Neurolymphomatosis of the Brachial Plexus and its Branches: Case Series and Literature Review.

BACKGROUND: Neurolymphomatosis is a process of neoplastic endoneurial invasion, most strongly associated with non-Hodgkin's lymphoma. It must be distinguished from paraneoplastic, metabolic, nutritional and treatment-related causes of neuropathy that are common in this patient population. METHODS: This brief case series illustrates the protean manifestations of neurolymphomatosis of the brachial plexus, ranging from focal distal mononeuropathy to multifocal brachial plexopathy, either as the index manifestation of lymphoma or as a complication of relapsing disease. RESULTS: Prominent asymmetry, pain and nodular involvement on neuroimaging may help distinguish neurolymphomatosis from paraneoplastic immune demyelinating radiculoneuropathy. MR neurography criteria for the diagnosis of neurolymphomatosis include hyperintensity on T2 and STIR sequences, focal and diffuse nerve enlargement with fascicular disorganization and gadolinium enhancement. No specific anatomical distribution within the brachial plexus has, however, been found to be characteristic. Fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging is the imaging modality with the highest sensitivity for detection of nodal or extranodal spread in lymphoma. CONCLUSIONS: Brachial plexus neuropathy in neurolymphomatosis is highly protean in its distribution, semiology and relation to lymphoma staging. Dedicated MRI and PET-CT imaging are leading diagnostic modalities.

Concomitant high expression of Toll-like receptor (TLR) and B-cell receptor (BCR) signalling molecules has clinical implications in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an aggressive disease with frequent relapse. Targeted therapies against B-cell receptor (BCR) molecules have demonstrated improved outcomes in relapsed cases. However, clinical responses are slow and selective, with failure to attain complete remission in a significant subset of patients. Complex interaction of BCR signal transduction with toll-like receptor (TLR) and other pathways in MCL remains unknown, thus averting progress in development of targeted therapies. We have performed detailed digital quantification of BCR/TLR signalling molecules and their effector pathways in a cohort (n = 81) of MCL patients and correlated these data with overall survival. Hierarchical clustering model based on BCR/TLR genes revealed two distinct (BCRhigh and BCRlow ) subsets of patients (n = 32; 40%) with significant differences in expression (>1.5-fold change; p < 0.05). Higher levels of BTK/SYK/BLNK/CARD11/PLCG signalosome and lower expression of MALT1/BCL10 genes suggested tonic pattern of BCR activation. Amplified expression of TLR6/TLR7/TLR9 was noted in concert with hyper-responsiveness of BCR machinery. MYD88, a key TLR adaptor molecule, was not upregulated in any of these clusters, which may suggest a 'cross-talk' between BCR and TLR pathways. In sync with BCR/TLR signalling, we recorded significantly enhanced expression of genes associated with NF-kB pathway in BCRhigh subset of MCL patients. On univariate analysis, the BCRhigh patients showed a trend towards inferior clinical response to a standardized treatment protocol, compared with the BCRlow group (log rank, p = 0.043). In conclusion, we have identified hyperactive BCR/TLR signalling pathways and their effector downstream targets in a subset of MCL patients and associated it with poor clinical outcomes. Our study provides quantitative evidence at RNA expression level of possible concomitant collaboration between TLR and BCR signalling molecules in MCL. These data will provide further insights for future functional studies and, hence, development of targeted therapies for MCL patients. Copyright © 2015 John Wiley & Sons, Ltd.

A rare case of anaplastic variant of diffuse large B-cell lymphoma presenting as a lung primary.

Primary pulmonary lymphoma is an uncommon neoplastic disorder representing approximately 0.5% to 1% of primary pulmonary malignancies. The vast majority are of low-grade, mucosa-associated lymphoid tissue type. Primary diffuse large B-cell lymphoma of the lung is rare, though cases of the centroblastic and immunoblastic variants have been described. We present herein an interesting case of an 80-year-old man who presented with both respiratory and constitutional symptoms and was found to have a 4.5 cm left hilar mass with bilateral hilar and mediastinal lymphadenopathy on imaging. Endobronchial biopsy revealed an aggressive large cell lymphoma, with scattered large, bizarre-shaped nuclei resembling Reed-Sternberg cells, positive for CD20, PAX5, CD30, and MUM-1, consistent with an anaplastic variant of diffuse large B-cell lymphoma. Imaging showed no evidence of extrathoracic disease. Standard treatment with cyclophosphamide/vincristine/prednisone and rituximab resulted in significant clinical and radiological response and the patient remains in remission 21 months later. To the best of our knowledge, this modified Ann Arbor stage II2E primary pulmonary lymphoma, is the first description in the English literature of anaplastic variant of diffuse large B-cell lymphoma presenting as a lung primary.

Langerhans cell sarcoma with an aberrant cytoplasmic CD3 expression.

Langerhans cell sarcoma is a rare and aggressive high grade hematopoietic neoplasm with a dismal prognosis. It has a unique morphological and immunotypic profile with a CD1a/ langerin/S100 + phenotype. T cell lineage markers except for CD4 in Langerhans cell sarcoma have not been documented previously. We report a case of 86 year-old male of Caucasian descent who presented with an enlarging right neck mass over 2 months with an underlying unknown cause of anemia. Computed tomography scan of the neck, chest and abdomen revealed generalized lymphadenopathy and mild splenomegaly suspicious for lymphoma. Diagnostic core biopsy performed on right neck mass revealed a possible T cell lymphoma with expression of T cell lineage specific marker CD3 but conclusive diagnosis could not be made due to insufficient core biopsy sample. Further excisional biopsy performed on a left inguinal node showed a hematopoietic neoplasm with features of Langerhans cell sarcoma with a focal cytoplasmic CD3 expression in 30-40% of the tumor cells. PCR for T cell receptor (TCR) gene rearrangement failed to demonstrate a clonal gene rearrangement in the tumor cells arguing against a T cell lineage transdifferentiation, suggesting an aberrant CD3 expression. To the best of our knowledge, this case represents the first report of Langerhans cell sarcoma with an aberrant cytoplasmic CD3 expression. VIRTUAL SLIDES: http://www.diagnosticpathology.diagnomx.eu/vs/2065486371761991.

Bilateral benign reactive lymphoid hyperplasia of the conjunctiva in a pediatric patient.

A 13-year-old boy presented with asymptomatic, bilateral, nasal bulbar conjunctival lesions. Excisional biopsy of the larger lesion showed a mature, mixed lymphocytic infiltrate with germinal centers, consistent with a diagnosis of benign reactive lymphoid hyperplasia, a rare condition in children.

Primary localized conjunctival amyloidosis simulating a lymphoproliferative disorder.

A 39-year-old previously healthy woman presented with a 3-year history of a painless lump in her left upper eyelid that had been increasing in size over the last 8 months. On examination, a soft, nontender mass was palpated in the medial left upper eyelid and anterior orbit. She had 2 mm of eyelid ptosis and 2 mm of inferior globe displacement. A salmon-pink mass of tissue was identified in the superomedial conjunctiva. The remaining ophthalmic examination was unremarkable. A lymphoproliferative process was suspected; however, an incisional biopsy revealed amyloid. Further workup showed no evidence of systemic amyloidosis, lymphoma, plasmacytoma, or multiple myeloma. The patient has been followed for more than 16 months with no new developments in her health. Amyloidosis has a variety of presentations in the periocular region and may be the sole manifestation of the disease process. It is not often considered in the differential diagnosis of conjunctival lesions. The classic "salmon-pink" conjunctival infitrate has been associated with lymphoproliferative disorders; however, amyloid should also be considered, as it may be clinically indistinguishable.

The reliability of lymphoma diagnosis in small tissue samples is heavily influenced by lymphoma subtype.

A specific pathologic diagnosis is important in malignant lymphoma because the diverse disease subtypes require tailored approaches to clinical management. Reliance on small samples obtained with cutting needles has been advocated as a less invasive alternative to using larger, excised samples. Although published studies have demonstrated the safety and apparent sufficiency of this approach in informing clinical care, none have systematically determined the accuracy of pathologic lymphoma subtyping based on very small samples. We used a tissue microarray representing 67 cases of malignant lymphoma and 17 samples of nonneoplastic lymphoid tissue to model lymphoma diagnosis in small samples. Overall, 73.8% of the cases were diagnosed with a level of confidence deemed sufficient for directing clinical management; 85.9% of these diagnoses were accurate. Small cell lymphomas with highly distinctive immunophenotypes, including small lymphocytic, mantle cell, and T-lymphoblastic lymphoma, were recognized most consistently and accurately in the small samples. In contrast, follicular lymphoma and marginal zone lymphoma were especially difficult. Our results indicate that the reliability of lymphoma diagnoses based on small samples is heavily influenced by lymphoma subtype.

The 3-dimensional structure of isolated and small foci of prostatic adenocarcinoma: the morphologic relationship between prostatic adenocarcinoma and prostatic intraepithelial neoplasia.

BACKGROUND: Transitional histopathologic changes from high-grade prostatic intraepithelial neoplasia (HGPIN) into early prostatic adenocarcinoma (PAC) have not been well studied to date. To investigate the histogenesis of PAC, we examined isolated and small foci of PAC (ISPAC) found in prostatectomy specimens and the 3-dimensional structure of these foci. DESIGN: Twelve consecutive radical prostatectomy specimens having ISPAC, performed for peripheral zone PAC (10 cases) and for transitional zone PAC (2 cases), of Gleason score were studied. One to 2 tissue blocks with representative sections were used. RESULTS: Eight ISPAC, with Gleason score 3 + 3 had complete serial sections of the entire lesion. PAC consisted of continuous, tortuous and branching tubules and acini arising from benign ducts displaying: (a) HGPIN in 5 ISPAC and (b) no HGPIN in 3 ISAPC. At the junctions between benign epithelia with or without HGPIN and malignant epithelia, there were transitional lesions with HGPIN involving small ducts and acini. CONCLUSIONS: PAC develops as a result of multiple outpouchings of the epithelium with formation of small ducts and acini showing cytologic atypia and gradual or abrupt loss of basal cells. Grade 3 ISPAC consists of a system of continuous duct pushing into the stroma. There is also evidence suggestive of HGPIN as being both a precursor lesion and an accompanying lesion of PAC.

Characterization of lymphoproliferative lesions of the conjunctiva: immunohistochemical and molecular genetic studies.

BACKGROUND: Conjunctival lymphoproliferative lesions have not been selected for independent analysis with newer immunohistochemical and molecular genetic techniques to highlight their unique profile. METHODS: Retrospective case series examined biopsies from 16 consecutive patients with conjunctival lymphoproliferative lesions. The histopathologic, immunohistochemical, and molecular genetic features were characterized, as well as the frequency of tumour type, prognostic implications, clinical features, and treatments offered. RESULTS: The diagnosis was lymphoma in 12 cases, atypical lymphoid hyperplasia (ALH) in 1 case, and reactive lymphoid hyperplasia (RLH) in 3 cases. The primary lymphomas consisted of 4 mucosa-associated lymphoid tissue lymphomas (MALTL), 1 follicular lymphoma (FL), 2 diffuse large B-cell lymphomas (DLBCLs), 1 lymphoplasmacytic lymphoma, and 1 T-cell lymphoma. Primary lymphomas were treated with radiation (n = 7), surgery (n = 1), and topical chemotherapy (n = 1). Complete remission was achieved in 8 of 9 primary lymphomas. Two cases of recurrence to the other conjunctiva were treated with radiation and both remained disease free. Secondary lymphomas included 2 DLBCL and 1 MALTL. Complete remission was seen in 2 patients after radiation plus chemotherapy, while the patient treated with chemotherapy alone was lost to follow-up. The 1 case of ALH presented bilaterally and achieved complete remission after topical chemotherapy treatments. The 3 RLH cases were surgically managed and 2 of the 3 recurred and were subsequently excised. Eleven lymphomas were of B-cell lineage by immunophenotyping. Molecular genetic studies of immunoglobulin heavy chain (IgH) gene rearrangement by polymerase chain reaction (PCR) showed clonal bands in 6 of 12 lymphomas, 1 of 3 RLH (polyclonal by immunophenotyping) and 1 ALH. BCL2-IgH [t(14;18)] rearrangement was seen in 8 of 12 cases (1 FL, 3 DLBCLs, 4 MALTLs) by real-time quantitative PCR. INTERPRETATION: Conjunctival lymphomas are predominantly B-cell type with a high prevalence of MALTL. An unexpected finding was the BCL2-IgH rearrangement seen in 4 of 5 MALTL cases in our series. The significance of this remains unclear.

Lymphoproliferative lesions of the lacrimal gland: clinicopathological, immunohistochemical and molecular genetic analysis.

BACKGROUND: Lacrimal gland lymphoproliferative disorders are usually classified as orbital adnexal tumours. Because the lacrimal gland is the only orbital structure with native lymphocytes, we examined cases with primary involvement of the gland. METHODS: The 14 cases were selected from a review of all cases in the surgical pathology files of the Ottawa Hospital between 1992 and 2003. The lesions were categorized according to the latest World Health Organization classification of tumours of lymphoid tissues. We conducted a clinical, histopathological, immunohistochemical, immunophenotypic and molecular genetic analysis of the cases. RESULTS: The 8 female and 6 male patients, aged 20 to 88 (mean 60) years, were followed for an average of 4 years (range 11 months to 13 years). All presented with supratemporal orbital swelling. The 5 primary lymphomas, of mucosa-associated lymphoid tissue (MALT), were confined to the lacrimal gland (stage IE); 1 tumour transformed to diffuse large B-cell lymphoma, necessitating chemotherapy, and the other 4 were treated with radiation. One of the 5 patients had previously had Sjögren's syndrome. The 6 secondary lymphomas (4 follicular) presented either concurrently with systemic lymphoma or up to 12 years afterwards and were treated in a variety of ways; all the patients had an orbital relapse. At the last follow-up assessment, 6 of the patients with lymphoma had no evidence of disease, 3 were alive with disease, 2 had died (1 of lymphoma, the other with no evidence of disease), and the status of 1 patient was not known. Of the 3 patients with reactive proliferations, 2 had reactive lymphoid hyperplasia (associated with Sjögren's syndrome in 1), and 1 had Rosai-Dorfman disease. All 9 lymphomas that underwent molecular genetic analysis were of B-cell lineage, and 8 had a monoclonal rearrangement in the immunoglobulin heavy-chain gene (IgH); the 9th lymphoma showed an oligoclonal rearrangement. One lymphoma showed the t(14;18) translocation, typical of follicular lymphoma; no lymphoma showed the t(11;18) translocation, commonly found in MALT lymphoma (but only 2 cases were studied). Molecular genetic analysis was performed in 2 of the cases of reactive lymphoid hyperplasia: monoclonal IgH rearrangement was detected in 1 case (the patient with Sjögren's syndrome), oligoclonal rearrangement in the other. INTERPRETATION: Lacrimal gland lymphomas are B-cell tumours that develop in older adults. Primary tumours, a hIgH proportion of which have MALT characteristics, have a favourable prognosis. Molecular genetic studies may be useful when morphologic and immunophenotypic studies give equivocal results.

Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin's lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group.

PURPOSE: We report results of a randomized trial comparing ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy alone with treatment that includes radiation therapy in patients with limited-stage Hodgkin's lymphoma. PATIENTS AND METHODS: Patients with nonbulky clinical stage I to IIA Hodgkin's lymphoma were stratified into favorable and unfavorable risk cohorts. Patients allocated to radiation-containing therapy received subtotal nodal radiation if favorable risk or combined-modality therapy if unfavorable risk. Patients allocated to ABVD received four to six treatment cycles. RESULTS: We evaluated 399 patients. Median follow-up is 4.2 years. In comparison with ABVD alone, 5-year freedom from disease progression is superior in patients allocated to radiation therapy (P = .006; 93% v 87%); no differences in event-free survival (P = .06; 88% v 86%) or overall survival (P = .4; 94% v 96%) were detected. In a subset analyses comparing patients stratified into the unfavorable cohort, freedom from disease progression was superior in patients allocated to combined-modality treatment (P = .004; 95% v 88%); no difference in overall survival was detected (P = .3; 92% v 95%). Of 15 deaths observed, nine were attributed to causes other than Hodgkin's lymphoma or acute treatment-related toxicity. CONCLUSION: In patients with limited-stage Hodgkin's lymphoma, no difference in overall survival was detected between patients randomly assigned to receive treatment that includes radiation therapy or ABVD alone. Although 5-year freedom from disease progression was superior in patients receiving radiation therapy, this advantage is offset by deaths due to causes other than progressive Hodgkin's lymphoma or acute treatment-related toxicity.

A simple technique for calculation of the volume of prostatic adenocarcinomas in radical prostatectomy specimens.

Tumor volume has been suggested as an important prognostic factor of prostatic adenocarcinoma (PAC) treated with radical prostatectomy (RP). The calculation of tumor volume is complicated by the difficulty in appreciation of tumor nodules at gross examination, multifocality, and variation in the shape of tumor nodules. We propose a simple technique for the calculation of tumor volume. One hundred consecutive specimens of RP were studied with special attention to the shape of tumor nodules. Most small PAC, transitional zone (TZ) PAC, peripheral zone (PZ) PAC without associated benign prostatic hyperplasia (BPH), and PZPAC with Gleason's score (GS) > 3 + 4 had an ovoid shape. Most large sized nodules of PZPAC with GS < 4 + 3 tended to mold according to the boundaries of the TZ that were themselves often compressed by hyperplastic nodules. Therefore, these large tumor nodules were crescentically shaped and had tapering pole(s). We deduced from that tendency that the ratio of height of the tumor nodule = D1 x the height/greatest horizontal diameter of the prostate (D1 = the greatest diameters of the largest section of tumor nodule). Using the mathematical formula for volume of an ellipsoid structure, we propose the following formula to calculate the volume of each tumor nodule = 0.8 x K x D1(2)x D2 (D2 = greatest diameter orthogonal to D1, and K = coefficient for correction of tumor volume due to the compression of hyperplastic nodules). K is empirically estimated as 2/3 for PZPAC in mid prostate and 1/2 for tumor nodules at the apex and base. The total tumor volume is the sum of all tumor nodule volumes. By measuring the two greatest orthogonal diameters, D, and D2, of the largest horizontal section of a tumor nodule, we were able to calculate the corresponding volume and consequently the total tumor volume of the prostate. Analysis of the calculated total tumor volume showed a good correlation with the current technique of measurement on each section of the prostate, particularly for tumors ranging from 1.5 to 3.0 cm3.