p53 mutation is associated with progression in follicular lymphomas

The majority of low-grade follicular lymphomas will eventually transform to an aggressive intermediate, or high-grade lymphoma. The molecular mechanisms responsible for this transformation have not been determined. We studied serial biopsies from 34 patients with follicular lymphomas that underwent histologic transformation, for abnormalities of the p53 tumor suppressor gene by a combination of immunohistochemistry, single strand conformation polymorphism analysis (SSCP), and sequencing. We found overexpression of p53 in 10 of the 34 transformed aggressive lymphomas, 9 of which contained mutations identified by SSCP analysis and subsequent sequencing. Matched pretransformation low-grade follicular lymphoma biopsies were available for 7 of the 10 cases. None of six studied by immunohistochemistry showed overexpression of p53 and only 1 of 4 studied by SSCP/sequencing showed the presence of mutation in the pretransformation biopsy. Interestingly, an eighth p53 positive transformed lymphoma recurred with a clonally related, p53 negative low-grade lymphoma 5 years after the patient had achieved a complete remission. Immunohistochemistry also showed that several pretransformation biopsies from p53 positive transformed cases showed rare p53 positive cells and in one case we could document an increase in their number over time. Twenty-five additional low-grade follicular lymphoma biopsies were also examined. Three patients had lymphomas positive for p53 mutation. One of the three subsequently transformed within a year of the biopsy studied; the second patient had an earlier (unavailable) biopsy at a different site that showed transformed histology. The third patient was treated with ProMACE-MOPP combination chemotherapy and attained a complete remission. We conclude that (1) mutations of p53 are associated with histologic transformation in approximately 25% to 30% of follicular lymphomas and (2) p53 positive cells can be detected before histologic transformation, but do not comprise a significant percentage of the neoplastic cell population (identifiable by SSCP) until late in the disease, just before or after histologic progression. Finally, the data also suggest that p53 positive low-grade lymphomas are at risk for progression and that in this subset, aggressive therapy may be warranted.     

Autologous bone marrow transplantation in follicular non-Hodgkin's lymphoma before and after histologic transformation

Patients with disseminated follicular non-Hodgkin's lymphoma (NHL) are only occasionally cured with standard chemotherapy regimens. Although most of these tumors are initially responsive to chemotherapy, in 40% to 70% of patients the lymphoma will eventually transform to an NHL of higher grade malignancy and a poorer prognosis. We treated 18 patients having an original diagnosis of follicular NHL with high-dose therapy and autologous bone marrow transplantation. The lymphomas of 10 of the patients had already undergone histologic transformation and eight still had a follicular histologic pattern. The former group had been followed for a longer time from the diagnosis of NHL and had been more extensively treated with conventional chemotherapy regimens. All eight patients with follicular NHL at the time of transplantation are alive for 246+ to 1,804+ days and seven of the patients are in complete remission. In contrast, of the 10 patients in histologic transformation only 1 is alive and in CR. This reflects the inability of these patients to tolerate the high-dose chemotherapy and myelosuppression as well as resistance of their lymphoma to this therapy. This difference in survival between the two groups was highly significant (P = .002). We conclude that the outcome of patients with follicular NHL transplanted early before histologic transformation is better than for those who are transplanted later in the course of their illness. Because of the relapsing behavior of follicular NHL, a longer follow-up is necessary to prove any impact on the natural history of the disease.     

Two cases of discordant lymphomas consisting of MALT lymphoma and follicular lymphoma

We report here rare cases of discordant lymphoma consisting of MALT lymphoma and follicular lymphoma. Case 1: A 53-year-old woman was diagnosed with MALT lymphoma of the left parotid gland and follicular lymphoma of the duodenum and small intestine. Case 2: A 38-year-old woman was diagnosed with MALT lymphoma of the intestine and follicular lymphoma of the duodenum and bone marrow. Recently, it has been suggested that duodenal follicular lymphoma has intermediate characteristics of nodal follicular lymphoma and MALT lymphoma. It is interesting that both of these cases demonstrated duodenal follicular lymphoma. These cases suggest that MALT lymphoma and duodenal follicular lymphoma share some common pathological condition.     

p53 mutations are associated with histologic transformation of follicular lymphoma

The majority of low-grade non-Hodgkin's lymphomas (NHL) undergo clinical progression toward intermediate- and high-grade lymphomas. This progression is often associated with histologic transformation from follicular to diffuse-type NHL. The pathogenetic mechanisms underlying this evolution are presently unknown. In this study, we have analyzed the role in NHL progression of relevant genetic lesions affecting proto-oncogenes and tumor suppressor genes. Sequential biopsies from 21 patients with clinical progression with (5 cases) or without (16 cases) evidence of histologic transformation were analyzed for karyotypic changes, c-myc rearrangements and deletions affecting 6q27 by Southern blot analysis, and p53 mutations by single-strand conformation polymorphism (SSCP) analysis coupled with direct sequencing of polymerase chain reaction-amplified products. No novel cytogenetic aberration was detected in association with progression, and all samples analyzed displayed a normal c-myc gene. Mutations of the p53 gene were detected in 4 of 5 cases displaying histologic transformation from follicular to diffuse-type NHL and in none of the 16 cases displaying clinical progression in the absence of histologic transformation. In 1 of these positive cases, the same mutation was also present in the pretransformation biopsy, correlating with the presence of diffuse-type areas within a predominant follicular pattern. In 1 of these cases, a deletion of 6q27 was also detected in the posttransformation biopsy along with a p53 mutation. These findings indicate that p53 mutations are associated with and may be responsible for histologic transformation of follicular lymphoma.     

Primary duodenal lymphoma: successful rituximab treatment and evaluation by FDG-PET

A 68-year-old woman has been suffering from chronic inactive hepatitis with hepatitis C virus. Upper endoscopic and pathological findings revealed the typical features of duodenal follicular lymphoma and Helicobacter pylori (H. pylori) infection with her stomach was confirmed by the histological and cultural examinations. No other abnormal findings suspicious for tumor formation were observed by the various examinations such as computed tomography, abdominal ultrasonography and 67Ga-citrate scintigraphy. Primary duodenal follicular lymphoma: stage I according to the Modified Ann Arbor classification was diagnosed by these procedures. The eradication therapy was effective for the withdrawal of H. pylori but not for lymphoma. Four months later, abdominal ultrasonography and magnetic resonance imaging showed the progression of abdominal lymph nodes. Positron emission tomography (PET) with 18F-fluorodeoxyglucose showed radioactive uptake in mesenteric lymph nodes. Systemic chemotherapy using rituximab was started, since these findings suggested the clinical progression from stage I to II2. After 2 courses of the therapy, endoscopic and histological improvement of duodenal lymphoma and lower uptake in mesenteric lymph nodes suggested us complete remission. Rituximab may be useful for duodenal follicular lymphoma and PET with 18F-fluorodeoxyglucose has a potential value for the evaluation of mesenteric lymph nodes spread.     

Follicular lymphoma-related colitis resembling ulcerative colitis

Among the various manifestations of colonic involvement in malignant lymphomas, an ulcerative colitis-like appearance is rare. Herein, we describe a case in which extranodal colonic involvement resembled ulcerative colitis in a patient with advanced follicular lymphoma. A 59-year-old Japanese man with diarrhea and body weight loss was referred to our hospital. Computed tomography (CT) revealed systemic lymphadenopathy, splenomegaly, and thickening of the sigmoid colon and rectum walls. ¹⁸F-fluorodeoxy-glucose positron emission tomography (¹⁸F-FDG-PET/CT) revealed intense tubular ¹⁸F-FDG accumulation extending from the rectum to the colon at the hepatic flexure and much weaker accumulation in the systemic lymph nodes, bone marrow, and spleen. The isotope-enriched areas had an ulcerative colitis-like appearance as shown via colonoscopy. The patient was ultimately diagnosed with follicular lymphoma (stage IV A, grade 1) based on a pathological examination of the neck lymph nodes, iliac bone marrow, and colon. After six courses of chemotherapy (R-CHOP), ¹⁸F-FDG-PET/CT confirmed complete remission of the lymphoma including the colonic lesion. This is presumably the first case of ulcerative-like colitis caused by a follicular lymphoma. As a novel approach, the lymphoma-related colitis was detected by comparing the pathology results and the ¹⁸F-FDG-PET/CT results.     

Spontaneous remission of low-grade B-cell non-Hodgkin's lymphoma following withdrawal of methotrexate in a patient with rheumatoid arthritis: case report and review of the literature

A 69-year-old woman, who had suffered from deforming rheumatoid arthritis since the age of 40 years, had been treated with methotrexate for 3 years. She presented with a 7 week history of neck lymphadenopathy. Biopsy revealed low-grade marginal-zone B-cell non-Hodgkin's lymphoma. Computerized tomography and bone marrow biopsy confirmed stage IIIA disease. Spontaneous complete remission of the lymphoma was achieved 14 months after withdrawing immune suppression with methotrexate.     

Somatic hypermutation analysis in follicular lymphoma provides evidence suggesting bidirectional cell migration between lymph node and bone marrow during disease progression and relapse

In follicular lymphoma, somatic hypermutation of the immunoglobulin heavy chain genes facilitates the identification of different lymphoma cell clones, and the construction of genealogical trees. To investigate the dissemination of lymphoma cells, and the role of bone marrow in disease progression, we simultaneously analyzed the somatic hypermutation patterns of lymph node and bone marrow specimens taken from three patients at onset and relapse of their disease. Immunoglobulin heavy chain genes were amplified by polymerase chain reaction, cloned and sequenced. Mutational pedigrees were constructed in a hierarchical order. When direct transition of one mutation pattern into that of a successor clones was not feasible, hypothetical predecessor clones were created, and a probability measurement calculation was introduced. Eighty-five sequenced clones were generated. The average mutation rates were 13.45% for the lymph node specimens, and 9.78% for the bone marrow ones. Forty-two hypothetical predecessor clones were introduced into inter-compartment pedigrees. The genealogical trees showed that early lymphoma clones with a low mutational load quickly migrate from lymph nodes into the bone marrow. Bi-directional lymphoma cell migration was detectable between the two compartments. In one case of follicular lymphoma, a clone identical to the initial lymph node clone was detected 2 years later in the bone marrow. The newly introduced algorithm allows the evaluation of both time and direction of follicular lymphoma cell migration. We found evidence that follicular lymphoma originates in the lymph node, and infiltrates the bone marrow early in the course of the disease. Moreover, inter-compartment migration between lymph nodes and bone marrow occurs in both directions.     

What do we know about duodenal-type follicular lymphoma? From pathological definition to treatment options

Duodenal-type follicular lymphoma (DFL) is a newly recognised variant of follicular lymphoma (FL), although little is known about its biology and clinical evolution. In general, patients tend to have mild symptoms and do not require therapy, comparable with other forms of low-tumour burden asymptomatic FL. Specific pathological features, such as a dendritic cell meshwork, low expression of CD10 and upregulation of activation-induced cytidine deaminase can help the diagnosis. The molecular landscape of DFL is similar to the classical nodal presentation of FL, although studies using gene expression profiling demonstrate a close relation with MALT lymphomas. Markers associated with inflammation have suggested that the microenvironment plays a likely role in the pathogenesis of DFL and its low progression rate. Clinical series published vary between 20–63 patients with an estimated overall survival between 92–100% and a median follow-up ranging between 20 and 107 months. Treatment options include a watch and wait strategy, rituximab monotherapy and radiotherapy. In this review, we summarise current pathological data and treatment studies in DFL.     

Imaging in follicular NHL

Imaging contributes to management of follicular lymphoma (FL) through guiding biopsy, determining disease stage and assessing therapeutic response. Molecular imaging with positron emission tomography (PET), especially when combined with computer tomography (PET/CT), is more accurate than conventional imaging and extends the role of imaging to lesion characterisation, including non-invasive assessment of high-grade transformation. There is strong data to support the use of FDG PET/CT for primary staging, resulting in significant management change. In patients with early stage follicular lymphoma (stage I or II), there is a clear role for PET/CT to avoid futile involved-field radiotherapy in patients with widespread disease and to optimise the treatment field in patients with confirmed localised disease. For restaging, use of PET/CT allows discrimination between scar tissue and viable tumour in residual masses. Molecular imaging is likely to play an increasing role in selection of patients for specific treatments and in prognostic stratification.     

Pneumocystis carinii infection of bone marrow in patients with malignant lymphoma and acquired immunodeficiency syndrome. Original report of three cases

Pneumocystis carinii (PC) pneumonia was reported with increased frequency in patients presenting with acquired immunodeficiency syndrome (AIDS) or in patients receiving immunosuppressive chemotherapy for hemopathies. Extrapulmonary dissemination of PC is rare. In this study, three patients had PC infection of the bone marrow. Two of them presented with malignant lymphoma that had apparent immunosuppression, and the third patient presented with AIDS. In all three cases, such an infection was observed before or concomittantly with PC pneumonia. A bone marrow biopsy, bone marrow aspirate, or both can be useful, readily available tools for the diagnosis of a PC infection and especially its dissemination in patients with malignant lymphoma after intensive treatment or in patients with AIDS. The appreciation of such a dissemination may have some implications in the treatment of PC infection.     

Diagnosis of follicular lymphoma of the gastrointestinal tract:A better initial diagnostic workup

Due to an increasing incidence and more frequent recognition by endoscopists, gastrointestinal follicular lymphoma has been established as a variant of follicular lymphoma. However, due to its rarity, there are no established guidelines on the optimal diagnostic strategy for patients with primary gastrointestinal follicular lymphoma or secondary gastrointestinal involvement of systemic follicular lymphoma. This review offers an overview and pitfalls to avoid during the initial diagnostic workup of this disease entity. Previously reported case reports, case series, and retrospective studies are reviewed and focus on the disease’s endoscopic and histological features, the roles of computed tomography and positron emission tomography scanning, the clinical utility of the soluble interleukin-2 receptor, and the possible pathogenesis.     

Primary salivary gland lymphoma: a clinicopathologic study of 23 cases in Taiwan

Twenty-three patients with primary salivary gland lymphoma were diagnosed between 1990 and 2001. The sites of involvement were the parotid gland in 13, the submandibular gland in 9 and the minor salivary gland in 1. The sites of lymphoma involvement beyond the salivary glands were the cervical lymph nodes in 7, bone marrow in 3, the axillary lymph nodes in 3, the nasopharynx in 2, the abdominal lymph nodes in 2, the palate, the subconjunctiva, and the spleen in 1 each patient. Histologically, 19 patients had lymphomas of mucosa-associated lymphoid tissue (MALT) with myoepithelial sialadenitis in 13, 3 patients had diffuse large cell lymphomas and 1 had follicular lymphoma. Six patients were in stage I, 4 in II, 1 in III and 12 in IV. Eight of 23 patients (35%) had autoimmune diseases before or after the diagnosis of NHL and all suffered from MALT lymphoma. Four patients with parotid MALT lymphoma had primary or secondary Sjogren's syndrome. One each patient suffered from hyperthyroidism, systemic lupus erythematosus, membranoproliferative glomerulonephritis and cryoglobulinemia, respectively. All the 6 stage I patients had achieved complete remission (CR) without relapses 17-84 months (median 44 months) after treatment. Excluding a stage IV patient with follicular lymphoma who died at 3.5 months without treatment, CR was achieved in all of the remaining 16 patients. However, a high relapse rate (9/16, 56%) was noted in stage II-IV patients. These patients tended to relapse in the original sites, but achieved CR again after chemotherapy or radiotherapy. One patient with MALT lymphoma developed histologic transformation into diffuse large lymphoma during relapse and died of refractory disease. Overall, only 2 patients succumbed. The overall survival and relapse-free survival rates at 5 years were 94.7 and 51.4%, respectively. Thus, salivary gland lymphoma proved to be an indolent disease.     

Non-Hodgkin's lymphomas: characteristics of long-term survivors following conservative treatment

A most important set of prognostic factors for survival among 467 patients with non-Hodgkin's lymphoma receiving conservative treatment was determined statistically by the Cox proportional hazards model. Non-Hodgkin's lymphoma was diagnosed in these patients between 1958 and 1969. Initial biopsy material was classified according to the Working Formulation, and the Rappaport, Kiel, and Lukes-Collins systems. The Cox analysis identified a group of 37 patients with a median survival of 150 months. These patients had the following characteristics: small lymphocyte, plasmacytoid lymphocyte, small cleaved, large cleaved or non-cleaved follicular center cell histologic subtype (Lukes-Collins); no bulky involvement of mesenteric nodes or critical organs--kidney, urinary tract, or pleura; stages I to III disease (78 percent stage I or IE); no B symptoms; age below 60 years; initial resection as a reflection of localized disease. Patients with advanced-stage non-Hodgkin's lymphoma receiving conservative treatment have a relatively short survival (median, less than five years) regardless of histologic subtype.     

High-grade non-Hodgkin lymphoma relapsing as low-grade follicular lymphoma: so-called downgraded lymphoma

Evolution of low-grade Non-Hodgkin Lymphoma (NHL) into a more aggressive neoplasm is a common, well-documented event in NHL. The reverse process, in which a less aggressive component becomes evident during the course of treatment for a higher-grade NHL, has only recently been recognized. This lymphoma "downgrading" has been reported at the time of relapse in both radiation- and chemotherapy-treated patients who initially presented with high- or intermediate-grade lymphoma. The etiology of this unusual transformation has not yet been determined. We present the clinical, morphologic, immunologic, and flow-cytometric features of a patient with diffuse immunoblastic lymphoma who achieved a complete response to chemotherapy and then relapsed with follicular small-cleaved-cell lymphoma 3 years later. Morphologic and immunophenotypic findings suggest that both immunoblasts and small cleaved cells were present in the initial biopsy. DNA content analysis of the initial and relapse biopsies suggests that the immunoblastic component was more susceptible than the small cleaved cells to the chemotherapy that the patient received. Successful eradication of the rapidly proliferating immunoblasts with survival of less rapidly proliferating small cleaved cells may account for the unusual histologic transformation seen in this case.     

Follicular bronchiolitis in surgical lung biopsies: clinical implications in 12 patients

BACKGROUND: Follicular bronchiolitis is a histopathologic finding that occurs in diverse clinical contexts. The current study was conducted to characterize clinico-radiologic features, and assess outcomes associated with follicular bronchiolitis. SUBJECTS AND METHODS: Twelve subjects with follicular bronchiolitis on lung biopsy were seen over a 9-year period, between 1996 and 2005. Medical records, biopsy and radiographic findings, and details of outcome at the time of last follow-up were recorded. RESULTS: The study population included 4 men and 8 women; the median age at diagnosis was 54 years (range, 33-81 years). Four patients had underlying systemic diseases that included: 2 with common variable immunodeficiency, 1 Sj?gren's syndrome and 1 undifferentiated connective tissue disease. The diagnosis was obtained by surgical lung biopsy in all cases. Follicular bronchiolitis was the major histologic pattern in 9 patients; organizing pneumonia, nonspecific interstitial pneumonia and usual interstitial pneumonia was seen in 1 patient each with follicular bronchiolitis being an associated secondary histopathologic component. Computed tomographic findings included reticular opacities, small nodules and ground-glass opacities. Clinical course was characterized by relative stability with partial response to immunosuppressive agents. During a median follow-up period of 47 months, only one death occurred--out of 9 patients where the outcome information was available--and was unrelated to lung disease. CONCLUSIONS: The histologic lesion of follicular bronchiolitis may be seen as the predominant finding or a relatively minor feature in interstitial pneumonias. The clinical course and prognosis for most patients with follicular bronchiolitis is relatively good, and progressive lung disease is uncommon.     

Localized herpes simplex lymphadenitis mimicking large-cell (Richter's) transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma.

We report a patient with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who presented with rapid enlargement of a cervical lymph node due to localized herpes simplex lymphadenitis, which was clinically indistinguishable from large cell (Richter's) transformation. The diagnosis was made by excisional lymph node biopsy, which demonstrated CLL/SLL and zonal necrosis due to herpes simplex infection. The herpetic zone was surrounded by a brisk proliferation of immunoblasts. This case demonstrates the need for excisional biopsy and histologic examination of rapidly enlarging nodes in patients with CLL/SLL. The diagnosis of herpes simplex lymphadenitis in patients with CLL/SLL is especially important because, unlike large cell transformation, the infection usually responds well to treatment.     

The Non-Hodgkin Lymphoma Pathologic Classification Project. Long-term follow-up of 1153 patients with non-Hodgkin lymphomas

STUDY OBJECTIVE: To document the long-term prognosis of patients with non-Hodgkin lymphoma treated between 1971 and 1975 and to determine how the prognosis varies by histologic subtype and stage. SETTING: Three cancer referral centers in the United States and one center in Italy. PATIENTS: A consecutive sample of 1153 previously untreated patients with non-Hodgkin lymphoma. At the time of analysis, 71% of the patients had died and the median follow-up for patients still alive was 11.2 years. MEASUREMENTS and MAIN RESULTS: The 10-year survival proportions were 45% (CI, 40% to 50%); 26% (CI, 22% to 30%); and 23% (CI, 18% to 30%) for patients with low-, intermediate-, and high-grade lymphomas, respectively. Patients with intermediate- and high-grade lymphomas were curable, but this was not apparent for patients with advanced stage low-grade lymphomas. For the low-grade follicular small cleaved and follicular mixed lymphomas, the Ann Arbor staging system distinguished the prognosis of patients with stage I disease from those with more extensive involvement. For the diffuse large cell and immunoblastic lymphomas, the Ann Arbor staging system distinguished long-term prognosis for patients with stage I disease from patients with stage II disease and those with more disseminated involvement. CONCLUSIONS: The probability of long-term survival for unselected patients with non-Hodgkin lymphoma can be substantial. Long-term prognosis depends on the histologic subtype of the tumor and the extent of dissemination. The Working Formulation for non-Hodgkin lymphomas is a simple and useful nomenclature for selecting treatment and reporting results. The Ann Arbor staging system is a useful but imperfect prognostic indicator.     

How we diagnose and treat vitreoretinal lymphoma

The eye is a rare site for the development of malignant lymphoma. Based on cell type and involved intraocular structures, which as a whole represent an immune‐privileged site, several subtypes of primary intraocular lymphoma need to be discerned. Primary vitreoretinal lymphoma (PVRL), the most common form, is an aggressive B‐cell malignancy and considered a subtype of primary central nervous system (CNS) lymphoma. Ocular symptoms are non‐specific and often mimic uveitis, frequently resulting in delayed diagnosis. Bilateral ocular involvement and dissemination/relapse in the CNS are common. Diagnosis of PVRL is usually based on the analysis of vitreous biopsy material. In addition to cytological and immunocytochemical examination, measurements of cytokine levels and molecular determination of B‐cell clonality and recurrent mutations increase the diagnostic yield. Both systemic chemotherapy and exclusively local treatment, including ocular radiotherapy and intravitreal chemotherapy, are successful approaches for the management of PVRL, although it is currently not predictable which patients require systemic treatment in order to avoid cerebral dissemination, a complication associated with a considerably worse prognosis.