Michael Jeffers

Fine Needle Aspiration Cytology in Symptomatic Breast Lesions: Still an Important Diagnostic Modality?

Abstract:u2002 The objective of this study was to make an assessment of the utility of fine needle aspiration cytology (FNAC), in a “one‐stop” symptomatic breast triple assessment clinic. Controversy surrounds the optimal tissue biopsy methodology in the diagnosis of symptomatic breast cancer and the identification of benign disease. FNAC in the context of a Rapid Assessment Breast Clinic (RABC) allows the same day diagnosis and early treatment of breast cancer, with the immediate reassurance and discharge of those with benign disease. We analyzed prospective data accrued at a RABC, over a 4‐year period from 2004 to 2007. All patients were triple assessed, with FNACs performed on site by two consultant cytopathologists. Investigations were reported immediately, and clinical data were captured via a database using compulsory data field entry. There were 4487 attendances at our RABC, with 1572 FNACs were performed. The positive predictive value of FNAC with a C5 cancer diagnosis was 100%, 95.6% for a C4 report, with a complete sensitivity of 94%. The full specificity of correctly identified benign lesions was 77.4%, with a false negative rate of 3.85%. This enabled 66% of patients attending the RABC to receive a same day diagnosis of benign disease and discharge. FNAC is highly accurate in the diagnosis of symptomatic breast cancer in an RABC. FNAC allows accurate diagnosis of benign disease and immediate discharge of the majority of patients. In this era, when a large majority of patients have benign disease, we believe that FNAC provides an equivalent, if not better, method of evaluation of patients in a triple assessment RABC.:u2002 The objective of this study was to make an assessment of the utility of fine needle aspiration cytology (FNAC), in a “one-stop” symptomatic breast triple assessment clinic. Controversy surrounds the optimal tissue biopsy methodology in the diagnosis of symptomatic breast cancer and the identification of benign disease. FNAC in the context of a Rapid Assessment Breast Clinic (RABC) allows the same day diagnosis and early treatment of breast cancer, with the immediate reassurance and discharge of those with benign disease. We analyzed prospective data accrued at a RABC, over a 4-year period from 2004 to 2007. All patients were triple assessed, with FNACs performed on site by two consultant cytopathologists. Investigations were reported immediately, and clinical data were captured via a database using compulsory data field entry. There were 4487 attendances at our RABC, with 1572 FNACs were performed. The positive predictive value of FNAC with a C5 cancer diagnosis was 100%, 95.6% for a C4 report, with a complete sensitivity of 94%. The full specificity of correctly identified benign lesions was 77.4%, with a false negative rate of 3.85%. This enabled 66% of patients attending the RABC to receive a same day diagnosis of benign disease and discharge. FNAC is highly accurate in the diagnosis of symptomatic breast cancer in an RABC. FNAC allows accurate diagnosis of benign disease and immediate discharge of the majority of patients. In this era, when a large majority of patients have benign disease, we believe that FNAC provides an equivalent, if not better, method of evaluation of patients in a triple assessment RABC.

Anaplastic large cell lymphoma: a unique presentation with urinary bladder involvement: a case report.

Anaplastic large cell lymphoma (ALCL) is a T-cell lymphoma composed of large pleomorphic CD30-positive cells. While systemic ALCL frequently involves extranodal sites, involvement of the urinary bladder is extremely rare. We report a case of systemic ALCL presenting with bladder involvement. A 28-year-old man presented with hematuria, dysuria, and lower abdominal pain. Imaging revealed pelvic lymphadenopathy and a thickened bladder wall. Bladder biopsies showed diffuse infiltration of the lamina propria by large pleomorphic cells, with preservation of the overlying urothelium. Immunohistochemistry demonstrated cell membrane and Golgi region staining for CD30 and epithelial membrane antigen. This is the first documented instance of systemic ALCL presenting with bladder symptoms.

A pathologist's survey on the reporting of sessile serrated adenomas/polyps

Aim The purpose of this survey was to ascertain reporting habits of pathologists towards sessile serrated adenomas/polyps (SSA/P). Methods A questionnaire designed to highlight diagnostic criteria, approach and clinical implications of SSA/P was circulated electronically to 45 pathologists in the UK and North America. Results Forty-three of 45 pathologists agreed to participate. The vast majority (88%) had a special interest in gastrointestinal (GI) pathology, had great exposure to GI polyps in general with 40% diagnosing SSA/P at least once a week if not more, abnormal architecture was thought by all participants to be histologically diagnostic, and 11% would make the diagnosis if a single diagnostic histological feature was present in one crypt only, while a further 19% would diagnose SSA/P in one crypt if more than one diagnostic feature was present. The vast majority agreed that deeper sections were useful and 88% did not feel proliferation markers were useful. More than one-third did not know whether, or did not feel that, their clinicians were aware of the implications of SSA/P. Conclusions 98% of pathologists surveyed are aware that SSA/P is a precursor lesion to colorectal cancer, the majority agree on diagnostic criteria, and a significant number feel that there needs to be greater communication and awareness among pathologists and gastroenterologists about SSA/P.

Case Study: Diffuse Large B-Cell Lymphoma Arising in Ovarian Mature Cystic Teratoma.

We describe an unexpected finding of diffuse large B-cell lymphoma associated with mature cystic teratoma of the ovary. A 68-yr-old woman with a complex left ovarian cystic mass on imaging underwent bilateral salpingo-oophorectomy, lymphadenectomy, appendicectomy, and omentectomy. Histopathologic examination revealed nodules of malignant non-Hodgkin lymphoma within the teratoma. A diagnosis of diffuse large B-cell lymphoma, germinal center cell subtype by Hans criteria was made after immunostaining and molecular studies. The patient was treated with R-CHOP chemotherapy and remains disease-free at 14-mo follow-up.

MRI features of bilateral amyloidosis of breast.

A 64-year-old lady with a remote history of Non-Hodgkins lymphoma, presented with a palpable lump in her left breast. On mammography, both breasts contained clusters of elongated tubular homogenous well-defined opacities with coarse calcifications (Fig. 1), which was indeterminate on ultrasound. On Magnetic Resonance Imaging (MRI) the tubular lesions demonstrated low T1 signal (Fig. 2) and high T2 (Fig. 3) and Short Tau Inversion Recovery signal, with no significant enhancement, however, there was some faint peripheral delayed enhancement. Histopathological analysis with positive Congo red histological staining was consistent with the presence of amyloid (Fig. 4). The diagnosis of amyloid in the breast is a very rare occurrence with few reports in the literature. It appears to occur in postmenopausal elderly women.

Potentially important miRNAs in Enteropathy-Associated T-cell lymphoma Pathogenesis: a pilot study

Enteropathy associated T-cell lymphoma (EATL) is a rare form of Non Hodgkin Lymphoma occurring primarily in the intestinal tract and which arises from intra-epithelial T-lymphocytes (IELs) [1]. Previously known as Type 1 EATL, this lymphoma has a strong association with coeliac disease and occurs with a higher frequency in Northern Europe where coeliac disease is most prevalent. Morphologically the lymphoma cells primarily consist of medium-sized to large tumour cells with round or angulated vesicular nuclei, prominent nucleoli, and pale-staining cytoplasm and is often associated with a moderate to abundant reactive infiltrate of eosinophils, histiocytes, and small lymphocytes [2]. These lymphomas are characteristically CD56 negative but may express CD30. Prior genetic studies have shown that homozygosity for HLA-DQ2 (HLA-DB1*02) and allelic variants of the MYO9B gene region maybe associated with previously classified EATL and indeed, data from comparative genomic hybridization studies on tumour DNA suggest that chromosomal gains of 1q and 5q and segmental amplification of 9q or deletion in 16q are important in EATL pathogenesis [2]. Following the new WHO classification of lymphoid neoplasms Type 2 EATL has been reclassified as monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) [1]. MEITL is less commonly associated with coeliac disease and is characterized by a monomorphic infiltrate of smallto medium-sized lymphoma cells. CD30 is often negative in MEITL, and CD56 positivity suggests that a different mechanism underlies the lymphomagenic process of this tumour in contrast to EATL [2]. In EATL cases, there is often a variable time lapse between the initial diagnosis of coeliac disease and the onset of lymphoma and EATL is a significant cause of mortality in adult onset coeliac disease patients. Standard chemotherapeutic regimens with CHOP are associated with a cure rate of about 20% in EATL, though intensified therapy with autologous stem cell transplant have been associated with 5-year overall survival rates of 60% [3]. miRNAs are a class of small noncoding RNAs, approximately 22 nucleotides long that have been found to negatively regulate gene expression. Over 4500 miRNAs have been identified in humans and nearly all human protein encoding genes are controlled by miRNAs. They have been found to have roles in cell growth, differentiation, apoptosis and tumourigenesis [4]. No study to date has characterised miRNA expression in EATL. In this pilot study we characterised the miRNA profile of a cohort of EATL from formalin fixed paraffin embedded tissue using TaqMan low density arrays targeting specifically miRNAs associated with T-cell neoplasia and normal T-cell function. Ten formalin fixed paraffin embedded cases of EATL classified according to WHO 2016 criteria [2] were identified from Irish patients in the surgical pathology files of St. Jamess Hospital and The Adelaide and Meath National Childrens Hospital Tallaght Dublin (Fig. 1 and Supplemental Figure 1). Control tissue comprised duodenal biopsies from patients with no history of enteropathy (n= 5) and those with a history of untreated coeliac disease (n= 4). The relative expression of 95 miRNAs was quantified from extracted tumour RNA (the list of miRNA genes and the qPCR-based methodology is provided in Supplemental Table 1 and Supplemental Methods respectively). Unsupervised hierarchical clustering of miR expression of the entire cohort showed that EATL samples formed a distinct cluster relative to the control group (Supplemental Fig. 2). To identify an EATL miR signature we performed comparative marker selection (http:// genepattern.broadinstitute.org) and identified 13 downregulated miRs which distinguished EATL from the control group (Fig. 2 and Supplemental Table 2). We then assessed what pathways are potentially targeted by the 13 miR gene signature of EATL using KEGG pathway analysis. There were 571 validated gene targets for the 13 miR gene signature and several major target pathways were over-represented including the JAK/STAT, MAPK and PI3K-AKT pathways (Supplemental Figs. 3 and 4). In this pilot study we demonstrate for the first time a potentially distinct miR signature associated with EATL and have identified several miRs that may potentially have a role in EATL pathogenesis. Interestingly all of the 13 miRs present in the EATL signature were downregulated indicating their role as potential tumour suppressor genes. Not surprisingly, we identified several pathways potentially affected by miR dysregulation in EATL, including several genes independently enriched in the JAK/STAT signalling pathway, which is frequently mutated in intestinal T-cell lymphoma highlighting its important role in EATL pathogenesis [5]. Indeed, with the development of new therapies and ongoing clinical trials, targeting both the JAK/STAT and MAPK pathway maybe worth considering in patients with EATL. Importantly several of the miRs

FISH studies in DLBCL: correlations with cell of origin: the Irish experience

Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin’s lymphoma, and while the majority of patients will be successfully treated using immunochemotherapy, a significant number, up to 30%, will either fail primary therapy or quickly relapse. Gene expression profiling (GEP) and the identification of rearrangements (R) involving MYC, BCL2 and/or BCL6 can be used to stratify patients with DLBCL into prognostic subgroups. GEP identifies three molecular subgroups, germinal centre B (GCB), activated B (ABC) and type 3, which reflect stages of GCB cell development. Patients in the GCB subgroup have the best prognosis, while those of ABC subtype have inferior overall survival rates.1 This ‘cell of origin’ (COO) classification is now a mandatory requirement in the diagnostic work-up of DLBCL. GEP is expensive however and not widely available, in contrast to immunohistochemistry (IHC). As such, IHC algorithms based on B cell differentiation antigens were developed, which are shown to have variable degrees of concordance with GEP.2nnHigh-grade Bxa0cell lymphoma with MYC, BCL2 and/or BCL6 R also characterise a distinct group of aggressive lymphomas, known as double or triple hit lymphomas (DH/TH), and can occur in 5%–10% of DLBCL cases.3 DH/TH are usually associated …

NOTCH1 mutation in type II Hodgkin transformation of chronic lymphocytic leukemia

Brianan McGovern*, Fiona Quinn*, Clare Andrews, Michael Jeffers, Christopher L. Bacon, Brian Bird, Gerard Crotty, Elisabeth Vandenberghe† and Richard Flavin† Department of Histopathology, St. James’s Hospital, Dublin, Ireland; Department of Cancer Molecular Diagnostics, St. James’s Hospital, Dublin, Ireland; Department of Haematology, St. James’s Hospital, Dublin, Ireland; Department of Medical Oncology, Bons Secours Hospital, Cork, Ireland; Department of Haematology, Midland Regional Hospital, Tullamore, Ireland

Burkitt leukaemia/lymphoma: R-CODOX-M/R-IVAC remains gold standard treatment in BL

BackgroundSporadic Burkitt lymphoma (BL), characterised by translocation-associated C-MYC upregulation is a rare, aggressive lymphoma with a cure rate up to 90xa0% using the R-CODOX-M/R-IVAC (RCRI) protocol. RCRI is active in HIV-associated BL in combination with HAART. The WHO classification system defines lymphomas intermediate between DLBCL and BL, in which lymphomas with t(14;18)(q32;q21) and C-MYC-carrying translocation, i.e. ‘double-hit’ are included (BL-DH), and these patients are conventionally treated with RCRI.ResultWe describe the SJH experience of 25 patients with BL, BLxa0+xa0HIV and BL-DH treated with RCRI between 2002 and 2011. Twelve BL patients (8M/4F), median age 49.1xa0years (range 20–73xa0years); of whom 9 had extensive disease, including 8 with marrow and 2 with CNS involvement. Eleven patients remain in remission at 80.5xa0months (range 37–147xa0months) from completion of treatment and one died of progressive BL giving an OS of 91.6xa0% at 1xa0year with no late relapses. Eight patients with BLxa0+xa0HIV were treated (6M/2F) with a median age 40.25xa0years (range 24–64). Five remain in complete remission (CR) at 65xa0months (range 13–109xa0months), three patients died, two of progressive disease and one of treatment-associated hepatotoxicity in CR. Five patients with BL-DH were included; (3M/2F), age 47.8xa0years (range 42–55xa0years); and all patients died of progressive disease, 4 on RCRI therapy and a further patient despite an allogeneic transplantation.ConclusionThese results confirm that RCRI is an effective treatment in adults with BL and BLxa0+xa0HIV and remains the gold standard against which other regimens should be compared. We confirm the poor prognosis found in BL-DH, indicating new treatment approaches are needed for this sub-group which should be identified at diagnosis by FISH analysis.

A coincidence or a rare occurrence? A case of plasmablastic lymphoma of the small intestines following infliximab treatment for Crohn’s disease

Dear Editor, Plasmablastic lymphoma (PBL) is an extremely rare lymphoma usually associated with an immunocompromised state, particularly HIV. It is an aggressive lymphoma and, despite initial response to treatment, most patients relapse and die within 12–14 months of diagnosis [1, 2]. We report a 50-year-old gentleman with a 12-year history of ileo-caecal Crohn’s disease who was admitted with vomiting, abdominal pain, and diarrhoea due to small-bowel obstruction. He underwent laparotomy with resection of a small-bowel mass. This patient had multiple prior therapies for Crohn’s disease including 6-Mercaptopurine, Sulphasalazine, steroids and most recently infliximab commenced 9 months previously (four doses in total). The resected small bowel showed a fungating mass measuring 7×7 cm with invasion through the muscularis propria involving the serosa. Microscopically, a diffuse infiltrate of large neoplastic lymphoid cells was seen, some with recognisable plasmablastic morphology. Some areas showed a ‘Starry-sky’ appearance and multiple reactive histiocytes were present. The neoplastic cells expressed CD138 and MUM-1 and lacked panB cell markers, most notably CD20 (Fig. 1). There was no evidence of lymphomatous involvement elsewhere. HIV 1 and 2 antibody tests by ELISA were negative and the serology showed previous exposure to EBV. EBER of the tumour tissue by in situ hybridisation was negative (positive in 46 % of HIV-negative PBL cases). The patient received chemotherapy with dose-adjusted EPOCH (etoposide, vincristine, daunorubicin, cyclophosphamide) and prophylactic intrathecal chemotherapy for 6 cycles given the aggressive nature of PBL. He tolerated chemotherapy well and remains in remission for over 3 years following completion of treatment. Infliximab therapy was discontinued after the diagnosis of lymphoma. PBL was first described in 1997 as a distinct subtype of diffuse large B-cell lymphoma occurring in immunocompromised patients, particularly HIV infection. Oral cavity and gastrointestinal tracts are the most commonly involved sites and 60 % of patients present with advanced clinical stage [2]. Over the last decade, an association between immunosuppressive therapy with antiTNF-α agents and an increased risk of malignancy including lymphoma has been described. In 2004, the FDA expressed concerns regarding a greater frequency of lymphoma in all clinical trials involving antiTNF-α agents. A meta-analysis of all randomised controlled trials in patients with rheumatoid arthritis treated with antiTNF-α therapy over a 10-year period by Wong in 2011 showed an increased incidence of lymphoma in the antiTNF group compared to controls (1.65 versus 0.36 per 1000 person-years) [3]. However, other studies by Seigel and Biancone described the risk as being low or even absent for patients with Crohn’s disease treated with anti-TNF agents. Other risk factors may be present such as age, fistulising pattern of disease and reactivation of EBV by other immunosuppressive agents [4, 5]. To our knowledge, PBL following infliximab therapy has only been described as case reports [6, 7]. The excellent outcome in our patient was favoured by early presentation, localised disease allowing complete resection of the tumour and aggressive * Su Wai Maung Suwmaung@physicians.ie