A 77-year-old Japanese woman who had been treated for follicular lymphoma for 8 years developed abdominal pain and intra-abdominal lymphadenopathies. Colonoscopy revealed an elevated lesion in the rectum, which presented as two humps with erosions. A diagnosis of histologic transformation of follicular lymphoma to diffuse large B-cell lymphoma was made by endoscopic biopsy. This case underscores the importance of endoscopy examinations and biopsy of newly emerged gastrointestinal lesions for the prompt diagnosis of histologic transformation, since salvage chemotherapy must be initiated quickly in such cases

Asada, Noboru

Hiraoka, Sakiko

Iwamuro, Masaya

Kawahara, Yoshiro

Matsuoka, Ken-ichi

Okada, Hiroyuki

Tanaka, Takehiro

Yamasaki, Yasushi

English

Okayama University Scientific Achievement Repository

M ost patients with follicular lymphoma have an indolent clinical course [1 , 2].  However,  devel-opment of a high-grade,  aggressive non-Hodgkin lym-phoma occurs in some follicular lymphoma patients via a process called histologic transformation [3].  Because histologic transformation necessitates prompt initiation of treatment,  the diagnosis of histologic transformation is crucial in the management of follicular lymphoma.We herein report the case of a follicular lymphoma patient who had histologic transformation to diffuse large B-cell lymphoma (DLBCL).  Of note,  histologic transformation was detected during colonoscopy as a newly emerged rectal lesion.  Endoscopic features of the colorectal lesions of follicular lymphoma and DLBCL are discussed later in this report.Case PresentationA 69-year-old Japanese woman visited her family clinic with abdominal pain.  Computed tomography (CT) scanning revealed intra-abdominal and inguinal lymphadenopathies.  She was referred to our hospital for further investigation and treatment.  A diagnosis of follicular lymphoma (grade 1,  stage IIA) was made by biopsy examination of the inguinal lymph nodes.  Six cycles of cyclophosphamide,  doxorubicin,  vincristine,  prednisone,  and rituximab resulted in a decrease of the lymphadenopathies.  However,  tracer uptake persisted in the mesenteric lymph nodes on fluorodeoxyglucose- positron emission tomography (FDG-PET).  At 71 years of age her mesenteric lymph nodes were enlarged again,  and she was treated with 6 cycles of bendamustine and rituximab.  Her right neck lymph nodes were still avid for FDG-PET tracer after bendamustine and rituximab treatment.  Thus,  rituximab monotherapy,  spaced 3 to Acta Med.  Okayama,  2021Vol.  75,  No.  5,  pp.  625-629CopyrightⒸ 2021 by Okayama University Medical School.http ://escholarship.lib.okayama-u.ac.jp/amo/Case ReportHistologic Transformation from Follicular Lymphoma to Diffuse Large B-cell Lymphoma Detected during ColonoscopyMasaya Iwamuroa＊,  Yasushi Yamasakia,  Takehiro Tanakab,  Noboru Asadac,   Ken-ichi Matsuokac,  Sakiko Hiraokaa,  Yoshiro Kawaharad,  and Hiroyuki OkadaaDepartments of aGastroenterology and Hepatology,  bPathology,  and cHematology and Oncology,  Okayama University Graduate School of Medicine,  Dentistry and Pharmaceutical Sciences,   dDepartment of Practical Gastrointestinal Endoscopy,  Okayama University Hospital,  Okayama 700-8558,  JapanA 77-year-old Japanese woman who had been treated for follicular lymphoma for 8 years developed abdominal pain and intra-abdominal lymphadenopathies.  Colonoscopy revealed an elevated lesion in the rectum,  which presented as two humps with erosions.  A diagnosis of histologic transformation of follicular lymphoma to dif-fuse large B-cell lymphoma was made by endoscopic biopsy.  This case underscores the importance of endos-copy examinations and biopsy of newly emerged gastrointestinal lesions for the prompt diagnosis of histologic transformation,  since salvage chemotherapy must be initiated quickly in such cases.Key words:  colorectal lymphoma,  follicular lymphoma,  diffuse large B-cell lymphoma,  histologic transformationReceived February 17, 2021 ; accepted March 25, 2021.＊Corresponding author. Phone : +81-86-235-7218; Fax : +81-86-225-5991E-mail : iwamuromasaya@yahoo.co.jp (M. Iwamuro)Conflict of Interest Disclosures: No potential conflict of interest relevant to this article was reported.4 months apart,  i.e.,  rituximab maintenance,  was started at 72 years of age.  Colonoscopy performed at 72 years of age revealed an adenoma in the rectosig-moid junction,  while there was no lymphoma involve-ment in the colorectum.At 77 years of age,  the patient experienced persistent abdominal pain.  Physical examination revealed no abnormalities,  and there was no evidence of hepato-splenomegaly or peripheral lymphadenopathy.  Laboratory tests showed slightly elevated values for lactate dehydrogenase (237 U/L;  normal range: 124-222 U/L),  aspartate aminotransferase (38 U/L),  alkaline phosphatase (394 U/L),  urea nitrogen (28.1 mg/dL),  creatinine (0.82 mg/dL),  and uremic acid (6.6 mg/dL).  Her hemoglobin,  serum calcium,  and soluble interleu-kin 2-recepter levels were within the normal ranges.  Computed tomography revealed intra-abdominal lymphadenopathies (Fig . 1A) and tracer accumulation was observed on FDG-PET (Fig . 1B).  Therefore,  lym-phoma progression was considered to be the cause of her abdominal pain.Colonoscopy revealed an elevated lesion in the rec-tum,  which presented as 2 humps with subepithelial tumor-like appearance (Fig . 2A).  Linked color imaging observation (Fig . 2B) and indigo carmine dye spraying (Fig . 2C) emphasized the lesion’s reddish color.  Magnifying observation with blue laser imaging showed dilated microvessels (Fig . 2D) and erosions (Fig . 2E) on the surface.  Because the colorectum had been intact on colonoscopy performed 5 years previously,  we sus-pected the lesion to be a lymphomatous rectal involve-ment.  A biopsy showed dense infiltration of atypical lymphoid cells of medium to large size in the intersti-tium (Fig . 3A).  Immunostaining revealed that the lym-phoid cells were positive for CD20 (Fig . 3B),  CD10 (Fig . 3C),  and BCL2 (Fig . 3D),  and were negative for CD3 (Fig . 3E) and CD5 (Fig . 3F).  Cells were diffusely 626 Iwamuro et al. Acta Med.  Okayama　Vol.  75,  No.  5BAFig. 1　 Radiological images.  Computed tomography revealed intra-abdominal lymphadenopathies (A).  Fluorodeoxyglucose-positron emission tomography showed tracer accumulation in the lymph nodes (B).A BD ECFig. 2　 Colonoscopy images.  An elevated lesion is observed in the rectum (A).  Linked color imaging observation (B) and indigo carmine dye spraying (C) emphasized the lesionʼs reddish color.  Magnifying observation with blue laser imaging revealed dilated microvessels (D) and erosions (E).positive for Ki-67 (Fig . 3G).  Therefore,  we diagnosed the patient with histologic transformation of follicular lymphoma to DLBCL.  Salvage chemotherapy with 6 cycles of bendamustine and rituximab resulted in the disappearance of metabolic tumor activity in lym-phoma lesions on FDG-PET.DiscussionIn the patient presented in this case report,  histo-logic transformation of follicular lymphoma to DLBCL occurred during maintenance therapy with rituximab.  Histologic transformation is generally defined as an increase in the proportion of large cells infiltrating the lymph nodes diffusely and leading to effacement of the follicular architecture [3-5].  Clinically,  DLBCL is the most commonly observed histologic transformation of follicular lymphoma.  The annual incidence of histo-logic transformation of grade 1,  2,  and 3a follicular lymphoma into an aggressive lymphoma has been esti-mated at 1% to 2% [6].  An open-label,  multicenter,  international,  randomized phase III study of 2 years of rituximab maintenance after first-line immunochemo-therapy (PRIMA study) revealed that rituximab mainte-nance provided a significant long-term progression-free survival in follicular lymphoma patients,  whereas such maintenance was not associated with a difference in overall survival [7 , 8].  The prevalence of and time to histologic transformation were not different between patients with and without rituximab maintenance.  Thus,  the evolution of follicular lymphoma to a clini-cally aggressive lymphoma can occur even during maintenance therapy with rituximab,  as observed in our patient.In the present case,  transformation to DLBCL was pathologically confirmed by endoscopic biopsy of the rectal lesion.  In our earlier work,  we investigated the endoscopic features of colorectal lesions in 12 patients with follicular lymphoma [9 , 10].  Macroscopic appear-ance of colorectal follicular lymphoma was classified as papular (n = 4),  polypoid (n = 4),  and flat elevated lesions (n = 4).  We also reviewed 8 previously reported cases in which detailed morphological characteristics of colorectal involvement with follicular lymphoma were described [11-18].  Among these cases,  the macro-scopic appearance of the colorectal lesions could be categorized into papular (n = 1),  polypoid (n = 5),  and flat elevated (n = 1),  with ulcerative tumor occurring in only one patient with grade 3a follicular lymphoma [19].  Apart from the latter exceptional case [19],  no erosions or ulcers were found in the previously reported cases.  Therefore,  we speculate that follicular lymphoma,  particularly that of grade 1-2,  presents as elevated lesions without erosions or ulcers in the colorectum.Colorectal lesions of DLBCL exhibit a diverse range of morphologies,  including ulcers [20 , 21],  large masses with or without ulceration [22-24],  nodular masses [25],  and colitis-like changes [26].  Maeshima et al.  investigated the clinicopathological characteristics of 126 patients with DLBCL involving the small and October 2021 Histologic Transformation of Lymphoma 627CD20CD5CD3 Ki-67CD10 BCL2AEBFC DGFig. 3　 Pathology images.  A biopsy shows dense infiltration of atypical lymphoid cells (A).  The lymphoid cells are positive for CD20 (B),  CD10 (C),  and BCL2 (D), and are negative for CD3 (E) and CD5 (F).  Cells are diffusely positive for Ki-67 (G).large intestines [27].  They reported that rectal lesions were observed as ulcerated (n = 1,  17%),  nodular (n = 2,  33%),  multiple polyposis (n = 2,  33%),  and flat elevated (n = 1,  17%).  Ileocecal lesions of DLBCL most frequently presented as ulcerated (n = 31,  56%),  fol-lowed by nodular (n = 22,  39%),  and flat elevated lesions (n = 3,  5%).  In the colon,  ulcerated (n = 8,  73%),  nodular (n = 2,  18%),  and flat elevated lesions (n = 1,  9%) were observed.  Thus,  ulcerative lesions are predominant features of DLBCL occurring in the large intestine,  while follicular lymphoma lesions in the large intestine generally lack erosions or ulcers.  We speculate that histologic transformation should be considered when colorectal lesions with erosions and/or ulcers emerge in patients with follicular lymphoma,  as observed in the present patient.It was also noteworthy that the rectal lesion was not detected on FDG-PET but was identified during colo-noscopy.  FDG-PET is generally recommended for stag-ing of DLBCL patients because of its superior sensitivity for the detection of nodal and extra-nodal lymphoma involvement [28 , 29].  However,  because the tracer concentration corresponds to the regional glucose uptake,  it is likely that small lesions cannot be detected.  Another hypothesis is that treatment for follicular lym-phoma resulted in the false-negative FDG-PET results.  It has been reported that not a few patients with DLBCL show false-negative results for relapse after chemother-apy [29 , 30].  Moreover,  we previously investigated FDG-PET results in 41 patients with follicular lym-phoma,  and found that false-negative tracer uptake was detected in 24 patients (58.5%) [31].  In this context,  we consider that endoscopic examinations should be per-formed in follicular lymphoma patients irrespective of FDG-PET results,  in order to detect histologic trans-formation as well as lymphoma progression to the gas-trointestinal tract.In conclusion,  in our patient with follicular lym-phoma,  histologic transformation to DLBCL was iden-tified as a rectal lesion with erosions.  Although such a manifestation is considered to be infrequent,  the clini-cal course of our patient underscores the importance of endoscopy examinations and biopsy of newly emerged gastrointestinal lesions,  particularly those with ero-sions,  for prompt diagnosis of histologic transforma-tion.References 1. Dreyling M,  Ghielmini M,  Rule S,  Salles G,  Vitolo U,  Ladetto M and ESMO Guidelines Committee: Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diag-nosis,  treatment and follow-up.  Ann Oncol (2017) 28: 3109. 2. 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Histologic Transformation from Follicular Lymphoma to Diffuse Large B-cell Lymphoma Detected during Colonoscopy

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Histologic Transformation from Follicular Lymphoma to Diffuse Large B-cell Lymphoma Detected during Colonoscopy

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