Morphologic and Immunopathologic Spectrum of Malignant Lymphoma: Review of 211 Cases

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1 Morphologic and Immunopathologic Spectrum of Malignant Lymphoma: Review of 211 Cases M. Ashraf Ali, MD, FRCP(C); Mohammed Akhtar, MD; Magid Amer, MD, FRCS From the Department of Pathology and Laboratory Medicine (Drs. Ali and Akhtar), and Department of Oncology (Dr. Amer), King Faisal Specialist Hospital and Research Centre, Riyadh. Address reprint requests and correspondence to Dr. Ali: Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia. Accepted for publication 12 October A series of 211 malignant lymphomas in adults were reviewed and classified according to the international working formulation. Of those classified, five (2.4%) were low-grade, 115 (54.5%) intermediate-grade, and 85 (40.3%) highgrade lymphomas. Immunohistologic typing of 106 lymphomas was performed using a panel of monoclonal antibodies against T- and B-cell surface antigens. This revealed 51 (48.1%) B-cell and 41 (38.7%) T-cell lymphomas with 14 (13.2%) indeterminate. These results were compared with those from several recently published studies from other countries. The proportion of aggressive lymphomas in our series appeared to be relatively high. Furthermore, immunohistologic data in our study indicated a significantly higher proportion of T-cell lymphomas as compared to other studies. MA Ali, M Akhtar, M Amer, Morphologic and Immunopathologic Spectrum of Malignant Lymphoma: Review of 211 Cases. 1989; 9(4): Malignant lymphoma is one of the most common malignant neoplasms in Saudi Arabia. 1 A few studies describing various clinical and therapeutic aspects of malignant lymphoma in Saudi Arabia have been previously reported. 2-4 However, to the best of our knowledge, a detailed study outlining the histopathologic and immunohistologic characteristics of malignant lymphoma in this country has not been published. The purpose of this study was to review the morphologic and immunopathologic features of malignant lymphomas seen in our laboratories and compare our findings with those from recently published studies from centers in other countries. Materials and Methods All malignant lymphomas in adults diagnosed histologically between January 1984 and December 1987 were identified. Cases in which the biopsies were performed in other institutions as well as those cases in which the biopsy material was inadequate were excluded. A total of 211 cases were selected in which the biopsy was performed at King Faisal Specialist Hospital and Research Centre and the tissue obtained was adequate for histologic diagnosis. Tissues were fixed in 10% buffered formaldehyde solution and B-5 solutions, dehydrated in graded alcohols, and embedded in paraffin in a routine manner. Three- to four-micron sections were stained with hematoxylin and eosin. Special stains such as periodic acid-schiff (PAS) and methyl green-pyronine (MGP) were used in selected cases whenever indicated. Imprint smears from the fresh tissues were made and stained by Diff-Quik stain. Appropriate pieces of tissue were snap-frozen for cryostat sections which were used for immunohistologic staining.

The sections were stained using avidin-biotic complex technique using a panel of monoclonal antibodies against a variety of T- and B-lymphocyte surface antigens.

2 The sections were stained using avidin-biotic complex technique using a panel of monoclonal antibodies against a variety of T- and B-lymphocyte surface antigens. Immunohistologic staining for phenotyping of malignant lymphoma was carried out in all cases where unfixed fresh tissue was available, and therefore there was no selection of cases. Slides from all the cases were reviewed by two pathologists (M.A.A. and M.A.). All lymphomas were classified according to the international working formulation. 5 The lymphomas containing large cells (less than five per highpower field) were classified as small cell type. The lymphomas containing 5 to 15 large cells per high-power field were classified as mixed, while those with large cells more than 15 per high-power field were categorized as large cell lymphomas. 6 Results Histopathologic classification of the 211 lymphomas according to the working formulation is given in Table 1 (Figures 1-7). Five lymphomas (2.4%) were classified as low grade, 115 (54.5%) as intermediate grade, and 85 (40.3%) as high grade. Thus, of the 211 malignant lymphomas, 200 (94.8%) were aggressive lymphomas (intermediate or high grade). Table 1. Classification of 211 non-hodgkin's lymphomas using the working formulation. Low grade Small lymphocytic 3 Follicular small cleaved 2 Follicular mixed 0 Subtotal 5( 2.4%) Intermediate grade Follicular large cell 4 Diffuse small cleaved 22 Diffuse mixed 11 Diffuse large cell 78 Subtotal 115( 54.5%) High grade Immunoblastic 79 Lymphoblastic lymphoma 3 Small non-cleaved 3 Subtotal 85(40.3%) Others 6( 2.8%) Total 211(100.0%) Figure 1. Well-differentiated lymphocytic lymphoma (hematoxylin and eosin stain, original magnification, 150).

Diffuse small cleaved lymphoma (hematoxylin and

3 Figure 2. Follicular small cleaved lymphoma (hematoxylin and eosin stain, original magnification, 100). Figure 3. Diffuse small cleaved lymphoma (hematoxylin and eosin stain, original magnification, 150). Figure 4. Diffuse large cell lymphoma (hematoxylin and eosin stain, original magnification, 150).

4 Figure 5. Immunoblastic sarcoma (hematoxylin and eosin stain, original magnification, 150). Figure 6. Lymphoblastic lymphoma (hematoxylin and eosin stain, original magnification, 150). Figure 7. Small noncleaved lymphoma (hematoxylin and eosin stain, original magnification, 150). Immunophenotyping of the lymphoma was carried out in 106 cases. Of these, 51 (48.1%) were B-cell type, 41

5 (38.7%) were T-cell type, and 14 (13.2%) could not be classified with certainty. Of the 75 large cell lymphomas, 37 (49.3%) were B-cell type, and 28 (37.3%) were T-cell type, while in 10 cases (13.3%) the results were indeterminate. Comparison With Recently Published Studies Our findings from this study were compared with data from recently published studies from several other countries in which a similar classification of malignant lymphoma was used (Table 2). 5,7,8 This comparative evaluation revealed that in our series, low-grade lymphomas were extremely uncommon, representing only 2.4% of the entire group. This is in sharp contrast to the studies from the United States where low-grade lymphomas constitute 18.9% to 34.2% of the total. Another significant difference is in the relative proportion of high-grade lymphomas. These lymphomas constitute 2.6% to 26.3% of the total in studies from the United States. By contrast, in our series, 40.2% of the lymphomas were high grade. This is similar to the figures from East China where 43.2% of the lymphomas were categorized as high grade. Immunohistologic studies in our series indicated that 37.3% of large cell lymphomas were of T-cell origin. In several previously published studies, the proportion of T-cell lymphoma varied from 3% to 23% In one study, however, T-cell lymphomas represented 42% of the total. 13 Table 2. Comparison of classification of malignant lymphomas using the working formulation. US & Milan, Present Puerto Rico 8 Nebraska 7 East China 7 US 5 Italy 5 study No. (%) No. (%) No. (%) No. (%) No. (%) No. (%) Low grade 4227(34.3) 94(18.9) 24(12.5) 393(49.0) 67(18) 5( 2.4) Intermediate grade 7865(63.9) 269(54.0) 75(39.1) 304(37.9) 194(52) 115(54.5) High grade 227( 1.8) 131(26.3) 83(43.2) 96(12.0) 112(30) 85(40.3) Others 4( 0.8) 10( 5.2) 9( 1.1) 6( 2.8) Total 12,319(100) 498(100) 192(100) 802(100) 373(100) 211(100) Discussion The results from our study indicate that, compared to studies from the United States, the relative proportion of low-grade lymphomas in our series was considerably lower. The percentage of high-grade lymphomas in our series by contrast was considerably higher. These differences were less striking when our results were compared with data from eastern China and Milan, Italy (Table 3). Table 3. Immune marker expression in aggressive lymphomas. Stud B-cell T-cell Indeterminate Total No. (%) No. (%) No. (%) no. Pallesen et al 9 32(60) 12(23) 9(17) 53 Doggett et al 10 47(54) 12(14) 28(32) 87 Cossman et al 13 31(53) 25(42) 3(5) 59 Aisenberg et al 11 15(55) 4(15) 8(30) 27 Rudders et al 12 10(33) 1( 3) 19(64) 30 Present series 37(49) 28(37) 10(13) 75 The reasons for the occurrence of a relatively high proportion of aggressive lymphoma in Saudi Arabia as compared to other countries, most notably the United States, are not clear. One possible explanation may be that the patients in this country tend to seek medical advice at a much later stage when the disease is clinically advanced. Several studies have shown that low-grade lymphomas, such as poorly differentiated lymphocytic lymphomas, may undergo progression into higher-grade lymphomas in a significant proportion of cases. 14,15 Therefore, it is conceivable that if the patients are diagnosed at a later stage during the clinical course, a higher proportion of aggressive lymphomas would be encountered. This would explain some, but probably not all, cases of aggressive

6 lymphoma. Another explanation for these differences may be that the etiology and pathogenesis of malignant lymphoma in Saudi Arabia is different from that in Western countries. Different etiopathogenetic factors could conceivably give rise to lymphomas which vary in morphologic appearance as well as clinical behavior. The etiology and pathogenesis of malignant lymphoma are poorly understood. There may be a role for such factors as personal hygiene, socioeconomic status, living standards, and exposure to various bacterial, parasitic, and viral infections. In addition, ionizing radiation and a variety of chemicals, such as fertilizers and herbicidal agents, have been implicated. 7,16 In Saudi Arabia, the practice of intermarriage within families may be an additional contributing factor. Conceivably, such marriages could result in an abnormal aggregation of genes which are especially susceptible to development of aggressive lymphoma. Detailed epidemiologic studies are needed in order to understand the etiology and pathogenesis of malignant lymphoma in this country. Malignant lymphoma represents a major challenge to the medical profession in Saudi Arabia, not only because it is one of the commonest malignancies but also because an overwhelming majority of the lymphomas in this country are aggressive in nature. The aggressive lymphomas are a major group of non-hodgkin's lymphomas characterized by advanced disease in most cases and a rapidly progressive clinical course. Until recently, the disease was fatal, with most of the patients dying within 1 to 2 years. However, over the last 10 years, use of intermittent high-dose combination chemotherapy has significantly increased the survival time for patients with both local and advanced disease. It is also felt that many of the patients can be cured if the complete remission can be sustained for 2 years or more. Paradoxically, these tumors may have a better prognosis than indolent lymphomas if they are aggressively and appropriately treated. 17,18 In our series, 37.3% of the large cell lymphomas were the T-cell type. This is considerably higher than the frequencies reported in most of the studies (Table 3). In some geographic locations, notably southwestern Japan, the Caribbean islands, and eastern China, an endemic infection by human T-cell leukemia virus type 1 (HTLV-1) is associated with an increased incidence of a particularly aggressive form of peripheral T-cell lymphoma.7,19-21 The possibility of a relationship between HTLV-1 infection and increased incidence of T-cell lymphoma in Saudi Arabia is intriguing. Unfortunately, there are no published data available regarding the frequency of HTLV-1 infection in the Saudi population in general, and Saudi patients with malignant lymphoma in particular. In our laboratory, HTLV-1 antibody determinations were performed in 130 consecutive patients with malignant lymphoma. Of these, only seven (5.4%) were positive. These included five T-cell and two B-cell lymphomas. While the numbers of patients studied for HTLV-1 infection in our series are small, the data seem to indicate that HTLV-1 infection may be responsible for at least some of the T-cell lymphomas in this country. Further studies are currently under way at our institution to assess the role of HTLV-1 infection in the pathogenesis of malignant lymphoma in Saudi Arabia. Acknowledgment The authors thank Richard Kadlup and Phil Yri for their technical help and Erlinda M. Umali for secretarial assistance. References 1. Mahboubi E. Epidemiology of cancer in Saudi Arabia Ann Saudi Med 1987;7(4): Gelpi AP. Malignant lymphoma in the Saudi Arab. Cancer 1970;25: Bin Ahmed OS, Sabbah RS. Childhood non-hodgkin's lymphoma in Saudi Arabia: clinical features of 100 cases. King Faisal Spec Hosp Med J 1982;2(4): Sabbah RS, Ali MA, Lewall DB, Aur RJA. Burkitt's lymphoma in Saudi Arabia: clinical, pathological, and epidemiological analyses of 16 cases. King Faisal Spec Hosp Med J 1982;2(2): The non-hodgkin's Lymphoma Pathologic Classification Project. National Cancer Institute sponsored study of classification of non-hodgkin's lymphomas: summary and description of a working formulation for clinical usage. Cancer 1982;49: Mann RB, Berard CW. Criteria for cytologic subclassification of follicular lymphomas: a proposed alternative method. Hematol Oncol 1983;1(2): Harrington DS, Ye YL, Weisenburger DD, et al. Malignant lymphoma in Nebraska and Guangzhou, China: a comparative study. Human Pathol 1987;18(9):924-8.

7 8. Newell GR, Cabanillas FG, Hagemeister FJ, Butler JJ. Incidence of lymphomas in the US classified by the working formulation. Cancer 1987;59(4): Pallesen G, Madsen M, Schifter S. Immune marker expression in 53 lymphomas of high-grade malignancy. Histopathology 1983;7(6): Doggett RS, Wood GS, Horning S, et al. The immunologic characterization of 95 nodal and extranodal diffuse large cell lymphomas in 89 patients. Am J Pathol 1984;115(2): Aisenberg AC, Wilkes BM, Long JC, Harris NL. Cell surface phenotype in lymphoproliferative disease. Am J Med 1980;68(2): Rudders RA, Ahl ET, DeLellis RA. Surface marker and histopathologic correlation with long-term survival in advanced large-cell non-hodgkin's lymphoma. Cancer 1981;47(6): Cossman J, Jaffe ES, Fisher RI. Immunologic phenotypes of diffuse, aggressive, non-hodgkin's lymphomas: correlations with clinical features. Cancer 1984;54(7): Hoppe RT. Histologic variation in non-hodgkin's lymphomas: commentary. Cancer Treat Rep 1981;65(11-12): Oviatt DL, Cousar JB, Collins RO, et al. Malignant lymphomas of follicular center cell origin in humans: V. Incidence, clinical features, and prognostic implications of transformation of small cleaved cell nodular lymphoma. Cancer 1984;53(5): Miller RW. Recent advances in the epidemiology of leukemia and lymphoma in malignant lymphoma. In: Berard CW, Dorfman RF, Kaufman N, eds. International Academy of Pathology Monograph. Baltimore: Williams and Wilkins, 1987: Jaffe ES. Relationship of classification to biologic behaviour of non-hodgkin's lymphomas. Semin Oncol 1986;13(4, suppl 5): Skarin A. Diffuse aggressive lymphomas: a curable subset of non-hodgkin's lymphomas. Semin Oncol 1986;13(4, suppl 5): Uchiyama T, Yodoi J, Sagawa K, et al. Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood 1977;50(3): Jaffe ES, Blattner WA, Blayney DW, et al. The pathologic spectrum of adult T-cell leukemia/lymphoma in the United States: human T-cell leukemia/lymphoma virus-associated lymphoid malignancies. Am J Surg Pathol 1984;8(4): Catovsky D, Greaves MF, Rose M, et al. Adult T-cell lymphoma/leukemias in blacks from West Indies. Lancet 1982;1(8273):

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