Reactive Infiltrate Research Articles

Mycosis Fungoides Misdiagnosed As Squamous Cell Carcinoma

Mycosis Fungoides Misdiagnosed As Squamous Cell Carcinoma

Mitotic errors, aneuploidy and micronuclei in Hodgkin lymphoma pathogenesis

The Reed-Sternberg (RS) cell is the driving force behind Hodgkin lymphoma (HL), a unique malignancy in which the rare RS cell creates an inflammatory microenvironment that recruits a reactive tumor infiltrate. Well-known oncogenic factors such as nuclear factor kappa B (NFκB) signaling and Epstein-Barr virus infection are linked to HL pathogenesis but do not adequately explain the RS cell’s key pathologic features of multi-nucleation, abnormalities of centrosome function and number and aneuploidy. Chromosomal instability is also considered a key pathway in the origin of the RS cell, though the molecular mechanisms have largely been a “black box.” We demonstrated that the midbody kelch domain protein KLHDC8B protects against mitotic errors, centrosomal amplification and chromosomal instability. Here we discuss how the new findings linking KLHDC8B to mitotic integrity and faithful chromosomal segregation are providing mechanistic explanations for the origin of the RS cell and the molecular pathogenesis of chromosomal instability in HL.

Spindle-shaped CD163+ rosetting macrophages replace CD4+ T-cells in HIV-related classical Hodgkin lymphoma

Combination antiretroviral therapy is highly effective in HIV infection, leading to decreased incidences of AIDS-defining neoplasms. However, HIV patients still have a 10-fold increased risk of developing classical Hodgkin lymphoma compared with the general population. As Hodgkin- and Reed–Sternberg cells represent only a minority in the tumor infiltrate, the aim of the present study was to characterize the microenvironment of HIV-related classical Hodgkin lymphoma and compare it with classical Hodgkin lymphoma cases of immunocompetent individuals. The major morphologic differences were the presence of necrotic foci and the absence of epithelioid cell formation in HIV-related Hodgkin lymphoma. We observed a significantly decreased number of CD4+ T-cells and a significantly increased number of CD163+ macrophages in HIV-related Hodgkin lymphoma. Cases exhibiting a ‘sarcomatoid' pattern of the reactive infiltrate exhibited significantly greater numbers of macrophages, associating the ‘sarcomatoid' pattern to the presence of spindle-shaped macrophages. Whereas, rosetting of CD4+ T-cells around Hodgkin- and Reed–Sternberg cells was frequently observed in classical Hodgkin lymphoma in immunocompetent persons; rosetting in a subset of HIV-related Hodgkin lymphoma cases appeared to involve cytoplasmic protrusions of spindle-shaped macrophages. HIV-related Hodgkin lymphoma, therefore, is characterized by unique morphologic features, which should be recognized by pathologists.

Primary bone marrow T-cell/histiocyte-rich large B-cell lymphoma: a diagnostic challenge

We report a primary bone marrow diffuse large B-cell lymphoma in a 52-year-old post-menopausal woman that evaded definitive diagnosis initially due to deceptive clinical features, non-contributory radiological findings, and an extensive reactive lymphoid infiltrate masking the relatively few neoplastic B-cells on bone marrow biopsy. The correct diagnosis was apparent only after a repeat bone marrow procedure and review of the previous histology and immunohistochemistry. The case illustrates the pitfall of assuming mixed B- and T-cell infiltrates in the bone marrow to be invariably benign. A high index of suspicion regardless of the clinical and/or radiological absence of lymphadenopathy or organomegaly and critical examination of each individual cell population in immunohistochemically stained material are essential for correct identification of this rare entity.

Extranodal and splenic small B-cell lymphoma

Although almost any non-Hodgkin lymphoma can involve the spleen or an extranodal site as part of more widely disseminated disease, there is a group of small B-cell lymphomas that specifically arise in these locations. These are important to recognise as some appear to have a behaviour and prognosis that is distinct from their nodal counterparts. In addition, there are entities that are specific to extranodal locations (such as extranodal marginal zone lymphoma) and to the red or white pulp of the spleen. In this review, the characteristics of these entities will be presented as well as clues to help distinguish lymphoma from reactive infiltrates in extranodal sites and measure to distinguish between small B-cell lymphomas encountered in the spleen and at extranodal locations.

Incidence of preclinical manifestations of mantle cell lymphoma and mantle cell lymphoma in situ in reactive lymphoid tissues

Recently, the occurrence of cyclin D1-positive B cells with mantle cell lymphoma phenotype in the inner mantle zones of morphologically inconspicuous lymph nodes has been described and termed mantle cell lymphoma 'in situ'. Prevalence and clinical significance of this lesion and related minimal mantle cell lymphoma infiltrates in reactive lymphoid tissues of healthy individuals, and of mantle cell lymphoma patients are unknown. All 1292 reactive lymph nodes from unselected consecutive surgical specimens of 131 patients without a history of lymphoma obtained over a 3-month period were stained for cyclin D1. In addition, all morphologically reactive lymph nodes and benign-appearing extranodal lymphoid infiltrates of patients diagnosed with mantle cell lymphoma in the years 2000–2011 were studied. Samples predating the lymphoma diagnosis for at least 2 months were available from 37/423 (9%) patients. A mantle cell lymphoma 'in situ' was not identified in any of the two groups. However, in four patients with subsequent mantle cell lymphoma diagnosis, an early manifestation of mantle cell lymphoma was detected retrospectively, antedating the lymphoma diagnosis for 2–86 months. In six mantle cell lymphoma patients, only small groups of cyclin D1-positive cells in morphologically reactive extranodal infiltrates were detected >2 months before the diagnosis of mantle cell lymphoma (range 3–59 months). Mantle cell lymphoma 'in situ' is an extremely rare phenomenon in morphologically reactive lymph nodes, in line with the low prevalence of t(11;14)-positive cells described in the peripheral blood of a healthy population. In mantle cell lymphoma patients, however, immunohistochemically detectable infiltrates of mantle cell lymphoma cells antedating the lymphoma diagnosis were found in a significant proportion of cases (10/37=27%). These consisted either of early mantle cell lymphoma with mantle zone growth pattern, or small extranodal accumulations of cyclin D1+ cells, whereas typical mantle cell lymphoma 'in situ' was not detected.

Strong HLA Class I Expression Is Positively Correlated with the Number of PML Nuclear Bodies and Negatively with the Percentage of SATB1 Positive HRS Cells in EBV+ Classical Hodgkin Lymphoma (cHL)

AbstractAbstract 3633 Introduction:Classical Hodgkin lymphoma (cHL) is a malignant neoplasm of the immune system, characterized by the presence of an abundant reactive infiltrate and a minority of Hodgkin Reed-Sternberg cells (HRS cells). HRS cells retain their professional antigen presenting phenotype in most cases. In EBV- cHL, membranous HLA class I expression is retained in HRS cells in approximately 30% of the cases, whereas in EBV+ cHL HLA class I expression is retained in HRS cells in 79% of the cases. Moreover, a proportion of the EBV+ cHL cases shows an enhanced HLA class I expression as compared to the surrounding infiltrating cells.The mechanism of the enhanced or lost HLA class I expression is unknown. Special AT-rich region binding protein 1 (SATB1) and promyelocytic leukemia protein (PML) are two proteins that have been shown to regulate HLA class I expression. Downregulation of SATB1 in Jurkat cells results in an enhanced expression of HLA-A, HLA-G, HLA-H and HCG4P6, whereas downregulation of PML results in a reduced HLA-A and HLA-G expression. PML is the main component of nuclear bodies (NBs) that organize the chromatin structure into loops by anchoring matrix attachment regions to the nuclear matrix. SATB1 has been shown to be associated with the PML-NBs in the HLA region. Aim:To investigate the possible role of SATB1 and PML-NBs in the regulation of HLA class I expression in EBV+ cHL. Methods:We analyzed 64 EBV+ cHL cases and as a control included 29 EBV- cHL cases. HLA class I membranous staining (HC10 antibody) by HRS cells was scored as positive or strongly positive, cases that lacked membrane staining were scored negative. ß2-microglobulin served as an additional marker for membranous HLA class I expression. For SATB1 (14/SATB1), we scored the percentage of HRS cells with nuclear SATB1 staining. For PML (PG-M3), we scored HRS cells based on the number of PML nuclear bodies in two categories; 10 or less NBs per cell or >10 NBs per cell (per 4 um tissue section). Results:In the EBV+ group 24 cases stained strongly positive, 22 positive and 18 negative for HLA class I. In the EBV- group, none of the cases showed a strong positive staining, 7 cases stained positive and 22 cases were negative for HLA class I. HLA class I staining results were consistent with the ß2-microglobulin staining results in all cases. The percentage of SATB1 positive HRS cells varied from 0–100% in both EBV+ and EBV- cHL. The number of PML-NBs was between 0–10 in 46 and >10 in 18 EBV+ cHL cases and between 0–10 in 23 and >10 in 6 EBV- cHL cases.We observed no correlation between HLA class I staining in the EBV- cHL cases and the percentage of SATB1 positive HRS cells or the number of PML-NBs in the HRS cells. In EBV+ cHL cases we observed significant differences in the percentages of SATB1 positive cells between the HLA class I negative, normal and strongly positive groups (p=0.0412). The cases with normal HLA class I staining had significantly higher percentages of SATB1 positive cells as compared to the cases with strong HLA class I staining pattern (p<0.05) (Figure 1). There was no significant difference between negative and normal or negative and strongly positive HLA class I groups with respect to the percentage of SATB1. The percentage of EBV+ cHL cases with >10 PML-NBs significantly increased from HLA class I negative (1 out of 18, i.e. 5%) to normal (4 out of 22, i.e. 18%) and strong (13 out of 24, i.e. 54%) positive cHL cases (p=0.0011). Conclusion:We found an inverse correlation between the percentages of SATB1 positive HRS cells in the HLA class I strong and normal EBV+ cHL groups. The number of cases with >10 PML-NBs were significantly increased in HLA class I strong as compared to the HLA class I normal and negative EBV+ cHL groups. Thus SATB1 and PML may play an important role in the regulation of HLA class I expression levels in EBV+ cHL. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Ovarian Teratoma Associated With Anti-N-Methyl D-Aspartate Receptor Encephalitis

Anti-N-methyl D-aspartate receptor (NMDAR) encephalitis is a recently described severe neurological disorder predominantly affecting young women, which presents with psychosis, memory deficits, seizures, and encephalopathy, often requiring prolonged hospitalization. The condition is frequently associated with an underlying neoplasm, most often an ovarian teratoma, and in such cases appears to be a para-neoplastic, immune-mediated encephalopathy. The histologic features of the teratomas associated with anti-NMDAR encephalitis have seldom been described in detail. Therefore, in this report, we have compared ovarian teratomas (4 mature and 1 immature) from 5 patients with anti-NMDAR encephalitis with 22 sporadic control teratomas (14 mature and 8 immature) that included neuroglial elements. The encephalitis-associated tumors ranged from 0.7 to 9.5 cm diameter, and 1 case was bilateral; the second teratoma was discovered 13 mo after the first when symptoms recurred. In comparison with control teratomas, the anti-NMDAR-associated tumors showed a more marked intratumoral lymphoid infiltrate that colocalized to the mature neuroglial elements. Reactive germinal centers (3 cases) and diffuse lymphoplasmacytic infiltrates within the neuroglial matrix (4 cases), and degenerative neuronal changes (2 cases), were seen only in the anti-NMDAR-positive cases. Pathologists encountering ovarian teratomas with these distinctive reactive lymphoid elements should consider the possibility of anti-NMDAR encephalitis, particularly because the neurological symptoms may develop after tumor resection. Careful histopathologic examination may be required to identify small, radiologically occult teratomas, and to demonstrate the presence of subtle neoplastic neuroglial components in teratomas associated with anti-NMDAR encephalitis.

Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids Following Influenza Vaccination

Inflammatory processes within the central nervous system are challenging for the clinician, radiologist, and pathologist alike. They often can mimic other more well-known and defined disease processes. We present the case of a patient with a newly described inflammatory process that primarily involves the pons and adjacent structures, which is called chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). An 80-year-old man presented with numbness of his right hand that ultimately progressed to involve both lower extremities and face and was associated with mild dysarthria and ataxia. He had received the influenza vaccination 2weeks prior. The biopsy revealed primarily reactive T-cell lymphocytic infiltrates with macrophages and gliosis. Treatment required long-term immunosuppressive therapy. CLIPPERS is a recently described central nervous system inflammatory condition that should be considered in the differential diagnosis when a prominent lymphocytic inflammatory infiltrate is encountered in brainstem, spinal cord, midbrain, or cerebellar biopsies.

PML IRIS: A Difficult Diagnosis (P02.271)

Objective: Consider Progressive Multifocal Leucoencephalopathy- Immune Reconstitution Inflammatory Syndrome (PML-IRIS) with worsening neurological symptoms and improved Cluster of Differentiation 4 (CD4) count and viral load. Background PML is a severe demyelinating disease of Central Nervous System, caused by the JC Polyomavirus. IRIS describes paradoxical worsening of pre existing infectious processes following initiation of Highly Active Anti Retroviral Therapy (HAART) and improvement in immunologic function. Design/Methods: Case Report from a Tertiary Medical Centre. Results: 41 year old man with Human Immunodeficiency Virus (HIV, non compliant with medications) presented with Right hand weakness. CD4 count was 53, Viral load was high, MRI Brain showed lesion in Left precentral gyrus, bright on Diffusion Weighted Imaging and moderate intensity on Apparent Diffusion Coefficient. He was thought to have subacute infarct, started on Aspirin, anticholesterol agent and HAART. Patient returned 6 weeks later with Right arm plegia, CD4 count had improved to 60 and viral load was undetectable. MRI Brain showed increased signal Left frontoparietal region with mild enhancement, no mass effect. Lumbar Puncture (LP) had normal cells, chemistry, and a viral PCR panel including JCV was negative. Patient was continued on HAART and sent home. He returned 3 weeks later with Right sided hemiplegia and aphasia. MRI Brain showed worsening mass effect, cavitation in the lesion with patchy nodular enhancement. Repeat CSF was normal including cytology and viral PCR. Brain biopsy showed inflammatory reactive infiltrate with abundant lipid laden macrophages, perivascular lymphocytes and rare cells reactive with JCV. A third CSF sample also revealed JCV detected at lower limit of quantitation. The patient was continued on HAART and Intra Venous (IV) Steroids started. His symptoms progressively improved. Conclusions: Increase in CD4 count and improved viral load can mount IRIS response in PML patients and IV Steroid therapy should be instituted without delay. Disclosure: Dr. Kannaditharayil has nothing to disclose.

Reactive granular histiocytosis secondary to arthroplasty prosthesis: a novel reaction pattern

A reactive histiocytic infiltrate can be seen as an incidental finding in a lymph node biopsy from a patient with a history of joint arthroplasty. We report the case of a 74-year-old female who underwent surgical revision of a polyethylene-based right total knee prosthesis due to chronic wear. At the time of surgery, a soft tissue mass adjacent to the tibial prosthetic insert was noted and excised. Histopathologic examination revealed a sheet-like proliferation of large, histiocytoid cells within the subcutis and superficial fascia. The cells showed abundant eosinophilic, granular cytoplasm and small round bland nuclei. Immunohistochemical evaluation revealed the cells to be positive only for CD68. In addition, abundant PAS-positive cytoplasmic granules were found, and minute particles of polarizable material were noted intracellularly and scattered throughout the interstitium of the infiltrate. These findings were interpreted as consistent with a reactive, non-Langerhans cell histiocytosis secondary to the patient's polyethylene knee prosthesis. This finding appears to be a local correlate of the process previously described in regional lymph nodes as reactive granular histiocytosis. Dermatopathologists should be cognizant of this uncommon reaction pattern to avoid mistaking it for a neoplastic process.

Classical Hodgkin lymphoma: Differential diagnosis and tumour microenvironment

Hodgkin lymphoma (HL) accounts for approximately 15% to 30% of all malignant lymphomas. according to current diagnostic criteria, approximately 90% to 95% of HLs fall into the Classical Hodgkin lymphoma (CHL) category; the remaining cases are nodular lymphocyte-predominant subtype of Hodgkin’s lymphoma (NLPHL) which is recognized as a separate entity in the World Health Organization (WHO) classification1. WHO classification is based on the fact that there are clear and consistent histologic, epidemiologic, immunologic, and genetic differences between NLPHL and CHL. NLPHL is an indolent germinal center (GC) B-cell malignancy, that represents a nodular proliferation comprised of a minority of large neoplastic centroblasts with multilobated nuclei, the so-called popcorn or lymphocyte-predominant (LP) cells. Immunohistochemically LP cells are Cd20+, PaX5+, BCL6+, EBV-LMP1-, Cd30and Cd15-. Background inflammatory infiltrate represent mixture of small B and T lymphocytes1. This type of tumour is characterised clinically by a relatively indolent course and a very good response to standard therapy in cases with low stage disease. Unfortunately, the prognosis is unfavourable for advanced stages2. CHL is also a clonal, malignant lymphoproliferation originating from germinal center B cells3. CHL has a bimodal age curve in western countries, showing a peak at 15-35 years of age and a second peak later in life at 45-60 years1. a histopathologic diagnosis of CHL is based on the identification of diagnostic reed-sternberg (rs) cells in an appropriate inflammatory background of mixed infiltrate by histiocytes, small lymphocytes, eosinophils, neutrophils, plasma cells, fibroblasts and colagen. Based on characteristics of the reactive infiltrate and the specific features of neoplastic cells, cases may be subclassified into one of four subtypes: nodular sclerosis (NsCHL), lymphocyte-rich (LrCHL), mixed cellularity (MCCHL) and lymphocyte-depleted classical Hodgkin lymphoma (LdCHL)1,4. although most cases can be diagnosed on the basis of morphology alone, diagnostic criteria include the characteristic immunophenotype of the neoplastic population. rs cells and variants express the Cd30 and Cd15 antigens in the majority of cases and lack the common leukocyte antigen Cd455,6. The LMP-1 protein of EBV is expressed in approximately 25% to 50% of CHLs depending on the histologic subtype and patient age7. The staining is membranous and cytoplasmic, and usually most neoplastic cells are positive. Etiology of CHL is still questionable, but due to the unique epidemiologic and clinical features of the disease, an infectious cause has long been suspected. Currently, immunohistochemistry for the EBV latent membrane protein-1 (LMP-1) and nonradioactive in situ hybridization for EBV-encoded early rNas (EBErs) are the methods of choice for the detection of EBV in routinely fixed, paraffin-embedded tissues8. recent data suggest that the EBV status of tumour cells in classical HL could have prognostic significance for patients with this heterogenous disease9.

Orbital Inflammation: A Rare Association of Common Variable Immunodeficiency

Purpose: Ocular associations with common variable immunodeficiency (CVID) are very rare which include granulomatous uveitis, mulitfocal choroiditis and retinal vasculitis. However there have been no reports of orbital involvement, either inflammatory or neoplastic in association with CVID. We describe a unique case of a patient with CVID who developed orbital inflammation.Methods: Clinical, histological and radiological findings and the management of this case is presented.Results: A 58 year old male with known CVID treated with regular intravenous immunoglobulin infusion, presented with left peri-orbital redness, pain, proptosis and restriction of ocular movements. CT scan showed an ill-defined mass in the left lateral orbit, adjacent to the lacrimal gland. An orbital biopsy revealed a monomorphic lymphocytic infiltrate forming loose lymphoid aggregates in the lacrimal gland tissue. Immunocytochemistry confirmed this to be a reactive inflammatory infiltrate. The patient was successfully treated with a course of oral prednisolone which resulted in improvement of orbital inflammation, ocular movements and proptosis.Conclusion: To our knowledge this is the first reported case of non-granulomatous orbital inflammation in association with CVID. This case serves to remind ophthalmologists encountering a patient with CVID that they may have associated orbital inflammatory disease which is responsive to steroid therapy similar to sterile inflammatory masses described in other organs.

The rectal tonsil in children: a reactive lymphoid proliferation that may mimic a lymphoma

Prominent and localized lymphoid hyperplasia in the rectum is also known as rectal tonsil (RT) [1, 2]. When the reactive lymphoid infiltrate is very exuberant with atypical lymphoid cells it can be difficult to distinguish from lymphoma on histology [3]. To avoid overdiagnosis and overtreatment, immunophenotypic and genotypic studies are necessary [3–5]. A 4-year-old girl, without relevant medical antecedents, was referred to our department with rectal bleeding. The hemogram was normal. Rectal examination revealed a polypoid mass arising from posterior rectal wall. A pelvic MRI showed a 3 cm × 3 cm polypoid mass in the distal rectum without infiltration beyond the submucosa (Fig. 1a). Endoscopy revealed raised and nodular mucosa without ulceration arising from the posterior rectal wall (Fig. 1b). Two fragments were removed surgically to establish the correct diagnosis. At histology, a dense lymphoid infiltrate was present in the lamina propria and submucosa; there were abundant macrophages inside the germinal follicles, atypicalappearing enlarged and mature lymphocytes with numerous mitotic figures and well-formed germinal centers of different size. Immunohistochemistry suggested follicular type of proliferation with B cells markers (CD20+, CD10 and bcl-6+). The germinals centers were bcl-2 negative. Immunohistochemical staining for CD21 demonstrated a follicular pattern by delineating follicular dendritic cells. PCR studies helped to exclude a lymphoid malignancy because there was no evidence of monoclonal expansion of B cells. These studies confirmed a reactive lymphoid proliferation, and excluded lymphoma, and other forms of non-neoplastic lymphoid proliferation with intact follicles such as lymphoid follicular proctitis and lymphoid polyps of the rectum. A normal-appearing rectal mucosa was seen during endoscopy 14 months later. Histology and their inmunohistochemical and molecular studies help to differentiate benign condition from a malignant one [3–5]. The etiology of RT hyperplasia is unknown. Histologically RT hyperplasia may be distinguished from malignant lymphoma by the polymorphic nature of the infiltrate, absence of significant cytologic atypia and the presence of reactive follicles within the lesion. Mitotic figures are frequent in the germinal centers but absent in the surrounding lymphoid tissue. The lymphoid infiltrate usually is confined to the mucosa and the submucosa; the involvement of the muscularis mucosa is unlikely [2]. In contrast, lymphomas have an infiltrative growth pattern, an P. F. Eire (*) :M. P. Arias :A. L. Carril Department of Pediatric Surgery, Complejo Hospitalario Universitario de Vigo, Pizarro 22, 36204 Vigo, Spain e-mail: pilar.fernandez.eire@sergas.es

Histopathology of Femoral Head Donations: A Retrospective Review of 6161 Cases

Although total hip arthroplasty is one of the most common orthopaedic surgical procedures, it remains unclear whether histopathological examination of the excised femoral head adds to the quality of patient care. We propose that assessment of femoral heads resected during total hip arthroplasty and donated for allograft use may provide a profile of femoral head pathology that benefits total hip arthroplasty patients and bone donors. We retrospectively analyzed the histological findings reported for 6161 femoral heads donated for allograft use between 1993 and 2006. Specimens obtained during total hip arthroplasty and specimens donated at death were reviewed. Follow-up investigations that resulted from abnormal histopathological findings were also reviewed. The Western Australian Cancer Registry was used to determine whether patients with a suspected neoplasm were subsequently diagnosed with such a disease. A retrospective review of the histopathological findings was conducted to evaluate and reclassify all previous observations of abnormalities. One hundred and five femoral heads demonstrated abnormal or reactive histopathological features not reported prior to surgery and were rejected for allograft use. A reactive lymphocytic infiltrate, most likely due to osteoarthritis, was the most commonly identified feature (forty-five cases). Other features observed in twenty-seven cases were also most likely due to the presence of severe osteoarthritis. Ten femoral heads demonstrated plasmacytosis, which may have been related to osteoarthritis. Two patients were diagnosed with Paget's disease, and two, with rheumatoid arthritis. Nineteen patients had a suspected neoplasm. Of these nineteen, eight cases of non-Hodgkin's lymphoma or chronic lymphocytic leukemia and one case of myelodysplastic syndrome were confirmed on further investigation. One subsequently confirmed malignancy was detected per 770 femoral heads examined. Our findings indicate that, even with a detailed medical history and careful physical examination, clinically important diseases including neoplasms and Paget's disease are observed in patients diagnosed with osteoarthritis prior to total hip arthroplasty. Histological examination plays an integral role in quality assurance in femoral head banking, and it also represents a possible early diagnostic test for bone and bone-marrow-related diseases in patients undergoing total hip arthroplasty.

Lymphoepithelial Carcinoma: Two Case Reports and a Systematic Review of Oral and Sinonasal Cases

Lymphoepithelial carcinoma (LEC) is a rare malignancy. Histologically, it is an undifferentiated carcinoma with an intermixed reactive lymphoplasmacytic infiltrate. Herein, we report two cases of LEC in the head and neck region that presented to Oulu University Hospital. Our first case is a 30-year-old man with LEC in the left maxillary sinus. The second case is a 49-year-old man with LEC in the soft palate and uvula with regional lymph node metastases at diagnosis. In addition, a systematic review of the literature from 1980 to 2010 was performed with MEDLINE and cross-references were searched manually. Case reports and clinical series of oral, oropharyngeal, nasal, and paranasal sinus LECs were reviewed revealing a total of 110 cases. Most of the oral cases were found in the tonsils (n=29), oropharynx (n=19), and in oral mucosa (n=18), while sinonasal cases (n=40) were mainly in the paranasal sinuses and nasal cavity. From 37 case reports, including ours, the median age was 58 and 62years for sinonasal and oral/oropharyngeal LECs, respectively. Oral and oropharyngeal LECs have a 70.0% tendency to metastasize and 16.6% spread locally. In contrast, none of the nasal and paranasal LECs metastasized, but 60% spread locally. Epstein-Barr virus (EBV) had been detected in 87.5% of all tested LEC cases. Treatment of LECs, during the last decade, has largely consisted of surgery, combined with radiotherapy or chemoradiation. Although local spread or nodal metastases are fairly common at the time of diagnosis, the mortality rate of adequately treated LEC patients is low.

Therapy Outcome of a T-Cell-Rich-B-Cell Lymphoma (TCRBCL) Patient with Rituximab-CHOP in Ibadan, Nigeria: a Case Report.

T-cell-rich B-cell lymphoma (TCRBCL) is considered a rare variant of aggressive B cell lymphoma characterized by few neoplastic B cells and a large reactive infiltrate with striking similarities to nodular lymphocyte predominant Hodgkin’s lymphoma.A case of a 46 year old man referred with a 5 months history of generalized lymphadenopathy, weight loss, low grade pyrexia and two separately reported lymph node histology consistent with TCRBCL is described.The clinical course was indeed aggressive because in spite of initial treatment with four cycles of CHOP combination chemotherapy, followed by R+CHOP(x 6 cycles), signs of tumor re-growth/infiltration were frequently observed. Also, recurrent infection was frequent, troublesome and eventually became overwhelming resulting to the loss of the patient.This case, being the first case of TCRBCL diagnosed by immunohistochemical confirmation and managed at this centre with R-CHOP, is presented to highlight the dilemma in making diagnosis, clinical challenges faced and rituximab therapy outcome especially in resource poor country. It will also serve to increase our index of suspicion and the need reinforce immunohistochemistry in the diagnosis of lymphoma.

Protective and Predisposing HLA Alleles In Dutch Classical Hodgkin Lymphoma Patients

AbstractAbstract 749Classical Hodgkin lymphoma (cHL) is characterized by an overwhelming reactive infiltrate and the involvement of Epstein Barr virus (EBV) as a causative agent in a proportion of patients. We previously did a population-based genetic screening study of the Human Leukocyte Antigen (HLA) region in Dutch cHL patients and found a strong association between HLA class I (HLA-A1) and susceptibility to EBV+ cHL. This association might be explained by the known lack of HLA-A1 restricted T cell responses to EBV latent antigens. We now performed a case-control study to determine allele frequencies of all major HLA class I and class II genes in this cHL population. HLA genotyping of 294 cHL patients was performed by a polymerase chain reaction-based sequence-specific oligonucleotide probe hybridization (PCR-SSOP) approach in Luminex assays. The resulting single nucleotide polymorphism (SNP) data were converted into two-digit HLA typing for the HLA class I and class II genes. Phenotype frequencies of serologically defined HLA-A, HLA-B and HLA-DR blood donors were retrieved from the database of the blood bank of the University Medical Center Groningen. Allele frequency differences between these controls and cHL patients (total group and EBV+ and EBV- subgroups separately) were analyzed by Chi-square tests. In addition, we analyzed the HLA genotyping data for every PCR-SSOP probe to assess potential differences between the EBV+ and EBV- cHL group using PLINK software. Frequencies of HLA-DR4 and HLA-DR7 were significantly decreased and HLA-B5 and HLA-B37 were significantly increased in cHL as compared to the controls. In EBV+ cHL, HLA-A1, HLA-B37 and HLA-DR10 frequencies were significantly increased and HLA-A2 was decreased. An increase in HLA-B8, an allele that can present EBV peptides and that usually is in strong linkage disequilibrium with HLA-A1, was not present in these patients. In EBV- cHL, HLA-DR5 was significantly more common and HLA-DR4 was underrepresented. The SNP analysis revealed significant differences for 16 HLA-A probes between EBV+ and EBV- cHL. Eight probes that represented a high susceptibility for EBV+ cHL were specific for HLA-A1, whereas the other 8 probes correlated with a low risk for EBV+ cHL and were specific for HLA-A2. Most of the corresponding SNPs had a presumed antigenic peptide or T cell receptor binding function. In conclusion, the current study demonstrates that certain HLA alleles are protective or predisposing for cHL with specific associations for the EBV+ and EBV- cHL subgroups. The genotype analysis indicates that the complete HLA-A1 and HLA-A2 alleles are more important than individual T-cell receptor or antigen binding polymorphisms for the association with EBV+ cHL. Disclosures:No relevant conflicts of interest to declare.

Mirna EXPRESSION SIGNATURES as PROGNOSTIC Markers IN ADVANCED Classical HODGKIN LYMPHOMA

AbstractAbstract 4157In spite of the progress in the therapy of advanced stage classic Hodgkin lymphoma (cHL), still a significant proportion of patients fail to respond or relapse after complete remission. MicroRNAs (miRNA) are essential regulators of cell differentiation, emerging as robust predictor and prognostic markers. Specific miRNA signatures from the Hodgkin and Reed Sternberg cells (HRS) cells and their microenvironment have been proposed, but the potential prognostic role of them remains unclear. Here, we investigated whether miRNA signatures can allow to a better understanding of cHL pathogenesis and being applied in patient outcome prognostication.We have used mirRNA gene expression data from 32 samples of advanced cHL patients and 5 cHL derived cell lines (L540, L1236, L428, HDLM2, and KHMZ) to identify specific miRNA profiles from the tumoral cells and their non-tumoral microenvironment. A miRNA signature was identified in the cHL cell lines, probably reflecting functional properties of the HRS, whereas the others informed from properties of the reactive infiltrate. Selected miRNAs were further validated by performing laser capture microdissection using frozen samples in order to look for specific miRNAS preferentially expressed for either HRS cells and their surrounding microenvironment.In addition, logistic regression and Cox analysis allowed us to identify a set of 102 miRNAs differentially expressed (p<0.05) among patients with favourable and unfavourable outcome that included members of the miR-17-92 cluster such us mir-17, mir-92a and mir-92b* and other miRNAs known to be involved in cancerogenesis. A restricted group of 32 miRNAS with better prognostic capacity was further selected to set up a quantitative RT-PCR assay and explore the potential diagnostic application of their expression in an independent series of 96 formalin-fixed paraffin-embedded (FFPE) cHL samples.Bioinformatics target prediction (miRBase and TargetScan) and the web based computational tool DIANA-mirPath, were used in the identification of molecular pathways and target genes potentially regulated by the expression of these mirRNAs. Combined analysis of miRNAs, paired with bioinformatic target prediction, revealed a series of genes and pathways targeted by a small number of miRNAs, including essential pathways for lymphoma survival like MAPK signaling pathway, cell cycle, Jak-STAT signaling pathway and others.In conclusion, specific miRNA signatures for the HRS cells and their microenvironment can be identified in cHL samples, and improve our understanding in cHL pathogenesis. Selected miRNAs can be used in paraffin-embedded tissue for prognosis of advanced cHL cases, and can be incorporated in an RT-PCR assay with potential clinical application in advanced cHL. Disclosures:No relevant conflicts of interest to declare.

Familial Mycosis Fungoides: Model of Genetic Susceptibility

in terms of phenotype and clinical outcome. The familial clustering of MF, together with the detection of certain human leukocyte antigen (HLA) class II alleles with this malignancy (sporadic and familial), suggest that genetic factors might play a role in MF. With the increasing evidence supporting the importance of genetic determinants in lymphomagenesis, further attempts with international collaboration should be made to elucidate the possible genetic basis of the familial clustering of MF. Such consortial efforts will enable others to better define the epidemiology and phenotype of familial cases and, with the use of advanced molecular approaches, enhance our ability to identify susceptibility genes involved in familial MF. Mycosis fungoides is the most common cutaneous lymphoma, characterized by a CD4+ clonal expansion in the skin, admixed with a reactive lymphocytic infiltrate composed largely of CD4+ cells. The etiopathogenesis is still unknown; however, researchers suggest that it arises from a state of persistent antigenic cell stimulation1 to infectious agents, chemical agents, or other environmental factors. The majority of MF cases are diagnosed with no discernible family history of cancer and specifically of MF. Familial clustering of MF is regarded as a rare occurrence that could be explained by a common exposure to a causal agent, a genetic predisposition, or both. By contrast to MF, familial clustering of non-Hodgkin lymphoma,2 Hodgkin lymphoma,3 and chronic lymphocytic leukemia (CLL)4 is well established. These observations, together with the coaggregation of different chronic lymphoproliferative neoplasms in the same family reported on large-scale studies, support a genetic role in such high-risk families.5,6 The aim of the this report is to present the sparse literature on the epidemiology and phenotype of familial MF, review the limited genetic studies performed on familial MF, and discuss possible future clinical and genetic studies. Epidemiology and Phenotype of Familial Mycosis Fungoides Until the early 2000s, the occurrence of MF in relatives was regarded as an extremely rare event, with reports of only 8 such families from different parts of the world. Each report included an index patient from a single family in which another first-degree relative was also affected. Five families were from the United States,7-11 and 1 each were from Israel,12 Iraq,13 and Turkey.14 Four families had a parent-child pair,7,9,10,14 and 4 had sibling pairs,8,11-13