Jenny Turner

Anti-viral prophylaxis reduces the incidence of lymphoproliferative disease in lung transplant recipients

BACKGROUND Post-transplant lymphoproliferative disease (PTLD) is a serious, often fatal complication after solid organ transplantation. Primary Epstein-Barr virus (EBV) infection is the major risk factor for PTLD after lung transplantation, with 30% to 50% of EBV-naive patients who seroconvert and are diagnosed with PTLD. METHOD In this study, we analyzed the incidence of PTLD in lung and heart-lung transplant recipients before 1996 (historic group) and then compared the impact of long-term anti-viral prophylaxis on the development of PTLD in EBV-seronegative recipients from January 1996 to December 2000 (post-1996 group). Routine induction therapy was not given after 1995. Patients not surviving 30 days, 25 of 341 (7.3%), were excluded. RESULTS Historic group: PTLD developed in 7 of 167 (4.2%) patients, at a mean of 394 +/- 278 (95-885) days. The mortality was 87.5% at a mean follow-up of 186 +/- 207 (17-520) days after diagnosis. Post-1996 group: Eighteen of 149 (12.3%) patients were EBV seronegative at the time of transplantation, and of these 15 (83%) began receiving continuous anti-viral prophylaxis: acyclovir or valacyclovir or ganciclovir from January 1996. None of the EBV-seronegative recipients receiving continuous anti-viral prophylaxis were diagnosed with PTLD; however, 1 of 3 (33%) of the EBV-seronegative recipients who did not receive anti-viral prophylaxis were diagnosed with PTLD. In the EBV-seronegative recipients, no deaths had been caused by PTLD at a mean follow-up of 806 +/- 534 (39-1,084) days. In the post-1996 group, PTLD developed in 1 of 131 (0.76%) EBV-seropositive recipients. CONCLUSION Continuous, specific anti-viral prophylaxis in high-risk EBV-seronegative recipients significantly reduces the incidence of PTLD after lung transplantation in the absence of induction therapy.

Xanthomatous pituitary lesions: a report of two cases and review of the literature.

We describe two young men with cystic pituitary enlargement on magnetic resonance imaging (MRI) causing hypopituitarism. The first patient presented acutely unwell with headache and vomiting associated with anterior and posterior pituitary dysfunction. The second patient presented with hypopituitarism after a long history of hypogonadism. In both cases yellow/brown fluid was found at surgery and histological examination revealed inflammatory infiltrate with foamy histiocytes, lymphocytes and multinucleated giant cells containing cholesterol clefts. Full recovery of pituitary function occurred after surgery in the first but not the second patient. The first case is the first documented case of xanthomatous hypophysitis with recovery of pituitary function following surgery. The cases differed in duration of disease, as indicated by the long history of symptoms, the histological finding of marked fibrosis and the lack of recovery of pituitary function in the second. Xanthomatous pituitary lesions categorized in the literature as xanthomatous hypophysitis, xanthogranulomatous hypophysitis and xanthogranuloma of the sellar region have overlapping histological features. Our two cases revealed histological features that do not fit completely into any of the categories but share features of all three. These findings suggest that the various xanthomatous lesions of the sellar region may be a spectrum of a common inflammatory process rather than distinct pathological entities.

Routine testing for mismatch repair deficiency in sporadic colorectal cancer is justified.

This study prospectively examines the accuracy of immunohistochemical staining in the identification of mismatch repair defective (MMRD) colorectal cancer in routine clinical practice. The potential impact of this information on decisions regarding adjuvant treatment and germline testing were quantified. A consecutive series of fresh tissue (836 cancers) was obtained from 786 individuals undergoing curative surgery for colorectal cancer at one institution. As part of normal practice, each tumour was screened for the expression of MLH1 and MSH2 by immunohistochemical staining (IHC) and relevant clinicopathological details were documented. Microsatellite instability (MSI) was assessed using standard markers. Overall, 108 (13%) tumours showed loss of staining for either MLH1 (92 tumours) or MSH2 (16 tumours). The positive predictive value of mismatch repair IHC when used alone in the detection of MSI tumours was 88%, and the negative predictive value was 97%. Specificity and positive predictive value were improved by correlation with microsatellite status. Tumour stage (HR 3.5, 95% CI 2.0–6.0), vascular space invasion (HR 1.9, 95% CI 1.2–3.0) and mismatch repair deficiency (HR 0.2, 95% CI 0.05–0.87) were independent prognostic factors in stages II and III disease. Screening by mismatch repair IHC could reasonably have been expected to prevent ineffective treatment in 3.6% of stage II and 7.6% of stage III patients. The frequency of germline mismatch repair mutations was 0.8%, representing six unsuspected hereditary non‐polyposis colorectal cancer (HNPCC) cases. Routine screening of colorectal cancers by mismatch repair IHC identifies individuals at low risk of relapse, and can prevent unnecessary adjuvant treatments in a significant number of individuals. Abnormal immunohistochemistry should be confirmed by microsatellite testing to ensure that false‐positive results do not adversely impact on treatment decisions. Copyright

The role of molecular studies in lymphoma diagnosis: a review

Lymphoma classification is based on a multiparametric approach to diagnosis, in which clinical features, morphology, immunophenotype, karyotype and molecular characteristics are important to varying degrees. While in most cases, a diagnosis can be confidently established on the basis of morphology and immunophenotype alone, a small proportion of diagnostically difficult cases will rely on molecular studies to enable a definitive diagnosis. This review discusses the various molecular techniques available including Southern blotting (SB), polymerase chain reaction (PCR), fluorescence in situ hybridisation (FISH)--including multicolour-FISH/spectral karyotyping and comparative genomic hybridisation--and also gene expression profiling using cDNA microarray technology. Emphasis is given to the analysis of antigen receptor gene rearrangements and chromosomal translocations as they relate to lymphoma diagnosis and also in the setting of minimal residual disease (MRD) detection and monitoring. Laboratories performing these tests need to have expertise in these areas of testing, and there is a need for greater standardisation of molecular tests. It is important to know the sensitivity and specificity of each test as well as its limitations and the pitfalls in the interpretation of results. Above all, results of molecular testing should never be considered in isolation, and must always be interpreted in the context of clinical and other laboratory data.

Impact of microsatellite testing and mismatch repair protein expression on the clinical interpretation of genetic testing in hereditary non-polyposis colorectal cancer

Abstract Purpose. Identification of germline mutations in mismatch repair genes is increasingly being used to guide clinical practice in hereditary non-polyposis colon cancer. The aim of this study was to retrospectively assess the clinical utility of immunostaining and microsatellite instability testing in a group of individuals in whom germline testing of hMSH2 and hMLH1 had already been performed. Methods. Individuals were identified from the records of family cancer clinics. A total of thirty-eight tumour blocks were retrieved from 28 kindreds. DNA was extracted and PCR amplification of six microsatellite markers was performed. Immunostaining was used to examine the expression of hMSH2 and hMLH1 protein. Results. Of the 32 assessable tumours, 24 (75%) showed microsatellite instability. Most of the MSI-H cancers (92%) failed to express either hMLH1 or hMSH2. Deleterious germline mutations were identified in the proband in 12 of 28 families. Missense mutations were identified in 11 cases and no mutations in six probands. Conclusions. The use of germline genetic testing is indicated for a highly selected group of individuals. MSI testing and immunostaining are extremely useful tools which significantly improve the clinical interpretation of germline results. Ambiguity regarding the significance of missense mutations in hereditary bowel cancer suggests that these findings should be interpreted with caution.

Endolymphatic sac tumors: a review of the St. Vincent's hospital experience.

Objective: To describe the clinical, radiologic and histopathologic features of endolymphatic sac tumors using the St Vincent’s Hospital experience with these tumors to highlight important aspects of tumor diagnosis and treatment. Possible explanations are given for the apparent increasing incidence of these tumors. Study Design: Retrospective review of the senior author’s (P.A.F.) database of skull base lesions. Setting: Tertiary referral teaching hospital. Patients: All patients with a proven diagnosis of endolymphatic sac tumor treated at St Vincent’s Hospital, Sydney. Outcome Measures: Survival in months, after surgery. Results: Seven cases of endolymphatic sac tumors. All were treated surgically. Mean follow-up of 70.2 months (range, 6–144 mo). Conclusion: Endolymphatic sac tumors are becoming increasingly recognized because of awareness of their existence as a separate entity from middle ear tumors. This has been achieved by improved imaging and histopathologic techniques. Surgery is the mainstay of treatment.

Autopsy findings in bone marrow transplantation

Summary Autopsies were performed on 2 patients with aplastic anaemia and 7 with acute leukaemia dying after bone marrow transplantation. Neutropenic enterocolitis was found in 2 of the 3 early deaths occurring before marrow engraftment and was related to radiation or cytotoxic drug damage to the bowel mucosa in the presence of profound neutropenia, allowing infection by bowel organisms. Cytomegaloviral infection was universal in engrafted patients. One had cytomegaloviral (CMV) pneumonia, one CMV hepatitis and enteritis and one CMV enteritis. Three patients had occasional CMV inclusions in various organs without obvious harmful effects. One nonengrafted patient also had CMV pneumonia. Graft versus host disease (GVHD) was a significant finding in 4 engrafted patients. This was difficult to separate histologically from the effects of CMV in the bowel, but easier in liver and skin. The skin changes of GVHD were the most easily interpretable. Interstitial pneumonia was due to CMV in one nonengrafted and one engrafted patient and had no obvious infective cause in 2 engrafted patients. The presence of bizarre epithelial cells in the lungs of these patients suggested an aetiological role for radiation or cytotoxic drugs. Modification of the conditioning regimen may reduce tissue damage and lessen many of these side‐effects.

Renal carcinoma metastasis: an unusual cerebellopontine angle tumor.

Of all intracranial tumors, 8% to 10% arise in the cerebellopontine angle. The majority of these tumors are vestibular schwannomas, followed by meningiomas, primary choleasteatomas, and facial nerve schwannomas. Metastatic lesions to the cerebellopontine angle are rare (0.2% of all lesions)1 and are known to arise from primary neoplasms of lung, breast, prostate, nasopharynx, and oropharynx and cutaneous melanoma.2 In the literature only one case arising from the kidney has been previously reported, and in this, there was gross involvement of the temporal bone as well.3 We describe a case of renal carcinoma metastatic to the cerebellopontine angle. Clinical presentation and diagnostic problems are discussed.

Diagnostic pathology of lymphoproliferative disorders

Summary The last 20 years have seen a dramatic change in the way we classify, and therefore diagnose, lymphoma. Two decades ago, the International Working Formulation enabled diagnosis and management on the basis of H&E sections alone, with no mandatory requirement for immunophenotyping, molecular studies or any other ancillary investigations. The concept of categorisation by ‘clinicopathological entities’ defined by clinical features, morphology, immunophenotype and more recently, genotype, began with the Kiel, and Lukes and Collins classifications in the late 1970s, becoming fully expressed in the REAL and subsequently WHO classifications. The current, multidisciplinary approach to categorisation adds significantly to the task facing the anatomical pathologist, since it requires distribution of biopsy material to all the appropriate specialised laboratories, the gathering of a range of cross‐disciplinary information, the correlation of all diagnostic findings, deduction of a definitive diagnosis and, finally, integration of all the above into a single multi‐parameter report. In this review, we summarise the contemporary approach to the biopsy, diagnosis and reporting of lymphoproliferative disorders.Abbreviations: DLBCL, diffuse large B‐cell lymphoma; FCM, flow cytometry; FL, follicular lymphoma; FLIPI, Follicular Lymphoma International Prognostic Index; FNA, fine‐needle aspiration; HL, Hodgkin lymphoma; IPI, International Prognostic Index; LPD, lymphoproliferative disorders; NCB, needle core biopsy; NHL, non‐Hodgkin lymphoma; PI, proliferative index.

Neurotropic T-cell lymphocytosis : a cutaneous expression of CLIPPERS

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory disease of the central nervous system that predominantly involves the pons and cerebellum and that improves with immunosuppressive treatment. Only recently described, the etiology is unknown, diagnosis is difficult and long‐term neurological sequelae may occur without aggressive treatment. Herein, we describe a 59‐year‐old woman who presented with subcutaneous nodules affecting her face, trunk, limbs and an indurated annular erythematous lesion on her forearm. This was associated with marked dysesthesia of her skin, refractory to treatment. There was a 4‐year history of dysequilibrium, vertigo, truncal and gait ataxia with progressive neurological symptoms. Skin biopsy of the annular nodular lesion showed a lymphohistiocytic infiltrate in dermis and subcutis with a striking lymphocyte‐dominant infiltrate that was perineural and formed a nodular collection extending along a prominent subcutaneous nerve. Immunophenotyping indicated a marked predominance of T cells that were CD3 positive with a 2 : 1 CD4 : CD8 ratio. Scattered histiocytes were present but no well‐formed granulomas or vasculitis. Magnetic resonance imaging studies showed changes in the pontine, brain stem and cerebellar region, which subsequently were defined as characteristic for CLIPPERS, but no brain biopsy was pursued. The marked neural skin symptoms and the cutaneous histopathological findings indicate that the skin may be an additional target organ in CLIPPERS, and the immune response may be directed against a common neural antigen. In radiologically typical CLIPPERS, identification of clinical skin lesions particularly subcutaneous nodules and biopsy may potentially form a basis for tissue diagnosis in this syndrome.