Benign Lymphoid Aggregates Research Articles

Role of immunoglobulin heavy and light chain gene rearrangement analysis in differentiating between benign and malignant bone marrow B-cell lymphoid aggregates

Lymphoid aggregates are found in a minority of bone marrow biopsy and aspirate specimens, and when present, the distinction between benign and malignant aggregates can represent a diagnostic challenge. Morphologic and immunophenotypic evaluation of the aggregates can aid in that distinction but in a few cases, detection of immunoglobulin heavy chain (IGH) and kappa light chain (IGK) gene rearrangements may be needed to rule in or out a malignant disease process. We studied the role of testing for IGH/IGK rearrangements in the distinction between benign and malignant B cell-predominant lymphoid aggregates. Only a few studies have addressed this issue and most lacked an adequate number of cases for establishing statistical significance. Our study retrospectively evaluated 120 bone marrow aspirate and biopsy specimens, 79 cases originally diagnosed with benign lymphoid aggregates [4,5], and 41 demonstrating a B-cell lymphoma with malignant aggregates. Immunohistochemical stains were performed on all cases in our study and flow cytometry results were available in the vast majority of cases (98%). All patients included in our study but 9 had at least 2 years of clinical follow-up information. Of the malignant lymphoma cases, IGH/IGK rearrangements were demonstrated by polymerase chain reactionin 60% of the cases. Moreover, clonal rearrangements were identified in 15% of the cases with benign aggregates. After at least 2 years of follow-up, only one case with a positive clonality study occurring in the setting of morphologically benign-appearing bone marrow lymphoid aggregates experienced a relapse of non-Hodgkin lymphoma. Molecular analysis of the IGH and IGK genes may have utility in confirming the presence of malignancy in bone marrow aspirates and biopsy specimens. False-negative results, however, are possible due to testing limitations and sampling issues. Moreover, patients with conditions such as autoimmune disorders or infectious diseases are shown to also develop clonal B-cell lymphoid aggregates. As a result, we recommend a thorough morphological examination, informative immunohistochemical staining, accurate flow cytometric analysis, and current IGH/IGK rearrangement testing when evaluating bone marrow specimens containing B cell-predominant lymphoid aggregates, with the knowledge that molecular clonality results should be carefully interpreted in the context of morphological and immunophenotypic findings to prevent misdiagnosis.

Challenges Encountered and Pattern-Based Analysis of Bone Marrow Biopsy in Lymphomas: An Institutional Experience.

Objective The evaluation of bone marrow (BM) status is an integral part of the initial workup of patients diagnosed with lymphoma as it plays an important role in staging and predicting prognosis in these patients. This article determines the incidence and pattern of BM involvement in lymphoma cases and distinguishes benign from malignant lymphoid aggregates in BM biopsies. Materials and Methods The study group included 121 cases of Hodgkin and non-Hodgkin lymphomas for which BM biopsies were performed, fixed in acetic acid-zinc formalin solution, decalcified using 10% formic acid, and subjected to hematoxylin and eosin and immunohistochemistry. Results The overall incidence of BM biopsy involvement in our study was 31.4% (37/118), including 34.7% (35/101) in cases of B cell lymphomas, 25% (2/8) in cases of T cell lymphomas, and no involvement in Hodgkin lymphoma. The predominant histological pattern of BM involvement was diffused (14/37; 37.8%), followed by interstitial (10/37; 27.1%). Five cases revealed benign nonparatrabecular lymphoid aggregates which could be confused with lymphomatous involvement, especially in low grade lymphomas. Conclusion A careful examination of the BM biopsies along with clinical history, peripheral blood examination, flow cytometry, and immunohistochemistry will help in arriving at the correct diagnosis.

Morphology and Immunoprofiling of Benign Lymphoid Aggregates in Bone Marrow Biopsies of Lymphoma Patients.

Morphology and Immunoprofiling of Benign Lymphoid Aggregates in Bone Marrow Biopsies of Lymphoma Patients.

Bone marrow examination of HIV-infected children in HAART era reveals a spectrum of abnormalities: a study from single tertiary care center of North India

Pediatric HIV is a significant contributor to childhood morbidity and mortality. As HIV infects bone marrow CD34-positive progenitor cells, the hematological abnormalities are well-expected. The viral load is much higher in children predisposing them to opportunistic infections and hematopoietic malignancies. The present study aimed to determine the spectrum of hematological abnormalities that may yield clinically useful information in HIV-infected children. This was a retrospective study of 19 HIV-infected children who underwent bone marrow examination. Overall, 20 peripheral blood and bone marrow samples were analyzed for morphological changes in all hematopoietic lineages. Immunohistochemistry was performed on trephine biopsy sections for evaluation of B and T cells and cytomegalovirus inclusions. Anemia was the most common cytopenia (95%), followed by thrombocytopenia (45%) and leukopenia (40%). Myelodysplasia was noted in 70% of cases. Dysmegakaryopoiesis was predominant in 65% of cases, while dyserythropoiesis was noted in 25% of cases. Hemophagocytosis and reactive cellular changes were noted in 20% of cases each. Benign lymphoid aggregates and granulomatous inflammation were observed in 15% and 10% of cases, respectively. Significant myelofibrosis was found in 35% of cases. One case showed infiltration by Burkitt lymphoma. Parvoviral inclusions were identified in 1 case. An interstitial increase and aggregates of CD8 + T cells and reduced CD4 + T cells were noted. CD20 + B cells were normal to mildly increased in the bone marrow. Bone marrow examination provides clinically significant information in pediatric HIV revealing the underlying cause of hematopoietic abnormalities and allows the exclusion of major hematological neoplasms.

S3482 Management of Therapy in a Crohn’s Disease Patient With Secondary Loss of Response to Infliximab

INTRODUCTION: Infliximab is a widely-used biological therapy in Crohn’s disease. Up to 40% of patients exhibit loss of response in the first year of therapy. Currently, there is no established guideline based on strong evidence to direct care in such cases. We present a case of a patient with Crohn’s disease who developed secondary loss of response to infliximab therapy. CASE DESCRIPTION/METHODS: A 46 year-old male with a history of Crohn’s disease presented to the office for a follow up visit. Patient was started on infliximab and achieved remission about a year ago after a Crohn’s flare, but started to develop worsening epigastric abdominal pain, fatigue, and joint pain. Colonoscopy revealed acute inflammation in the transverse colon and benign lymphoid aggregates in the descending and rectosigmoid colon. Infliximab trough and anti-drug antibody level were 7.9 µg/mL and 13 AU (≥10 AU indicates detectable serum levels per laboratory guidelines) respectively. Infliximab dosing interval was decreased and 6-mercaptopurine was started. Patient showed resolution of symptoms and repeat blood tests in 3 months revealed increased trough level and undetectable anti-drug antibody level. DISCUSSION: Secondary loss of response is defined as recrudescence of clinically active disease after an initial response. Production of anti-drug antibodies is commonly seen and it is thought to accelerate drug clearance, neutralizing its effects. In such situation, one or combination of the following is suggested – continue current treatment with shortened dosing interval or increased dosing, add an immunomodulator, or switch to another drug within the same class or of another class. There is conflicting evidence regarding benefit of dose escalation especially in the presence of high drug-antibody titer. Switching to another agent may be preferable, but optimizing current therapy should be attempted before doing so, especially given that there are limited treatment options for IBD and patients with high drug-antibody level to infliximab are more likely to poorly respond to an alternative anti-TNF agent. Pre-treatment or co-treatment with an immunomodulator appears to be superior to monotherapy with infliximab, but the benefit in those with secondary loss of response to infliximab alone is unclear. Optimal drug concentration and meaningful drug antibody level should be established and further research should be pursued to guide therapy in patients with secondary loss of response to anti-TNF therapy.

Small Bowel Intussusception Secondary to Inflammatory Fibroid Polyp of the Ileum

Introduction: Inflammatory fibroid polyps (IFP) are rare, benign, tumor-like lesions that can develop anywhere in the gastrointestinal tract. Most frequently, they are localized in the gastric antrum. Ileum is the most common site where these polyps cause small bowel obstruction. Most IFPs are polypoid masses smaller than 5 cm, although sizes up to 20 cm have been reported. Case report: We report a case of a 56-year-old man presented with progressive abdominal pain for 7 days. He denied any nausea and vomiting but did have foul smelling bloody diarrhea. His abdomen was soft, slightly distended, tympanic to percussion, and tender in left lower quadrant. Bowel sounds were hyperactive. CT scan revealed a tubular, elongated, both intraluminal and extraluminal ileal mass causing mild partial obstruction and short segment intussusception. The patient underwent resection; gross examination showed a large solid tan-white elongated mass protruding into the small bowel lumen on one side and pushing the serosal surface on the other side. The large luminal portion of the protruding tumor measured 15.0 x 5.5 x 4.0 cm, and the extraluminal portion measured 5.5 x 4.0 cm. The total length was 20.5 cm. Multiple sections showed a well demarcated, non-encapsulated, polypoid, fibrohistiocytic mass, composed of hypocellular stroma with proliferation of widely spaced bland spindled and stellate-shaped cells emdedded in a collagenous fibromyxoid stroma. The intervening stroma demonstrated prominent vascularity, diffuse eosinophils, and few scattered plasma cells with foci of benign lymphoid aggregates. No mitoses or necrosis was present. There was no other histologic evidence of malignancy. The histopathologic features, as well as the immunoperoxidase stains, were consistent with a benign, non-neoplastic tumor-like mass, consistent with a Giant Inflammatory Fibroid Polyp-Tumor Like (Vanek Tumor). Discussion: The present lesion is the largest inflammatory fibroid polyp reported to date. The ileal location is rare. Even if inflammatory fibroid polyps are benign lesions, surgical treatment is the only option when they present with intestinal intussusception. Preoperative diagnosis of inflammatory fibroid polyps is often difficult, and confirmation can only be obtained by histological and immunohistochemical examination.Figure

Utility of CD279/PD-1 immunohistochemistry in the evaluation of benign and neoplastic T-cell-rich bone marrow infiltrates.

CD279 expression is used to help identify angioimmunoblastic T-cell lymphoma (AITL) or other T-cell lymphomas of T-follicular helper (TFH) cell origin; however, its utility in assessing lymphoid infiltrates in the bone marrow (BM) is not well established. Immunohistochemistry for CD279 was performed on normal staging BM and in BM with benign lymphoid aggregates (LAs), AITLs, and other T-cell lymphomas. Seven of 10 staging BMs demonstrated scattered, usually weakly CD279+ cells. Thirty-four of 38 BMs had scattered weakly/variably intense CD279+ cells within LAs, but only four contained 11% to 25% CD279+ cells. Three of four AITLs were strongly CD279+, but one contained only around 10% CD279+ cells. Eleven of the other 38 T-cell lymphomas were CD279+, including five possible AITLs; four peripheral T-cell lymphomas, not otherwise specified; and two T-cell large granular lymphocytic leukemias. Although useful in assessing selected BM lymphoid infiltrates, CD279 expression may be limited in AITLs, is not specific for TFH lymphomas, and can be seen in benign lymphoid infiltrates, although without extensive strong positivity.

Successful Radiotherapy of a Rectal MALT B Lymphoma in an Adolescent

Purpose: We report the case of an adolescent with a rectal MALT lymphoma manifesting with hematochezia who was treated successfully with radiotherapy. Pediatric gastrointestinal (GI) malignancies are very rare. Of these, lymphomas are the most common. In adults, primary GI non-Hodgkin lymphomas (NHL) account for 4-20% of all NHL. WHO classifies NHL as Burkitt's, diffuse large B cell, mantle cell, follicular cell, and extranodal marginal zone mucosa-associated lymphoid tissue lymphoma (MALT). Colorectal lymphomas are very rare (10-20% of GI NHL and 0.2-0.6% of all colonic malignancies), and only 10-25% localize in the sigmoid and rectum. MALT lymphomas represent 5% of NHL and the majority occur in the stomach. MALT rectal lymphomas are extremely rare and have been treated with surgery, chemotherapy, antibiotics, or radiation therapy. A 16-year-old male presented with a history of painless hematochezia and constipation for 2 months. Past medical and family history were unremarkable. Rectal exam revealed redundancy of the posterior rectal mucosa and gross blood on the glove. The physical exam was otherwise normal. Colonoscopy was normal except for mild nodularity of the rectosigmoid, with cobblestoning of the first 5 cm of the rectum and the presence of two hypertrophic anal papillae. Biopsies of the first 5 cm of rectum, including the anorectal junction, showed an infiltrate of large atypical B cells CD20+, Pax 5+, CD 79a+, CD43+, MUM1+, BCL2+, BCL6+, CD5-, CD10-, BCL1-. Plasma cells were CD20- showing cytoplasmic IgA kappa restriction. CD79a was strongly expressed in plasmacytic cells and poorly in B cells. Ki67 proliferation index was low to moderate. EBER-ish was negative. The findings were consistent with marginal zone lymphoma with plasmacytic differentiation. PET scan showed a hypermetabolic uptake in the anal region (SUV 11.4). CT of the chest, abdomen and pelvis was negative. The patient received 24 GCE involved field proton beam radiotherapy in 12 fractions to the anorectal lesion. Pelvic and inguinal nodes were not irradiated. Repeat PET scan 5 months after radiotherapy showed decreased anal hypermetabolic uptake (SUV 4.4). Colonoscopy after 6 months showed mild nodularity of rectosigmoid. The anorectal margin had mild erythema and nodularity. Rectal biopsies showed benign lymphoid aggregates and the anorectal junction mucosa was normal. He reported occasionally minor anorectal bleeding when constipated. To our knowledge this is the first pediatric case of a rectal MALT lymphoma that was induced into remission by low dose proton beam radiotherapy. Although very rare, anorectal malignancies should be considered in the differential diagnosis of hematochezia in children and adolescents.

Bone Marrow Biopsy Findings in Patients with Hepatitis C Infection

AbstractAbstract 4840Patients with hepatitis C often present with cytopenias - thrombocytopenia, neutropenia and less commonly anemia. Hypersplenism may contribute to cytopenias but effects on the bone marrow due to the hepatitis C infection also likely play a role in its pathogenesis. Hepatitis C infection predisposes to development of lymphomas as well. The bone marrow findings in patients with hepatitis C infection are not well described and to our knowledge there has only been one peer reviewed study published till date.In order to elucidate this further, we conducted a retrospective review of bone marrow biopsies performed at our institution on patients with known hepatitis C infection.Between years 1999 and 2010, 56 adults (36 male and 20 female) patient with hepatitis C underwent bone marrow biopsies. The indications for bone marrow biopsy included evaluation or staging of lymphoma or myeloma (24 patients) OR investigation of cytopenias (32 patients). None of the patients were on treatment for Hepatitis C at the time of the bone marrow biopsy.Of the 24 patients with lymphoma/myeloma, 11 showed bone marrow involvement, while 10 patients had benign lymphocyte aggregates in the marrow. 9 out of 24 patients had a hypercellular marrow and 8 had a hypocellular marrow. Mild to moderate megaloblastic change in the erythrocyte series was seen in 5 patients and dyserythropoiesis in 2. Hyperplasia of megakaryocytes was seen in 11/24 and 6/24 showed atypical megakaryocytes with focal clustering in 7/24. Reticulin fibrosis was noted in 7 patients. Iron stores were increased in 13/24 with decreased sideroblasts in 15/24 patients.Review of the 32 patients who had the bone marrow biopsy done for cytopenias showed 16 were hypocellular and 9 were hypercellular while 4 patients had variable cellularity. Mild to moderate megaloblastic change in the erythrocyte series was seen in 12/32 and dyserythropoiesis in 11/32. Granulocytic hypoplasia was seen in 14/32. Benign lymphoid aggregates were noted in 20 patients. Hyperplasia in the megakaryocytes was seen in 8 while 11 had decreased megakaryocytes. Atypical megakaryocytes were noted in 10/32 with clustering seen in 4 patients. Reticulin fibrosis was noted in 13 patients. Iron stores were increased in 16/32 and sideroblasts were decreased in 13/32. Frank hemophagocytosis was observed in 5 patients. Of these 32 patients, 4 were HIV positive. Myelodysplastic syndrome was diagnosed in 2/32, AML and Hemophagocytic lymphohistiocytosis in one each. Conclusions:Bone marrow biopsies are usually performed in patients with Hepatitis C to investigate cytopenias and for diagnosis or staging lymphoma or myeloma. Even without lymphoma involving the marrow, a substantial number of patients have benign lymphocyte infiltrates seen in the marrow. Marrow hypocellularity is common. Megaloblastic change in the erythroid series, dyserythropoiesis, atypical megakaryocytes and reticulin fibrosis can be seen in a substantial minority of the patients which contribute to cytopenias. Disclosures:No relevant conflicts of interest to declare.

Benign lymphoid aggregates in the bone marrow: distribution patterns of B and T lymphocytes

Benign lymphoid aggregates are seen in only a minority of bone marrow specimens, but their distinction from non-Hodgkin lymphoma, particularly B-cell lymphomas, can represent a diagnostic challenge. Although criteria have been proposed to help distinguish between benign and malignant aggregates, a detailed description of the distribution patterns of B and T lymphocytes within benign lymphoid aggregates has not been investigated. One hundred thirty-seven cases of bone marrow specimens containing benign aggregates were studied with a panel of immunostains. A subset of these cases was also examined for immunoglobulin gene rearrangements by polymerase chain reaction. The aggregates were categorized based on size, location (paratrabecular or random), presence of infiltrating edges, and distribution of lymphoid cell populations. In addition, we examined 40 cases of bone marrow biopsies with documented malignant lymphoid aggregates for comparison purposes. We report that the distribution of B and T lymphocytes within lymphoid aggregates may serve as a useful criterion to aid in the separation between benign and malignant aggregates. When aggregates exhibit a predominance of T cells, consist of a central core of T cells surrounded by a rim of B cells, or have a mixed distribution of B and T cells, they are more likely to be benign. On the other hand, an increased likelihood of malignancy occurs when aggregates exhibit a predominance of B cells or consist of a central core of B cells surrounded by a rim of T cells (excluding germinal center formation), and assessing other features worrisome of malignancy (large aggregate size, presence of infiltrative edges, cellular atypia, and paratrabecular location, among others) is warranted.

Acute Myeloid Leukemia Evolving from JAK 2-Positive Primary Myelofibrosis and Concomitant CD5-Negative Mantle Cell Lymphoma: A Case Report and Review of the Literature

Primary myelofibrosis (formerly known as chronic idiopathic myelofibrosis), has the lowest incidence amongst the chronic myeloproliferative neoplasms and is characterized by a rather short median survival and a risk of progression to acute myeloid leukemia (AML) noted in a small subset of the cases, usually as a terminal event. As observed with other chronic myeloproliferative neoplasms, the bone marrow biopsy may harbor small lymphoid aggregates, often assumed reactive in nature. In our paper, we present a 70-year-old Caucasian male who was diagnosed with primary myelofibrosis, and after 8 years of followup and therapy developed an AML. The small lymphoid aggregates noted in his bone marrow were neoplastic in nature and represented bone marrow involvement by a CD5-negative mantle cell lymphoma (MCL) that presented without any associated lymphadenopathy. We reviewed the English medical literature to identify a single case report of simultaneous association of AML and a MCL in the bone marrow. The unusual association presented here suggests an increase in observer awareness to apparently benign lymphoid aggregates in chronic myeloproliferative neoplasms.

Bone marrow trephines containing lymphoid aggregates from patients with rheumatoid and other autoimmune disorders frequently show clonal B-cell infiltrates

In bone marrow trephines, morphological and immunohistochemical criteria may not be sufficient to discriminate reactive from malignant lymphoid infiltrates. The aim of this study was to determine whether the detection of clonal immunoglobulin heavy chain (IGH) gene rearrangements is a reliable and specific marker for malignant B-cell clones in bone marrow biopsies. Bone marrow trephines with infiltration by different types of low-grade B-cell non-Hodgkin lymphoma (n = 32), reactive lymphoid hyperplasia (n = 18), and reactive lymphoid aggregates (n = 15), including 5 patients with rheumatoid or other autoimmune disorders, were analyzed by morphology, immunohistochemistry, IGH gene rearrangement (polymerase chain reaction), and DNA sequence analysis in selected cases. In 22 (68.8%) of 32 patients with B-cell non-Hodgkin lymphoma, a clonal IGH gene rearrangement was detected. Of the reactive cases, 1 of 18 patients with lymphoid hyperplasia demonstrated clonality, and 9 (60%) of 15 patients with reactive lymphoid aggregates gave a clonal result (GeneScan analysis). DNA sequence analysis was performed in 7 of the latter patients confirming clonality in 6. Four of the patients with B-cell clonality had an autoimmune disorder. None of these patients developed a malignant lymphoma during follow-up. Thus, the molecular detection of a clonal rearrangement of the IGH gene may support the diagnosis of a malignant lymphoma infiltrating the bone marrow. However, morphologically and immunohistochemically benign lymphoid aggregates might also harbor B-cell clones especially in patients with autoimmune disorders. Therefore, the detection of clonality has to be interpreted with utmost care and does not qualify for the unequivocal diagnosis of a malignant B-cell lymphoma.

Spectrum of bone marrow findings in patients with angioimmunoblastic T‐cell lymphoma

Bone marrow (BM) biopsy is often performed early in the evaluation of patients with angioimmunoblastic T-cell lymphoma (AITL), and may be the first diagnostic tissue sample; yet the BM histopathology associated with this disease has not been well described. In this study, BM specimens from 13 patients with AITL were reviewed. Seven (54%) were involved by AITL, which was characterised by paratrabecular and interstitial polymorphous infiltrates containing cytologically atypical lymphocytes, histiocytes and eosinophils. The neoplastic cells were positive for CD10 and CXCL13 by immunohistochemistry in a subset of cases. As in lymph nodes, the lymphomatous infiltrate in some BMs contained numerous small or scattered large B cells, resembling either benign lymphoid aggregates or T cell rich large B cell lymphoma, respectively. Secondary haematological changes were frequent and presented independent of BM involvement by AITL; these included trilineage haematopoietic hyperplasia and plasmacytosis. When BM biopsy preceded the diagnosis of AITL, these secondary changes were misinterpreted as chronic myeloproliferative disease (n = 2), or plasma cell dyscrasia (n = 2). In two cases, these changes obscured the presence of BM involvement by AITL. The spectrum of BM findings in AITL patients is important to recognise for early and accurate diagnosis in this disease.

Do bcl‐2 and survivin help distinguish benign from malignant B‐cell lymphoid aggregates in bone marrow biopsies?

Bcl-2 and survivin are cellular proteins that are known to be inhibitors of apoptosis and are commonly found in malignant tissues, including lymphomas. In previous studies, it has been shown that staining for bcl-2 can help distinguish between benign and malignant lymphoid aggregates in bone marrow biopsies. To determine whether staining for survivin expression in lymphoid aggregates can aid investigators in making this clinically important distinction, we stained bone marrow biopsies from 10 patients with benign lymphoid aggregates, and 15 malignant ones derived from B cells (six mantle cell, four follicular cells, two diffuse large cell, two small lymphocytic cell, and one marginal zone lymphoma) with antibodies to CD3, CD20, bcl-2, and survivin by an indirect immunoperoxidase technique. Whereas staining for bcl-2 was significantly stronger in the malignant lymphoid aggregates (P=0.001), both the control and malignant cases were almost uniformly negative for survivin expression. Only three cases (two mantle cell and one small lymphocytic lymphoma) showed very faint expression of survivin. Although bcl-2 and survivin both act to inhibit apoptosis, their expressions do not parallel each other. Survivin is not significantly expressed in either benign or malignant bone marrow aggregates, and therefore measuring its expression does not help distinguish benign from malignant B-cell bone marrow lymphoid aggregates.

An immunohistochemical study of the bone marrow lesions of systemic mastocytosis: expression of stem cell factor by lesional mast cells.

The bone marrow biopsy in mastocytosis often reveals characteristic mast cell collections associated with lymphoid cell aggregates. There is limited information on the composition of these aggregates and whether they contain cytokines important to mast cell growth and development. We thus performed an immunohistochemical characterization of bone marrow lesions in 7 patients with systemic indolent mastocytosis. In nodular lesions, the collections of mast cells were surrounded by lymphoid aggregates; these aggregates consisted of a mixture of B and T cells. Immunohistochemical staining for stem cell factor (SCF) revealed the presence of this cytokine in the lesional mast cells with a granular staining pattern. These results show that the characteristic nodular lesions observed in bone marrow biopsy specimens of patients with mastocytosis bearfeatures of benign lymphoid aggregates and that SCF is present in these lesions, creating a potential autocrine or paracrine growth and differentiation loop for mast cells and lymphoid progenitors.

P27Kip1 Immunostaining for the Differential Diagnosis of Small B-Cell Neoplasms in Trephine Bone Marrow Biopsies

The distinction between mantle cell lymphoma (MCL) and other small B-cell non-Hodgkin lymphomas (NHL) is important because MCL has a more aggressive clinical course. In bone marrow (BM) biopsy specimens, this distinction can be particularly difficult. Although cyclin D1 immunostaining and molecular detection of the t(11;14) translocation are highly specific markers for MCL, they fail to detect a proportion of cases. We have recently described that MCL typically lacks detectable expression of the cyclin-dependent kinase inhibitor p27kip1 protein by immunostaining, which is expressed at high levels in most small B-cell NHL inversely correlated to the proliferation rate. We therefore examined whether p27kip1 immunostaining could be a useful adjunct for the differential diagnosis of small B-cell NHL infiltrates in the BM. Trephine BM biopsy specimens of 96 patients, including well-characterized MCL (19 cases), B-cell chronic lymphocytic leukemia (27 cases), follicular lymphoma (18 cases), hairy cell leukemia (22 cases), and marginal zone lymphoma (10 cases) as well as 10 reactive BM, including five with benign lymphoid aggregates were investigated. In addition, the presence of a t(11;14) translocation involving the major translocation cluster was studied by PCR in all MCL. All cases of B-cell chronic lymphocytic leukemia, follicular lymphoma, and marginal zone lymphoma revealed a strong p27kip1 nuclear staining in the majority of neoplastic cells. Fourteen (78%) cases of MCL were p27kip1-negative in the tumor cells, whereas four cases revealed a weak nuclear positivity. Seventeen (77%) cases of hairy cell leukemia were also either completely negative for p27kip1 or showed a faint positive staining in a minority of the neoplastic cells. Nine of 19 cases (47%) of MCL showed a bcl1 rearrangement involving the major translocation cluster region. These findings demonstrate that p27kip1 immunostaining is a valuable additional marker for the differential diagnosis of small B-cell NHL infiltrates in BM biopsies. The reduction or lack of p27kip1 protein expression in MCL, as well as in hairy cell leukemia, might be an important event in the pathogenesis of these disorders.

Focal lymphoid aggregates (nodules) in bone marrow biopsies: differentiation between benign hyperplasia and malignant lymphoma--a practical guideline.

AIMS: To provide practical guidelines for the differentiation between benign and malignant focal lymphoid aggregates (lymphoid nodules) in routinely referred bone marrow trephine biopsies, using a synoptic approach including clinical...

Endoscopic ultrasound in the evaluation of gastric small lymphocytic mucosa-associated lymphoid tumors.

Low-grade, small lymphocytic lymphomas of the mucosa-associated lymphoid tissue (MALT) have recently been shown to be associated with Helicobacter pylori infections. Regression of these tumors has been reported with antibiotic therapy. Here we evaluate endoscopic ultrasound (EUS) as on objective method to evaluate pretreatment disease and posttherapy response. We retrospectively reviewed 20 patients initially diagnosed elsewhere with MALT lymphoma. All patients had their initial endoscopic biopsies (EGDs) reviewed at Memorial Sloan-Kettering Cancer Center (MSKCC). All patients had EUS performed at the time of consultation and on completion of therapy if treated at our center. Antral biopsies were stained with a modified Steiner preparation to determine infection by H pylori. Gastric low-grade lymphoma was confirmed in 16 of 20 patients; 11 of 16 had previously received antibiotic therapy for biopsy-positive H pylori infection. All gastric lymphomas had an abnormal EUS: eight with discrete tumor masses and eight with gastric wall infiltration (submucosa, n = 4; muscularis propria, n = 3; serosa, n = 1). On completion of lymphoma treatment with chemotherapy, radiotherapy, or surgery, 11 of 16 patients underwent follow-up EUS. Five patients received care elsewhere and did not return for posttreatment EUS. The gastric wall was normal with no evidence of disease on EUS-guided biopsy in eight of 11 patients. The remaining three patients had abnormal gastric walls. One was biopsy-negative and two had residual lymphoma. Four patients were found to have benign lymphoid aggregates in association with H pylori on initial EGD and EUS biopsies. All four patients were previously untreated with antibiotics. EUS showed prominent mucosa, but no significant findings within the gastric wall. EUS appears useful to stage objectively and evaluate therapeutic outcome in the management of gastric, low-grade MALT lymphomas. It also helps to distinguish benign lymphoid aggregates from lymphoma associated with H pylori infection. EUS findings may have a significant impact on assessment and therapeutic recommendations.

THREE‐DIMENSIONAL RECONSTRUCTION OF NON‐HODGKIN'S LYMPHOMA IN BONE MARROW TREPHINES

The objective of this study was to analyse the location in the bone marrow of deposits of low-grade non-Hodgkin's lymphoma. This was achieved using computer-generated three-dimensional reconstruction techniques applied to serial tissue sections of five bone marrow trephines involved by lymphoma. For comparative purposes, previously published three-dimensional models of benign lymphoid aggregates in the bone marrow were used. The images generated by this new study showed that deposits of low-grade non-Hodgkin's lymphoma involving the bone marrow always assumed a paratrabecular pattern of infiltration at some point. This is in direct contrast to the pattern of bone marrow infiltration shown by benign lymphoid aggregates. It is concluded that location within the marrow space is a crucial factor in distinguishing between benign and low-grade malignant lymphoid infiltrates in the bone marrow. © 1997 by John Wiley & Sons, Ltd.

Three-dimensional reconstruction of non-Hodgkin's lymphoma in bone marrow trephines.

The objective of this study was to analyse the location in the bone marrow of deposits of low-grade non-Hodgkin's lymphoma. This was achieved using computer-generated three-dimensional reconstruction techniques applied to serial tissue sections of five bone marrow trephines involved by lymphoma. For comparative purposes, previously published three-dimensional models of benign lymphoid aggregates in the bone marrow were need. The images generated by this new study showed that deposits of low-grade non-Hodgkin's lymphoma involving the bone marrow always assumed a paratrabecular pattern of infiltration at some point. This is in direct contrast to the pattern of bone marrow infiltration shown by benign lymphoid aggregates. It is concluded that location within the marrow space is a crucial factor in distinguishing between benign and low-grade malignant lymphoid infiltrates in the bone marrow.