Background Pulmonary capillary hemangiomatosis (PCH) is a rare disease of capillary proliferation of unknown cause and with a high mortality. Families with multiple affected individuals with PCH ...suggest a heritable cause although the genetic etiology remains unknown. Methods We used exome sequencing to identify a candidate gene for PCH in a family with two affected brothers. We then screened 11 unrelated patients with familial (n = 1) or sporadic (n = 10) PCH for mutations. Results Using exome sequencing, we identified compound mutations in eukaryotic translation initiation factor 2 α kinase 4 ( EIF2AK4 ) (formerly known as GCN2 ) in both affected brothers. Both parents and an unaffected sister were heterozygous carriers. In addition, we identified two EIF2AK4 mutations in each of two of 10 unrelated individuals with sporadic PCH. EIF2AK4 belongs to a family of kinases that regulate angiogenesis in response to cellular stress. Conclusions Mutations in EIF2AK4 are likely to cause autosomal-recessive PCH in familial and some nonfamilial cases.
In 1990, an international grading scheme for the grading of pulmonary allograft rejection was adopted by the International Society for Heart and Lung Transplantation (ISHLT) and was modified in 1995 ...by an expanded group of pathologists. The original and revised classifications have served the lung transplant community well, facilitating communication between transplant centers with regard to both patient management and research. In 2006, under the direction of the ISHLT, a multi-disciplinary review of the biopsy grading system was undertaken to update the scheme, address inconsistencies of use, and consider the current knowledge of antibody-mediated rejection in the lung. This article summarizes the revised consensus classification of lung allograft rejection. In brief, acute rejection is based on perivascular and interstitial mononuclear infiltrates, Grade A0 (none), Grade A1 (minimal), Grade A2 (mild), Grade A3 (moderate) and Grade A4 (severe), as previously. The revised (R) categories of small airways inflammation, lymphocytic bronchiolitis, are as follows: Grade B0 (none), Grade B1R (low grade, 1996, B1 and B2), Grade B2R (high grade, 1996, B3 and B4) and BX (ungradeable). Chronic rejection, obliterative bronchiolitis (Grade C), is described as present (C1) or absent (C0), without reference to presence of inflammatory activity. Chronic vascular rejection is unchanged as Grade D. Recommendations are made for the evaluation of antibody-mediated rejection, recognizing that this is a controversial entity in the lung, less well developed and understood than in other solid-organ grafts, and with no consensus reached on diagnostic features. Differential diagnoses of acute rejection, airway inflammation and chronic rejection are described and technical considerations revisited. This consensus revision of the working formulation was approved by the ISHLT board of directors in April 2007.
Giant cell myocarditis (GCM) is a rare and highly lethal disorder. The only multicenter case series with treatment data lacked cardiac function assessments and had a retrospective design. We ...conducted a prospective, multicenter study of immunosuppression including cyclosporine and steroids for acute, microscopically-confirmed GCM. From June 1999 to June 2005 in a standard protocol, 11 subjects received high dose steroids and cyclosporine, and 9 subjects received muromonab-CD3. In these, 7 of 11 were women, the mean age was 60 ± 15 years, and the mean time from symptom onset to presentation was 27 ± 33 days. During 1 year of treatment, 1 subject died of respiratory complications on day 178, and 2 subjects received heart transplantations on days 2 and 27, respectively. Serial endomyocardial biopsies revealed that after 4 weeks of treatment the degree of necrosis, cellular inflammation, and giant cells decreased (p = 0.001). One patient who completed the trial subsequently died of a fatal GCM recurrence after withdrawal of immunosuppression. Her case demonstrates for the first time that there is a risk of recurrent, sometimes fatal, GCM after cessation of immunosuppression. In conclusion, this prospective study of immunosuppression for GCM confirms retrospective case reports that such therapy improves long-term survival. Additionally, withdrawal of immunosuppression can be associated with fatal GCM recurrence.
Summary Hypersensitivity pneumonitis (HP) is an immunologically mediated form of diffuse lung disease, with histopathologic features that include cellular bronchiolitis, interstitial pneumonia, ...poorly formed granulomas, isolated multinucleated giant cells (MNGCs), organizing pneumonia, and interstitial fibrosis. This study describes the clinical and histopathologic findings in a retrospective series of 40 consecutive patients diagnosed with HP at the Mayo Clinic in Rochester, MN, between 1997 and 2011. Because the literature indicates that granulomas and MNGCs are located in the interstitium, particular attention was given to their distribution. Of the 40 patients, 33 underwent surgical lung biopsy and 7 underwent lung transplantation. Thirty-eight (95%) patients had interstitial pneumonia; 37 (93%), cellular bronchiolitis; 32 (80%), nonnecrotizing granulomas; 31 (78%), isolated MNGCs; 34 (85%) organizing pneumonia, and 31 (78%); interstitial fibrosis. In 27 cases, the granulomas were within airspaces; and in 26, they were interstitial. In 25 cases, MNGCs were within airspaces; and in 24, they were interstitial. In 3 (8%) cases, both granulomas and MNGCs were seen only within airspaces. Interstitial fibrosis was centrilobular in 22 cases, resembled usual interstitial pneumonia in 18 cases, and resembled nonspecific interstitial pneumonia in 11 cases. The “classic triad” of bronchiolitis, interstitial pneumonia, and granulomas was seen in 29 (73%) cases and was most frequent in biopsy than explant specimens ( P = .004). This study confirms that granulomas and MNGCs are not confined to the pulmonary interstitium in HP.
Summary Angiosarcomas (AS) are uncommon endothelial malignancies, usually arising from sun-damaged skin in older adults. Although most AS are readily diagnosed by light microscopy alone, ...immunohistochemistry (IHC) for endothelial markers such as CD31, CD34, FLI1, and ERG plays a valuable adjunctive role. However, IHC studies of AS must be interpreted with caution, as aberrant expression of markers such as cytokeratins, CD30, and CD117 may be seen. We report 3 cases of AS showing aberrant expression of the neuroendocrine markers synaptophysin and/or chromogranin A, previously unreported phenomena. Cases presented as metastatic lesions in the lung of a 48-year-old woman and as primary tumors of the kidney and neck in a 29-year-old and a 51-year-old woman, respectively. All cases expressed synaptophysin and/or chromogranin A, and various neuroendocrine/endocrine neoplasms were strongly considered as diagnoses by the initial evaluating pathologists. Additional morphological study and confirmatory IHC for CD31, FLI1, and ERG established the diagnosis of AS in all cases. Coexpression of synaptophysin and chromogranin A in 1 case suggests that at least some AS show true neuroendocrine differentiation. Awareness of this potential diagnostic pitfall is important for correct diagnosis and treatment of this rare subset of AS.
Summary Dyskeratosis congenita (DC) is a disorder of poor telomere maintenance and is related to 1 or more mutations that involve the vertebrate telomerase RNA component. Most affected patients ...develop mucocutaneous manifestations and cytopenias in the peripheral blood between 5 and 15 years of age. DC patients may also develop pulmonary complications including fibrotic interstitial lung disease and pulmonary vascular abnormalities. The radiologic and pathologic features of pulmonary fibrosis associated with DC are poorly defined. Herein, we report 2 new DC cases and suggest that the radiologic and histopathologic findings may resemble usual interstitial pneumonia but may not neatly fit into the current classification of interstitial lung disease.
Neoplastic mimics or ìpseudotumorsî can simulate neoplasms on all levels of analysisóclinical, radiologic, and pathologicóand thus represent particular diagnostic pitfalls for the pathologist that ...can ultimately lead to therapeutic misdirection. Hundreds of color images and analysis of diagnostic mimics guide the pathologist through recognizing and distinguishing the unusual variants, morphologic anomalies, and misleading features that may easily lead to an inaccurate interpretation and missed diagnosis. Since many of the entities described are uncommon, Neoplastic Mimics in Thoracic and Cardiovascular Pathology emphasizes imaging and clinical correlations throughout to support the pathologist as consultant to the entire diagnostic and clinical management team. Every pathologist who sees skin cases will find this book an invaluable working tool to ensure accurate diagnosis. This book provides the pathologist with detailed morphologic descriptions and diagnostic guidance in recognizing these neoplastic mimics as they occur in the skin. In addition, descriptions and diagnostic guidance are provided for the range of skin lesions that may mimic benign masses but are in fact neoplastic. Throughout the book comparisons of neoplastic mimics with true neoplasms are provided, at clinical, gross, and histologic levels. In the presentation of every entity, the points that contribute to differential diagnosis are emphasized. Neoplastic Mimics in Dermatopathology Features: * Nearly 500 high-quality images showcase the full range of nonneoplastic and neoplastic mimics in skin * Concise, specific text descriptions to make the book easy to use as a visual reference * Expert authors guide the reader to recognizing and distinguishing misleading specimens
Adenovirus serotype 5 has remained the pre-eminent vector in pre-clinical gene therapy applications in cardiac transplantation. Concerns over the potential effects of adenoviral vectors on the later ...development of cardiac allograft vasculopathy (CAV) are addressed in this study.
Hearts (n = 22) harvested from Brown Norway rats were perfused ex vivo with either University of Wisconsin (UW) solution with no virus, Ad-CMV-LacZ or Ad-CMV-Null. Donor hearts were transplanted heterotopically into the abdomen of Lewis rats. All recipients received cyclosporine for the duration of the experiment. Transplanted hearts were recovered for analysis at 120 days. Sections of the heart were stained with elastic-van Gieson stain for morphometric analysis of the vessels to ascertain the degree of vascular luminal occlusion. Hematoxylin-eosin staining facilitated diagnosis of chronic rejection.
Seventy-seven percent of transplanted hearts showed signs of chronic rejection with no difference in the proportion of animals between groups (p = 0.797). No difference was noted in the degree of vascular luminal occlusion between the Ad-Null (0.57 +/- 0.22), Ad-LacZ (0.62 +/- 0.19) and UW (0.47 +/- 0.29) groups (p = 0.653).
Vascularized cardiac allografts transplanted from Brown Norway to Lewis rats demonstrated cardiac allograft vasculopathy CAV at 120 days. Adenoviral perfusion of the donor heart ex vivo did not affect the development of CAV.
PDF
