Proteasome Inhibitor Carfilzomib-Based Therapy for Antibody-Mediated Rejection of the Pulmonary Allograft: Use and Short-Term Findings.

We present this observational study of lung transplant recipients (LTR) treated with carfilzomib (CFZ)-based therapy for antibody-mediated rejection (AMR) of the lung. Patients were considered responders to CFZ if complement-1q (C1q)-fixing ability of their immunodominant (ID) donor-specific anti-human leukocyte antibody (DSA) was suppressed after treatment. Treatment consisted of CFZ plus plasma exchange and immunoglobulins. Fourteen LTRs underwent CFZ for 20 ID DSA AMR. Ten (71.4%) of LTRs responded to CFZ. DSA IgG mean fluorescence intensity (MFI) fell from 7664 (IQR 3230-11 874) to 1878 (653-7791) after therapy (p = 0.001) and to 1400 (850-8287) 2 weeks later (p = 0.001). DSA C1q MFI fell from 3596 (IQR 714-14 405) to <30 after therapy (p = 0.01) and <30 2 weeks later (p = 0.02). Forced expiratory volume in 1s ( FEV1 ) fell from mean 2.11 L pre-AMR to 1.92 L at AMR (p = 0.04). FEV1 was unchanged after CFZ (1.91 L) and subsequently rose to a maximum of 2.13 L (p = 0.01). Mean forced expiratory flow during mid forced vital capacity (25-75) (FEF25-75 ) fell from mean 2.5 L pre-AMR to 1.95 L at AMR (p = 0.01). FEF25-75 rose after CFZ to 2.54 L and reached a maximum of 2.91 L (p = 0.01). Responders had less chronic lung allograft dysfunction or progression versus nonresponders (25% vs. 83%, p = 0.04). No deaths occurred within 120 days and 7 patients died post CFZ therapy of allograft failure. Larger prospective interventional studies are needed to further describe the benefit of CFZ-based therapy for pulmonary AMR.

A case series describing common radiographic and pathologic patterns of hard metal pneumoconiosis.

INTRODUCTION: Hard metal pneumoconiosis is a rare but serious disease of the lungs associated with inhalational exposure to tungsten or cobalt dust. Little is known about the radiologic and pathologic characteristics of this disease and the efficacy of treating with immunosuppression. OBJECTIVE: We describe the largest cohort of patients with hard metal pneumoconiosis in the literature, including radiographic and pathologic patterns as well as treatment options. METHODS: We retrospectively identified patients from the University of Pittsburgh pathology registry between the years of 1985 and 2016. Experts in chest radiology and pulmonary pathology reviewed the cases for radiologic and pathologic patterns. RESULTS: We identified 23 patients with a pathologic pattern of hard metal pneumoconiosis. The most common radiographic findings were ground glass opacities (93%) and small nodules (64%). Of 20 surgical biopsies, 17 (85%) showed features of giant cell interstitial pneumonia. Most patients received systemic corticosteroids and/or steroid-sparing immunosuppression. CONCLUSIONS: Hard metal pneumoconiosis is characterized predominately by radiographic ground glass opacities and giant cell interstitial pneumonia on histopathology. Systemic corticosteroids and steroid-sparing immunosuppression are common treatment options.

C4d deposition in lung allografts is associated with circulating anti-HLA alloantibody.

UNLABELLED: The complement activation demonstrated by vascular C4d deposition is used to diagnose antibody-mediated rejection (AMR) in renal allografts, but remains controversial in lung transplantation (LTX). METHODS: C4d deposition was assessed by immunohistochemistry in 192 lung transplant biopsies from 32 patients. ELISA analysis was performed on 415 serum samples in those 32 temporally and rejection-grade matched LTX patients; 16 patients developed HLA-Ab, while the other 16 patients remained negative. The specificity of C4d staining was further compared in 18 additional LTX patients without HLA-Ab or acute cellular rejection (ACR), but in the presence of CMV-pneumonitis or reperfusion injury. RESULTS: Specific subendothelial C4d deposition was seen in 5 of 16 (31%) patients with HLA-Ab and was absent in 16 patients without HLA-Ab (p<0.05). All patients with specific C4d deposition exhibited donor-specific HLA-Ab. There were 13 patients with bronchiolitis obliterans syndrome in the group of 16 HLA-Ab positive patients, versus 2/16 in ELISA-negative patients (p<0.005). One of 7 patients with CMV pneumonitis and 2 of 11 patients with reperfusion injury also showed C4d positivity (not statistically significant). CONCLUSIONS: In this study, specific subendothelial C4d deposition was a marker for the involvement of HLA-Ab in lung allograft rejection. The patchy nature, low sensitivity, and specificity of C4d staining might limit clinical use in protocol biopsies. However, in patients with decreasing pulmonary function, refractory ACR and/or HLA-Ab, specific C4d deposition may serve as a marker of coexistent AMR.

Pulmonary apical cap: a distinctive but poorly recognized lesion in pulmonary surgical pathology.

Thirteen cases of pulmonary apical cap (PAC), resected for the exclusion of a clinical diagnosis of lung carcinoma, were reviewed, and their distinctive morphology was described. PAC occurred in older individuals, particularly in the apices of the upper lobes, and by radiographic examination appeared as spiculated subpleural masses ranging from 0.7 to 5.2 cm in diameter. Microscopically, these subpleural scars were pyramid shaped with overlying pleural adhesions and hyaline pleural plaques. They were characterized by a dense basophilic fibrosis of the pulmonary parenchyma with air spaces filled with old, mature collagen and the underlying elastic skeleton contracted in an accordion-like fashion with reduplicated curls of elastic fibers. Scar emphysema was prominent at the periphery of these fibrous nodules. PAC should be recognized for its unique histology because its appearance in the surgical pathology laboratory will likely increase in incidence with the evolution of more sensitive pulmonary radiographic studies. A chronic ischemic etiology is favored.

Lymphocytic bronchitis/bronchiolitis in lung allograft recipients.

Twenty-six cases of lymphocytic bronchitis/bronchiolitis (LBB) identified by transbronchial biopsy in 25 lung allograft recipients were studied to determine its relationships to acute rejection and bronchiolitis obliterans (OB). LBB occurred 355 days after transplantation on average (range, 15-2,118 days) and was manifested by a patchy or diffuse submucosal infiltrate of lymphocytes and plasma cells, which percolated deep to the smooth muscle layer of the bronchi in 15 cases. Submucosal granulation tissue and bronchiolitis were observed more frequently in patients who developed OB than in those who did not (44% and 88% vs 23% and 41%). Although 39% of patients progressed to OB overall, the majority of patients with LBB who received augmented immunosuppressive therapy (steroids, antithymocyte globulin, or both) improved or stabilized their pulmonary function abnormalities. Interestingly, LBB was preceded by acute rejection in 20 of 26 instances, and LBB frequently persisted as a histologic finding after the initial diagnostic transbronchial biopsy. LBB appears to be related to previous acute rejection episodes and responds to augmented immunosuppressive therapy.

Systemic light chain deposition disease presenting as multiple pulmonary nodules. A case report and review of the literature.

This case report describes the primary manifestation of systemic light chain deposition disease as bilateral nodules on chest radiographs. Although this case was initially classified as amyloidosis, a subsequent renal biopsy and ultrastructural, histochemical, and immunohistochemical studies allowed its distinction from amyloidosis. Kappa light chains were expressed with immunoperoxidase studies on paraffin-embedded tissue, and ultrastructural studies showed the dense, granular deposits characteristic of systemic light chain deposition disease. Serum and urine electrophoresis showed a monoclonal spike, but no plasmacytosis was identified at bone marrow biopsy and autopsy. The literature on this subject is also herein reviewed, with particular attention to the extrarenal manifestations of systemic light chain deposition disease.

Pulmonary histology for the surgical pathologist.

This is a review of the variety of pulmonary histologic artifacts and incidental findings that may come to the attention of the surgical pathologist. In some cases, these may lead to an erroneous diagnosis; in others, they may obscure the diagnosis. The following groups of lesions are discussed: artifacts seen in biopsy and resection material, site-specific changes commonly encountered, incidental findings and structures seen in biopsy and resection material, and age-related changes. A short review of normal histology is included for perspective and a discussion of the abnormal biopsy that appears normal on first review is presented.

MIB-1 as a predictor of response in lung allografts with moderate acute cellular rejection.

The major obstacle that long-term lung transplant recipients face is bronchiolitis obliterans. Prior episodes of acute rejection, specifically their frequency, persistence, and severity, are important predictors of bronchiolitis obliterans. Many cells contribute to the damage of acute rejection, and there is no sole cell type that can predict persistent rejection or bronchiolitis obliterans. In this study we evaluated 48 transbronchial biopsy samples from various grades of acute rejection with the proliferation marker MIB-1 and attempted to retrospectively predict response to standard corticosteroid in a subpopulation of nine responders and nine nonresponders, all with grade A3 rejection. We then characterized the proliferating cells by double labeling with MIB-1 and L26, CD3, OPD4, or KP1. Our results indicate that the proliferating cells in acute lung rejection are a heterogeneous pool of T- and B-lymphocytes, T-helper cells, macrophages, endothelial cells, and possibly parenchymal cells, and that MIB-1 is a valuable tool in the evaluation of total cellular activity in this setting. In addition, the overall proliferation rate, defined as the most intense proliferation rate regardless of location in the biopsy, closely matches the grade of acute rejection. Finally, a low lesional proliferation rate, defined as the proliferation rate at the site of perivascular inflammation diagnostic of acute rejection, is an indicator of excellent response to therapy and may have potential clinical importance.

Diffuse panbronchiolitis in North America. Report of three cases and review of the literature.

Diffuse panbronchiolitis is a disease largely restricted geographically to Japan. It is manifested clinically by an insidious onset of dyspnea, cough, and production of mucopurulent sputum. Histologically it is characterized by a suppurative bronchiolitis involving primarily the respiratory and terminal bronchioles with subsequent progression to bronchiolectasis. Pulmonary function tests show a mixed obstructive-restrictive pattern. This report presents two cases occurring in white patients and one in an Oriental immigrant to Canada.

Bronchioloalveolar adenocarcinoma of lung: monoclonal origin for multifocal disease.

In an attempt to understand the histogenesis and molecular pathogenesis of multifocal bronchioloalveolar lung carcinoma (BAC) we studied 28 cases of BAC using a topographic genotyping approach for the presence of K-ras exon 1 mutations and p53 loss of heterozygosity (LOH). This analytical approach demonstrated K-ras exon 1 mutations in 12.5% of solitary BACs, 40% of BACs with microscopic or macroscopic satellite lesions, and 60% of BACs with intrathoracic metastases. In all cases with K-ras mutations, the identical point mutation was present in the primary, satellite, and intrathoracic metastatic lesions. When p53 LOH was demonstrated in the primary lesion, it was also detected in the satellites and intrathoracic metastases. No significant association was noted between the presence of K-ras mutations and p53 LOH. The results strongly support a monoclonal origin of multifocal BACs. Furthermore, the findings support the theories explaining the origin of multifocal BAC by intraalveolar route of spread, intrapulmonary lymphatic spread, or aerosolization leading to implantation at different sites. A trend toward an increased frequency of K-ras mutations and p53 LOH in BACs with satellites or metastases compared to solitary BACs was noted.

Interstitial and airspace granulation tissue reactions in lung transplant recipients.

Twenty-three transbronchial and open-lung biopsies from patients who had received a lung allograft displayed fibromyxoid plugs of granulation tissue within airways, airspaces, and the interstitium in a patchy distribution. This granulation tissue-like reaction was identified in three clinicopathologic settings. First, 11 cases occurred with acute lung rejection, of which four cases had been partially treated with steroids for a previous rejection episode. Second, in seven cases the fibromyxoid tissue represented the healing phase of previously diagnosed diffuse alveolar damage resulting from preservation (harvest) injury to the allograft. Third, five cases were related to infection: herpes, Pseudomonas, Serratia, Staphylococcus, and Pneumocystis pneumonias. Although organizing pneumonia-like responses usually suggest an infectious episode, this reaction may be seen as a manifestation of acute lung rejection or ischemic lung injury.

Pulmonary Kaposi's sarcoma. Premortem histologic diagnosis.

Nine open lung biopsies and nine transbronchial biopsies from 10 patients with pulmonary Kaposi's sarcoma were reviewed to define the pattern of involvement in the lung by Kaposi's sarcoma and to determine the usefulness of transbronchial biopsy in making the diagnosis. There were nine patients with acquired immune deficiency syndrome (AIDS) and one patient with sporadic pulmonary Kaposi's sarcoma. A lymphatic distribution was seen in all cases. A spectrum ranging from distinctive polymorphous cellular infiltrates ultimately interpreted as Kaposi's sarcoma to "classic" Kaposi's sarcoma was found. Recognition of the former enabled retrospective recognition of Kaposi's sarcoma in four of eight transbronchial bronchial biopsies. The diagnosis of pulmonary Kaposi's sarcoma in one other patient was made solely on the basis of transbronchial biopsy. Eight patients died from pulmonary Kaposi's sarcoma; two patients are alive with extensive pulmonary Kaposi's at last follow-up. We believe that transbronchial biopsy may be useful in establishing a diagnosis of pulmonary Kaposi's sarcoma in many more patients than is generally appreciated.

Non-Hodgkin's lymphomas of the lung. A study of 19 cases emphasizing the utility of frozen section immunologic studies in differential diagnosis.

Nineteen cases of possible non-Hodgkin's lymphoma of the lung were studied by conventional morphologic methods and by immunohistochemical methods employing monoclonal antibodies applied to frozen tissue sections. In five of the 19 cases, the original histologic diagnoses were revised after review of the immunologic findings. Problem areas clarified by immunodiagnosis included the differential diagnoses of pseudolymphoma versus small lymphocytic lymphoma (two cases), Hodgkin's disease versus non-Hodgkin's lymphoma (two cases) and non-Hodgkin's lymphoma versus lymphomatoid granulomatosis (one case). Of the seven lymphomas presenting exclusively in the lung without a prior history of lymphoma, three were small lymphocytic, one was diffuse mixed small cleaved and large cell, and three were diffuse large-cell lymphomas. Four of these lymphomas typed as B-cell, two typed as T-cell, and one was of undefined phenotype.

p53 and K-ras mutational genotyping in pulmonary carcinosarcoma, spindle cell carcinoma, and pulmonary blastoma: implications for histogenesis.

In an attempt to understand the molecular pathogenesis of biphasic pulmonary neoplasms, the authors studied 25 cases of carcinosarcoma, spindle cell carcinoma, and pulmonary blastoma using a combined immunohistochemical and topographic genotyping approach for the presence of p53 abnormalities within the different epithelial and mesenchymal components of these tumors. Genotyping involved a search for point mutational damage in p53 exons 5-8, which was correlated with p53 immunoreactivity. This analytical approach demonstrated p53 missense point mutations in four of nine cases of spindle cell carcinoma with a 100% concordance rate between p53 immunopositivity and the presence of DNA mutational damage. One of six carcinosarcomas, heterologous in type, exhibited a p53 mutation. The concordance rate among carcinosarcomas was also 100%. However, the concordance rate among classic biphasic pulmonary blastomas was only 43%, with one of seven cases demonstrating a p53 mutation by DNA genotyping. The lack of concordance in pulmonary blastomas was possibly due to the existence of genotypically distinct subsets of tumor cells likely bearing mutations among largely nonmutated cells. In a similar fashion, among three well-differentiated fetal type adenocarcinomas, no p53 mutations were detected despite the presence of focal p53 immunopositivity in one of the cases. No K-ras mutations were detected in any of the 25 tumors examined. Monoclonal histogenesis from a single totipotential cell in a subset of these neoplasms (six of 22 cases) was supported by the finding of p53 overexpression and identical p53 mutational genotype in both the epithelial and spindle elements of the tumors. Furthermore, the finding of a small percentage of p53-positive tumor cells within one or both components suggests late acquisition of p53 mutational change in a subset of pulmonary blastomas.

Significance of acute bronchitis/bronchiolitis in the lung transplant recipient.

Acute bronchitis/bronchiolitis (ABB) in the lung allograft is characterized by a predominantly neutrophilic infiltrate in the small and large airways and accompanied by other features such as luminal dilatation, mucous plugging, and granulation tissue formation. The etiologies for ABB are varied and depend on the context in which this lesion is found. Fifty-nine biopsies from 49 patients were found to have these changes. By correlating the clinical and histopathologic features we found ABB in one of five clinico-pathologic categories: I) Harvest Injury (9 patients); II) Acute Cellular Rejection (7 patients); III) Bronchiolitis Obliterans Syndrome (14 patients); IV) Infection [prior to the development of bronchiolitis obliterans (OB)] (15 patients); and V) Other Manifestations of ABB (4 patients). In the context of early manifestations of harvest injury (Category I), ABB reflected severe ischemic lung injury with secondary acute inflammation of the airways. The prognosis was poor, with five patients dying and one requiring retransplantation because of irreversible harvest injury within 1 month of transplantation. When ABB was found in the setting of acute cellular rejection (Category II), it represented a severe manifestation of immunologic airway injury with a predominant lymphoplasmacytic response, and was followed by subsequent development of OB in five of seven patients. In those patients with histologically proven OB (Category III), the finding of ABB was present in a scarred or distorted airway and was a manifestation of airway rejection, infection, or both as demonstrated clinicopathologically, Infection-related ABB prior to the development of OB (Category IV) was managed as infection alone in 13 patients, but a coexistent perivascular lymphoplasmacytic infiltrate brought the concern for concurrent infection and rejection process in two patients. Since only two of the 15 patients in this category later developed OB, these patients with infectious ABB alone did not appear to be at a significant risk for the later development of OB. Finally, four patients demonstrated ABB without associated clinical manifestations and were placed in Category V (Other Manifestations of ABB). In this category, ABB was noted to be an indolent finding with all of the patients alive to date and none developing OB. Overall, the interpretation of ABB in the lung transplant setting depends on the recognition of the histologic clues and the clinical context in which one finds this airway lesion.

Giant-cell interstitial pneumonia and hard-metal pneumoconiosis. A clinicopathologic study of four cases and review of the literature.

We report four cases of giant-cell interstitial pneumonia that occurred in association with exposure to hard metals. All patients presented with chronic interstitial lung disease and had open-lung biopsies that revealed marked interstitial fibrosis, cellular interstitial infiltrates, and prominent intraalveolar macrophages as well as giant cells displaying cellular cannibalism. We also review the literature to determine the sensitivity and specificity of giant-cell interstitial pneumonia for hard-metal pneumoconiosis. Although hard-metal pneumoconiosis may take the form of usual interstitial pneumonia, desquamative interstitial pneumonia, and giant-cell interstitial pneumonia, the finding of giant-cell interstitial pneumonia is almost pathognomonic of hard-metal disease and should provoke an investigation of occupational exposure.

Pulmonary Langerhans' cell histiocytosis: molecular analysis of clonality.

Pulmonary Langerhans' cell histiocytosis (LCH) is a form of Langerhans' cell disease that primarily affects smokers in the third to fifth decade. Extrapulmonary manifestations are rare. Its clinical course is typically characterized by stabilization or regression of bilateral micronodular infiltrates seen on chest radiographs; progression to honeycomb fibrosis is rare. Because the clinical course of pulmonary LCH is distinct from systemic multiorgan LCH, currently thought to be a clonal proliferative disorder, we examined the X-linked polymorphic human androgen receptor assay (HUMARA) locus to assess clonality in female patients with one or more discrete LCH cell nodules in open lung biopsies. Langerhans' cells (LCH cells) were excised from formalin-fixed, paraffin-embedded tissue by microdissection to assure a relatively pure cellular population, and studies for differential methylation patterns at the HUMARA locus were performed. Twenty-four nodules in 13 patients were evaluated. Seven (29%) were clonal and 17 (71%) were nonclonal. Of six cases with multiple discrete nodules, three (50%) showed a nonclonal LCH cell population. In one biopsy with five nodules, two nodules were clonal with one allele inactivated, one nodule was clonal with the other allele inactivated, and two nodules were nonclonal. In contrast to systemic LCH, pulmonary LCH appears to be primarily a reactive process in which nonlethal, nonmalignant clonal evolution of LCH cells may arise in the setting of nonclonal LCH cell hyperplasia. Cigarette smoking may be the stimulus for pulmonary LCH in contrast to other forms of LCH.

So-called sclerosing hemangiomas of lung. An immunohistochemical study supporting a respiratory epithelial origin.

Sclerosing hemangiomas are benign pulmonary neoplasms. They were initially believed by Liebow and Hubbell to be of endothelial origin; however, subsequent ultrastructural studies have suggested an alveolar pneumocyte and mesothelial derivation. Using a panel of various antibodies on eight cases, the authors found that sclerosing hemangiomas expressed cytokeratin (seven cases), epithelial membrane antigen (seven cases), carcinoembryonic antigen (five cases), vimentin (seven cases), surfactant apoprotein (eight cases), and Clara cell antigen (five cases). These results support the hypothesis that sclerosing hemangiomas represent an epithelial tumor showing simultaneous bronchiolar epithelial and alveolar pneumocyte differentiation.

Erdheim-Chester disease: clinical, radiologic, and histopathologic findings in five patients with interstitial lung disease.

Erdheim-Chester disease is a clinicopathologic entity defined by a characteristic pattern of symmetric osteosclerosis caused by an infiltrate of mononuclear cells that include prominent numbers of foamy histiocytes. About half of patients have extraskeletal manifestations, including involvement of the hypothalamus/posterior pituitary, orbit, retroperitoneum, skin, lung, and heart. Pulmonary involvement is an uncommon but important manifestation of Erdheim-Chester disease because it causes significant morbidity and mortality. A review of the Mayo Clinic files produced four patients with confirmed Erdheim-Chester disease in whom lung biopsy had been performed. One additional patient was included from the University of Pittsburgh. Four patients were women. The mean age was 53.6 years (range 25-70 years). All patients had bilateral and symmetric sclerotic bone lesions characteristic of Erdheim-Chester disease, although in three the skeletal abnormalities were discovered only after lung biopsy. Four patients had dyspnea, and one also had a dry cough. One patient died 17 months after diagnosis. Chest radiographs showed diffuse interstitial infiltrates in all patients, with an upper zone predominance in three. Thoracic computed tomography (CT) scans showed thickening of the visceral pleura and interlobular septa with patchy associated fine reticular and centrilobular opacities and ground glass attenuation. Lung biopsy specimens showed an infiltrate of foamy histiocytes, lymphocytes, and scattered Touton giant cells with associated fibrosis in a striking lymphatic distribution. The infiltrate involved visceral pleura, interlobular septa, and bronchovascular bundles. Immunohistochemical stains were positive for CD68 in all cases and S-100 protein in four cases. Stains for CD1a were consistently negative. Ultrastructural studies in one case showed no Birbeck granules. Although in bone the histologic features of Erdheim-Chester disease may overlap with Langerhans' cell histiocytosis, its expression in the lung is distinct. Lung involvement in Erdheim-Chester disease has emerged as a unique radiographic and histologic entity.

Comparison of extracellular matrix antigens in subtypes of bronchioloalveolar carcinoma and conventional pulmonary adenocarcinoma. An immunohistochemical study.

In contrast to the conventional pulmonary adenocarcinomas (CPAs), bronchioloalveolar carcinoma (BAC) grows predominantly by spreading along the existing alveolar septal framework. Within the BAC category, three subtypes have been identified: mucinous, nonmucinous, and sclerosing BAC. Of these, mucinous and sclerosing BACs have worse prognoses compared with nonmucinous BAC. However, the manifestation of aggressive behavior is different between the mucinous and sclerosing types of BACs. Multifocality is often produced by aerogenous spread, especially in the case of mucinous BACs. To study the differences between the BAC subtypes and the conventional pulmonary adenocarcinomas, we employed a battery of immunohistochemical stains marking the extracellular matrix architecture (laminin, collagen IV, fibronectin, and collagen III), a degradative enzyme against a basement membrane component (anti-type IV collagenase) and cellular receptors for laminin and collagen IV (alpha 2 integrin) on 16 BACs (5 mucinous, 5 nonmucinous, and 6 sclerosing) and 30 CPAs. The mucinous and nonmucinous BACs demonstrated neoplastic epithelial cells growing along a continuous basement membrane. A similar growth pattern with intact basement membrane was noted in the periphery of sclerosing BACs. However, in contrast to mucinous and nonmucinous BACs, all cases of sclerosing BACs showed disruption or complete absence of basement membrane components (laminin and collagen IV) around the embedded glands located centrally in the sclerotic fibrous stroma, as was seen in the basement membrane analysis of conventional adenocarcinomas. Furthermore, increased type IV collagenase activity was seen in the small centrally located embedded glands in comparison to the peripheral glands. These architectural alterations of basement membrane disruption and phenotypic expression of degradative activity may be a reflection of the invasive behavior of the sclerosing BACs and their tendency to produce lymph node metastasis. Although the mucinous BACs did not show evidence of basement membrane disruption, there was a marked increase in their levels of type IV collagenase expression along with consistently low levels of alpha 2 integrin receptor (laminin and collagen IV receptor) expression. These findings may be related to the ability of the mucinous BACs to detach from the underlying basement membrane and spread aerogenously, and is to be contrasted with the stromal infiltration and desmoplasia of sclerosing BACs and CPAs.