3910111213141516171819202122232425262728293031] The development of second primary malignancies is related to the extent of the initial treatment, whether chemotherapy (CT), radiotherapy (RT) or a combination of chemo- and radiotherapy (CCRT) was employed, gender and age when treatment was initiated.[113233] The increased risk to develop second primary malignancies is attributable to the mutagenic- and immune-suppressive effects of CT or RT,[41734353637] and the risk seems to be higher among those treated by both modalities.[171831383940414243] Treatment with extended-field radiation, rather than involved field radiation or fractionalized radiation was also found to increase the risk for a second primary malignancy.[1344454647] It was proposed that the increased susceptibility for second primary malignancies are multi-factorial and due in part to persistent immune abnormalities seen in HD, coupled with the carcinogenic effects of RT, CT or CCRT.[6113536373841484950]

A survey of the literature revealed that 19 confirmed cases of peripheral T-cell lymphomas other than mycosis fungoides had developed after treatment of HD.[68195152] In 10 cases, clinical data was supplied, there were six males and four females-the ages varied between 14 and 65 years and they occurred in the pharynx (one case),[40] axillary nodes (two cases),[853] inguinal node (three cases),[353] lungs (one case),[54] abdominal nodes (two cases)[19] and mediastinal lymph nodes.[54] The interval between diagnosis of HD and appearance of a peripheral T-cell lymphoma varied between the reported cases from eight months to 25 years. Six patients were treated with CCRT, three with CT and one with RT alone. The paper by Oliva et al.,[52] was the only case of a secondary Lennert's lymphoma reported in the literature. Amini et al.,[54] recorded seven cases of T-cell NHL's that coexisted with HD at the time of diagnosis and Rueffer et al.,[55] also mentioned seven cases of T-cell NHL after HD among their study series, but without supplying clinical data. The T-cell character of all these cases was immunologically confirmed either by E-rosetting, surface marker analysis or gene re-arrangement studies. Three of the four peripheral T-cell lymphomas reported by Bennet et al.,[56] that developed after treatment of nodular lymphocyte predominant Hodgkin's disease (NLPHD) can be excluded, as the latter category is regarded as a B-cell NHL-variant, containing lymphocytic and histiocytic (L and H) cells (“popcorn cells”) that stain with pan-B markers.[57] Those T-cell lymphomas that developed after treatment of NLPHD reported by Rysenga et al.,[58] and by Arevalo et al.,[59] were also excluded on the same grounds.

CASE REPORT

A 74-year-old woman with a negative history of tobacco use was admitted to a teaching hospital with a palpable inguinal mass, which was biopsied. She had been treated by radiotherapy and alkylating agents for an Ann Arbor Stage I Hodgkin's disease nine years previously at another hospital. The original pathology slides were not available for review, but histological examination of the inguinal node biopsy revealed the presence of a mixed cellularity HD. The patient then received fractionalized extended field radiotherapy for a total of 24 rays over a 4-week period. A cervical mass then appeared 15 months after treatment. This mass was biopsied and diagnosed as Hodgkin's lymphoma mixed cellularity. A staging laparotomy was performed, which revealed evidence of liver and para-aortic lymph node involvement. A bone marrow trephine biopsy was found to be free of tumor. The malignancy was asymptomatic and involved more than one groups of lymph nodes on both sides of the diaphragm, with infiltrates into surrounding non-lymphoid tissues (or Stage III AE Hodgkin's disease). She received four cycles of MOPP-regime (mechlorethamine, ovocin/vincristine, procarbazine-prednisone) chemotherapy. The patient was re-admitted seven months later with a rapidly enlarging mass in the right tonsil, for which a tonsillectomy was performed. Clinical examination also revealed the presence of a diffuse swelling in the soft palate. The patient received two cycles of salvage ChlPP (chlorambucil, vinblastine, procarbazine, prednisone) chemotherapy, but died five months after re-admission. No autopsy was carried out. Sections were cut from the tonsillectomy tissue blocks and immunohistologically stained according to the avidin-biotin-peroxidase-complex method. The monoclonal antibodies were obtained from Dakopatts, Denmark and included CD45 (LCA), CD20 (L26), UCHL-1, CD3, CD15 (Leu-M1), CD30 (Ber-H2), CD68 (KP-1), S100, KER, EMA and monoclonal antibodies against the immunoglobulins G, -M, -A and kappa and lambda light chains.

Microscopic examination of the inguinal lymph node showed effacement of the normal architecture by a diffuse growth consisting of Reed-Sternberg cells and atypical mononuclear cells in a background of eosinophils, plasma cells, histiocytes and non-atypical T-lymphocytes [Figure 1]. The tumor cells stained with Leu-M1 and Ber-H2, but failed to react with any lymphoid markers used. The microscopic and immunologic features were considered typical of a Hodgkin's lymphoma, mixed cellularity type.

Figure 1

Mixed cellularity Hodgkin's lymphoma, arrow pointing to Reed-Sternberg owl-eye cell (H&E, ×200)

The tonsillar biopsy revealed a diffuse growth of small and medium-sized lymphocytes with atypical irregular nuclei. A small number of large lymphocytes with prominent nucleoli were noted and occasional large cells were binucleated. No Reed-Sternberg cells were present and mitoses averaged two per 200X magnification. Small clusters of epithelioid histiocytes with vesicular oval or retiform nuclei were scattered among the tumor cells [Figure 2]. The cytoplasm of the histiocytes was abundant, oxyphylic and many contained a pale rounded central vesicular area [Figure 3]. These cells reacted strongly with the monoclonal antibody KP-1, indicative of their macrophage lineage [Figure 4]. Multi-nucleated Langhans-like giant cells as well as scattered eosinophils were also observed. In areas, aggregates of plasma cells dominated and expressed polytypic immunoglobulins. The tumor cells stained with anti-CD45, UCHL-1, anti-CD3, [Figure 5] but not with any of the other monoclonal antibodies used. This tumor was diagnosed as a peripheral T-cell NHL (lympho-epithelioid variant or Lennert's lymphoma).

Figure 2

Lymphoepithelioid lymphoma, showing pale epithelioid cell clusters in a background of small atypical cells (H&E, ×200)

Figure 3

Multinucleated epithelioid histiocytes with large intracytoplasmic vesicles (H&E stain, ×200)

Figure 4

KP-1 positivity highlighting the presence of epithelioid histiocytes (IHC stain, ×100)

Figure 5

Anti-CD3 staining highlighting the presence of atypical small and medium-sized T-cells (IHC, ×400)

DISCUSSION

The case reported here represents an additional peripheral T-cell lymphoma that developed as a second primary malignancy after CCRT treatment for HD. The histological and immunological features of this tumor corresponded with that of a lymphoma described by Lennert and Mestdagh.[60] They proposed the term “lymphoepithelioid cell lymphoma”, also known as Lennert's lymphoma and this tumor is classified as a specific variant of a T-cell NHL.[61] It is a rare malignancy and diagnosis is based on the presence of clusters of epithelioid histiocytes, Langhans-type giant cells, rare inflammatory cells, atypical small cells and no evidence of increased vascularization.[58616263] Cytogenic- and gene re-arrangement studies of these atypical cells by various authors provided evidence that this tumor is a malignant proliferation of CD-4+ helper/inducer T-cells,[63] or CD8+ cytotoxic T-cells.[596364] Suchi et al.,[61] defined the essential diagnostic criteria for this tumor and proposed an updated classification system for peripheral T-cell lymphomas, in which Lennert's lymphoma was placed into the low-grade category. Lennert's Lymphoma have been described as a primary tumor in patents ranging from 23 to 81 years[5265] and cases were recorded in the nasopharynx, submandibular lymph nodes, Waldeyer's ring, tonsils and pharynx.[606667] This tumor was found to be associated with splenomegaly or hepatomegaly and symptoms in many cases.[66]

The histologic features of Lennert's lymphoma should be differentiated form toxoplasmosis and histiocyte-rich mixed cellularity HD on the grounds of immunologic and cellular findings.[67] A Giemsa-stain of the embedded palatine tissue was done, but revealed no Toxoplasma organisms. The tumor presented here was differentiated from a Hodgkin's lymphoma with a high content of epithelioid cells on the grounds of an absence of diagnostic CD-10- and Ber-H2 staining Reed-Sternberg cells and the presence of a spectrum of atypical T-cells. Almost all the atypical cells in the present case from the tonsil reacted with leucocyte common antigen (LCA) and with the pan-T-cell markers UCHL-1 and anti-CD3. No staining with Leu-M1, Ber-H2, EMA and the pan-B cell marker L26 was observed, confirming the T-cell lineage of this tumor. It was differentiated from the closely related angio-immunoblastic lymphoma by the absence of abundant high endothelial venules with hyalinized vessel walls and less appreciable morphological atypia.[666768] The presence of polytypic plasma cells in this tumor, differentiated it from a lymphoplasmacytoid lymphoma. The latter may have similar morphology, but the plasmacytoid cells herein express monotypic immunoglobulin.

The relation between a secondary peripheral T-cell NHL and primary HD is obscure as cases of T-cell NHL co-existing with a HL was also reported.[69] Loewenthal et al.,[8] suggested that the T-cells involved in the immune response against a HD may be “switched-on”, only to be at risk of neoplastic transformation. The possibility of transformation from a Hodgkin's lymphoma expressing T-cell receptor gene re-arrangements to a peripheral T-cell NHL was raised by Nakamura.[70] Although, a substantial number of NHL's developing after treatment of HD have been mentioned in risk-analysis studies,[303871727374] the number of reported T-cell non-Hodgkin's lymphomas are few, most of the cases reported in the literature developed in peripheral lymph nodes. Subsequent survival after diagnosis of a secondary NHL is said to be less favorable than that of patients with a primary lymphoma.[75] T-cell NHL's are more aggressive than B-cell NHL's,[65] having a poor prognosis[52] and a median survival of 15.6 months.[67] This is reflected in the case described here, as the patient passed away 5 months after diagnosis of the second malignancy.

The more relapses, the more advanced staging at initial diagnosis and additional therapy experienced by a survivor of HD, the higher the risk of developing a second tumor.[75] The increased risk for a second neoplasm in a survivor of HD underscores the importance of continued monitoring of such patients. Those presenting with an apparent relapse should not be accepted as such, but intensive examination and biopsy are mandatory to exclude the possibility of an emerging second tumor. Careful histological evaluation and immuno-profiling are necessary in differentiating a NHL as a second primary malignancy from a recurring Hodgkin's lymphoma. The benefit derived from treatment of HD outweighs the risk for a second primary malignancy and limiting the extent of the RT field, or employing non-alkylating agents coupled with and life-long monitoring and early detection strategies should be implemented to identify a second primary malignancy.