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Although animal models have been evaluated for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, none have fully recapitulated the lung disease phenotypes seen in humans who have been hospitalized. Here, we evaluate transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lungs, with spread to other organs. A decline in pulmonary function occurs 4 days after peak viral titer and correlates with infiltration of monocytes, neutrophils and activated T cells. SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with signatures of nuclear factor-κB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection shares many features of severe COVID-19 infection and can be used to define the basis of lung disease and test immune and antiviral-based countermeasures.

Antibody-mediated rejection (AMR) is an increasingly recognized form of lung rejection. C4d deposition has been an inconsistent finding in previous reports and its role in the diagnosis has been controversial. We conducted a retrospective single-center study to characterize cases of C4d-negative probable AMR and to compare these to cases of definite (C4d-positive) AMR. We identified 73 cases of AMR: 28 (38%) were C4d-positive and 45 (62%) were C4d-negative. The two groups had a similar clinical presentation, and although more patients in the C4d-positive group had neutrophilic capillaritis (54% vs. 29%, p = 0.035), there was no significant difference in the presence of other histologic findings. In spite of aggressive antibody-depleting therapy, 19 of 73 (26%) patients in the overall cohort died within 30 days, but there was no significant difference in freedom from chronic lung allograft dysfunction (CLAD) or survival between the two groups. We conclude that AMR may cause allograft failure, but the diagnosis requires a multidisciplinary approach and a high index of suspicion. C4d deposition does not appear to be a necessary criterion for the diagnosis, and although some cases may initially respond to therapy, there is a high incidence of CLAD and poor survival after AMR. This article is protected by copyright. All rights reserved.

Long-term survival after lung transplantation remains profoundly limited by graft rejection. Recent work has shown that bronchus-associated lymphoid tissue (BALT), characterized by the development of peripheral nodal addressin (PNAd)-expressing high endothelial venules and enriched in B and Foxp3+ T cells, is important for the maintenance of allograft tolerance. Mechanisms underlying BALT induction in tolerant pulmonary allografts, however, remain poorly understood. Here, we show that the development of PNAd-expressing high endothelial venules within intragraft lymphoid follicles and the recruitment of B cells, but not Foxp3+ cells depends on IL-22. We identify graft-infiltrating gamma-delta (γδ) T cells and Type 3 innate lymphoid cells (ILC3s) as important producers of IL-22. Reconstitution of IL-22 at late time points through retransplantation into wildtype hosts mediates B cell recruitment into lymphoid follicles within the allograft, resulting in a significant increase in their size, but does not induce PNAd expression. Our work has identified cellular and molecular requirements for the induction of BALT in pulmonary allografts during tolerance induction and may provide a platform for the development of new therapies for lung transplant patients.

Liver NRH is seen in all patients age; however, more frequently in those over the age of 60 years and associated with multiple systemic diseases. In liver allograft recipients, the development of DnNRH has been linked with the use of azathioprine or vascular abnormalities. We present the clinicopathologic characteristics of 17 pediatric patients who underwent liver transplantation and subsequently developed DnNRH. The patients were divided into early and late onset depending if DnNRH was diagnosed within or beyond 4 years after transplant. Eight patients (47%) presented as early onset, of which two had normal ultrasound at time of diagnosis. One patient (12.5%) with early onset lost the graft secondary to DnNRH. Nine patients (53%) presented as late onset, of which two (22%) had normal ultrasound at time of diagnosis. Two patients (25%) of the late onset lost their graft secondary to chronic rejection and DnNRH. Two patients (12%) died secondary to cytomegalovirus pneumonitis and pancolitis. Furthermore, both groups presented with symptoms differing from the adult population in prior studies and were not associated with the use of azathioprine or vascular abnormalities. Interestingly, episodes of acute cellular rejection were more common in the early-onset group compared to the late-onset group. In conclusion, DnNRH in the pediatric age group has a different clinical presentation, possibly reflecting a different pathogenesis compared to the adult population.

Identify and characterize pediatric pulmonary emboli present at autopsy.Retrospective single institution observational study with clinicopathologic correlation.Tertiary medical center.All autopsy cases performed at Washington University from 1997 to 2017 in pediatric patients (≤ 18 yr old).Of 1,763 pediatric autopsies, 13 cases of pulmonary emboli were identified, including thromboemboli (6/13, 46.1%), septic emboli (3/13, 23.1%), fat emboli, and foreign body emboli.Pulmonary embolus is a relatively rare but potentially fatal cause of death in pediatric age patients and is often associated with congenital abnormalities, malignancy, or recent surgical procedures. Half of the fatal pulmonary emboli found in our series (3/6) show microscopic and diffuse, rather than large central or saddle emboli, potentially make a clinicoradiographic diagnosis more difficult. This series is also the first to report a case of hemostatic matrix pulmonary embolism in a pediatric age patient.

Dr. Louis Dehner is an internationally renowned surgical pathologist who has published multiple textbooks and has authored or co-authored nearly 400 original articles in the medical literature. While many think of him as a pediatric pathologist, he has contributed to the literature across virtually the entire breadth of surgical pathology, and the lung and pleura is no exception. This review will highlight Dr. Dehner׳s contributions to the pulmonary and pleural pathology literature in the areas of infectious disease, medical lung disease and transplant pathology, and a number of neoplasms of the lung and pleura, with the remainder of this manuscript dedicated to the still evolving story of the pleuropulmonary blastoma as the signature contribution of his long and distinguished career.

Clostridial myonecrosis is an uncommon, highly lethal necrotizing soft tissue infection. The source may be occult at the time of clinical presentation. In cases caused by Clostridium septicum, there is an association with colorectal malignant disease, suggesting that underlying colonic pathology frequently is the source of the infection.Case report and literature review.A 37-year old man with acquired immunodeficiency syndrome, end-stage renal disease, and C. difficile colitis presented to the Emergency Department (ED) with a primary complaint of abdominal pain and incidental right forearm pain. While undergoing evaluation in the ED, he developed progressive erythema, edema, and emergence of bullae over his right forearm. After rapid imaging of his abdomen, he underwent guillotine amputation of his right upper extremity because of extensive myonecrosis and total abdominal colectomy secondary to right colonic necrosis and C. difficile colitis. Blood cultures were positive for C. septicum. Microscopic examination of both the necrotic colon and the right forearm musculature demonstrated invasion of gram-positive bacilli throughout.Myonecrosis caused by C. septicum frequently occurs in the presence of colonic pathology, typically malignant disease. This case report illustrates the development of this pathological process in an immunosuppressed patient who did not have colon cancer, but rather colonic mucosal inflammation produced by C. difficile.

To characterize the effect of diffusion time on short-range hyperpolarized (3)He magnetic resonance imaging (MRI) diffusion measurements across a wide range of emphysema severity.(3)He diffusion MRI was performed on 19 lungs or lobes resected from 18 subjects with varying degrees of emphysema using three diffusion times (1.6 msec, 5 msec, and 10 msec) at constant b value. Emphysema severity was quantified as the mean apparent diffusion coefficient (ADC) and as the percentage of pixels with ADC higher than multiple thresholds from 0.30-0.55 cm(2)/sec (ADC index). Quantitative histology (mean linear intercept) was obtained in 10 of the lung specimens from 10 of the subjects.The mean ADCs with diffusion times of 1.6, 5.0, and 10.0 msec were 0.46, 0.40, and 0.37 cm(2)/sec, respectively (P0.0001, analysis of variance [ANOVA]). There was no relationship between the ADC magnitude and the effect of diffusion time on ADC values. The mean linear intercept correlated with ADC (r = 0.91-0.94, P0.001) and ADC index (r = 0.78-0.92, P0.01) at all diffusion times.Decreases in ADC with longer diffusion time were unrelated to emphysema severity. The strong correlations between the ADC at all diffusion times tested and quantitative histology demonstrate that ADC is a robust measure of emphysema.

Objective: To determine the safety and efficacy of saline-linked surface radiofrequency ablation (SLSRFA) in a clinical setting. Summary Background Data: We have previously identified safe and effective parameters for use of SLSRFA in a porcine model. Methods: An initial study was conducted to determine if parameters defined in the porcine model were safe and effective in human livers. In 16 patients undergoing liver resection, normal areas of liver were treated with SLSRFA using various power/diameter combinations (10 W/1 cm; 15 W/2 cm; 45 W/4 cm) for 9 minutes with and without inflow occlusion. In a second study, superficial hepatic colorectal cancer (CRC) metastases were treated at 45 W/4 cm for 9 minutes without inflow occlusion in 11 patients. Ablation depth was measured and samples were examined for cell viability by nicotine adenine dinucleotide stain. This study was registered in the ClinicalTrials.gov database and has the following ID number, NCT00869843. Results: Ablation depth in normal liver varied from 3 to 20 mm. Depth was significantly dependent on power, lesion size, and inflow occlusion. Nicotine adenine dinucleotide stains showed total cell necrosis to the full depth of ablation. In the second study, large hepatic CRC metastases showed total cell necrosis to a mean depth of 12 mm. Two tumors less than 7 mm in depth showed complete necrosis. Metastases were more susceptible to SLSRFA than normal liver. Conclusion: SLSRFA completely and safely ablates normal liver to a depth of at least 4 mm at 45 W/4 cm treatment parameters. Remarkably, it is even more effective in ablating metastatic CRC. SLSRFA is an effective tool for extending resection margins and for ablating superficial small tumors or superficial parts of large tumors.

Expression of gastrointestinal biomarkers MUC1, MUC2, MUC5AC, small-intestinal mucin antigen (SIMA), villin, and CDX2 has been studied in colorectal adenocarcinoma (CRC). Little is known, however, about their expression in small-intestinal adenocarcinoma (SIA). We immunohistochemically compared 30 SIAs with 48 CRCs for the expression of these biomarkers. The results showed that all 6 proteins were variably expressed in SIA, but the frequencies of expression were significantly lower than those for CRC with the exception of MUC1. Specifically, positive staining for MUC1, MUC2, MUC5AC, SIMA, villin, and CDX2 was observed in 16 (53%), 17 (57%), 12 (40%), 15 (50%), 20 (67%), and 18 (60%) of SIAs and 25 (52%), 43 (90%), 39 (81%), 45 (94%), 47 (98%), and 47 (98%) of CRCs, respectively. In addition, SIAs more frequently exhibited a focal staining pattern for MUC2, MUC5AC, SIMA, and villin, whereas more diffuse immunoreactivity was evident in CRCs. Focal staining for MUC1 and diffuse staining for CDX2 were common for SIAs and CRCs. Furthermore, poorly differentiated SIAs tended to express MUC1 more frequently when compared with well- and moderately differentiated SIAs. These observations further support the notion that SIA is immunophenotypically distinct from CRC despite their morphologic similarity.

In the skin, separation of selected lymphomas from lymphoid hyperplasia can be challenging. The authors examined 45 cutaneous lymphomas, excluding mycosis fungoides (26 small lymphocytic or mixed tumors; 19 large cell lymphomas), 10 "atypical" lesions, and 40 lesions of presumed lymphoid hyperplasia, comparing morphologic attributes of such proliferations with their immunophenotypes in paraffin sections. The object of this study was to determine whether immunologic data obtained from routinely-processed specimens could be used to further objectify morphologic interpretations. Features favoring lymphoma included a lesional epicenter in the lower dermis or subcutis; poor circumscription of lymphoid aggregates; and dissection of lymphoid cells between collagen bundles. Immunostains included antibodies to CD20, CD43, CD45, CD45RO, CD45RA, CD68, proliferating cell nuclear antigen (PCNA), and MB2. Eleven of 26 small lymphocytic or mixed-cell lymphomas and 3 of 10 "atypical" cases demonstrated an abnormal immunophenotype, including co-expression of CD43 and CD20 or non-physiological CD45RA distribution. In contrast, none of 40 cases with benign features manifested aberrant antigen expression. Thirty-one of 37 cases in which > or = 75% of the cells typed as B lymphocytes showed malignant morphologic features, 5 were "atypical" and possibly lymphomatous, and only one had benign features. PCNA stains showed greater positivity of the lymphoid nuclei in lymphomas, and a labeling index of > 30% was correlated with malignancy in this context. These observations indicate that immunostaining may provide useful adjunctive information in distinguishing benign from malignant cutaneous lymphoid proliferations in paraffin sections.

Sarcomatoid carcinomas are rare malignancies which represent poorly differentiated epithelial tumors that may be difficult to recognize as such. While some cases may have obvious epithelial areas, the sarcomatoid areas are poorly distinguishable from true sarcoma at the light microscopic level and, by immunohistochemistry, often show only limited staining for traditional epithelial markers such as cytokeratin or epithelial membrane antigen. This can be particularly problematic for diagnosis on small biopsy specimens. We sought to assess the diagnostic utility of several immunohistochemical markers of epithelial differentiation including p63, MOC-31, and thyroid transcription factor-1 on sarcomatoid carcinomas of the head and neck (19 cases; 'spindle cell carcinomas'), lung (19 cases), and urinary bladder (11 cases). These results were compared to immunohistochemistry for the traditional epithelial markers pan-cytokeratin and epithelial membrane antigen. Staining for p63 showed the greatest diagnostic utility, positive in 63, 50, and 36% of head and neck, lung, and urinary bladder sarcomatoid carcinomas, respectively. p63 stains were positive in many cases where immunohistochemistry was negative for both pan-cytokeratin and epithelial membrane antigen. All three alternative markers were quite specific for epithelial differentiation, each staining less than 10% of the control group of 73 various primary and metastatic sarcomas, melanomas, and benign spindle cell lesions. In conclusion, immunostaining beyond traditional pan-cytokeratin and epithelial membrane antigen may have diagnostic utility in this context.

Background The Lung Rejection Study Group (LRSG) created a scheme for grading acute allograft rejection in 1990 and then revised it in 1996, but virtually no studies have evaluated the reliability of this formulation. This investigation assessed the reliability of the current LRSG system by determining inter- and intrareader agreement for grading transbronchial biopsy samples from lung transplant recipients. Methods Biopsy samples from a cohort of 204 recipients were reviewed and classified by a single pathologist who was blinded to original interpretations. The "A" and "B" rejection grades from this contemporary review were compared with original grades by the kappa statistic. Results For "A" grading, weighted kappa was 0.65 (95% confidence interval [CI] 0.60–0.70) for interreader agreement ( n = 529 specimens) and 0.65 (95% CI 0.53–0.76) for intrareader agreement ( n = 97 specimens). For "B" grading, weighted kappa was 0.26 (95% CI 0.14–0.39) for interreader agreement ( n = 164 specimens) and 0.33 (95% CI 0.15–0.51) for intrareader agreement ( n = 58 specimens). Conclusions On the basis of the analysis of the LRSG scheme, "A" grades exhibit very good reliability, but "B" grades have only fair reliability, and steps to improve this shortcoming should be taken.

Fulguration of surface tumors using radiofrequency (RF) energy is a well-established technique. However, the depth of tissue destruction has been limited to a few millimeters because of charring of the surface at the point of electrode contact. Charring converts the surface from a good to a poor electrical conductor, and causes such a steep rise in the impedance (resistance) that current effectively ceases. This limits the depth of tissue destruction. Therefore fulguration has not been useful for solid organ tumors such as hepatic tumors. Saline-linked surface radiofrequency ablation is a new technique designed to prevent surface charring. The strategy was first applied to catheter ablation of cardiac lesions.1 The saline-linked RF device provides a continuous flow of saline, a good coolant, and electrical conductor that maintains the temperature of the surface below 100°C. Charring does not occur, and greater depths of tissue destruction are possible. However, although the surface is maintained below 100°C, temperatures in the subsurface may rise above 100°C. This can lead to steam formation and expansion and then to disruption of the surface. This undesirable side effect is called “steam popping.”2,3 This study had 2 purposes. The first was to determine factors that lead to steam popping and, subsequently, to learn how to avoid it. Once safe nonpopping parameters were established, it was possible to pursue the second aim, which was to determine factors that affect the depth of tissue destruction. Of particular interest was the effect of inflow occlusion, which has been shown to extend the size of ablations induced by interstitial radiofrequency electrodes.4

We describe 2 men, ages 69 and 49 years, who experienced fatal rupture of pulmonary infarcts. Both patients had documented prior thromboembolic events and subsequently had abrupt deterioration in cardiorespiratory function. Autopsies showed massive unilateral hemothorax in both patients. Rupture of a pulmonary infarct may occur spontaneously or iatrogenically due to aggressive anticoagulation. This may be difficult to distinguish from secondary hemothorax with an intact pleura, but rupture typically has a considerably more rapid clinical evolution. Treatment should include immediate withdrawal of thrombolytic or anticoagulant medications and evacuation of the pleural space. Surgical intervention can be considered, although the utility of that approach must await prospective trials.

Transforming growth factor alpha (TGF-alpha) is expressed in respiratory epithelial cells and alveolar macrophages during development and following lung injury. In the present study, the presence and sites of synthesis of TGF-alpha and its receptor, the epidermal growth factor receptor (EGF-R), were assessed in lung tissue from patients with severe lung disease caused by cystic fibrosis (CF). Lung sections from 24 individuals with CF, obtained at the time of lung transplantation, were compared to lung sections from five lung donors without CF. Cellular sites of TGF-alpha, EGF-R, and cellular sites of proliferation were assessed by immunohistochemistry. All CF lung sections contained multiple cell types with detectable TGF-alpha. Compared to control sections, intensity of TGF-alpha immunostaining in macrophages, airway epithelial cells, and peribronchial submucosal cells was increased. EGF-R was detected in respiratory epithelial and peribronchial stromal cells but not in alveolar macrophages. The intensity of EGF-R staining in CF lung tissue did not differ from that of controls. An increased number of cells expressing Ki-67 nuclear antigen was detected in peribronchial submucosal cells but not bronchiolar epithelial cells in the CF lungs. The increased expression of TGF-alpha in CF lung tissue supports the concept that TGF-alpha plays a role in paracrine/autocrine regulation of lung remodeling associated with injury and repair in the lungs of individuals with cystic fibrosis.

Spindle cell proliferations of the skin are diverse, both morphologically and mechanistically. The authors have encountered four examples of a distinctive reactive/reparative cutaneous spindle cell lesion that shows homology with ones seen in the genitourinary tract and oral cavity and that is known as "postoperative/posttraumatic spindle cell nodule" (PSCN). These occurred in the skin of the face and scalp (2 cases), arm (1 case), and vulvar skin (one case), and were clearly related historically to prior episodes of trauma. The proliferations were characterized by variably-apposed and cytologically-bland spindle cells with numerous mitotic figures, set in a highly vascular stroma containing extravasated erythrocytes and inflammatory cells. All lesions were immunoreactive for vimentin, actin, and desmin, with no labeling for keratin. Postoperative/posttraumatic spindle cell nodule of the skin is a significant pseudoneoplastic lesion that is related (and perhaps identical pathogenetically) to nodular fasciitis; as such, it may be mistaken for a sarcoma or a spindle cell carcinoma. Careful attention to clinicopathologic and histologic details should result in its accurate recognition.

The diagnosis of gastrointestinal (GI) lymphoid infiltrates can be challenging when based only on conventional microscopic assessment. When marked cytologic atypia is present, a diagnosis of malignant neoplasm is readily made; however, the distinction between a low-grade malignant neoplasm and a reactive process is much more difficult. If unfixed tissue is available, immunohistologic or genotypic methods that are usually aimed at defining B-lymphocytic monotypism can be applied. However, paraffin-embedded tissue has generally been deemed unsuitable for these techniques. We assessed the value of a panel of immunohistochemical stains and a seminested polymerase chain reaction (PCR) for the analysis of lymphoid infiltrates in routinely processed GI biopsy specimens from 49 archival cases, including morphologically benign, indeterminate, and overtly malignant lesions. Clinical outcome was used as the retrospective diagnostic standard; end points were death (of lymphomatous disease or otherwise) and clinical evidence of lymphoma. According to light microscopic criteria, 19 cases were classified as benign, 17 as malignant, and 13 as atypical. Immunophenotyping correctly identified 28 of 31 benign and 14 of 18 malignant lesions (7 cases had an indeterminate immunoprofile). Genotypic analysis correctly identified 12 of 18 malignant and 29 of 31 benign lesions, but spurious monoclonal bands were produced by PCR amplification of 2 of the latter 31 cases. No single technique exists for correct categorization of all paraffin-embedded specimens of GI lymphoid infiltrates. We recommend a sequential approach to the use of available diagnostic modalities.

Morphologic mimicry among human malignant neoplasms is a well-known phenomenon in surgical pathology; both undifferentiated and "committed" neoplasms may exhibit this trait. One particularly common group of histologic simulants includes ductal carcinomas of the breasts, the cutaneous appendages, and the salivary glands. One hundred three tumors in this structural cluster were analyzed microscopically and immunohistologically to codify points of potential pathologic similarity and difference. All the lesions were typified by irregularly permeative clusters and cords of atypical polygonal cells with variable luminal differentiation. A proportion of primary neoplasms in each site demonstrated in situ ductal components; in the absence of the latter elements, however, it was not possible to make topography-related morphologic distinctions among them. Immunostains for gross cystic disease fluid protein-15 (GCDFP-15), carcinoembryonic antigen, S100 protein, c-erbB-2 oncoprotein, estrogen receptor protein, and progesterone receptor protein also showed largely overlapping phenotypes in each of the three tumor categories, with selected exceptions. These differences were elucidated through paired chi 2 analysis and included a statistically significant infrequency of GCDFP-15 in eccrine sweat gland carcinomas, a paucity of carcinoembryonic antigen in breast cancers, and an absence of estrogen receptor protein in salivary duct carcinomas. Such findings may be useful in predefined differential diagnostic settings involving the distinction between primary and metastatic ductal cancers of the breasts, skin, and salivary glands. Nevertheless, because of the striking homologies between such tumors at structural and protein-synthetic levels of comparison, it is mandatory that all available clinicopathologic information be used in this context.

Angiomyofibroblastoma (AMFB) of the genital region is a relatively recently described tumor of the superficial soft tissues with a marked preference for female patients. Three cases of AMFB were reviewed, two of which involved adult men. To further elucidate the pathologic features of AMFB, these three cases were compared with 10 cases of aggressive angiomyxoma (AA), a salient diagnostic alternative, and 28 cases of other myxoid tumors that may show morphologic similarities to these neoplasms. Conventional histologic and immunohistochemical features of AMFBs were compared with those of AA, myxoid leiomyoma, myxoid leiomyosarcoma, myxoid liposarcoma, myxoid malignant fibrous histiocytoma, myxoid neurofibroma, and myxoid malignant peripheral nerve sheath tumor. The ultrastructure of two of the three AMFBs also was analyzed. Genital AMFBs were circumscribed, partially myxoid proliferations that demonstrated considerable variation in cellular density. Neoplastic elements were bland cytologically and showed both fusiform and epithelioid profiles, with a tendency to concentrate around intralesional blood vessels. Mitotic activity and necrosis were absent, and the vessels assumed an arborizing configuration and were venule or capillary sized. In contrast, all other tumor types evaluated were infiltrative, cytologically atypical, or both. All AMFBs showed immunoreactivity for vimentin, desmin, actin, and estrogen receptor protein. These results were shared by most examples of AA and smooth muscle tumors as well, but were not seen in any other neoplasms in this study. Electron microscopic findings in cases of AMFB supported the presence of myofibroblastic differentiation in the tumor cells. These results indicate that conventional morphologic analysis is paramount in the recognition of genital AMFB but that immunohistology may be helpful in a limited context in excluding other differential diagnoses. They also support the conclusion that AMFB, AA, and superficial smooth muscle tumors have similar morphotypes and immunohistologic attributes regardless of their origin in men or women.

Six solitary, dermal or subcutaneous lesions occurring in adult patients are presented. These masses had a circumscribed, lobulated configuration; they were composed of fusiform and epithelioid cells that lacked atypical nuclear features. The pattern of growth featured fascicles and nests, a myxofibrous stroma, and prominent blood vessels with a focally "hemangiopericytoid" appearance. Immunohistochemical analyses showed uniform reactivity for vimentin and alpha isoform-actin, with negativity for desmin and neural determinants. The overall appearance of the lesions was similar to that of "infantile myofibromatosis," and corresponded to previous descriptions of "solitary myofibroma(tosis)" in adults. Immunophenotypic and ultrastructural support exists for a proposed myofibroblastic nature for such proliferations. Differential diagnostic considerations include neurothekeomas, plexiform fibrous histiocytomas, nodular fasciitis, cutaneous inflammatory pseudotumors, dermatomyofibromas, leiomyomas, and other forms of fibromatosis affecting the skin and superficial soft tissues.

We tested the hypotheses that Epstein-Barr virus (EBV) DNA levels in peripheral blood leukocytes (PBL) of transplant recipients with posttransplant lymphoproliferative disease (PTLD) (1) exceed those of patients without PTLD, (2) rise with or before clinical detection of the disease, and (3) fall with effective therapy. Using the polymerase chain reaction (PCR) and an endpoint dilution technique, we compared EBV DNA levels in sequential specimens from 5 patients with PTLD, 16 solid organ transplant recipients without PTLD, and 5 young adults with primary infectious mononucleosis (IM), and in single specimens from 21 healthy seropositive subjects. EBV DNA levels in the first two groups rose with induction of immunosuppression despite prophylactic acyclovir. Markedly elevated levels of EBV DNA were seen in 4 of 5 patients with PTLD at or before clinical diagnosis. The peak levels in these patients exceeded those of transplant recipients without PTLD (P = 0.02) and healthy adults with IM (P = 0.02). EBV DNA levels fell dramatically with effective therapy. Four of 21 healthy seropositive subjects demonstrated low levels of EBV DNA, similar to levels seen late in the course of patients with IM. We conclude that a semiquantitative PCR assay for EBV DNA in PBL can assist in the detection of PTLD and in monitoring the effect of therapy.

The false-positive interpretation of malignancy is a potential pitfall of exfoliative respiratory tract cytopathology. However, the underlying causes of this problem are still relatively under-recognized. The authors herein present two additional examples in which bronchial brushing and washing specimens were misinterpreted as showing carcinoma of the lung. The first case concerned a patient with a granulomatous mass that simulated a malignancy on chest radiographs and was the apparent cause of atypical bronchial squamous metaplasia (ABSM). Exfoliated cells from the latter process were thought to explain the false-positive cytologic result in that instance. In the second case, a large-cell angiocentric T-cell lymphoma replaced the lower lobe of the left lung. It was likewise associated with ABSM as the cause of a mistaken diagnosis of carcinoma in exfoliative respiratory cytology specimens, representing the first instance of such an association of which the authors are aware. Repeated evaluation of all bronchial cytology samples by several experienced pathologists yielded no reliable observations that might have been used to avoid an erroneous interpretation in either case. A review is provided of the spectrum of underlying conditions that may be associated with false-positive respiratory cytology results.

Recent reports have suggested that the retention of blood group antigen expression on tumor cells may be an important prognostic factor for survival. From 1986 to 1991, 136 patients underwent operative resection for their T1 N0 non-small cell lung carcinoma. One hundred twenty tissue blocks were available for antigen testing, and the histologic types were as follows: adenocarcinoma (73 patients), squamous cell (39 patients), large cell/undifferentiated (7 patients), and mucoepidermoid (1 patient). Follow-up is complete for all patients (mean, 41 months). This distribution of patients among the blood groups was as follows: A, 56 (47%); O, 53 (44%); B, 9 (7.5%), and AB, 2 (1.7%). Immunostaining was performed for A, B, and H blood group antigens. The 5-year actuarial survival in the blood group A patients (53%) did not differ significantly from that in the blood group O patients (59%). Similarly, when tumors were examined for their respective antigens, no significant differences were found in the 5-year survival of either blood group A or O patients between the tumors that retain and those that lose blood group antigen expression. Retention or loss of blood groups A or O antigen expression does not predict survival in patients with early-stage lung carcinomas.

The B-cell leukemia/lymphoma gene (bcl-2) produces a unique protein product (BCLP) that is believed to protect lymphoid cells from apoptosis. The bcl-2 gene is frequently' rearranged in nodal follicular lymphomas as well as in diffuse lymphoproliferations, but has generally been regarded as most useful in the recognition of the former of these lesions. However, little is known regarding BCLP expression in cutaneous lymphoid infiltrates. Using an immunohistochemical technique and a monoclonal antibody (clone no. 124) the authors examined 67 examples of cutaneous lymphoid infiltrates ― 31 cases of malignant lymphoma of the skin (MLS) and 36 examples of cutaneous lymphoid hyperplasias (CIH) ― to determine if patterns of BCLP reactivity could distinguish CLH from MLS or primary from secondary involvement of the skin by malignant lymphoma. Fifty-eight per cent of MLS cases were BCL- positive, as were 33% of CLH. Three of four eases of follicular cutaneous lymphoma showed BCLP-positivity in neoplastic follicles, whereas similar structures in cases of CLH with a follicular pattern were BCLP-negative. Sixty per cent of primary MLSs and 57% of secondary lymphomas were reactive for BCLP. These data suggest that immunostains for BCLP are of little help in the separation of benign from malignant cutaneous lymphoid infiltrates, and that they are likewise incapable of separating primary from secondary MLS. BCLP immunostains may have a limited adjuvant diagnostic role in distinguishing reactive from neoplastic follicular lymphoid lesions of the skin

In evaluating histologically malignant infiltrates in the skin, it is often challenging to distinguish granulocytic sarcoma (GS) from selected cases of peripheral T-cell lymphoma (PTCL). These lesions have clinical features in common, in addition to shared histologic attributes. These include similarity in dermal distribution and growth pattern, nuclear characteristics, propensity to recruit other inflammatory cell types, and production of matrical sclerosis. In order to determine if immunohistology could contribute to differential diagnosis in this setting, we analyzed 15 cases of mucocutaneous GS, and compared them with 11 cases of well-documented PTCL. Antibodies in the CD15, CD20, CD34, CD43, CD45, CD45RO, and CD68 groups were used, as well as anti-myeloperoxidase (anti-MPX), anti-lysozyme (anti-LYSO), Mac387, and MB2. Anti-LYSO and anti-MPX were sensitive and specific markers of GS, labeling 93% and 80% of GS cases, respectively, and no cases of PTCL. Anti-CD15 and MB2 were also specific for GS, but each labeled only 60% of GS cases. CD34, CD68, and Mac 387 were specific but insensitive markers of GS. CD43 and CD45 were not particularly useful discriminants, with each being seen in 93% of GS cases, but also 64% and 100% of cases of PTCL, respectively. CD45RO was specific for PTCL; it was present in 82% of PTCL cases and no GS cases. Thus, conjoint reactivity for CD43, CD45, MPX, and LYSO characterizes GS, and differs from the pattern of PTCL, which is characterized by reactivity for CD45 and CD45RO, occasional reactivity for CD43, and lack of other specified markers.

Breast papillomas often are diagnosed with core needle biopsy (CNB). Most studies support excision for atypical papillomas, because as many as one half will be upgraded to malignancy on final pathology. The literature is less clear on the management of papillomas without atypia on CNB. Our goal was to determine factors associated with pathology upgrade on excision.Our pathology database was searched for breast papillomas diagnosed by CNB during the past 10 years. We identified 277 charts and excluded lesions associated with atypia or malignancy on CNB. Two groups were identified: papillomas that were surgically excised (group 1) and those that were not (group 2). Charts were reviewed for the subsequent diagnosis of cancer or high-risk lesions. Appropriate statistical tests were used to analyze the data.A total of 193 papillomas were identified. Eighty-two lesions were excised (42%). Caucasian women were more likely to undergo excision (p = 0.03). Twelve percent of excised lesions were upgraded to malignancy. Increasing age was a predictor of upgrading, but this was not significant. Clinical presentation, lesion location, biopsy technique, and breast cancer history were not associated with pathology upgrade. Two lesions in group 2 ultimately required excision due to enlargement, and both were upgraded to malignancy.Twenty-four percent of papillomas diagnosed on CNB have upgraded pathology on excision--half to malignancy. All of the cancers diagnosed were stage 0 or I. For patients in whom excision was not performed, 2 of 111 papillomas were later excised and upgraded to malignancy.

Asbestosis has long been defined as a diffuse interstitial "fibrotic" process, in similarity to other chronic interstitial pulmonary diseases. To address the hypothesis (which was based on morphological nuances) that the interstitial connective tissue response in asbestosis may be fibroelastotic rather than fibrotic, a comparative characterization of the connective response in cases of asbestosis and other forms of interstitial lung disease was performed. Archival open lung biopsies or autopsy specimens of pulmonary diseases featuring interstitial connective tissue abnormalities (15 of asbestosis, 21 of organizing pneumonia, 15 usual interstitial pneumonitis/idiopathic pulmonary fibrosis [IPF], 9 organizing diffuse alveolar damage, 9 "nonspecific" interstitial pneumonitis, 4 sarcoidosis, 3 each of desquamative interstitial pneumonia and chronic amiodarone toxicity, 2 cryptogenic organizing pneumonias, and 1 each of chronic hypersensitivity pneumonitis and chronic eosinophilic pneumonitis [85 total]) were stained histochemically with hematoxylin and eosin, Perl's method, Gomori's trichrome procedure, and the Verhoeff-van Gieson technique. Representative subsets of the cases (n = 20) were also studied immunohistologically using an antibody to elastin. Fibroelastosis in each of the samples was assessed for the degree of response and its location using a 3-tiered scale. The degree of fibroelastosis in the 15 cases of asbestosis was variable, with the pattern being peribronchial and perivascular in all instances; at least 2 asbestos bodies were identified in fibroelastotic foci in each of the 15 cases as highlighted with Perl's stain. Forty-seven cases of nonasbestotic lung disease (71%) showed interstitial fibrosis with a variable (usually modest) amount of admixed elastic tissue; when present, elastic fibers were distributed in a diffuse interstitial pattern, with or without perivascular accentuation. All cases of IPF also showed areas of fibroelastosis, but those foci were confined to regions of overt "honeycomb" change. No asbestos bodies were seen in any disease except asbestosis, and a predominantly peribronchial pattern of fibroelastosis was not identified in any nonasbestotic interstitial lung disease in this study. The authors conclude that the types and patterns of pulmonary connective tissue response in interstitial lung diseases may provide additional diagnostic clues to the presence of asbestosis.

The response of rectal cancers to neoadjuvant chemoradiotherapy is variable. Tumor hypoxia reduces the effectiveness of both radiation therapy and chemotherapy and is a well-known risk factor for tumor radioresistence. We hypothesized that imaging with the novel hypoxia-detecting agent, (60)Cu-diacetyl-bis (N(4)-methylthiosemicarbazone) ((60)Cu-ATSM), previously validated in cervical and lung cancers, would predict the response of rectal cancers to neoadjuvant chemoradiotherapy and prognosis.Patients with locally invasive (T2-4) primary or node-positive rectal cancer located12 cm from the anal verge were recruited for this pilot study. Pretreatment tumor size and stage were determined by endorectal ultrasonography, CT, and magnetic resonance imaging. Eleven patients also underwent clinical positron emission tomography with (18)F-fluorodeoxyglucose at the discretion of the treating clinician. The primary tumor was imaged by positron emission tomography with (60)Cu-ATSM, and accumulation of the tracer was measured semiquantitatively by determining the tumor-to-muscle activity ratio. Neoadjuvant chemoradiotherapy was then administered (within 2 weeks of (60)Cu-ATSM-positron emission tomography) and consisted of 45 Gy given in 25 fractions to the pelvis with continuous intravenous infusion of 5-fluorouracil (225 mg/m(2)/day). Proctectomy was performed six to eight weeks after neoadjuvant chemoradiotherapy and the tumor submitted to pathology for size measurement and staging. Tumor-to-muscle activity ratios were compared with tumor (18)F-fluorodeoxyglucose uptake, tumor response to neoadjuvant chemoradiotherapy, and with patient survival.Nineteen patients were enrolled in the study, two of whom were excluded from final analysis (1 death during neoadjuvant chemoradiotherapy and 1 tumor perforation during neoadjuvant chemoradiotherapy requiring emergent surgery). Of the 17 remaining patients, 14 had a reduction in tumor size and 13 were downstaged. The median tumor-to-muscle activity ratio of 2.6 discriminated those with worse prognosis from those with better prognosis. Both overall and progression-free survivals were worse with hypoxic tumors (tumor-to-muscle activity ratio2.6) than with nonhypoxic tumors (tumor-to-muscle activity ratioor=2.6; both P0.05). In addition, 2 of the 3 tumors with no change in size had tumor-to-muscle activity ratios2.6 (positive predictive value 66 percent), whereas 6 of 14 with decreased size had tumor-to-muscle activity ratios2.6 (negative predictive value 57 percent). Three of the 4 tumors not downstaged had tumor-to-muscle activity ratios2.6 (positive predictive value 75 percent), whereas 5 of 13 downstaged tumors had tumor-to-muscle activity ratios2.6 (negative predictive value 62 percent). The mean tumor-to-muscle activity ratio for downstaged tumors (2.2) was significantly lower than that of nondownstaged tumors (3.3) (P = 0.03). The difference in mean tumor-to-muscle activity ratio between downsized (2.3) and nondownsized (2.9) tumors did not reach statistical significance (P = 0.36). Tumor (18)F-fluorodeoxyglucose uptake (n = 11) did not correlate with (60)Cu-ATSM uptake (r = 0.4; P = 0.9) and there was no significant difference in mean tumor (18)F-fluorodeoxyglucose uptake between patients with hypoxic tumors and those with normoxic tumors (P = 0.3).The results of this small pilot study suggest that (60)Cu-ATSM-PET may be predictive of survival and, possibly, tumor response to neoadjuvant chemoradiotherapy in patients with rectal cancer. A larger Phase II study is warranted to validate these results.

The role of radiation and endocrine therapy in the treatment of intracystic papillary carcinoma (IPC) remains unclear. The aim of the current study was to review the management of IPC in order to determine factors associated with use of adjuvant therapies.A retrospective review of our surgical and pathology databases from 1995-2006 identified 45 women with IPC. These patients were further divided into those with pure IPC (n = 21), IPC with associated ductal carcinoma in situ (DCIS) (n = 18), and IPC with associated microinvasion with or without DCIS (n = 6). Patient characteristics were compared between groups using the chi-square test.Patients with IPC and microinvasion were more likely to undergo an axillary staging procedure (6/6, 100%) compared to patients with pure IPC (6/21, 29%) or IPC with DCIS (5/18, 28%) (P.001). Patients with pure IPC were less likely to have radiation therapy than patients with IPC and DCIS or microinvasion (P.001). However, within the subset of patients with pure IPC, women less than 50 years of age were more likely to have radiation therapy than those older than 50 years (P.001). Patients with IPC and DCIS or microinvasion had significantly increased use of endocrine therapy versus patients with pure IPC (P.01).In our patient population, those patients with IPC and associated DCIS or microinvasion are treated with adjuvant radiation and endocrine therapy on the basis of this associated pathology. The use of adjuvant radiation and/or endocrine therapy should be considered in patients with pure IPC who are of young age (50 years).

We report a rare case of a mycotic pulmonary artery pseudoaneurysm that was detected on CT examination. The pulmonary artery pseudoaneurysm appeared as a rapidly growing enhancing mass without a draining vein and with evidence of surrounding acute hemorrhage on CT.

Alpha-methylacyl coenzyme A racemase (AMACR), a novel immunomarker for prostatic adenocarcinoma, has recently been shown to be expressed in a number of malignancies including colorectal adenocarcinoma. In the current study, 59 surgically resected primary small intestinal adenocarcinomas (34 ampullary and 25 non-ampullary) were immunohistochemically examined for AMACR expression and compared with 66 colorectal adenocarcinomas (including 24 secondary tumors involving the small intestine by direct extension or metastasis). The results show that no AMACR immunoreactivity was detected in normal-appearing small and large intestinal mucosa. While 41 of 66 (62%) colorectal adenocarcinomas exhibited a variable degree of cytoplasmic staining, only 1 of 25 (4%) non-ampullary and 2 of 34 (6%) ampullary small intestinal adenocarcinomas showed positive AMACR immunoreactivity (P < 0.0001). Interestingly, AMACR appeared to be less frequently expressed in mucinous or poorly differentiated colorectal adenocarcinomas when compared with non-mucinous or better-differentiated counterparts, suggesting an association with microsatellite instability status. These results extend our previous observations that small intestinal adenocarcinomas differ markedly from colorectal adenocarcinomas despite their morphologic similarity. The different AMACR expression patterns may not only provide an additional diagnostic tool in the distinction between adenocarcinomas of the small and large intestinal origins but may also shed light on further understanding of intestinal tumorigenesis.

We studied 68 sporadic colorectal carcinomas (CRCs) with medullary features (MCRCs) and compared them with 35 poorly differentiated purely "enteric" CRCs (ECRCs) and 15 purely neuroendocrine carcinomas (NECs) of grades II and III, all in patients lacking a family history of CRC. Potential clinicopathologic differences between the study groups were assessed. MCRCs were significantly more common in the ascending colon than were ECRCs, but there was no significant dissimilarity to NECs. ECRCs occurred more often in the rectosigmoid than MCRCs or NECs. MCRCs arose in older patients, and a marked sex difference also was noted. Despite an infiltrative growth pattern, MCRC was less likely than ECRC to manifest with stage III or IV disease, but there was no stage-related difference from NECs. Although the histologic images of MCRCs were evocative of neuroendocrine differentiation, chromogranin positivity and synaptophysin reactivity in that group did not differ meaningfully from that of ECRCs but was dissimilar to the 100% labeling of NECs. p53 immunolabeling was similar in the 3 tumor groups. Follow-up data in the study cases showed that 5-year mortality was 40% (27/68) for MCRC, 59% (19/32) for ECRC, and 93% (14/15) for NEC. Medullary CRC seems to be a distinct clinicopathologic variant of CRC, which does not have a neuroendocrine lineage. The biologic behavior of MCRC was better than that of ECRC or NEC.

870 The Journal of Thoracic and Cardio Case Presentation Dr Lee: The patient is a 62-year-old man who had a brief episode of substernal chest pressure while lifting a heavy object at home. The pressure was alleviated with a few minutes of rest. Because the patient immediately felt better, he decided to wait to see his primary care physician at an appointment that was previously scheduled. He had asked for the appointment because of symptoms of dizziness and nose bleeding that had occurred during the 3 weeks before the episode of chest pressure. His medical history is significant for prostate cancer, for which he underwent a prostatectomy in 1995, and new-onset hypertension that is controlled without medication. On review of systems, he reported a little bit of increased shortness of breath over the past 6 months. He was able to walk a mile on flat ground, but after 2 flights of stairs, he became dyspneic. Also, over the past 6 months, he had a morning cough, with clear, thin mucous production. He reported long-standing reflux and constipation, for which he took stool softeners. Neurologically, he mentioned having 3 episodes of dizziness over 3 weeks, but he never had syncope. He also had a history of ocular migraines for approximately 2 years. Social history consisted of working as a serviceman for a heating and airconditioning company. He had been exposed to asbestos about 35 years prior. He has a 50 pack-year smoking history but stopped smoking 12 years before presentation. He drinks an occasional glass of wine. His family history is only significant for a heart attack that his father had at the age of 61 years and a mother with dementia. His allergies include tetanus shots made from horse serum and poison ivy. The results of his physical examination were unremarkable. He had no palpable adenopathy. His neck and head were not edematous. His lungs were clear, and his heart had a regular rate and rhythm. He had no chest wall tenderness. His abdomen was soft without mass, and his extremities had no cyanosis or clubbing. After the episode of chest pressure, he was fine for the next several days. Eventually, he went to his primary care physician about the nosebleeds and dizzi

BackgroundInfections with common respiratory tract viruses can cause high mortality, especially in immunocompromised hosts, but the impact of human metapneumovirus (hMPV) in this setting was previously unknownMethodsWe evaluated consecutive bronchoalveolar lavage and bronchial wash fluid samples from 688 patients—72% were immunocompromised and were predominantly lung transplant recipients—for hMPV by use of quantitative real-time polymerase chain reaction (PCR), and positive results were correlated with clinical outcome and results of viral cultures, in situ hybridization, and lung histopathological assessmentResultsSix cases of hMPV infection were identified, and they had a similar frequency and occurred in a similar age range as other paramyxoviral infections. Four of 6 infections occurred in immunocompromised patients. Infection was confirmed by in situ hybridization for the viral nucleocapsid gene. Histopathological assessment of lung tissue samples showed acute and organizing injury, and smudge cell formation was distinct from findings in infections with other paramyxoviruses. Each patient with high titers of hMPV exhibited a complicated clinical course requiring prolonged hospitalizationConclusionsOur results provide in situ evidence of hMPV infection in humans and suggest that hMPV is a cause of clinically severe lower respiratory tract infection that can be detected during bronchoscopy by use of real-time PCR and routine histopathological assessment

To determine and compare the diagnostic performance of computed tomography (CT), magnetic resonance (MR) imaging, ultrasonography (US), and positron emission tomography (PET) in the detection of hepatocellular carcinoma (HCC) or cholangiocarcinoma in liver transplant candidates and to determine interobserver variability between the readers.Twenty-five patients were examined prospectively with CT, MR imaging, US, and PET. Each test result was interpreted independently by two radiologists. Explanted liver specimens were examined histologically to determine presence and type of lesion. Results were analyzed on a patient-by-patient basis with marginal homogeneity and effect likelihood ratio tests.HCC was diagnosed in nine patients. US diagnostic performance was superior to that of CT and MR imaging on a patient-by-patient basis. Sensitivities were higher for US (0.89 for both US readers) than they were for CT (0.67 and 0.56 for readers 1 and 2, respectively), MR imaging (0.56 and 0.50 for readers 1 and 2, respectively), and PET (0 for both readers). None of the differences (within test) between readers were significant (Por=.32). Ratings by US and MR observers and one CT observer were significantly associated with truth (Por=.04). One or more imaging tests depicted 68 lesions. Histologic analysis revealed 18 HCC nodules; of these, 13 were correctly identified at CT, 14 at MR imaging, 13 at US, and none at PET. There were nine false-positive diagnoses of HCC with CT, five with MR imaging, and nine with US.Although US had the best diagnostic performance in depicting HCC on a patient-by-patient basis and was substantially better than were MR imaging and CT (which had nearly equivalent diagnostic performances), CT, US, and MR imaging performed similarly on a lesion-by-lesion basis. Small tumor nodules were the most common cause of missed HCCs with all tests. PET did not depict any HCCs.

Neuroendocrine tumors of the lung continue to be difficult nosologic and diagnostic problems, centering on the time-honored terms of "carcinoid," "atypical carcinoid," and "small cell carcinoma." Problems that are encountered in the classification of such neoplasms revolve around the differing criteria that have been advanced for their definition and variable application of such criteria in common practice. This review considers the epithelial and nonepithelial lesions of the lung that may demonstrate neuroendocrine and neuroectodermal differentiation. A proposal is made for a simplified system of classifying the epithelial tumors, dividing them into 3 grades with appended descriptive modifiers.

Ki-67 labeling of paraffin sections has been correlated with the number of cells in non-G(o) phases of the replicative cell cycle, and this immunohistochemical technique has been applied to the evaluation of a variety of human neoplasms. Similarly, immunolabeling for p53 protein has been used to detect mutations in the corresponding gene, as a reflection of possible cellular transformation in the same context. Both of these techniques were applied to 253 melanocytic tumors of the skin to assess their possible utility in the diagnosis and subcategorization of such lesions. They included 76 banal (common) nevi (CN), 39 Spitz nevi (SN), 62 superficial spreading malignant melanomas in radial growth (SSMMs), 32 nodular malignant melanomas (NMMs), 21 lentigo maligna melanomas in radial growth (LMMs), and 23 melanomas arising in association with preexisting compound nevi (MCN). One hundred cells were counted randomly in each tumor, and dark, exclusively nuclear reactivity was scored as positive labeling; results were recorded as percentages. Negligible Ki-67 and p53 labeling was seen in CN and SN, at a level that was similar to that obtained in cases of LMM and MCN. The largest proportion of Ki-67-positive and p53-positive cells was observed in NMMs, followed by SSMMs. Radial growth-phase SSMMs and LMMs demonstrated immunoprofiles that were similar to those of melanocytic nevi, and MCN did so as well. The prototypical malignant melanocytic tumor representing the vertical growth phase-nodular melanoma--demonstrated a statistically significant difference from all other lesions in this study with respect to Ki-67 index (P = .008, chi2) and p53 reactivity (P < .000001, chi2). Subsequent concurrent use of a Ki-67 threshold index of 10% and a p53 index of 5% correctly indicated the presence of vertical growth in 75% of NMMs, whereas only 8% of radial growth phase melanomas of other types were colabeled at the same levels of reactivity for the two markers (P < .00001, chi2). Thus, although the distinction between benign and malignant melanocytic tumors could and should not be based on immunohistology for Ki-67 and p53, these results suggest that the latter determinants may, in fact, be used as an adjunct to morphology in the recognition of the vertical growth phase in cutaneous malignant melanomas.

Videoendoscopy allows for close scrutiny of fine mucosal detail. Subtle lesions of the GI mucosa are being recognized with increasing frequency. We have previously identified many patients with whiteyellow mucosal speckling that resulted from accumulation of fat in foamy macrophages in the lamina propria adjacent to colonic neoplasms.1,2 During this study of “chicken skin mucosa,” other conditions were identified with a similar endoscopic appearance but investigation disclosed a different histopathology. In this report, 7 cases of speckling caused by focal mucin accumulation and 1 case of diffuse colonic lipid accumulation in macrophages are described.

Male breast carcinoma (MBC) accounts for only 1% of total mammary carcinomas. Controversy exists about whether MBC differs clinically and pathologically from female breast carcinoma (FBC). We compared 10 archival cases with 75 stage-matched FBCs. Clinical data, histologic details, immunostains for mammary lineage markers, and results of several putative "prognostic" analyses were addressed, including DNA ploidy and expression of c-erbB-2 (neu) oncoprotein and p53 protein. Cumulative literature data on 2,530 MBCs were contrasted with information from 135 institutional cases of FBC. A statistically significant difference in grade 3 lesions at low stage persisted when MBCs of all stages were compared with similar FBCs. For stages I and IIA, 5-year survival was 60% and 86% for MBCs and FBCs, respectively (also statistically significant). This difference disappeared when all stages were compared. A similar number of MBCs and FBCs, regardless of stage, demonstrated DNA aneuploidy with or without synthesis of S-100 protein, gross cystic disease fluid protein-15, c-erbB-2 protein, and p53 protein. Hormone receptor positivity was more common in MBC than in FBC at high tumor stages. Low-stage MBC and FBC differ biologically; MBCs tend to manifest at a higher grade with lessened 5-year survival. However, aside from distinctions in hormone receptor proteins, broader comparison of MBC and FBC at stages IIB and higher shows no significant differences in 5-year survival or expression of breast cancer-associated gene products.

The distinction between squamoid basal cell carcinoma and basaloid squamous cell carcinoma (or between BCC and trichoepithelioma variants) is usually made readily on the basis of defined histological criteria. However, these differential diagnoses occasionally can pose difficult morphological problems. The stated distinctions are clinically important because the risk of progressive disease is significantly higher with squamous carcinoma of the skin than with basal cell carcinoma (BCC), and a trichoepithelioma misinterpreted as BCC burdens the patient with an inaccurate diagnosis that may result in inappropriate surgery. Recent reports have suggested that reactivity with the monoclonal antibody Ber-EP4 is capable of separating histologically similar basal cell and squamous carcinomas, and that the expression of bcl-2 or CD34 antigen is able to distinguish BCC from trichoepithelioma. However, corroborative studies of these contentions are few in number. In order to investigate the usefulness of the stated immunostains in the above-cited differential diagnoses, the authors analyzed 45 basal cell carcinomas and 22 squamous carcinomas, as well as 36 trichoepitheliomas. The monoclonal antibodies Ber-EP4, My10 (CD34), and anti-bcl-2 were applied to formalin-fixed paraffin sections in all cases, using a standard avidin-biotin-peroxidase complex method. Most BCCs demonstrated strong, diffuse cytoplasmic labeling with Ber-EP4 and anti-bcl-2. In contrast, the squamous carcinomas were uniformly negative for the former marker and only focally reactive for the latter in four examples. 'Peripheral' bcl-2 staining of trichoepitheliomas was noted in 24 of 33 of the immunoreactive tumors, but the remainder were marked diffusely and similarly to most BCCs. Among the latter, immature trichoepitheliomas were diffusely reactive for this marker in 6 of 8 cases. Labeling of epithelium for CD34 failed to discriminate between any of the tumor types under evaluation, whereas staining of peritumoral stroma was characteristic of the majority of trichoepitheliomas and more than one-third of metatypical basal cell carcinomas. These data support the suggestion that Ber-EP4 and bcl-2 are useful in the separation of BCC from squamous carcinomas. Nevertheless, they also serve to caution against reliance upon bcl-2 and CD34 immunostains in attempting to distinguish BCC from trichoepithelioma in histologically enigmatic cases. There is currently no certain method other than conventional microscopy that can be applied successfully to the latter problem.

Background . The identification, classification, and appropriate treatment of patients with pulmonary carcinomas demonstrating neuroendocrine differentiation remains controversial. Methods . Patients undergoing resection of lung cancer at Washington University since 1986 were reviewed to identify all large cell neuroendocrine carcinomas. Cases were segregated into large, small, or mixed cell categories, and graded as moderate ("atypical carcinoid") or poorly differentiated (all higher grade lesions). All patients' charts were reviewed and referring physicians contacted to ascertain cancer treatment after resection and follow-up status. Results . Forty patients were identified with large cell neuroendocrine carcinoma: 8 moderate and 32 high-grade. Average follow-up was 19.8 months. Stage distribution was as follows: I, 25; II, 6; III, 6; and VI, 3. Fifteen patients have no evidence of disease, 15 are dead of disease, and 6 are alive with disease. Five-year survival of the stage I patients is 18%; all-stage 5-year survival is 13%. Of the 15 patients who died of their disease, 80% had stage I or II disease. Postoperative chemotherapy, radiation therapy, or both were given to 9 of 26 patient in stage I, with six deaths (67%). Six of 17 patients (35%) with stage I disease died after no postoperative intervention. Conclusions . Large cell neuroendocrine carcinomas identified by histologic examination have a remarkably poor prognosis even in very early stage disease. Adjuvant therapy did not improve survival. (Ann Thorac Surg 1997;63:180–5)

Although the capacity for some pulmonary carcinomas to mimic sarcomas is well recognized, their potential resemblance to selected benign lesions of the lung is currently underappreciated. The authors herein report three examples of sarcomatoid bronchogenic carcinoma with a deceptively bland appearance and an investment of reactive inflammation, such that they resembled pseudotumors histologically. These lesions occurred in two men and one woman who were 44, 61, and 63 years old, respectively, at diagnosis. All patients presented with a productive cough, hemoptysis, or chest pain. Their pulmonary masses were irregularly marginated radiographically, and ranged in size from 2.5 to 5.5 cm. Two were treated with lobectomy, and one underwent a wedge excision, followed by radiotherapy to the thorax. Despite these measures, each patient with inflammatory sarcomatoid carcinoma (ISC) died of disease or is likely to do so. Microscopically, ISCs were composed of uniform spindle cell proliferations with only modest nuclear pleomorphism, limited mitotic activity, and an arrangement in fascicles, storiform configurations, or haphazard arrays. Lymphocytes and plasma cells were interspersed throughout each of them, and keloidal stromal collagen was apparent internally in two examples. Two of the neoplasms also invaded pulmonary blood vessels or bronchi. A comparison group of 10 adults with pulmonary inflammatory pseudotumors (IPs) of the fibrous histiocytoma type shared several clinical attributes with ISC and showed closely similar histological features, except that the IPs lacked mitoses and invasiveness, and contained xanthoma cells or multinucleated elements in some cases in this series. Immunohistochemical analyses showed consistent dissimilarities between ISC and IP; keratin and epithelial membrane antigen were present in ISC but not IP, whereas actin was observed only in the proliferating spindle cells of IP. In summary, the potential clinicopathologic overlap between ISC and IP suggests that caution should be exercised in the separation of these two lesions. In particular, it is unwise to attempt to make this distinction in an intraoperative frozen section setting.

CD31 has recently been reported as a specific marker of endothelial differentiation among non-hematopoietic human neoplasms. In order to address this contention in particular regard to tumors of the skin and subcutis, the authors undertook a comparative study that surveyed 145 mesenchymal lesions. The antibodies used were directed against CD31 (clone JC/70A) and CD34 (clone My10), and these were compared with binding of Ulex europaeus I agglutinin (UEA). Proliferations that were included in the category of vascular tumors included cavernous and capillary hemangiomas (17 cases); lymphangiomas (8); epithelioid ("histiocytoid") hemangiomas (3), papillary endovascular hemangioendothelioma (1), angiosarcoma (7), and Kaposi's sarcoma of the mixed angiomatoid and spindle-cell type (17). CD31-immunoreactivity was observed in 35 of 53 vascular lesions; the neoplastic cells in a single angiosarcoma and the spindle cells in each case of Kaposi's sarcoma (KS) were not labeled. In all of the latter tumors, however, staining for CD31 was identified in the endothelia of angiomatoid areas and non-neoplastic blood vessels. These results compared favorably with those seen with anti-CD34, which decorated 36 of 53 vascular tumors--including 8 of 17 KS cases--and UEA, which bound to the neoplastic cells of 36 lesions. In contrast, all of 92 non-endothelial tumors included in this study (34 nerve sheath tumors [30 benign; 4 malignant]; 39 fibrohistiocytic neoplasms [11 benign; 28 malignant]; 9 smooth muscle tumors [6 benign; 3 malignant]; 7 glomus tumors; and 3 giant cell fibroblastomas) were negative for CD31. UEA labeled 3 non-vascular neoplasms, whereas 38 lesions of that type were CD34-positive.(ABSTRACT TRUNCATED AT 250 WORDS)

The authors report an example of an unusual subcuticular spindle cell tumor with histologic features which were most like those of “pleomorphic fibroma.” However, the tumor cells exhibited bifid differentiation immunohistologically, with conjoint reactivity for vimentin, S-100 protein, Leu-7 antigen (CD57), myelin basic protein, and desmin. A hamartomatous origin was favored for this lesion, given its overall morphologic features, circumscription, and apparently heterogeneous cellular lineages. Although speculative, it is thought that this unusual cutaneous mass may represent a subcuticular analogue of the benign Triton tumor (neuromuscular choristoma) of deep soft tissues.

To report four cases of leg pain resembling transient bone marrow edema (TBME).Four women aged 51-71 years had lower leg pain that regressed over 3-13 months. All patients underwent physical examination, clinical testing, radiography, scintigraphy, and magnetic resonance (MR) imaging. One patient underwent computed tomography; two underwent biopsy.All patients had tenderness at physical examination, and one had erythema and mild swelling over part of the leg. No laboratory results suggested systemic illness or infection. All had normal radiographs and abnormal bone scans, with increased radiopharmaceutical uptake in the tibial diaphyses. MR imaging showed decreased signal intensity with T1-weighting and increased signal intensity with inversion recovery. There were also signal intensity changes consistent with edema in the surrounding soft tissues. Biopsies showed focal marrow fibrosis and new bone formation with foci of devitalized bone.These cases resemble TBME but are unusual in their distribution. Whether they represent a previously undescribed clinical syndrome or a variant of TBME remains to be clarified.