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Pathology International 2014; 64: 527–532
doi:10.1111/pin.12197
Case Report
A case of diffuse large B-cell lymphoma transformed from primary duodenal follicular lymphoma
Tomoko Miyata-Takata,1 Katsuyoshi Takata,1 Yasuharu Sato,1 Kohei Taniguchi,1 Yuka Takahashi,2 Nobuya Ohara2 and Tadashi Yoshino1 1
Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and 2Department of Pathology, Japanese Red Cross Okayama Hospital, Okayama, Japan
Primary intestinal follicular lymphoma (FL) is a variant of FL characterized by frequent duodenal involvement and a very indolent clinical behavior without therapy. Unlike nodal FL, there have been no reports of histologic transformation (HT) or death attributable to primary intestinal FL. Here, we report the first case of primary duodenal FL showing HT. A Grade 1 FL in the duodenum was incidentally detected in a 73-year-old man. A watch-and-wait strategy was adopted because the disease was stage IE. Six months later, bone marrow involvement was suspected. The intestinal lesions had not changed during the first year since the initial diagnosis. Sixty-two months after the initial diagnosis, a biopsy specimen showed diffuse large B-cell lymphoma (DLBCL). A perforation of the intestine occurred before chemotherapy was started. Partial resection was performed and subsequent chemotherapy was administered. The clone of the initial FL and DLBCL were identical according to PCR analysis, indicating that the primary intestinal FL had transformed into DLBCL. Although HT is rare, it could occur in some patients with primary intestinal FL. Based on this case, it may be necessary to re-evaluate the clinical watchand-wait strategy for primary intestinal FL in some patients. Key words: transformation
clonality,
follicular
lymphoma,
intestine,
In extranodal B-cell lymphoma, the gastrointestinal tracts are the most frequently involved sites. Primary intestinal follicular lymphoma (FL) has characteristic clinicopathological traits
Correspondence: Katsuyoshi Takata, MD, PhD, Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, kita-ku, Okayama City, Okayama 700-8558, Japan. Email: katsuyoshi.t @h5.dion.ne.jp Conflicts of interest: The authors declare that they have no conflict of interest. Funding sources: None. Received 7 May 2014. Accepted for publication 31 July 2014. © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
and is documented as a variant of FL in the current WHO classification.1 In most cases of primary intestinal FL, the lesions are located in the duodenum. In a previous case series, we observed that primary duodenal FL accounted for 61% of all primary intestinal FLs. Further, we determined that primary duodenal FL has characteristic clinicopathological features; small whitish nodules in endoscopic examination were specific to duodenal FL and had a diagnostically useful appearance. Compared with nodal FL, duodenal FL was usually a localized disease and could be followed-up without any therapy in most cases. However, nodal and duodenal FL did not differ in terms of morphology, immunohistochemical results, or BCL2 translocation.2,3 In our previous report, which investigated 125 cases of primary intestinal FL (including primary duodenal FL), the 5-year overall and progression-free survival rates were 100% and 93%, respectively, indicating that primary intestinal FL is quite indolent in comparison with nodal FL. During the follow-up period (median follow-up: 40 months) only 6 cases (5%) showed disease progression, and no patient died of this disease or showed histological transformation (HT).2 In a retrospective clinicopathological analysis of 63 cases of stage I duodenal FL, Schmatz et al. found that all patients achieved complete remission or stable disease following eradication alone, rituximab alone, or watchful waiting. Indeed, no deaths were attributable to this disease and no cases showed HT.3 Accordingly, duodenal FL is a very indolent FL. In the present case, the final diagnosis was diffuse large B-cell lymphoma (DLBCL) that had transformed from primary duodenal FL. This is the first case of HT from duodenal FL to the best of our knowledge and, here, we describe its clinicopathological and molecular characteristics.
CLINICAL SUMMARY A 73-year-old man was incidentally found to have small whitish nodules in the duodenum by an endoscopic
528
T. Miyata-Takata et al.
Figure 1 (a) Endoscopic examination (right: stained by indigocarmine). Characteristic small whitish polypoid lesions were found in the duodenum. (b) Flow cytometric analysis of the peripheral blood. Abnormal B-cell clusters of CD20+ and lambda-chain+ phenotype were found.
examination, which were diagnosed as FL Grade 1 by histological examination (Fig. 1a). He had no B symptoms and no other lesions, including bone marrow (BM) or lymph nodes lesions, in a positron emission tomography (PET)–computed tomography (CT) scan. There was no detected involvement of lymphoma by bone marrow examination. The disease was estimated to be at Ann Arbor stage IE and Lugano classification stage I, and the patient was estimated to be at low risk according to the Follicular Lymphoma International Prognostic Index (FLIPI). Accordingly, he was followed-up without any treatment.4,5 Six months after the diagnosis, an increased white blood cell (WBC) count was identified in the peripheral blood (PB), although the case’s histology of the duodenum remained FL Grade 1. Flow cytometric analysis of PB showed increased B-cells with light chain restriction, and involvement of the BM and PB was suspected (Fig. 1b). BM examination was not performed. Because the increase in lymphocytes persisted 15 months after it was first identified, administration of etoposide alone was initiated (1 year 9 months after the initial diagnosis). A whole gastrointestinal examination using capsule endoscopy found multiple FL lesions from the jejunum to the ileum. There was no bulky mass. No progression of the multiple lesions was observed, even 1 year after the whole gastrointestinal exami-
nation. Thirteen months after starting etoposide, it was changed to cyclophosphamide and prednisolone because the patient complained of nausea. Five months later, anemia deteriorated, with little recovery even following transfusion. A biopsy of the duodenum was performed 1 year later (5 years 2 months after the initial diagnosis) and showed DLBCL. Chemotherapy was scheduled because a PET–CT scan indicated substantial tumor burden. In the meantime, however, a perforation of the ileum occurred and an emergency operation was performed. Histological examination of the surgical specimen showed DLBCL. After the operation, the patient received half dose of THP-COP (pirarubicin, cyclophosphamide, vincristine, and prednisolone) therapy and is in the 6th course. Hepatic lesions detected before the chemotherapy reduced remarkably and no new lesions have emerged so far.
PATHOLOGICAL FINDINGS The histological appearance of the initial duodenal biopsy specimen is presented in Fig. 2. Small- to medium-sized cleaved lymphoid cells proliferated in the mucosal to submucosal area, forming compact follicles. Large cells were not mixed. The proliferating cells were CD20+, CD3−, CD10+, and BCL2+ by immunohistochemistry. Antibodies and
© 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
Transform of duodenal follicular lymphoma
529
Figure 2 (a) Follicular lymphoma Grade 1 arising in the duodenum (primary lesion). The neoplastic follicles were present in the mucosa. (b) At higher power, tumor cells were composed of small cleaved lymphoid cells. The follicles were positive for (c) CD20, (d) CD10, and (e) BCL2. (f) Follicular dendritic cells highlighted by CD21 were located at the periphery of the follicles, showing the duodenal pattern. (g) The Ki-67 labeling index was low.
dilutions were listed in the Table 1. The Ki-67 labeling index was low (90%), there is a unique FDC structure that is only present on the periphery of the neoplastic follicles and is termed the ‘duodenal pattern’.6 This duodenal pattern of FDCs was evident in the present case. It has been reported that many cases of the HT of nodal FL are accompanied by additional genomic aberrations, including in MYC.13 In this case’s DLBCL specimen, overexpression of MYC protein was detected by immunohistochemistry, but an MYC translocation was not found. This HT occurred through a mechanism other than a double hit that included BCL2 and MYC. Overexpression of MYC protein through another mechanism might also lead to HT. For nodal FL, it has been assumed that a single case can include multiple progenitor cells that are capable of HT.14,15 In the present case, the PCR analysis of the DLBCL sample (i.e., the transformed FL) revealed that the main peak was accompanied by a shorter and lower peak at 106nt (Fig. 4b). Although the investigation of this lower peak was not successful, its presence suggests the existence of a new minor clone in the DLBCL. In summary, we have reported the first case of primary duodenal FL showing HT. HT is rare, but could occur in patients with primary intestinal FL. The clinical watch-andwait strategy for primary intestinal FL may need to be re-evaluated in a further investigation that includes a larger number of cases.
© 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
532
T. Miyata-Takata et al.
REFERENCES 1 Swerdlow SH, Campo E, Harris NL et al., eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edn. Lyon: International Agency for Research on Cancer, 2008. 2 Takata K, Okada H, Ohmiya N et al. Primary gastrointestinal follicular lymphoma involving the duodenal second portion is a distinct entity: A multicenter, retrospective analysis in Japan. Cancer Sci 2011; 102: 1532–6. 3 Schmatz AI, Streubel B, Kretschmer-Chott E et al. Primary follicular lymphoma of the duodenum is a distinct mucosal/ submucosal variant of follicular lymphoma: A retrospective study of 63 cases. J Clin Oncol 2011; 29: 1445–51. 4 Zucca E, Roggero E, Bertoni F, Cavalli F. Primary extranodal non-Hodgkin’s lymphomas. Part 1: Gastrointestinal, cutaneous and genitourinary lymphomas. Ann Oncol 1997; 8: 727–37. 5 Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res 1971; 31: 1860–61. 6 Takata K, Sato Y, Nakamura N et al. Duodenal and nodal follicular lymphomas are distinct: The former lacks activationinduced cytidine deaminase and follicular dendritic cells despite ongoing somatic hypermutations. Mod Pathol 2009; 22: 940– 49. 7 van Dongen JJ, Langerak AW, Bruggemann M et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: Report of the BIOMED-2
8
9
10
11
12
13 14 15
Concerted Action BMH4-CT98-3936. Leukemia 2003; 17: 2257–317. Miyata-Takata T, Takata K, Yamanouchi S et al. Detection of T-cell receptor gamma gene rearrangement in paraffinembedded T or natural killer/T-cell lymphoma samples using the BIOMED-2 protocol. Leuk Lymphoma 2014; 55: 2161–4. Yano T, van Krieken JH, Magrath IT, Longo DL, Jaffe ES, Raffeld M. Histogenetic correlations between subcategories of small noncleaved cell lymphomas. Blood 1992; 79: 1282– 90. Montoto S, Davies AJ, Matthews J et al. Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol 2007; 25: 2426–33. Takata K, Tanino M, Ennishi D et al. Duodenal follicular lymphoma: Comprehensive gene expression analysis with insights into pathogenesis. Cancer Sci 2014; 105: 608–15. Gine E, Montoto S, Bosch F et al. The Follicular Lymphoma International Prognostic Index (FLIPI) and the histological subtype are the most important factors to predict histological transformation in follicular lymphoma. Ann Oncol 2006; 17: 1539–45. Pasqualucci L, Khiabanian H, Fangazio M et al. Genetics of follicular lymphoma transformation. Cell Rep 2014; 6: 130–40. Montoto S, Fitzgibbon J. Transformation of indolent B-cell lymphomas. J Clin Oncol 2011; 29: 1827–34. Okosun J, Bodor C, Wang J et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet 2014; 46: 176–81.
© 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
Copyright of Pathology International is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Pathology International 2014; 64: 527–532
doi:10.1111/pin.12197
Case Report
A case of diffuse large B-cell lymphoma transformed from primary duodenal follicular lymphoma
Tomoko Miyata-Takata,1 Katsuyoshi Takata,1 Yasuharu Sato,1 Kohei Taniguchi,1 Yuka Takahashi,2 Nobuya Ohara2 and Tadashi Yoshino1 1
Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and 2Department of Pathology, Japanese Red Cross Okayama Hospital, Okayama, Japan
Primary intestinal follicular lymphoma (FL) is a variant of FL characterized by frequent duodenal involvement and a very indolent clinical behavior without therapy. Unlike nodal FL, there have been no reports of histologic transformation (HT) or death attributable to primary intestinal FL. Here, we report the first case of primary duodenal FL showing HT. A Grade 1 FL in the duodenum was incidentally detected in a 73-year-old man. A watch-and-wait strategy was adopted because the disease was stage IE. Six months later, bone marrow involvement was suspected. The intestinal lesions had not changed during the first year since the initial diagnosis. Sixty-two months after the initial diagnosis, a biopsy specimen showed diffuse large B-cell lymphoma (DLBCL). A perforation of the intestine occurred before chemotherapy was started. Partial resection was performed and subsequent chemotherapy was administered. The clone of the initial FL and DLBCL were identical according to PCR analysis, indicating that the primary intestinal FL had transformed into DLBCL. Although HT is rare, it could occur in some patients with primary intestinal FL. Based on this case, it may be necessary to re-evaluate the clinical watchand-wait strategy for primary intestinal FL in some patients. Key words: transformation
clonality,
follicular
lymphoma,
intestine,
In extranodal B-cell lymphoma, the gastrointestinal tracts are the most frequently involved sites. Primary intestinal follicular lymphoma (FL) has characteristic clinicopathological traits
Correspondence: Katsuyoshi Takata, MD, PhD, Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, kita-ku, Okayama City, Okayama 700-8558, Japan. Email: katsuyoshi.t @h5.dion.ne.jp Conflicts of interest: The authors declare that they have no conflict of interest. Funding sources: None. Received 7 May 2014. Accepted for publication 31 July 2014. © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
and is documented as a variant of FL in the current WHO classification.1 In most cases of primary intestinal FL, the lesions are located in the duodenum. In a previous case series, we observed that primary duodenal FL accounted for 61% of all primary intestinal FLs. Further, we determined that primary duodenal FL has characteristic clinicopathological features; small whitish nodules in endoscopic examination were specific to duodenal FL and had a diagnostically useful appearance. Compared with nodal FL, duodenal FL was usually a localized disease and could be followed-up without any therapy in most cases. However, nodal and duodenal FL did not differ in terms of morphology, immunohistochemical results, or BCL2 translocation.2,3 In our previous report, which investigated 125 cases of primary intestinal FL (including primary duodenal FL), the 5-year overall and progression-free survival rates were 100% and 93%, respectively, indicating that primary intestinal FL is quite indolent in comparison with nodal FL. During the follow-up period (median follow-up: 40 months) only 6 cases (5%) showed disease progression, and no patient died of this disease or showed histological transformation (HT).2 In a retrospective clinicopathological analysis of 63 cases of stage I duodenal FL, Schmatz et al. found that all patients achieved complete remission or stable disease following eradication alone, rituximab alone, or watchful waiting. Indeed, no deaths were attributable to this disease and no cases showed HT.3 Accordingly, duodenal FL is a very indolent FL. In the present case, the final diagnosis was diffuse large B-cell lymphoma (DLBCL) that had transformed from primary duodenal FL. This is the first case of HT from duodenal FL to the best of our knowledge and, here, we describe its clinicopathological and molecular characteristics.
CLINICAL SUMMARY A 73-year-old man was incidentally found to have small whitish nodules in the duodenum by an endoscopic
528
T. Miyata-Takata et al.
Figure 1 (a) Endoscopic examination (right: stained by indigocarmine). Characteristic small whitish polypoid lesions were found in the duodenum. (b) Flow cytometric analysis of the peripheral blood. Abnormal B-cell clusters of CD20+ and lambda-chain+ phenotype were found.
examination, which were diagnosed as FL Grade 1 by histological examination (Fig. 1a). He had no B symptoms and no other lesions, including bone marrow (BM) or lymph nodes lesions, in a positron emission tomography (PET)–computed tomography (CT) scan. There was no detected involvement of lymphoma by bone marrow examination. The disease was estimated to be at Ann Arbor stage IE and Lugano classification stage I, and the patient was estimated to be at low risk according to the Follicular Lymphoma International Prognostic Index (FLIPI). Accordingly, he was followed-up without any treatment.4,5 Six months after the diagnosis, an increased white blood cell (WBC) count was identified in the peripheral blood (PB), although the case’s histology of the duodenum remained FL Grade 1. Flow cytometric analysis of PB showed increased B-cells with light chain restriction, and involvement of the BM and PB was suspected (Fig. 1b). BM examination was not performed. Because the increase in lymphocytes persisted 15 months after it was first identified, administration of etoposide alone was initiated (1 year 9 months after the initial diagnosis). A whole gastrointestinal examination using capsule endoscopy found multiple FL lesions from the jejunum to the ileum. There was no bulky mass. No progression of the multiple lesions was observed, even 1 year after the whole gastrointestinal exami-
nation. Thirteen months after starting etoposide, it was changed to cyclophosphamide and prednisolone because the patient complained of nausea. Five months later, anemia deteriorated, with little recovery even following transfusion. A biopsy of the duodenum was performed 1 year later (5 years 2 months after the initial diagnosis) and showed DLBCL. Chemotherapy was scheduled because a PET–CT scan indicated substantial tumor burden. In the meantime, however, a perforation of the ileum occurred and an emergency operation was performed. Histological examination of the surgical specimen showed DLBCL. After the operation, the patient received half dose of THP-COP (pirarubicin, cyclophosphamide, vincristine, and prednisolone) therapy and is in the 6th course. Hepatic lesions detected before the chemotherapy reduced remarkably and no new lesions have emerged so far.
PATHOLOGICAL FINDINGS The histological appearance of the initial duodenal biopsy specimen is presented in Fig. 2. Small- to medium-sized cleaved lymphoid cells proliferated in the mucosal to submucosal area, forming compact follicles. Large cells were not mixed. The proliferating cells were CD20+, CD3−, CD10+, and BCL2+ by immunohistochemistry. Antibodies and
© 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
Transform of duodenal follicular lymphoma
529
Figure 2 (a) Follicular lymphoma Grade 1 arising in the duodenum (primary lesion). The neoplastic follicles were present in the mucosa. (b) At higher power, tumor cells were composed of small cleaved lymphoid cells. The follicles were positive for (c) CD20, (d) CD10, and (e) BCL2. (f) Follicular dendritic cells highlighted by CD21 were located at the periphery of the follicles, showing the duodenal pattern. (g) The Ki-67 labeling index was low.
dilutions were listed in the Table 1. The Ki-67 labeling index was low (90%), there is a unique FDC structure that is only present on the periphery of the neoplastic follicles and is termed the ‘duodenal pattern’.6 This duodenal pattern of FDCs was evident in the present case. It has been reported that many cases of the HT of nodal FL are accompanied by additional genomic aberrations, including in MYC.13 In this case’s DLBCL specimen, overexpression of MYC protein was detected by immunohistochemistry, but an MYC translocation was not found. This HT occurred through a mechanism other than a double hit that included BCL2 and MYC. Overexpression of MYC protein through another mechanism might also lead to HT. For nodal FL, it has been assumed that a single case can include multiple progenitor cells that are capable of HT.14,15 In the present case, the PCR analysis of the DLBCL sample (i.e., the transformed FL) revealed that the main peak was accompanied by a shorter and lower peak at 106nt (Fig. 4b). Although the investigation of this lower peak was not successful, its presence suggests the existence of a new minor clone in the DLBCL. In summary, we have reported the first case of primary duodenal FL showing HT. HT is rare, but could occur in patients with primary intestinal FL. The clinical watch-andwait strategy for primary intestinal FL may need to be re-evaluated in a further investigation that includes a larger number of cases.
© 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
532
T. Miyata-Takata et al.
REFERENCES 1 Swerdlow SH, Campo E, Harris NL et al., eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edn. Lyon: International Agency for Research on Cancer, 2008. 2 Takata K, Okada H, Ohmiya N et al. Primary gastrointestinal follicular lymphoma involving the duodenal second portion is a distinct entity: A multicenter, retrospective analysis in Japan. Cancer Sci 2011; 102: 1532–6. 3 Schmatz AI, Streubel B, Kretschmer-Chott E et al. Primary follicular lymphoma of the duodenum is a distinct mucosal/ submucosal variant of follicular lymphoma: A retrospective study of 63 cases. J Clin Oncol 2011; 29: 1445–51. 4 Zucca E, Roggero E, Bertoni F, Cavalli F. Primary extranodal non-Hodgkin’s lymphomas. Part 1: Gastrointestinal, cutaneous and genitourinary lymphomas. Ann Oncol 1997; 8: 727–37. 5 Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res 1971; 31: 1860–61. 6 Takata K, Sato Y, Nakamura N et al. Duodenal and nodal follicular lymphomas are distinct: The former lacks activationinduced cytidine deaminase and follicular dendritic cells despite ongoing somatic hypermutations. Mod Pathol 2009; 22: 940– 49. 7 van Dongen JJ, Langerak AW, Bruggemann M et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: Report of the BIOMED-2
8
9
10
11
12
13 14 15
Concerted Action BMH4-CT98-3936. Leukemia 2003; 17: 2257–317. Miyata-Takata T, Takata K, Yamanouchi S et al. Detection of T-cell receptor gamma gene rearrangement in paraffinembedded T or natural killer/T-cell lymphoma samples using the BIOMED-2 protocol. Leuk Lymphoma 2014; 55: 2161–4. Yano T, van Krieken JH, Magrath IT, Longo DL, Jaffe ES, Raffeld M. Histogenetic correlations between subcategories of small noncleaved cell lymphomas. Blood 1992; 79: 1282– 90. Montoto S, Davies AJ, Matthews J et al. Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol 2007; 25: 2426–33. Takata K, Tanino M, Ennishi D et al. Duodenal follicular lymphoma: Comprehensive gene expression analysis with insights into pathogenesis. Cancer Sci 2014; 105: 608–15. Gine E, Montoto S, Bosch F et al. The Follicular Lymphoma International Prognostic Index (FLIPI) and the histological subtype are the most important factors to predict histological transformation in follicular lymphoma. Ann Oncol 2006; 17: 1539–45. Pasqualucci L, Khiabanian H, Fangazio M et al. Genetics of follicular lymphoma transformation. Cell Rep 2014; 6: 130–40. Montoto S, Fitzgibbon J. Transformation of indolent B-cell lymphomas. J Clin Oncol 2011; 29: 1827–34. Okosun J, Bodor C, Wang J et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet 2014; 46: 176–81.
© 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
Copyright of Pathology International is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
