Search

To assess the vascular component of small lung cancers.We identified 105 resected non-small-cell lung carcinomas without pathologic evidence of vascular, lymphatic, bronchial, or pleural invasion. The percentage of BAC (% BAC) of all adenocarcinomas was determined by a pulmonary pathologist. A representative histology slide of each carcinoma was digitally scanned and the number of blood vessels (#V) with at least a diameter of 200microm was identified as well as the area of these blood vessels (VA) and of the tumor (TA) was obtained. The CT consistency of the cancers was also recorded as non-solid (NS), part-solid (PS) and solid.The number of blood vessels per cm(2) of tumor area (#V/TA) was higher for adenocarcinoma (7.3+/-4.7) as compared with large- and squamous-cell carcinoma (3.6+/-2.1, 2.3+/-1.1, respectively, P0.0001). For adenocarcinoma, #V/TA decreased with decreasing % BAC from 10.3 vessels per cm(2) of tumor area for 100% BAC to 5.1 vessels per cm(2) of tumor area for 0% BAC. The ratio of the total vascular area to tumor area (VA/TA), however, did not differ significantly by cell type nor for the adenocarcinoma by % BAC (P=0.87). While #V/TA decreased from 9.6 for non-solid nodules, to 7.5 for part-solid nodules and to 5.1 for solid nodules, there was no significant difference (P=0.27) in the VA/TA ratio by nodule consistency. Overall, VA comprised 2.7% of the total tumor area (TA) for 105 cancers.These results suggest that tumor vessels experience a continuous temporal and spatial remodeling as tumors grow and that bigger tumors tend to have fewer but larger blood vessels. It also suggests that, on average, squamous- or large-cell carcinomas have a larger average vessel diameter as compared with adenocarcinomas and that the vasculature of an adenocarcinoma might remodel as the % BAC decreases. The overall proportion of tumor volume comprised of vessels 200microm or larger is small and unlikely to influence overall tumor volume and doubling time estimates.

Objective: Pulmonary hamartomas have a characteristic heterogeneous radiological appearance. However, when composed predominantly of undifferentiated mesenchymal fibromyxoid component, their homogeneous appearance on computed tomography is indeterminate for malignancy. Rendering an accurate preoperative diagnosis in these cases can alter management. The aim of this study was to determine the incidence and accuracy of cytodiagnosis for hamartomas ‘indeterminate’ by imaging. Methods: We retrospectively reviewed records for hamartomas diagnosed by transthoracic fine needle aspiration (FNA) including immediate impressions and final diagnoses. Cytological features evaluated included the presence of fibromyxoid stroma, bronchioloalveolar cell hyperplasia, fibroadipose tissue, cartilage and smooth muscle. Results: Eighteen (1.3%) hamartomas were identified from 1355 transthoracic FNAs. The immediate impression was hamartoma in 13 (72%), carcinoid in one (6%), mucinous bronchioloalveolar carcinoma in two (11%) and non-diagnostic in two (11%). The final diagnosis of hamartoma in cases diagnosed as carcinoid, mucinous bronchioloalaveolar carcinoma and non-diagnostic on immediate impression was rendered following assessment of all cytological material. Conclusion: Overall, FNAs are highly reliable for diagnosing hamartomas even when composed principally of undifferentiated mesenchymal fibromyxoid stroma, especially with the aid of all available preparations including Diff-Quik smears, Papanicolaou smears, ThinPreps and cell block material.

OBJECTIVE To study diagnostic efficacy of direct smears (DS) vs. cell block (CB) alone in hemorrhagic thyroid fine needle aspirations (FNAs) performed without a cytotechnologist or cytopathologist. STUDY DESIGN Ultrasound-guided thyroid FNAs from an offsite location were retrospectively searched during a 53-month period. Aspirates in the initial 13 months were submitted as air-dried DSs. Subsequent specimens were submitted as CBs. Each case was classified into 1 of 4 categories: (1) nondiagnostic, (2) nonneoplastic, (3) follicular lesions and (4) papillary thyroid carcinoma (PTC). RESULTS There were 77 aspirates: DS = 20 (26%) and CB = 57 (74%). Two cases had both DSs and CBs. Diagnoses of DS: nondiagnostic = 12 (60%); nonneoplastic = 7 (35%); follicular lesion = 1 (5%). Diagnoses of CB cases: nondiagnostic = 4 (7.0%); nonneoplastic = 43 (75.4%); follicular lesion, including 1 Hurthle cell neoplasm = 7 (12.3%), PTC = 3 (5.3%). Repeat FNAs on 4 nondiagnostic cases (3 DSs, 1 CB) utilizing the CB-only technique were diagnostic and included nodular goiter, follicular neoplasm, PTC, and reactive lymph node. CONCLUSION Without onsite assessment, CB alone is superior to DSs for hemorrhagic thyroid FNAs. It shows increased diagnostic efficacy and slide reduction and obviates repeat FNAs.

BACKGROUND. Baseline screening for lung cancer of 2968 high-risk men and women utilizing HRCT enrolled in ELCAP (Early Lung Cancer Action Project) was performed between 1993-2002. Among them, 65 people had surgical resection of their screen-diagnosed lung cancer, 53 of them on the basis of a diagnosis of malignancy or atypical bronchioloalveolar proliferation (ABP) on fine needle aspiration (FNA) biopsy at Weill Medical College of Cornell University (WMC) prior to surgery. The authors compared the diagnosis obtained from the FNA with the subsequent diagnosis from the surgical specimen to assess the reliability of a cytologic diagnosis of lung cancer on FNA of these screen-diagnosed lung cancers. METHODS. The FNA biopsies were performed with a 22-gauge Wescott needle by 1 radiologist (D.Y.), with preliminary on-site as well as final diagnosis rendered by a cytologist (M.V., J.K.). These results were correlated with histologic diagnoses obtained as a result of consensus diagnosis by a panel of 5 expert pulmonary pathologists. RESULTS. Of the 53 cases of lung cancer resected following FNA, 4 were diagnosed as atypical bronchioloalveolar proliferation (ABP), 14 as adenocarcinoma with bronchioloalveolar features (ADC-BAC), 28 as adenocarcinoma, not otherwise specified (ADC-NOS), 1 as squamous cell carcinoma (SQCC), 4 as nonsmall-cell carcinoma (NSCC), and 2 as typical carcinoid. In the 49 cases with a malignant cytology and 4 cases of ABP, lung cancer was confirmed histologically. The tumor sizes ranged from 4 mm to 40 mm, mean size 13mm. The final expert panel histologic diagnosis was adenocarcinoma in 47 cases; of these, 42 were invasive (mixed subtype or acinar subtype), and 5 were a noninvasive (bronchioloalveolar carcinoma, BAC). Three of the 42 invasive adenocarcinoma that had a predominant BAC component and 1 case of BAC were diagnosed as ABP on FNA; all were sampled at the periphery of the tumor. Three of 4 cases of invasive adenocarcinoma of high nuclear grade were diagnosed as NSCC, and 1 was inaccurately classified as SQCC on FNA. One case of high-grade noninvasive BAC associated with a scar was diagnosed as NSCC on FNA. Two cases classified as nonkeratinizing SQCC and 2 cases of large cell neuroendocrine carcinoma on histology were misclassified as ADC-NOS by FNA. Two cases of typical carcinoid on histology were also diagnosed as typical carcinoid on FNA. CONCLUSIONS. Preoperative diagnosis of lung cancer detected by screening with HRCT could be reliably made by FNA. Difficulty in classification occurs in carcinomas of high nuclear grade with prominent nucleoli, including poorly differentiated SQCC and large cell neuroendocrine carcinoma. These are best diagnosed as NSCC on cytomorphology with further subclassification based on immunohistochemistry, which these authors generally perform on cell-block material. A diagnosis of ABP on FNA may be indicative of noninvasive BAC or an invasive adenocarcinoma with prominent BAC features, usually sampled at its periphery. Cancer (Cancer Cytopathol) 2007. © 2007 American Cancer Society.

Objective Recent studies have validated the use of cytologic materials to determine HER-2/neu status. Good concordance has been shown between results obtained by immunocytochemistry (ICC), immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) on cytologic and surgical specimens. However, the utility of cytologic cell block material in determining HER-2/neu status has not been reported and is the subject of this study. Study Design HER-2/neu status was determined in 25 cases of primary or metastatic breast carcinoma by IHC and FISH. All cases were formalin-fixed, paraffin-embedded (FPPE) cell block preparations. ICC was performed using monoclonal antibodies TAB250 (Zymed) and CB11 (Novacastra Laboratories). FISH analysis was performed using the PathVysion HER-2 probe kit (Vysis, Inc.). Results of ICC and FISH were compared in each case. Results Of 25 cases studied, 17 showed no protein overexpression or amplification. Five cases showed protein overexpression and amplification. The remaining 3 cases showed 2+ staining intensity by ICC in 10, 20, and 50% of carcinoma cells, respectively, and all demonstrated lack of amplification. Conclusion Immunocytochemistry performed on FFPE cell block material is a reliable method for determining HER-2/neu status in cytologic specimens. We recommend routine preparation of FFPE cell block material in instances of suspected primary of metastatic breast carcinoma.

Introduction: Advances in the pathology and computed tomography (CT) of lung adenocarcinoma and bronchioloalveolar carcinoma (BAC) have demonstrated important new prognostic features that have led to changes in classification and diagnostic criteria. Methods: The literature and a set of cases were reviewed by a pathology/CT review panel of pathologists and radiologists who met during a November 2004 International Association for the Study of Lung Cancer/American Society of Clinical Oncology consensus workshop in New York. The group addressed the question of whether sufficient data exist to modify the 2004 World Health Organization (WHO) classification of adenocarcinoma and BAC to define a "minimally invasive" adenocarcinoma with BAC. The problems of diffuse and/or multicentric BAC and adenocarcinoma were evaluated. Results: The clinical concept of BAC needs to be reevaluated with careful attention to the new 2004 WHO criteria because of the major clinical implications. Existing data indicate that patients with solitary, small, peripheral BAC have a 100% 5-year survival rate. The favorable prognostic impact of the restrictive criteria for BAC is already being detected in major epidemiologic data sets such as the Surveillance Epidemiology and End-Results registry. Most lung adenocarcinomas, including those with a BAC component, are invasive and consist of a mixture of histologic patterns. Therefore, they are best classified as adenocarcinoma, mixed subtype. This applies not only to adenocarcinomas with a solitary nodule presentation but also to tumors with a diffuse/multinodular pattern. The percentage of BAC versus invasive components in lung adenocarcinomas seems to be prognostically important. However, at the present time, a consensus definition of "minimally invasive" BAC with a favorable prognosis was not recommended by the panel, so the 1999/2004 WHO criteria for BAC remain unchanged. In small biopsy specimens or cytology specimens, recognition of a BAC component is possible. However, it is not possible to exclude an invasive component. The diagnosis of BAC requires thorough histologic sampling of the tumor. Conclusion: Advances in understanding of the pathology and CT features of BAC and adenocarcinoma have led to important changes in diagnostic criteria and classification of BAC and adenocarcinoma. These criteria need to be uniformly applied by pathologists, radiologists, clinicians, and researchers. The 2004 WHO classification of adenocarcinoma is readily applicable to research studies, but attention needs to be placed on the relative proportion of the adenocarcinoma subtypes. Other recently recognized prognostic features such as size of scar, size of invasive component, or pattern of invasion also seem to be important. More work is needed to determine the most important prognostic pathologic features in lung adenocarcinoma.

International audience; Sixty-five people had a resection of their baseline screen-diagnosed lung cancers in the Early Lung Cancer Action Program. Forty-nine of the carcinomas were solitary, and 42 of these were adenocarcinomas. More than 1 carcinoma was found in 16 patients after pathologic examination of the lobectomy specimen; 15 of the 16 second carcinomas were adenocarcinomas, mixed subtype. Eighteen cases were submitted by local pathologists as Bronchioloalveolar carcinomas but were found to be invasive adenocarcinomas according to the World Health Organization classification by the Pathology Review Panel. Of the 65 resected cases, 57 were N0, 7 were N1, and 1 was N2. Upon careful review of the lobectomy specimens, 49 cases had solitary malignancies, 30 were Stage IA, 13 Stage IB, 3 Stage IIA, 2 Stage IIB, and 1 Stage IIIA on the basis of the American Joint Committee on Cancer/International Union for Cancer Control criteria. In the 16 cases found to have multiple malignancies, 6 had histologically different carcinomas and the remaining 10 had histologically identical malignancies. Eighty-three percent (76/92) of the carcinomas invaded the stroma with destruction of normal lung, and 21% (19/92) also showed either pleural or angiolymphatic invasion, even though 88% (57/65) of the carcinomas were free of lymph node metastases. This report describes the pathologic findings of the resected cases. Histopathologic distinctions among atypical adenomatous hyperplasia, bronchioloalveolar carcinomas, and invasive adenocarcinoma are described in detail.

Cervical/endocervical cytology screening has decreased morbidity and mortality, and implementing adjunctive human papilloma virus (HPV) DNA testing for atypical squamous cells of undetermined significance has improved the specificity for detecting premalignant squamous lesions. Currently, there are no guidelines to perform HPV DNA testing on cervical/endocervical ThinPreps with atypical glandular cells (AGC). To assess the potential role of HPV DNA testing on AGC cases, Hybrid Capture 2 (Digene Corp.) testing was performed on 144 cervical/endocervical AGC specimens. One hundred three of 144 cases had follow-up; 60/103 (58.3%) were high-risk HPV negative and 43/103 (42.3%) were high-risk HPV positive. Of 43 HPV-positive patients, 37 had adenocarcinoma in situ (AIS), atypical squamous cells of undetermined significance (ASCUS), or cervical squamous intraepithelial neoplasia, while only one patient without high-risk HPV had a squamous intraepithelial neoplasia. Furthermore, most high-risk HPV positive AGC cases harbored high-grade squamous intraepithelial lesion (HSIL) rather than AIS. Our data support HPV DNA testing of all AGC specimens to detect cervical, especially squamous, neoplasia. neoplasia. Diagn. Cytopathol. 2006; 34:235–239. © 2006 Wiley-Liss, Inc.

Purpose The aim of this study was to assess the significance of Stage I diagnoses of lung cancer in the baseline cycle of screening for this disease, with special reference to the potential for overdiagnosis. Methods We reviewed all 69 cases of Stage I lung cancer diagnosis resulting from our baseline CT screening. Among these 69 cases of lung cancer, 24 presented as solid, 30 as part-solid, and 15 as nonsolid nodules. The extent to which these represented genuine malignancy was assessed by a panel of experts on lung pathology, and the “aggressiveness” of these cases was addressed by the criterion of the tumor's volume doubling time being less than 400 days. Results The expert panel confirmed all 69 cases as representing genuine malignancy. Among the 69 cases without evidence of metastases, the proportion that satisfied the aggressiveness criterion was 60/69=87%. The corresponding proportions by presentation as solid, part-solid, and nonsolid nodule were 23/24 (96%), 27/30 (90%), and 10/15 (67%), respectively. Conclusions In baseline CT screening for lung cancer, overdiagnosis of the disease is uncommon, with cases presenting as a nonsolid nodule a possible exception to this.

Increased use of chest computed tomography (CT) as well as improvements in CT resolution has led to increased detection of subcentimeter pulmonary nodules. Although the majority of these nodules are benign in etiology, a subset will harbor bronchioloalveolar carcinoma. The diagnosis of malignancy in this setting can be challenging to radiologists, surgeons, and occasionally pathologists as well. The challenge is compounded by a lack of knowledge about the natural course of these lesions--specifically, whether they represent life-threatening aggressive malignancies or indolent lesions of little or no consequence. Given the relative infrequency of these abnormalities, it will be essential to establish a sufficiently large database, to organize multi-institutional registries, and to collaborate on correlative studies. Only in this way will we be able to determine the clinical and molecular characteristics of these lesions and thus hopefully gain insight into their clinical relevance.

Mammary carcinoma with osteoclast-like giant cells (OGCs) is an extremely rare tumor. To the best of our knowledge, only 45 cases have been reported in the literature. Here we report four additional cases of this tumor. The fine-needle aspiration cytology was performed in all four cases, showing an abundance of giant cells and mononucleated stromal cells in intimate association with low- or medium-grade malignant epithelial clusters. Histologically, cribriform patterns predominated in three cases. In one case, OGCs were more pronounced in the vicinity of ductal carcinoma in situ accompanied by marked stromal angiogenesis. This study, as well as review of the literature, underlines the characteristic features of this rare histologic type of carcinoma.

Lung cancer is a leading cause of cancer death. Currently there are no major health organizations endorsing lung cancer screening. This is primarily based on the results of four randomized, controlled trials conducted in the 1970s comparing screening using sputum cytology (some with chest radiography as well) with no screening for lung cancer. The Early Lung Cancer Action Project (ELCAP), initiated in 1992, demonstrated the enormous potential of low radiation dose (low-dose) helical CT to detect lung cancer at an early stage, and its superiority over conventional chest radiography. As compared to the initial baseline screening evaluation, ELCAP has shown that on repeat annual screening, there is a substantially lower number of false-positive studies and a higher percentage of malignancy among the newly detected lung nodules. Adherence to the diagnostic algorithm, which included the use of high-resolution computed tomography (HRCT) in the follow-up of lung nodules, enabled confirmation of lung cancer within short time intervals while minimizing unnecessary interventional procedures. The use of computer-generated three-dimensional image reconstruction can be helpful in the detection of nodular growth after a follow-up interval as short as 1 month. The role of low-dose CT in screening for lung cancer is currently under investigation but seems promising. Additional techniques, such as the use of biomarkers, may also aid in early detection of lung cancer. The precise role of these techniques relative to low-dose CT screening continues to evolve.

Background The Early Lung Cancer Action Project (ELCAP) was designed to evaluate the usefulness of annual computed tomography (CT) screening for lung carcinoma. With the baseline results having been reported previously, the focus of the current study was on the early results of the repeat screenings. Methods A cohort of 1000 high-risk individuals was recruited for baseline and annual repeat CT screening. At last follow-up, a total of 1184 annual repeat screenings had been performed. A positive result from the screening test was defined as newly detected, one to six noncalcified pulmonary nodules with interim growth. The diagnostic workup of the individuals was guided by recommendations supplied by the ELCAP investigators to the collaborating clinicians. Results Of the 1184 repeat CT screenings, the test result was positive in 30 (2.5%). In 2 of these 30 cases, the individual died (of an unrelated cause) before diagnostic workup and the nodule(s) resolved in another 12 individuals. In the remaining 16 individuals, the absence of further growth was documented by repeat CT in 8 individuals and further growth was documented in the remaining 8 individuals. All eight individuals with further nodular growth underwent biopsy and malignancy was diagnosed in seven. Six of these seven malignancies were nonsmall cell carcinomas (five of which were Stage IA and one of which was Stage IIIA) and the one small cell carcinoma was found to be of limited stage. The median size dimension of these malignancies was 8 mm. In another two subjects, symptoms prompted the interim diagnosis of lung carcinoma. Neither of these malignancies was nodule-associated but rather were endobronchial; one was a Stage IIB nonsmall cell carcinoma and the other was a small cell carcinoma of limited stage. Conclusions False-positive screening test results are uncommon and usually manageable without biopsy; compared with no screening, such screenings permit diagnosis at substantially earlier and thus more curable stages. Annual repetition of CT screening is sufficient to minimize symptom-prompted interim diagnoses of nodule-associated malignancies.

Evaluation of screening for lung cancer depends on accurate pathologic diagnosis of the disease. The majority of CT-detected malignancies are peripheral adenocarcinomas; therefore, patient specimens include putative precursor lesions such as atypical adenomatous hyperplasia, solitary noninvasive, nonmucinous bronchioloalveolar adenocarcinomas (BAC), and small invasive adenocarcinomas. Although not all cytologists and surgical pathologists are familiar with the current 1999 World Health Organization (WHO)/International Association for the Study of Lung Cancer (IASLC) classification of lung tumors, the diagnosis of lung cancer is made with a high degree of accuracy. Difficulties in diagnosis most often are related to tumor sampling, the size of the sample, and artifacts. A potential problem of CT screening for lung cancer is the detection, or overdiagnosis, of carcinomas that do not interfere with the life or outcome of the patient. The concept of overdiagnosis should not be confused with a false-positive diagnosis of lung cancer by pathologists as these are exceedingly rare. When they occur, false-positive diagnoses most frequently are in the setting of atypical hyperplasia associated with granulomatous inflammation, fibrous scars, and in reactive atypia after radiation and chemotherapy (Fig. 1) . 4 The WHO/IASLC recently has completed a new proposal for the histologic classification of lung tumors. 34 Two major changes are the addition of atypical adenomatous hyperplasia as a preinvasive lesion and a new definition of BAC that requires the tumor to have a purely lepidic pattern without invasive growth. These lesions are likely to be encountered in surgical specimens from patients who are found to have growing nodules on CT.

Lung tumors with neuroendocrine (NE) morphology constitute only 20% of lung malignancies, yet no other group of lung neoplasms has generated so much interest and conflicting opinions among pathologists over the past several decades. The classification of these tumors has evolved with our understanding of the human NE system. Diverse morphologic patterns, a never-ending variety of immunohistochemical markers demonstrating NE function, and molecular techniques have led to complex classification schemes and confusion among not only clinicians, tumor registries, and patients, but also among the surgical pathologists responsible for reproducible tumor diagnoses. For many years lung tumors with NE morphology were diagnosed as either bronchial carcinoid tumors or small cell carcinomas (SCLC). Since 1972, these lesions have been classified as low-grade, intermediate-grade, and high-grade carcinomas. 10 The recently published 1999 World Health Organization (WHO) Histological Typing of Lung and Pleural Tumors serves as an impetus to review our current understanding of pulmonary NE cells, present the current classification scheme, and explore some of the peculiarities of lung NE tumors. Neuroendocrine cells, also known as Kulchitsky's cells, were first recognized by Feyrter 14 in 1938 and referred to as epithelial clear cells as part of a "diffuse epithelial endocrine system." The ability of these cells to take up and decarboxylate amine precursors including 3,4-dihydroxyphenylalanine (l-dopa) and 5-hydroxytryptophan (serotonin) led to the term amine precursor uptake and decarboxylase cells , which were thought to be neural crest cells. 46 The currently accepted dispersed NE system theory postulates that NE cells in different sites of the body are linked by a common NE phenotype and that these cells originated from pluripotent cells that differentiated locally under the control of unique site or organ factors. These cells are postulated to be of three derivations: (1) neural crest derivatives, such as adrenal medulla, paraganglia, and melanocytes; (2) neural tube and ridge-derived cells, such as epiphyseal, hypophyseal, and hypothalamic cells; and (3) derivatives of the NE programmed ectoblast including the gastroenteropancreatic system and bronchopulmonary tree. 47 Frohlich 16 first described NE cells of the lung in 1949 and he postulated that the solitary and nodular cellular aggregates in the walls of bronchi had a chemoreceptive or neurosecretory function. The nonciliated basally located cylindrical cells with clear cytoplasm are individually scattered throughout the bronchi and bronchioles and when clustered in groups of 4 to 10 cells with neural attachments are known as neuroepithelial bodies . NE cells are not found along the alveolar septa. Serotonin immunoreactive pulmonary NE cells are first seen at 8 weeks of gestation, increase in density through embryonic and fetal life, and peak in density at term suggesting a role in pulmonary morphogenesis and maturation. 12 Pulmonary NE cell hyperplasia is seen in a variety of physiologic and pathologic states. Increased numbers and small clusters of pulmonary NE cells are seen in persons living at high altitude; in children with bronchopulmonary dysplasia, cystic fibrosis, and bronchiectasis; in cigarette smoke–associated adult pulmonary diseases, including lung cancer; and in patients with carcinoid tumors. 19,21,30 Increased concentrations of bombesin-like peptides in bronchoalveolar lavage fluid of cigarette smokers and nonsmokers with diffuse idiopathic NE cell hyperplasia with obliterating small airways disease have also been reported. 1,2,21 In 1954, Feyrter 15 suggested that bronchial carcinoid tumors arose from NE cells, and in the mid-1960s Bensch et al 5 and Gmelich et al 18 first described the ultrastructural appearance of NE cells and related these cells to bronchial carcinoid tumors and SCLC. Many now consider the NE cell to be the cell of origin for most NE tumors of the lung, 4,20 a concept that impacts not only on histogenesis but also on classification. One group of investigators describes dysplastic NE cells in the lungs of patients with pulmonary neoplasms and chronic bronchitis and bronchiectasis, 21 and larger aggregates of NE at least partially outside the confines of airway basement membrane are termed carcinoid tumorlets (Fig. 1). These possible precursor lesions usually are incidental lesions found in normal lung or in patients with lung cancer, carcinoid tumors, pulmonary fibrosis, and granulomatous nodules. 10 Rare lymph node metastases have been reported, sometimes in the setting of multiple tumorlets. 13 Interestingly, one recent study reported that almost one third of patients, predominantly women, with resected peripheral carcinoid tumors also had diffuse NE cell hyperplasia and obliterative bronchiolitis. 40 These findings support the association between tumorlets and carcinoid tumors and raise the possibility that the NE hyperplasia causes obliterative bronchiolitis, and not vice versa as previously believed. 40 Although tumorlets of macroscopic size and carcinoid tumor merge as a pathologic entity, 9,39 an arbitrary 0.5 cm cutoff is used by the WHO to distinguish between these entities. 66 It must be emphasized that despite early speculation that carcinoid tumorlets might represent early or in situ SCLC, 6,48 there is no established clinical or pathologic association between these lesions. The current WHO classification recognizes four distinct tumors with NE morphology among the nine major histologic types of malignant epithelial neoplasms 66 : Squamous cell carcinoma Small cell carcinoma Adenocarcinomas Large cell carcinoma Large cell neuroendocrine carcinoma Adenosquamous carcinoma Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements Carcinoid tumor Typical carcinoid tumor Atypical carcinoid tumor Carcinomas of salivary gland type Unclassified carcinoma Typical carcinoid tumor (TC) is a low-grade carcinoma; atypical carcinoid tumor (AC) is an intermediate-grade carcinoma; SCLC and large cell NE carcinoma (LCNEC) are considered high-grade carcinomas (Table 1). Although consideration was given to a conceptual grouping of tumors with NE morphology, differences in epidemiologic, clinical, and biologic characteristics argue against such a classification (Tables 2 and 3).

Objective The aim of the study was to determine if the ThinPrep Imaging System (T1S) improves the positive predictive value (PPV) of atypical glandular cell (AGC) diagnosis for identifying HPV-related squamous and/or glandular lesions over manual screening (MS), and if human papilloma virus (HPV)-DNA testing improves the diagnostic yield. Materials and Methods 85 ThinPrep cervical cytology specimens with a diagnosis of AGC by TIS (n = 51) and MS (n = 34) were retrieved. The diagnoses were correlated with corresponding histologic follow-up and high risk (HR)-HPV testing results. Results The PPV of AGC by TIS and MS for HPV-related squamous lesions were similar. In the MS group, more cases of glandular pathology were identified, however only three represented adenocarcinoma in-situ (AIS), and the remaining ten were endometrial carcinomas (EMCA). Conclusions TIS and MS are comparable in the detection of AGC representing squamous histology and the addition of HPV DNA testing does not differentially improve performance. Although the MS group harbored more glandular pathology, the differences in the detection of AIS were not statistically significant. Diagn. Cytopathol. 2010;38:705–709. © 2009 Wiley-Liss, Inc.

We retrospectively assessed the computed tomography features of intrapulmonary lymph nodes confirmed by cytology in 18 patients. The median size of the lymph nodes was 5.8 mm (range=3.3-8.5 mm). All were below the carina, and only one nodule, which was associated with an interlobar fissure, was over 20 mm from the chest wall. The nodules were oval, round, triangular, or trapezoidal; had sharply defined borders; were solid and homogenous; and were without calcification. Six nodules (33.3%) had a discrete thin tag extending to the pleura. Intrapulmonary lymph nodes can reliably be confirmed by fine needle aspiration with cytological diagnosis.

Purpose: We seek to establish a genetic test to identify lung cancer using cells obtained through computed tomography–guided fine needle aspiration (FNA). Experimental Design: We selected regions of frequent copy number gains in chromosomes 1q32, 3q26, 5p15, and 8q24 in non–small cell lung cancer and tested their ability to determine the neoplastic state of cells obtained by FNA using fluorescent in situ hybridization. Two sets of samples were included. The pilot set included six paraffin-embedded, noncancerous lung tissues and 33 formalin-fixed FNA specimens. These 39 samples were used to establish the optimal fixation and single scoring criteria for the samples. The test set included 40 FNA samples. The results of the genetic test were compared with the cytology, pathology, and clinical follow-up for each case to assess the sensitivity and specificity of the genetic test. Results: Nontumor lung tissues had ≤4 signals per nucleus for all tested markers, whereas tumor samples had ≥5 signals per nucleus in five or more cells for at least one marker. Among the 40 testing cases, 36 of 40 (90%) FNA samples were analyzable. Genetic analysis identified 15 cases as tumor and 21 cases as nontumor. Clinical and pathologic diagnoses confirmed the genetic test in 15 of 16 lung cancer cases regardless of tumor subtype, stage, or size and in 20 of 20 cases diagnosed as benign lung diseases. Conclusions: A set of only four genetic markers can distinguish the neoplastic state of lung lesion using small samples obtained through computed tomography–guided FNA.

Objectives Although the chemokine CXCL12 and its receptor CXCR4 have been implicated in metastasis of non–small cell lung carcinoma, the prognostic significance of these molecules is poorly defined. This study aimed to determine whether expression of these molecules is associated with clinicopathologic features and disease-free survival in non–small cell lung carcinoma. Methods Immunohistochemical staining for CXCL12 and CXCR4 was performed on 154 primary non–small cell lung carcinomas. Staining intensity was compared with tumor histotype, TNM stage, and disease-free survival; correlation was assessed by using the Fisher's exact test, and Kaplan–Meier and Cox multivariate proportional hazards regression analysis. Results Intense CXCL12 immunostaining was associated with nodal metastasis, although no difference in survival was observed. The prognostic relevance of CXCR4 was dependent on its subcellular location: in univariate analysis intense nuclear staining was significantly associated with lower T classification and improved disease-free survival in patients with adenocarcinoma, whereas cytomembranous staining was associated with distant metastasis and decreased disease-free survival. On multivariate analysis, cytomembranous CXCR4 expression conferred a significantly worse disease-free survival (relative risk, 2.8; 95% confidence interval, 1.4–5.7; P = .004). Conclusions Cytomembranous expression of the chemokine receptor CXCR4 in adenocarcinoma of the lung is an independent risk factor associated with worse disease-free survival, whereas nuclear staining confers a survival benefit. These findings are consistent with a model in which CXCR4 promotes tumor cell proliferation and metastasis when present in the cytoplasm or cell membrane, whereas localization of this molecule in the nucleus prevents it from exerting these effects.

The World Health Organization classification of lung tumors recognizes 4 histologic subtypes of pulmonary neuroendocrine carcinomas (NECs), which include typical carcinoids (TCs), atypical carcinoids (ACs), small cell carcinomas (SCCs), and large cell NECs (LCNECs). These tumors can be misclassified owing to morphologic parallels, indicating the necessity for adjunctive tests for correct classification. We evaluated immunohistochemical expression of PAX-5 in histologic and fine-needle aspiration (FNA) specimens of pulmonary NECs. Staining was stratified by intensity (0 to 3+) and percentage of cells stained as focal (

Purpose To study the histopathologic features of CT screen-detected Stage IA adenocarcinomas to determine whether survival differed by the proportion of bronchioloalveolar component (BAC) or by the presence of multiple lesions in node-negative patients. Methods Five pathologists with expertise in pulmonary pathology examined 279 resected cases of adenocarcinomas, 30 mm or less in length diagnosed by CT screening for lung cancer. The panel determined the consensus diagnosis for each case, identified additional cancers, and classified each case as solitary or non-solitary. The presence and proportion of BAC was also documented. Results Of the cases of adenocarcinoma, 20 (7%) were BAC subtype, 246 (88%) mixed subtype and 13 (5%) adenocarcinoma-OTHER. BAC cases manifested as non-solid and part solid nodules, mixed as solid and part-solid, and other as solid only. Kaplan–Meier 10-year survival rates were 100% for BAC and adeno-MIXED with 90–99% BAC cases, 95% for mixed with 1–90% BAC, 90% for those without a BAC component, and 75% for other cases. Fifty (18%) cases were non-solitary carcinomas and 44 of these were node negative; the non-solitary node-negative cases had the same excellent prognosis as solitary node-negative cases. Conclusions The proportion of BAC component was a positive prognostic factor and correlated with CT consistency. Contrary to staging predictions, cases of non-solitary node-negative adenocarcinoma had the same excellent prognosis as solitary node-negative cases, suggesting that most of the small, node-negative multiple carcinomas probably represent multiple primaries rather than intrapulmonary metastasis.

To evaluate prospectively the diagnostic performance of the New York Early Lung Cancer Action Project (NY-ELCAP) regimen in the diagnosis of early lung cancer at baseline and annual repeat computed tomographic (CT) screenings.Informed consent and institutional review board approval were obtained for this HIPAA-compliant study of baseline and annual repeat low-dose CT screening performed with a common regimen in asymptomatic individuals at 12 institutions in New York State. All 6295 participants were aged 60 years or older, had smoked for at least 10 pack-years, had no prior cancer, had not undergone chest CT in the previous 3 years, and were medically fit to undergo thoracic surgery. Median age was 66 years, and median smoking history was 40 pack-years. The proportion (and 95% exact confidence intervals [CIs]) of subjects with a positive result, as determined by using nodule size; the diagnoses of lung cancer resulting from subsequent work-up; and the distribution by cancer stage and cell type were determined. When relevant, 95% CIs for the proportions were calculated.Initial CT imaging led to recommendations for further work-up in 14.4% (95% CI: 13.5%, 15.3%) of the 6295 baseline screenings and 6.0% (95% CI: 5.1%, 6.6%) of the 6014 annual repeat screenings. Of 101 patients in whom the diagnosis of lung cancer resulted from baseline screening and three in whom a diagnosis of lung cancer was prompted by symptoms prior to the first scheduled repeat screening, 95 (91.3%) had no clinical evidence of metastases. Of the 20 patients in whom the diagnosis of lung cancer resulted from annual repeat screening, 17 (85%) showed no evidence of metastases. Of the 134 recommended biopsies, 125 (93.3%) resulted in diagnosis of lung cancer or another malignancy, while none of the 24 biopsies performed outside of the recommendation of the regimen resulted in diagnosis of lung cancer.The NY-ELCAP regimen of screening revealed that annual CT screening for lung cancer resulted in identification of a high proportion of patients with early-stage disease.

International audience; Screening for lung cancer produces two groups of lung cancers. Baseline cases include all prevalent cases with the expectation that slower-growing cancers and those that have achieved higher stage will be found in greater frequency. Repeat examination is expected to detect those cancers which have crossed the threshold for detection during the screening interval - 1 year in this study - and these are typically more rapidly growing cancers. The two groups encompass the full spectrum of lung cancers. Comparison of the baseline and annual repeat cases revealed differences in types of lung cancer. There were 202 baseline-detected cancers spanning the spectrum of pulmonary neoplasms with some slowly growing, some rapidly progressive and some at high stage; the 48 annual repeat cancers also included a spectrum of lung cancers but with more of the rapidly growing types, and more closely approximated the clinical spectrum of lung cancers. The NE carcinomas showed this trend best; small-cell carcinomas were under-represented and typical carcinoids were only found in the baseline group. Repeat cancers were found to grow rapidly, were typically smaller, less often multiple and the adenocarcinomas were less often pure BAC and less frequently contained a BAC component when invasive. The baseline adenocarcinomas included most of the BAC's, which is a diagnosis that requires special attention to its WHO definition. AAH was found to be frequently associated with adenocarcinoma, particularly BAC. Both baseline and annual repeat cases had a high percentage of invasive carcinomas with comparably high rates of resectability, high rates of node negativity and consequently a high proportion of cases in low stage.

The aim of this study was to assess the significance of Stage I diagnoses of lung cancer in the baseline cycle of screening for this disease, with special reference to the potential for overdiagnosis.We reviewed all 69 cases of Stage I lung cancer diagnosis resulting from our baseline CT screening. Among these 69 cases of lung cancer, 24 presented as solid, 30 as part-solid, and 15 as nonsolid nodules. The extent to which these represented genuine malignancy was assessed by a panel of experts on lung pathology, and the "aggressiveness" of these cases was addressed by the criterion of the tumor's volume doubling time being less than 400 days.The expert panel confirmed all 69 cases as representing genuine malignancy. Among the 69 cases without evidence of metastases, the proportion that satisfied the aggressiveness criterion was 60/69=87%. The corresponding proportions by presentation as solid, part-solid, and nonsolid nodule were 23/24 (96%), 27/30 (90%), and 10/15 (67%), respectively.In baseline CT screening for lung cancer, overdiagnosis of the disease is uncommon, with cases presenting as a nonsolid nodule a possible exception to this.

Purpose To review recent advances in pathology and computed tomography (CT) of lung adenocarcinoma and bronchioloalveolar carcinoma (BAC). Methods A pathology/CT review panel of pathologists and radiologists met during a November 2004 International Association for the Study of Lung Cancer/American Society of Clinical Oncology consensus workshop in New York. The purpose was to determine if existing data was sufficient to propose modification of criteria for adenocarcinoma and BAC as newly published in the 2004 WHO Classification of Lung Tumors, and to address the pathologic/radiologic concept of diffuse/multicentric BAC. Results Solitary small, peripheral BACs have an excellent prognosis. Most lung adenocarcinomas with a BAC pattern are not pure BAC, but rather adenocarcinoma, mixed subtype with invasive patterns. This applies to tumors presenting with a diffuse/multinodular as well as solitary nodule pattern. The percent of BAC versus invasive components in lung adenocarcinomas appears to be prognostically important. However, a consensus definition of “minimally invasive” BAC with a favorable prognosis could not be achieved. While recognition of a BAC component is possible, the diagnosis of BAC with exclusion of invasive adenocarcinoma cannot be made by small biopsy or cytology specimens. Conclusion There is a need to work toward a mutual understanding and consensus between pathologists, clinicians, and researchers with the use of the term BAC versus adenocarcinoma. Future studies should make some attempt to quantitate these components and/or other features such as size of scar, size of invasive component, or pattern of invasion. Hopefully, this work will allow definition of a category of adenocarcinoma, mixed subtype with predominant BAC/minimal invasion and a favorable prognosis.

Elastofibroma is a well-recognized tumor-like process which typically occurs in the soft tissue of the shoulder. Although fine-needle aspiration (FNA) represents a quick and simple method for definitive diagnosis, the possibility of a false-negative diagnosis is high due to the hypocellularity of the smears. However, a high index of suspicion based on the clinical presentation of a firm mass in a typical location in an elderly person, usually female, aids in the diagnosis. We describe the FNA findings of elastofibroma dorsi in an 89-yr-old woman which, although hypocellular, contained diagnostic aggregates of petaloid globules within a collagenous matrix. The cytologic material showed a green-yellow autofluorescence of the altered elastic fibers with ultraviolet light. Transmission electron microscopy revealed an elongated beaded appearance with small electron densities and obliteration of the central elastin core. The presence of a hypocellular aspirate with autofluorescent elastic fibers should suggest the possibility of elastofibroma dorsi.

Objective: As bronchioloalveolar carcinoma (BAC) is noninvasive but, in its later stages, has a worse prognosis than adenocarcinoma with bronchioloalveolar features (ACB), early identification and differentiation is important for therapeutic and prognostic purposes. We wanted to identify features of BAC, which differentiated it from ACB when both presented as ground-glass opacities (GGOs) on CT. Materials and methods: We reviewed all pathologic specimens of patients who were diagnosed with BAC and ACB in the lung from 1991 to 1999 in our institution and whose malignancy presented as a GGO on CT. This yielded 29 patients, 15 with BAC and 14 with ACB with GGOs on CT. Both univariate frequency table and multivariate logistic regression approaches were used to analyze the CT characteristics of these GGOs (location, GGO pattern, size, shape, margin, presence and type of air bronchogram and pseudocavitation). Results: BAC most frequently had a "GGO halo" around a solid opacity, often was a GGO "mixed with consolidation" with the smallest BACs being "pure GGO." Air bronchograms were frequently present in the largest GGOs. Pseudocavitations were rare. ACB, on the other hand, most frequently presented as a GGO "mixed with consolidation," less frequently with a "GGO halo" and rarely with "superimposed lymphangitis." The air bronchograms, frequently present, were usually tortuous and ectatic. Pseudocavitation was present in about one-third of the cases. The most useful CT features of GGO in separating those due to BAC from those due to ACB were pure (uniform) ground-glass attenuation and absence of lymphangitis. Conclusion: The CT features of BAC and ACB presenting as GGO reflect the histologic descriptions of these carcinomas.

In this article, we review the various causes of solitary pulmonary nodules. Based on the underlying histology, we attempt to account for the radiologic pattern associated with each. This includes features related to density, edge characteristics, and texture. Similarly, the radiologic appearance of the nodule can be helpful to the cytologist when interpreting cytological samples obtained through image guidance.

Transthoracic needle biopsy (TNB) of pulmonary nodules requires the skills of two specialists: (1) the radiologist and (2) the pathologist. From the radiologist's perspective, the goal is very simple: to obtain a sufficient amount of material through the needle to allow the pathologist to make a diagnosis with a minimum of complications to the patient. Similarly, the goal of the pathologist is to determine quickly and accurately whether the specimen procured is adequate, thereby avoiding having the radiologist obtain additional samples that would lengthen the procedure and increase the risk of complications. The pathologist must then determine how the specimen should be analyzed to maximize yield. Special techniques in TNB are used with a view toward these goals. This article defines three distinct aspects of TNB and for each describes various techniques that we believe are helpful in enhancing them. These include placement of the needle tip within the nodule, cytologic techniques for maximizing specimen yield for immediate review, and strategies for pathologic analysis and minimizing complications.