Differentiating cytological features of bronchioloalveolar carcinoma from adenocarcinoma of the lung in fine-needle aspirations: A statistical analysis of 27 cases

Bronchioloalveolar carcinoma (BAC) is an uncommon type of lung carcinoma that is important to distinguish from adenocarcinoma (adenoCA) because of its different biological behavior. Although the features of BAC have often been described in cytological material other than fine-needle aspirations (FNA), they have rarely been detailed in FNA specimens. We undertook to delineate the differentiating cytological features of 13 cases of BAC (7 of the nonsecretory type and 6 of the secretory type) and of 14 cases of bronchogenic adenoCA in FNA material, looking at 17 cytological criteria and using statistical analysis. When statistically analyzed with chi-square and Pearson's correlation, only 3 of the 17 features were found to be good discriminants for distinguishing nonsecretory BAC (NS-BAC) from adenoCA: prominence of monolayered tumor sheets, fine chromatin pattern, and mild cellular pleomorphism correlated significantly with NS-BAC. On the other hand, only the prominence of nuclear grooves and the abundance of extracellular mucin correlated significantly with secretory BAC (S-BAC) when compared to adenoCA. When using a logistic regression analysis, NS-BAC and S-BAC were best discriminated from adenoCA by the prominence of monolayered tumor sheets and by the abundance of extracellular mucin, respectively. We conclude that, in most instances, it is possible to make an accurate diagnosis of BAC and to distinguish it from adenoCA of the lung in FNA material. Diagn. Cytopathol. 16:253–257, 1997. © 1997 Wiley-Liss, Inc.     

Integrative analysis correlates donor transcripts to recipient autoantibodies in primary graft dysfunction after lung transplantation

Up to one in four lung-transplanted patients develop pulmonary infiltrates and impaired oxygenation within the first days after lung transplantation. Known as primary graft dysfunction (PGD), this condition increases mortality significantly. Complex interactions between donor lung and recipient immune system are the suspected cause. We took an integrative, systems-level approach by first exploring whether the recipient''s immune response to PGD includes the development of long-lasting autoreactivity. We next explored whether proteins displaying such differential autoreactivity also display differential gene expression in donor lungs that later develop PGD compared with those that did not. We evaluated 39 patients from whom autoantibody profiles were already available for PGD based on chest radiographs and oxygenation data. An additional nine patients were evaluated for PGD based on their medical records and set aside for validation. From two recent donor lung gene expression studies, we reanalysed and paired gene profiles with autoantibody profiles. Primary graft dysfunction can be distinguished by a profile of differentially reactive autoantibodies binding to 17 proteins. Functional analysis showed that 12 of these proteins are part of a protein–protein interaction network (P=3 × 10⁻⁶) involved in proliferative processes. A nearest centroid classifier assigned correct PGD grades to eight out of the nine patients in the validation cohort (P=0·048). We observed significant positive correlation (r=0·63, P=0·011) between differences in IgM reactivity and differences in gene expression levels. This connection between donor lung gene expression and long-lasting recipient IgM autoantibodies towards a specific set of proteins suggests a mechanism for the development of autoimmunity in PGD.     

Distinction between bronchioloalveolar carcinoma and hyperplastic pulmonary proliferations: A cytologic and morphometric analysis

The objectives of this study were to identify key cytologic features for the morphologic differentiation of bronchioloalveolar carcinoma from reactive pulmonary proliferations, and to determine if morphometry of the cytologic specimens could provide additional data to distinguish the two processes. We analyzed 15 morphologic criteria in pulmonary cytologic specimens from 17 histologically proven cases of bronchioloalveolar carcinoma and 13 cases with reactive cellular changes and compared the findings using univariate analysis. This revealed four statistically significant features more commonly associated with bronchioloalveolar carcinoma: (i) predominance of two- and three-dimensional tissue fragments, (ii) tenacious intercytoplasmic connections between cells, (iii) intranuclear cytoplasmic inclusions, and (iv) paucity of multinucleated cellular forms. Morphometric measurement revealed significant differences between the mean of the nuclear area of benign reactive cells and that of the malignant cells. The utilization of these criteria is helpful to diagnose bronchioloalveolar carcinoma and to distinguish it from reactive pulmonary processes. Diagn. Cytopathol. 16:396–401, 1997. © 1997 Wiley-Liss, Inc.     

Metastatic bronchioloalveolar carcinoma presenting as a solitary thyroid nodule: report of a case with fine-needle aspiration cytopathology

Although cancers metastatic to the thyroid are frequently mentioned in autopsy studies, such a finding is quite rare in routine clinical practice. Metastatic non-small-cell carcinomas to the thyroid may present a diagnostic dilemma, particularly when they share morphological similarities with primary thyroid tumors. Herein, we report a case of metastatic bronchioloalveolar carcinoma that presented as an isolated left thyroid nodule in a 68-year-old woman. The aspirates were cellular and showed numerous papillary-like tissue fragments, elongated nuclei with prominent nuclear grooves, frequent mitoses, and psammoma bodies. The latter features raised the possibility of papillary thyroid carcinoma. However, also seen were three-dimensional tumor nests and acinar-forming fragments. Immunostains (positive for cytokeratin-7 and carcinoembryonic antigen and negative for cytokeratin-20 and thyroglobulin) confirmed the metastatic nature of the carcinoma. In a patient with known primary neoplasm, the differential diagnosis of a thyroid nodule should always include a metastatic lesion along with primary neoplasia.     

Cell incohesiveness and pattern of extension in a rare case of bronchioloalveolar carcinoma

A unique case of adenocarcinoma of the lung that showed aerogenous extension is presented. Although the primary focus was the usual invasive bronchiolo-alveolar carcinoma, the tumor cells were dissociated, floating and filling the alveolar spaces, the bronchioli, and the small bronchi at the periphery of the primary tumor and in every involved area in other lobes of the lung. Massive tumor cells were expectorated in coincidence with the appearance of abnormal densities on chest X-ray films. Ultrastructurally the dissociated tumor cells had numerous microvilli on the cell surface and rarely showed intercellular junctions. The tumor cells also contained well-developed rough and smooth endoplasmic membranes, crista-vesicular-type mitochondria, electron-dense granules, and granules with myelinlike figures. No mucous granules and no Clara-cell-type secretory granules nor lamellar bodies of the type seen in normal granular pneumocytes were seen. From these findings, it was concluded that the tumor cells in this case were rather poorly differentiated but somewhat resembled the hyperplastic cuboidal alveolar cells seen in the damaged lung and that they proliferated freely in airways, presenting aerogenous metastases. The biologic behavior of this tumor might be partly explained by the incohesive nature of the tumor cells.     

Papillary adenocarcinoma of the lung is a more advanced adenocarcinoma than bronchioloalveolar carcinoma that is composed of two distinct histological subtypes

To clarify the clinicopathological nature of papillary adenocarcinoma (PA) of the lung, 20 cases of PA were collected consecutively from resected adenocarcinoma of the lung, studied immunohistochemically and, using molecular techniques, compared with bronchioloalveolar carcinoma (BAC). Clinicopathologically, PA occurred in 7.4% and dominantly in female patients. Morphologically, PA was divided into two subtypes according to the presence of residual alveolar structures, detected by elastica van Gieson stain. One of these subtypes was closely related to the morphology of BAC and might be diagnosed as adenocarcinoma with mixed subtypes. The other PA subtype was composed of tall columnar cells and grew compressively, which was similar to type F adenocarcinoma previously reported by Noguchi et al. Immunohistochemical studies using lung tissue-specific antigens, progression markers and tumor suppressor products found that PA seemed a more advanced adenocarcinoma than BAC, but no differences were observed among PA subtypes. Molecular biological analysis using three microsatellite markers at chromosome 3p revealed more frequent loss of heterozygosity in PA than BAC, with no differences among PA subtypes. These findings suggest that PA is a more advanced adenocarcinoma subtype than BAC. Further investigations are needed to clarify true PA as clinicopathologically and biologically independent from other histological subtypes of adenocarcinoma of the lung.     

Nuclear expression of p53, p21 and cyclin D1 is increased in bronchioloalveolar carcinoma

AIMS: The objectives of this study were: (1) to determine, using immunohistochemistry, the level of expression of the cell cycle factors p53, p21 and cyclin D1 in a group of bronchioloalveolar carcinomas (BACs), and to compare these data to relevant published data for lung carcinoma; (2) to determine if higher expression rates for these factors in BAC were associated statistically with advanced clinical stage, greater tumour size, tobacco abuse, and/or BAC subtype; (3) to seek, using Fisher's exact t-test and paired data groups, any significant associations within the expression data for p53, p21 and cyclin D1. METHODS AND RESULTS: A panel of monoclonal antibodies against p53, p21 and cyclin D1 was applied to 19 bronchioloalveolar carcinomas (17 surgical pathology cases and two autopsies) from the tissue archives of St. Louis University. These immunohistochemical stains were graded on a semiquantitative scale according to the prevalence of nuclear staining within the tumour (< 10% positive cells = 0, 10-25% = 1+, 25-50% = 2+, 50-75% = 3+ and 75-100% = 4+). Six of 19 (32%) of BACs showed 1+ or greater p53 positivity, six of 19 (32%) showed 1+ or greater nuclear cyclin D1 positivity, and nine of 19 (47%) of BACs showed 1+ or greater p21 nuclear positivity. A statistically significant correlation was found between p53 and cyclin D1 expression (P = 0.046, Fisher's exact t-test), but not between p53 and p21, or between p21 and cyclin D1. No statistically significant association was found between the cell cycle factor expression data and subtype of BAC (mucinous vs. nonmucinous), tumour diameter, clinical stage or tobacco-use history. CONCLUSIONS: BACs show p53 immunostain positivity at a frequency similar to that published for p53 mutations in lung adenocarcinomas in general. Cyclin D1 and p21 nuclear expression characterizes a significant proportion of BACs, with cyclin D1 and p53 expression showing a statistically significant association. Aberrations in p53, p21, and cyclin D1 expression may be important in the development of a significant proportion of BACs.     

Lymphangioleiomyomatosis: Recurrence after single lung transplantation

Lymphangioleiomyomatosis (LAM) is a rare disease which afflicts young women of childbearing age. Recently, it has been listed as an indication for lung transplantation. We describe a case of recurrent LAM in a 31-year-old woman occurring in the allograft of a male donor after single lung transplantation. Nonisotopic in situ hybridization shows that the smooth muscle cell proliferation is of donor origin.     

Prognostic analysis of pulmonary adenocarcinoma subclassification with special consideration of papillary and bronchioloalveolar types

AIMS: The third edition of the World Health Organization (WHO) classification of lung tumours has been published and is expected to become the standard nomenclature. The aim of this study was to assess the usability and prognostic significance of the WHO classification in comparison with other recent classifications. METHODS AND RESULTS: One hundred and forty-seven resected pulmonary adenocarcinoma cases were reviewed and histologically classified according to the WHO classification (1999) and the classification by Noguchi (1995). Papillary carcinomas as described by Silver and Askin (1997) were also identified. Since the papillary type in the WHO classification is not strictly defined, we compared the following two kinds of WHO classification: (i) WHO-N; WHO classification adopting Noguchi Type F as the definition of the papillary type, namely, pure papillary adenocarcinoma without a bronchioloalveolar component; (ii) WHO-SA; WHO classification adopting papillary carcinoma by Silver and Askin as the definition of the papillary type, namely, tumour with papillary structure constituting at least 75% of the lesion. The bronchioloalveolar carcinoma of the WHO classification showed a better prognosis than other subtypes in both overall and Stage I disease limited survival analysis. In analysis limited to Stage III disease, only the papillary type of WHO-SA showed a significantly worse prognosis. CONCLUSIONS: WHO-SA is recommended for prognostic correlation.     

脑死亡供体肺脏病理改变及临床移植应用前景探讨

目的观察脑死亡供体肺病理改变,探讨临床移植应用的可行性。方法对23例脑死亡供体肺进行了病理活检,HE染色、网状纤维染色及PASM染色观察肺脏组织变化,电镜观察超微结构变化。结果气管、支气管及肺泡结构尚完整,仅见局灶肺泡上皮细胞及支气管纤毛上皮细胞脱落,未见肺透明膜形成;肺泡间隔未见明显增宽、血管充血易见,血管内皮细胞未见明显改变,未见纤维化表现。电镜下肺泡Ⅱ型上皮细胞胞质轻微水肿,但结构尚完整;内质网扩张,基底膜未见明显改变。结论严格限定纳入标准,脑死亡供肺可以实施移植。     

Malignant lymphoma of donor origin after renal transplantation: A case report

A case of non-Hodgkin's lymphoma of polymorphous centroblastic type presenting in a renal allograft is reported. The kidney graft was explanted 10 months after transplantation because of chronic rejection. No other manifestations of lymphoma were found in the recipient. Since the human leukocyte antigen patterns of the renal allograft and the recipient differed at two loci, the donor origin of the malignancy could be clearly demonstrated by immunohistochemistry.     

Loss of alveolar basement membrane type IV collagen alpha3, alpha4, and alpha5 chains in bronchioloalveolar carcinoma of the lung

Type IV collagen, the major component of basement membrane (BM), is composed of six genetically distinct alpha(IV) chains. This study investigated for the first time the expression of these six alpha(IV) chains immunohistochemically, using alpha(IV) chain-specific monoclonal antibodies, in normal lung and in small (less than 2 cm in diameter) adenocarcinoma of the lung with a bronchioloalveolar growth pattern at the periphery. Small adenocarcinomas were histopathologically classified into three subtypes: bronchioloalveolar carcinoma (BAC) without collapse, BAC with collapse, and adenocarcinoma with bronchioloalveolar features. In normal lung, alveolar BM was composed of alpha1(IV)/alpha2(IV) chains and alpha3(IV)/alpha4(IV)/alpha5(IV) chains. In non-collapsed areas of BAC, alveolar BM was composed of linear alpha1(IV)/alpha2(IV) chains and discontinuous alpha3(IV)/alpha4(IV)/alpha5(IV) chains. In collapsed areas of BAC, alveolar BM was composed of linear and thick alpha1(IV)/alpha2(IV) chains only, because of the complete loss of alpha3(IV)/alpha4(IV)/alpha5(IV) chains. In invasive areas of adenocarcinoma with bronchioloalveolar features, alpha1(IV)/alpha2(IV) chains around the cancer cell nests were disrupted, in addition to the complete loss of alpha3(IV)/alpha4(IV)/alpha5(IV) chains. In conclusion, during the process of stromal invasion of lung adenocarcinoma, type IV collagen of alveolar BM is remodelled from the complete type, composed of alpha1(IV)/alpha2(IV)/alpha3(IV)/alpha4(IV)/alpha5(IV) chains, to the incomplete type, composed of only alpha1(IV)/alpha2(IV) chains, before the disruption of alpha1(IV)/alpha2(IV) chains. These findings may help to clarify the molecular mechanisms of cancer invasion.     

肺移植后闭塞性细支气管炎综合征的危险因素与发病机制

闭塞性细支气管炎综合征（bronchiolitis obliterans syndrome, BOS）是影响肺移植术后长期存活的最主?⒎⒅ⅲ壹忧棵庖咭种坪涂寡字瘟菩Ч患选７我浦埠蟮贾卤杖韵钢苎鬃酆险鞯幕粕婕懊庖吆头敲庖咭蛩仄舳郎掀ぁ⑾赴饣省⑿律芗傲馨凸芟低车慕行运鹕擞胍斐Ｔ錾厮埽纬啥裥匝贰Ｆ渲心谠葱悦庖呤堑贾孪钢鼙杖头⒄刮狟OS的主要致病因素,但各种感染或化学损伤可能导致激活树突状细胞的危险信号释放,从而激发排斥反应。因此,降低非依赖同种异体免疫因素的风险与治疗免疫排斥同样重要。     

Mucinous bronchioloalveolar carcinoma with K-rasmutation arising in type 1 congenital cystic adenomatoid malformation: a case report with review of the literature

Congenital cystic adenomatoid malformation (CCAM) of the lung is a rare hamartomatous cystic lesion, characterized by the presence of large cysts, which are histopathologically lined by pseudostratified ciliated cells. It has been recognized that rare cases of type 1 CCAM show malignant transformation, usually bronchioloalveolar carcinoma (BAC) or adenocarcinoma. Herein, we describe a case of BAC arising in type 1 CCAM with K-ras mutation. A 9-year-old Japanese girl presented with fever. Computed tomography demonstrated large cystic lesions in her right lower lung. Histopathological study of the resected specimen revealed multiple cysts, which were lined by pseudostratified ciliated cells, and occasionally interspersed with mucous cells without atypia. A small focus of proliferation of columnar cells showing lepidic growth pattern was present. These columnar cells had abundant mucin in the cytoplasm and mildly to moderately enlarged nuclei. Accordingly, a diagnosis of BAC arising in type 1 CCAM was made. Polymerase chain reaction analysis revealed K-ras mutation at codon 12 in the BAC component. The presence of mucous cell/goblet cell hyperplasia and atypical adenomatous hyperplasia is a well known phenomenon in type 1 CCAM. A recent study clearly demonstrated K-ras mutation in these lesions, which are thought to be precursors of BAC. Therefore, the concept of malignant transformation in the sequence from type 1 CCAM to mucous cell hyperplasia to atypical adenomatous hyperplasia to BAC and invasive adenocarcinoma due to K-ras mutation has been proposed. Careful histopathological analysis is important for evaluation of malignant lesions in type 1 CCAM.     

Significance of tumor necrosis factor microsatellite polymorphism in renal transplantation

Plasma levels of tumor necrosis factor (TNF) α are raised during acute rejection following organ transplantation. Variations in TNF á production have been found to be associated with the polymorphism of TNF microsatellite. Therefore, there is a possibility that a transplant recipient with some type of TNF microsatellite can be a high-risk patient of graft rejection. The purpose of this study was to examine whether TNF microsatellite polymorphism is related to acute allograft rejection. We investigated the relation of two microsatellites, TNFa and TNFd, to acute rejection after renal transplantation. Among 189 primary living-related renal transplantations from one haplotype-mismatched and one DRBI-mismatched donor, we analyzed TNF microsatellites of 163 patients whose DNA were available to this study. The frequency of the TNFa9 microsatellite allele was significantly higher in the rejection group compared to the rejection-free group. In contrast, the frequency of TNFd4 was significantly lower in the rejection group compared to the rejection-free group. TNFa9 and TNFd4 showed strong associations with HLA-B35 and B44, respectively. However, the TNF microsatellite locus was more closely related to acute rejection than HLA-B. It was suggested that the analysis of TNF microsatellite polymorphism can provide useful information in predicting prognosis after transplantation.     

棉子糖低钾右旋糖酐液供体肺灌注保存的临床病理学研究

目的探讨棉子糖低钾右旋糖酐液(raffinose-low-potassium dextran solution,R-LPD液)供肺灌注低温保存后的组织形态学变化。方法应用光镜、电镜和免疫组化技术对R-LPD液灌注的18例肺移植供肺标本按不同的时间段进行观察。结果R-LPD供肺灌注低温保存的最佳时间是6~8h,随着保存时间延长,供体肺的形态结构改变也逐渐明显,保存30h时,可见肺泡壁及血管周围间质组织水肿,肺泡间隔断裂,部分肺泡上皮细胞变性、坏死、脱落。结论R-LPD液在肺移植冷缺血保存期中起较好的肺泡上皮细胞保护作用,比低钾右旋糖酐液(low-potassium dextran solution,LPD液)具有明显的优越性。     

Incidence of atypical bronchioloalveolar cell hyperplasia of the lung: relation to histological subtypes of lung cancer

Summary The incidence of atypical bronchioloalveolar cell hyperplasia (ABH) of the lung was investigated to evaluate the possiblity of this lesion being a precancerous stage in the histogenesis of adenocarcinoma. Lobectomy and pneumonectomy specimens of 165 primary and 45 metastatic tumour cases were step-sectioned horizontally and examined histologically. An average of 51 blocks were taken in each case. Sixty-seven ABHs up to 10 mm in diameter were detected, only 2 lesions being associated with scar tissue. Age was one factor apparently related to ABH development, although not the major one. There was no correlation between smoking index and ABH occurrence. In males, the incidence was highest in association with adenocarcinoma (25.5% of cases, 0.8% of sections), followed by large cell carcinoma (25.0% of cases), squamous cell carcinoma (10.5% of cases) and metastatic tumours from other sites (4.8% of cases). In females, ABH was also more common together with adenocarcinoma (8.3% of cases) than with metastatic tumours (4.0% of cases). The differences in male incidences by case and by section between the adenocarcinoma and metastatic tumour categories were statistically significant (P<0.05,P<0.01 respectively) indicating that ABH may be a precancerous lesion capable of transformation of adenocarcinoma.     

MHC microsatellite diversity and linkage disequilibrium among common HLA-A, HLA-B, DRB1 haplotypes: implications for unrelated donor hematopoietic transplantation and disease association studies

Twenty-two human major histocompatibility complex (MHC) region microsatellite (Msat) markers were studied for diversity and linkage disequilibrium (LD) with HLA loci in hematopoietic cell transplant recipients and their HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 allele-matched unrelated donors. These Msats showed highly significant LD over much of the MHC region. The Msat diversity of five common Caucasian haplotypes (HLA-A1-B8-DR3, A3-B7-DR15, A2-B44-DR4, A29-B44-DR7, and A2-B7-DR15) was examined using a new measure called 'haplotype specific heterozygosity' (HSH). Each of the five haplotypes had at least one Msat marker with an HSH value of zero indicating that only one Msat allele was observed for the particular HLA haplotype. In addition, the ability of Msats to predict HLA-A-B-DRB1 haplotypes was studied. Over 90% prediction probability of two common haplotypes (HLA-A1-B8-DR3 and HLA-A3-B7-DR15) was achieved with information from three Msats (D6S265/D6S2787/D6S2894 and D6S510/D6S2810/D6S2876, respectively). We demonstrate how the HSH index can be used in the selection of informative Msats for transplantation and disease association studies. Markers with low HSH values can be used to predict specific HLA haplotypes or multilocus genotypes to supplement the screening of HLA-matched donors for transplantation. Markers with high HSH values will be most informative in studies investigating MHC region disease-susceptibility genes where HLA haplotypic effects are known to exist.