Junya Fukuoka

Napsin A, a new marker for lung adenocarcinoma, is complementary and more sensitive and specific than thyroid transcription factor 1 in the differential diagnosis of primary pulmonary carcinoma: evaluation of 1674 cases by tissue microarray.

CONTEXTnDifferentiation of non-small cell carcinoma into histologic types is important because of new, successful therapies that target lung adenocarcinoma (ACA). TTF-1 is a favored marker for lung ACA but has limited sensitivity and specificity. Napsin A (Nap-A) is a functional aspartic proteinase that may be an alternative marker for primary lung ACA.nnnOBJECTIVESnTo compare Nap-A versus TTF-1 in the typing of primary lung carcinoma and the differentiation of primary lung ACA from carcinomas of other sites.nnnDESIGNnImmunohistochemistry for Nap-A and TTF-1 was performed on tissue microarrays of 1674 cases of carcinoma: 303 primary lung ACAs (18.1%), 200 primary squamous cell lung carcinomas (11.9%), 52 primary small cell carcinomas of the lung (3.1%), and carcinomas of the kidney (n u200a=u200a 320; 19.1%), thyroid (n u200a=u200a 96; 5.7%), biliary (n u200a=u200a 89; 5.3%), bladder (n u200a=u200a 47; 2.8%), breast (n u200a=u200a 93; 5.6%), colon (n u200a=u200a 95; 5.7%), liver (n u200a=u200a 96; 5.7%), ovaries (n u200a=u200a 45; 2.7%), pancreas (n u200a=u200a 48; 2.9%), prostate (n u200a=u200a 49; 2.9%), stomach (n u200a=u200a 93; 5.6%), and uterus (n u200a=u200a 48; 2.9%). Cases were evaluated against a negative control as negative, weak positive, and strong positive.nnnRESULTSnNap-A was more sensitive than TTF-1 for primary lung ACA (87% versus 64%; P < .001). Nap-A was more specific than TTF-1 for primary lung ACA versus all tumors, excluding kidney, independent of tumor type (P < .001).nnnCONCLUSIONSnNap-A is superior to TTF-1 in distinguishing primary lung ACA from other carcinomas (except kidney), particularly primary lung small cell carcinoma, and primary thyroid carcinoma. A combination of Nap-A and TTF-1 is useful in the distinction of primary lung ACA (Nap-A(+), TTF-1(+)) from primary lung squamous cell carcinoma (Nap-A(-), TTF-1(-)) and primary lung small cell carcinoma (Nap-A(-), TTF-1(+)).

Overexpression of Phospho-eIF4E Is Associated with Survival through AKT Pathway in Non–Small Cell Lung Cancer

Purpose: The eukaryotic translation initiation factor complex 4E (eIF4E) is downstream in the mammalian target of rapamycin (mTOR) pathway. This study explored expression of eIF4E and its relationship with the PTEN/AKT and RAS/MEK/ERK pathways in non–small cell lung carcinoma (NSCLC). Experimental Design: The status of phosphorylated eIF4E (p-eIF4E), phosphorylated AKT (p-AKT), PTEN, phosphorylated tuberin (p-TSC2), phosphorylated mTOR (p-mTOR), phosphorylated S6 (p-S6), and phosphorylated Erk1/2 (p-Erk1/2) was studied using immunohistochemical analysis applied to a tissue microarray containing 300 NSCLCs. Staining results for each antibody were compared with clinical and pathologic features, and the relationship between staining results was explored. Results: Overexpression of p-eIF4E, p-AKT, p-TSC2, p-mTOR, p-S6, and p-Erk1/2 in NSCLC was found in 39.9%, 78.8%, 5.1%, 46.7%, 27.1%, and 16.6% of tumors, respectively. The phenotype of p-eIF4E correlated positively with that of p-AKT, p-TSC2, and p-S6 (P < 0.001). Overall survival in NSCLC patients was significantly shorter in cases with overexpression of p-eIF4E and p-AKT alone and in combination (log-rank P < 0.001, each). Cases with underexpression of PTEN were limited (6.4%), and this phenotype did not correlate with any clinical variable. In cluster analysis, the p-AKT/p-mTOR/p-eIF4E/p-S6–positive group had significantly shorter survival compared with the survival of all cases (P < 0.001). Multivariate analysis showed that p-eIF4E overexpression is an independent prognostic factor for NSCLC (P = 0.004). Conclusions: This study shows that p-eIF4E expression in addition to p-AKT predicts poor prognosis in NSCLC. Moreover, the correlation between expression of p-eIF4E with p-AKT, as well as p-TSC2 and p-S6, indicates that eIF4E activation through the AKT pathway plays an important role in the progression of NSCLC. Clin Cancer Res; 16(1); OF1–9

Peribronchiolar metaplasia: A common histologic lesion in diffuse lung disease and a rare cause of interstitial lung disease: Clinicopathologic features of 15 cases

Peribronchiolar metaplasia (PBM) is a histologic lesion consisting of peribronchiolar metaplasia (PBM) of bronchiolar-type epithelium. Although widely recognized, PBM has received little attention in the pathologic literature and is not known to have clinical significance. We identified 15 cases in which PBM was the only major histologic finding in surgical lung biopsies from patients with interstitial lung disease (PBM-ILD), and we reviewed the clinical, imaging, and pathologic findings. The mean age was 57 years (range, 44-74 years) with 13 females and 2 males. One patient had been a welder with fume and asbestos exposure; another had pigeon exposure. Smoking history was available for 13 patients: three current smokers, one cocaine user, two former smokers, and seven never smokers. Three patients had collagen vascular disease. One had elevated serum antinuclear antibody titers. Pulmonary function data were available for 10 patients: one obstructive, five restrictive, two mixed obstructive and restrictive, and two normal. Computerized tomography in 7 patients showed mosaic attenuation in 3 patients and air trapping in 1 patient; no bronchiectasis, septal lines, or honeycombing were seen in any cases. All 11 patients with available follow-up are alive; 4 of them have experienced symptomatic improvement (follow-up, 0.6-6.9 years; mean, 2.4 years). PBM was found focally in other interstitial lung diseases, which were assessed for this lesion: 59% of usual interstitial pneumonia (17 of 29), 50% of nonspecific interstitial pneumonia (10 of 20), desquamative interstitial pneumonia (3 of 6), hypersensitivity pneumonitis (9 of 18), and 11% of respiratory bronchiolitis (2 of 18). In summary, PBM is a common histologic finding in various interstitial lung disorders. It is rarely the sole major lung biopsy finding in patients presenting with interstitial lung disease (PBM-ILD). Patients are mostly older women, with mild symptoms and CT findings. Survival appears to be favorable.

Evaluation of Napsin A, Cytokeratin 5/6, p63, and Thyroid Transcription Factor 1 in Adenocarcinoma Versus Squamous Cell Carcinoma of the Lung

CONTEXTnThe distinction of lung adenocarcinoma from other types of primary lung malignancies is important clinically. Accurate morphologic classification is often hindered because 70% of lung cancers are diagnosed on limited fine-needle aspiration or transbronchial biopsy specimens. Although thyroid transcription factor 1 (TTF-1) has historically been the most specific marker for lung adenocarcinoma, a relatively new marker, napsin A, has recently been shown to be more sensitive and specific than TTF-1.nnnOBJECTIVEnTo find the most cost-effective panel to reliably distinguish lung adenocarcinoma from squamous cell carcinoma.nnnDESIGNnA total of 291 lung cancers were evaluated morphologically (197 adenocarcinomas [75%]; 66 squamous cell carcinomas [25%]; 28 cases could not be classified into either and were dropped). Immunohistochemistry for napsin A, Cytokeratin 5/6, p63, and TTF-1 was performed on a formalin-fixed tissue microarray obtained from Toyama, Japan. Cases were scored as positive or negative against a negative control.nnnRESULTSnNapsin A had 83% sensitivity and 98% specificity and TTF-1 had 60% sensitivity and 98% specificity for adenocarcinoma. Cytokeratin 5/6 had 53% sensitivity and 96% specificity and p63 had 95% sensitivity and 86% specificity for squamous cell carcinoma. A panel of napsin A and p63 has a specificity of 94% and a sensitivity of 96% for distinguishing adenocarcinoma from squamous cell carcinoma.nnnCONCLUSIONSnThe source of the antibody is important in avoiding false-negative results. The most cost-effective tissue-preserving panel for small biopsy specimens in the differential diagnosis of lung adenocarcinoma versus squamous cell carcinoma is a combination of p63 and napsin A.

Prognostic significance of NANOG and KLF4 for breast cancer

BackgroundSome of the induced pluripotent stem cell (iPS cell)-inducing factors have been reported to be expressed in breast cancer. The aim of the present study was to examine the relationship between the expression of iPS cell-inducing factors and the prognosis of breast cancer patients.MethodsIn 100 breast cancer patients, the expression of c-MYC, KLF4, NANOG, OCT4, and SOX2 was determined by immunohistochemistry using a tissue microarray analysis.ResultsPatients with strong expression of NANOG had significantly lower disease-free survival (DFS) and overall survival rates than those with weak expression of NANOG (Pxa0=xa00.004 and 0.033, respectively). In contrast, patients with strong expression of KLF4 had better DFS (Pxa0=xa00.014).ConclusionsStrong expression of NANOG is an indicator of a poor prognosis for breast cancer patients, whereas KLF4 is a favorable prognostic indicator. Our results suggest that NANOG stimulates the growth and metastasis of breast cancer cells, whereas KLF4 inhibits these processes.

Causes of pulmonary granulomas: a retrospective study of 500 cases from seven countries

Background The frequencies of various causes of pulmonary granulomas in pathological material are unknown, as is the influence of geographical location on aetiology. The aim of this study was to identify the causes of pulmonary granulomas in pathological specimens, to define their frequencies, and to determine whether these causes vary by geographical location. Methods 500 lung biopsies and resections containing granulomas were reviewed retrospectively by expert pulmonary pathologists from 10 institutions in seven countries. Fifty consecutive cases from each location were assigned a diagnosis based on histological features and available clinical/microbiological data. Results A specific cause was identified in 58% of cases (290/500), most commonly sarcoidosis (136, 27%) and mycobacterial or fungal infections (125, 25%). Mycobacteria were identified in 19% of cases outside the USA versus 8% within the USA. In contrast, fungi accounted for 19% cases in the USA versus 4% in other locations. Fungi were mostly detected by histology, whereas most mycobacteria were identified in cultures. In 42% of cases (210/500) an aetiology could not be determined. Conclusions Across several geographical settings, sarcoidosis and infections are the most common causes of pulmonary granulomas diagnosed in pathological specimens. Fungi are more commonly identified than mycobacteria in the USA, whereas the reverse is true in other countries. A definite aetiology cannot be demonstrated in more than a third of all cases of pulmonary granulomas, even after histological examination. These findings highlight the need to submit material for histology as well as cultures in all cases in which granulomatous disease enters the differential diagnosis.

Advanced malignant solitary fibrous tumor in pelvis responding to radiation therapy

Solitary fibrous tumor (SFT) is a rare spindle cell neoplasm that is benign in most cases. Although SFT was first recognized to arise only in the pleura, recent reports indicate that SFT can involve a wide range of anatomical sites. To date, 17 cases of pelvic SFT have been reported. Herein is reported a case of a 74‐year‐old woman with a giant malignant SFT in the pelvis. Along with massive invasion to adjacent organs and multiple lung metastases detected on radiography, biopsy from the tumor through the vaginal wall showed malignant looking spindle‐cell neoplasm with increased cellularity, areas of necrosis, and high mitotic activity (5/10u2003high‐power fields). Immunohistochemically, the tumor cells were diffusely and strongly positive for CD34, CD99, and bcl‐2. Based on pathological features and clinical presentation, diagnosis of malignant SFT was made. The patient received systemic and the intra‐arterial chemotherapy followed by whole pelvic radiation therapy (50u2003Gy). Initial chemotherapies failed to control the tumor. Afterwards, improvement was observed radiologically and pathologically in the 12u2003months follow up after the radiation therapy. This is the first report related to therapeutic remarks on advanced malignant SFT.

Tissue-preserving antibody cocktails to differentiate primary squamous cell carcinoma, adenocarcinoma, and small cell carcinoma of lung.

CONTEXTnWith the availability of cell type-specific therapies, differentiating primary lung squamous cell carcinomas (SCCs) and adenocarcinomas (ACAs) has become important. The limitations of small sample size and the need to conserve tissue for additional molecular studies necessitate the use of sensitive and specific marker panels on a single slide.nnnOBJECTIVEnTo distinguish SCC from ACA and small cell carcinoma (SmCC) of lung using 2 novel tissue-conserving cocktails.nnnDESIGNnWe compared two antibody cocktails, desmoglein 3 + cytokeratin 5/napsin A and p40/thyroid transcription factor 1 (Biocare Medical, Concord, California) in diagnosing SCC and ACA of the lung on tissue microarray, cytology, and surgical specimens. Both lung and nonlung tissue were evaluated on an 1150-core tissue microarray that contained 200 lung cancers. A microarray of 35 SmCCs and 5 small cell SCCs was also evaluated.nnnRESULTSnA cocktail of desmoglein 3 + cytokeratin 5/napsin A provided diagnostic accuracy in lung cancers with a sensitivity and specificity of 100% in SCCs and a sensitivity of 86% and a specificity of 100% in ACAs. A p40/thyroid transcription factor 1 cocktail showed p40 to have a specificity of 92% and a sensitivity of 93% in SCCs, whereas thyroid transcription factor 1 had a specificity of 100% and a sensitivity of 77% in ACAs. Cell blocks of fine-needle aspiration cytology compared with corresponding surgical (n = 20) specimens displayed similar findings. The p40 was useful in differentiating bladder from prostate carcinoma with 88% sensitivity. Isolated carcinomas from nonlung tissues were desmoglein 3 + cytokeratin 5 positive. Napsin A was positive in 22% of renal tumors as previously observed. Both cocktails were excellent in differentiating SmCCs and small cell SCCs because none of the SmCCs stained with p40.nnnCONCLUSIONSnBoth antibody cocktails are excellent in differentiating primary lung ACA from SCC, as well as excluding SmCC and ACAs from all other sites on small specimens. A cocktail of desmoglein 3 + cytokeratin 5/napsin A is slightly superior compared with p40/thyroid transcription factor 1 cocktail.

SNIP1 Is a Candidate Modifier of the Transcriptional Activity of c-Myc on E Box-Dependent Target Genes

Using a yeast two-hybrid screen, we found that SNIP1 (Smad nuclear-interacting protein 1) associates with c-Myc, a key regulator of cell proliferation and transformation. We demonstrate that SNIP1 functions as an important regulator of c-Myc activity, binding the N terminus of c-Myc through its own C terminus, and that SNIP1 enhances the transcriptional activity of c-Myc both by stabilizing it against proteosomal degradation and by bridging the c-Myc/p300 complex. These effects of SNIP1 on c-Myc likely contribute to synergistic effects of SNIP1, c-Myc, and H-Ras in inducing formation of foci in an in vitro transformation assay and also in supporting anchorage-independent growth. The significant association of SNIP1 and c-Myc staining in a non-small cell lung cancer tissue array is further evidence that their activities might be linked and suggests that SNIP1 might be an important modulator of c-Myc activity in carcinogenesis.

Respiratory involvement in IgG4-related Mikulicz’s disease

Abstract‘Immunoglobulin G4 (IgG4)-related disease’ is a new clinical concept of multi-organ diseases, with Mikulicz’s disease (MD) being a clinical phenotype of IgG4-related disease. To clarify the clinical characteristics of respiratory involvement associated with IgG4-related MD, we retrospectively assessed 25 patients with MD, 11 (44%) of whom had allergic symptoms, and 7 (28%) of whom complained of respiratory problems. Thirteen patients (52%) presented with pulmonary and/or mediastinal lesions (P-MD) on chest computed tomography (CT), and 11 (44%) had lesions limited to the lacrimal and/or salivary glands (L-MD). Mean serum total protein, IgG, and IgG4 concentrations were significantly higher and CH50 was significantly lower in the P-MD than in the L-MD group. Immune complex was present only in the P-MD group. Chest CT images showed bronchial wall thickening, consolidation, nodule(s), interlobular thickening, ground glass opacity, pleural thickening/effusion, and mediastinal lymphadenopathy. Five of seven patients who underwent histological examination of the lungs had abundant IgG4-positive plasma cell infiltrates (IgG4/IgG-positive plasma cells >40%), but the other two did not. These findings suggest that respiratory lesions are not rare in patients with IgG4-related MD, and that they present with various manifestations. IgG4-related MD should be differentiated from similar diseases, such as sarcoidosis, bronchial asthma, Sjögren’s syndrome, and malignant lymphoma.