Rare central nervous system lymphomas.

Central nervous system (CNS) lymphomas are rare malignancies characterised by lymphoid infiltration into the brain, spinal cord, cranial nerves, meninges and/or eyes in the presence or absence of previous or concurrent systemic disease. Most CNS lymphomas are of the diffuse large B-cell lymphoma (DLBCL) subtype for which treatment strategies, particularly the use of high-dose methotrexate-based protocols and consolidation with autologous stem cell transplantation, are well established. Other histopathological subtypes of CNS lymphoma are comparatively less common with published data on these rare lymphomas dominated by smaller case series and retrospective reports. Consequently, there exists little clinical consensus on the optimal methods to diagnose and manage these clinically and biologically heterogeneous CNS lymphomas. In this review article, we focus on rarer CNS lymphomas, summarising the available clinical data on incidence, context, diagnostic features, reported management strategies, and clinical outcomes.

Lacrimal gland extranodal marginal zone B-cell lymphoma in the presence of amyloidosis.

Amyloidosis is a protein metabolism disorder characterised by extracellular deposition of insoluble amorphous hyaline material. Orbital and ocular amyloid lesions account for only 4% of localised disease affecting the head and neck. Ocular adnexal lymphoma accounts for 1-2% of lymphoma, with lacrimal gland lymphomas being relatively uncommon. The most common form affecting the orbit is extranodal marginal zone lymphoma (EMZL) of mucosa-associated lymphoid tissue (MALT lymphoma). We report an extremely rare case of co-existent EMZL and amyloidosis of the lacrimal gland. Initial biopsy of the right lacrimal gland confirmed an EMZL with amyloid deposit, and a course of radiotherapy treatment was given. Recurrent lacrimal gland swelling developed within a year. Subsequent biopsy identified amyloidosis with scanty lymphoid tissue. To our knowledge, this is the first reported case of localised lacrimal gland amyloidosis of uncertain type with previous EMZL; the association described in this case report is not yet fully understood.

Improved survival outcomes despite older age at diagnosis: an era-by-era analysis of patients with primary central nervous system lymphoma treated at a single referral centre in the United Kingdom.

Observational studies with long-term follow-up of patients with primary central nervous system lymphoma (PCNSL) are scarce. Patient data over a period of four decades were retrospectively analysed from databases at Nottingham University Hospitals Trust, UK. The cohort was delineated by two distinct therapeutic eras; the first from 01/01/1982 to 31/12/2010 (n = 147) and the second 01/01/2011 to 31/07/2020 (n = 125). The median age at diagnosis was significantly older in the second era compared to the first (69 and 65 years respectively, P = 0·003). The 3-, 6- and 12-month overall survival (OS) rates in the second era were significantly higher compared to the first, at 85%, 77%, 62% versus 56%, 49%, 38% respectively (log-rank test P < 0·0001). On multivariate analysis, high-dose methotrexate (HD-MTX)-based induction protocols employed in the second era were associated with improved OS compared to those used in the first [hazard ratio (HR) 0·40, 95% confidence interval (CI) 0·28-0·57]. Within the second era, superior OS rates were seen with the use of intensive HD-MTX protocols (including consolidation with high-dose chemotherapy and autologous stem cell transplantation) compared to non-intensive HD-MTX schedules (HR 0·47, 95% CI 0·22-0·99). Initiating chemotherapy within 14 days of biopsy and use of rituximab were independently associated with improved OS and progression-free survival during the second era. These data suggest that prompt treatment initiation and use of intensive HD-MTX- and rituximab-based protocols have resulted in improved survival outcomes for patients.

Histological clues to the diagnosis of metastasis to the breast from extramammary malignancies.

AIMS: The aims of this study were to review the histological features useful for the identification of metastases to the breast and to investigate the impression that this diagnosis has become more common. METHODS AND RESULTS: The histological features of metastases to the breast from 2008 to 2018 were reviewed. Seventy-four biopsies from 66 patients were identified: 1% compared with primary carcinoma of the breast. Non-haematological metastases comprised 0.75% compared with 0.3% in a series from 1996 to 2005. The most common tumour types were pulmonary carcinoma (22), lymphoma (15), melanoma (13), gastrointestinal carcinoma (eight) and serous papillary carcinoma (four). In 73% there were histological features that were not typical of primary mammary carcinoma. Some metastases were histologically similar to breast cancer and the history was essential to making the correct diagnosis. Useful histological clues included small-cell morphology for pulmonary carcinoma, glands containing necrosis for gastrointestinal carcinoma, intranuclear inclusions, marked pleomorphism and spindle cells for melanoma, clear cells for renal carcinoma, papillary architecture for serous papillary carcinoma and sheets of centroblasts or nodules of centroblasts and centrocytes for lymphoma. Useful immunohistochemical markers included TTF-1 for pulmonary carcinoma, S100, melan-A and HMB45 for melanoma, CK20 and CDX2 for colorectal carcinoma, PAX8 and WT1 for serous papillary carcinoma and lymphoid markers for lymphomas, in addition to the absence of expression of mammary markers ER, GATA3 and GCDFP-15. CONCLUSION: The majority of metastases to the breast have histological clues to the diagnosis. Immunohistochemistry is helpful. This diagnosis is being made more frequently.

Delineating outcomes of patients with diffuse large b cell lymphoma using the national comprehensive cancer network-international prognostic index and positron emission tomography-defined remission status; a population-based analysis.

The recently devised National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) appears superior to the revised IPI (R-IPI) in delineating outcome in diffuse large B-cell lymphoma. We examined the outcome of a population-based cohort of 223 consecutive patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) or R-CHOP-like immuno-chemotherapy between January 2005 and December 2011 by both the NCCN-IPI and R-IPI, and further stratified outcome by the achievement of both computerized tomography (CT) and positron emission tomography (PET)-CT complete remission (CR), with the latter reassessed using blinded central review by an independent nuclear medicine and radiology specialist. The NCCN-IPI was superior to the R-IPI in identifying patients at very high risk of systemic and/or central nervous system relapse. Notably, both the NCCN-IPI and the R-IPI remained strongly predictive of relapse irrespective of CT or PET-defined remission status following R-CHOP. Patients with high-risk NCCN-IPI scores (≥6) have a dismal outcome following R-CHOP therapy regardless of PET-defined response to R-CHOP. Moreover, such patients appear refractory to salvage chemotherapy and thus require alternative therapeutic approaches, although age and performance status may, for many patients, preclude the safe delivery of a primary intensified regimen. By contrast, patients with NCCN-IPI 1-5 who achieve PET-CR following R-CHOP have excellent outcomes and may merit reduced follow up frequency.

Herpes Simplex Necrotic Lymphadenitis Masquerading as Richter's Transformation in Treatment-Naive Patients With Chronic Lymphocytic Leukemia.

Richter's transformation from chronic lymphocytic leukemia (CLL) to aggressive lymphoma is a relatively rare event with well-characterised clinical and radiological features, and can typically be distinguished from infectious complications of CLL. Opportunistic infections in CLL happen predominantly in the context of immunosuppressive therapy and/or relapsed/refractory disease. Herpes simplex viral (HSV) lymphadenitis is a rare phenomenon in treatment-naive CLL patients with only six cases reported in the English-language literature. Its diagnosis is challenging; its management and the outcome of the subsequent treatment for CLL are not well documented. We report three cases of rapidly progressive lymphadenopathy occurring in the context of previously untreated CLL, clinically and radiologically mimicking Richter's transformation, but histologically confirmed as necrotic HSV lymphadenitis. We describe the presentation, diagnosis and management of all three cases, including for the first time the positron emission tomography-computed tomography (PET-CT) appearance of this condition, as well as how we later on delivered CLL-directed immunochemotherapy safely and successfully without recrudescence of HSV-related disease. Our cases underscore the importance of obtaining biopsy in all cases of rapidly progressive or disconcordant lymphadenopathy in CLL patients, or in those with highly 18FDG-avid adenopathy on PET-CT.

COO and MYC/BCL2 status do not predict outcome among patients with stage I/II DLBCL: a retrospective multicenter study.

In advanced-stage diffuse large B-cell lymphoma (DLBCL), the presence of an activated B-cell phenotype or a non-germinal center (GCB) phenotype, coexpression of MYC and BCL2 by immunohistochemistry, and the cooccurrence of MYC and BCL2 or BCL6 rearrangements are associated with inferior outcomes. It is unclear whether these variables remain prognostic in stage I/II patients. In this retrospective study, we evaluated the prognostic impact of cell of origin (COO), as well as dual-expressor (DE) status and molecular double-hit (DH) status, in stage I/II DLBCL by positron emission tomography with computed tomography (PET-CT). A total of 211 patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimens, with or without radiotherapy, was included. The median follow-up in the entire cohort was 4 years (range, 0.4-9.4), with estimated 4-year progression-free survival (PFS) and overall survival (OS) rates of 85% (95% confidence interval [CI], 79-89) and 88% (95% CI, 83-92), respectively. By univariable analysis, DE (PFS: hazard ratio [HR], 1.27; 95% CI, 0.58-2.81, P = .55 and OS: HR, 1.40; 95% CI, 0.60-3.30; P = .44), DH (PFS: HR, 1.21; 95% CI, 0.27-5.31; P = .80 and OS: HR, 0.61; 95% CI, 0.08-4.73; P = .64), and non-GCB status (PFS: HR, 1.59; 95% CI, 0.83-3.03; P = .16 and OS: HR, 1.80; 95% CI, 0.89-3.67; P = .10) were associated with poorer outcomes. In patients with PET-CT-defined stage I/II DLBCL treated with R-CHOP-like therapy, with or without radiation, COO and DE and DH status were not significantly associated with inferior PFS or OS.

Single-center Series of Bone Marrow Biopsy-Defined Large Granular Lymphocyte Leukemia: High Rates of Sustained Response to Oral Methotrexate.

INTRODUCTION: Large granular lymphocyte (LGL) leukemia is a rare chronic lymphoproliferative disorder, with few large series reported to date. Series using stringent diagnostic criteria incorporating bone marrow biopsy (BMB), immunophenotyping, and T-cell receptor rearrangements are even scarcer. PATIENTS AND METHODS: The present study was a single-center series of 39 patients with LGL leukemia diagnosed using immunohistochemical analysis of BMB samples and flow cytometric and molecular data. RESULTS: With a median follow-up of 3.2 years (range, 1.0-15.1 years), 15 patients (38%) never required treatment. Of the remaining 24 patients requiring treatment, 13 were initially treated with prednisolone, for an overall response rate (ORR) of 84.6% and a median duration of response (DOR) of 13.5 months (range, 5.7-70.3 months). Of the 24 patients, 9 received oral low-dose weekly methotrexate as first-line therapy, with 8 (89%) achieving a hematologic response and a median DOR of 132.7 months (range, 6.7-180.5 months). Another 5 patients received methotrexate after prednisolone failure; all 5 responded, with a median DOR of 14 months (range, 4-96 months). Only 2 patients developed progression during methotrexate therapy, and 4 patients experienced responses lasting ≥ 5 years. CONCLUSION: Single-agent oral methotrexate appears to be highly efficacious, resulting in long response durations and minimal toxicity.

Reliable EGFR mutation testing in ultrasound-guided supraclavicular lymph node fine-needle aspirates: a cohort study with diagnostic performance analysis.

INTRODUCTION: 15-30% of patients with lung cancer will have supraclavicular and cervical lymphadenopathy (SCLN). Ultrasound (US)-guided fine-needle aspiration (FNA) cytology is regarded as an effective diagnostic tool in small size lymph nodes (LNs) and impalpable positron emission tomography detected nodes. We evaluated our diagnostic service performance in relation to the adequacy of samples for epidermal growth factor receptor (EGFR) mutation. METHODS: Retrospective data analysis from electronic records, searching for all suspected lung cancer referrals that underwent US of the neck±FNA, over a continuous period of 4 years. RESULTS: Of 306 cases with suspected lung cancer referred to our department for US FNA of SCLN, 228 patients underwent the procedure. Of the remaining 78 patients, LNs were not detected in 52 cases and appeared benign in 26. Cytological diagnosis was established in 171 patients (75%) for treatment decisions without further investigations. The remaining 57 patients had further investigations; 45 reconfirmed the US-guided FNA diagnosis. The average LN size was 12.9 mm, and positive cytology was obtained in LNs ranging from 3 to 45 mm. Of 57 adenocarcinoma cases, 34 were tested for EGFR confirming 4 positive, 25 negative and 5 insufficient samples. No complications were recorded. CONCLUSIONS: US-guided FNA of SCLN remains an important diagnostic tool in lung cancer. Adequate tissue can be obtained for reliable diagnosis from LNs and for EGFR mutational analysis, without the need for more invasive and expensive investigations in more than 80% of cases.

Bone marrow trephine biopsy involvement by lymphoma: review of histopathological features in 511 specimens and correlation with diagnostic biopsy, aspirate and peripheral blood findings.

AIMS: This study aimed to evaluate the key features of bone marrow trephine (BMT) biopsy involvement by lymphoma. METHODS: 511 cases were assessed for percentage of marrow involvement, pattern of involvement (diffuse, nodular, paratrabecular, interstitial or intrasinusoidal), presence/absence of granulomas, stromal fibrosis and necrosis, presence/absence of neoplastic/reactive follicles and discordance with other biopsy sites. Correlation with aspirate and peripheral blood findings was made in a subset of 345 patients (167 aspirates, 178 blood). RESULTS: The most frequent subtype was follicular lymphoma (26.2%) followed by extranodal marginal zone (23.1%), lymphoplasmacytic (19.2%), diffuse large B cell (DLBCL) (12.5%), Hodgkin (HL) (5.7%) and mantle cell lymphomas (4.3%). The predominant pattern in follicular lymphoma was paratrabecular. Marginal zone lymphomas of all types and lymphoplasmacytic lymphoma showed a relatively even distribution between diffuse, interstitial, paratrabecular and nodular patterns. The majority of mantle cell lymphoma cases showed either diffuse or nodular patterns. A diffuse pattern was common in DLBCL and Burkitt lymphomas. An intrasinusoidal pattern was seen only in extranodal and splenic marginal zone lymphomas. Granulomas and fibrosis were uncommon in small cell B cell lymphomas but frequent in DLBCL and HL. Aspirate and trephine results concurred in 73.8% of cases overall, but this varied widely between subtypes. Peripheral blood involvement rates by lymphoma also varied, with a mean of 37.1%. CONCLUSIONS: Different lymphomas often demonstrate reliably characteristic architectural patterns of marrow involvement which can help differentiate them even when cytological features do not permit this, and marrow stromal and other background changes may also be useful pointers towards a particular lymphoma subtype.