The pathologic distinction of small cell from non-small cell-lung carcinoma is of considerable therapeutic significance. In particular, the ability to distinguish poorly differentiated non-small-cell lung cancer from small-cell lung carcinoma (SCLC) is at times difficult based upon morphology alone; available immunohistochemical markers such as neuroendocrine markers are of limited utility. We have demonstrated the role of p63 and thyroid transcription factor-1 (TTF-1) in the differential diagnosis of poorly differentiated squamous-cell carcinoma (PDSCC) versus SCLC, mostly in biopsy samples (Wu et al., American Journal of Clinical Pathology 2003;119:696-702). Here, we examine further the utility of this panel in cytologic cell-block samples of lung cancers including both primary and metastatic cancers of pulmonary origin, and cases of nonpulmonary cancers metastatic to lung in which differential diagnoses included a lung primary.Four-micron thick sections of 30 alcohol-fixed paraffin-embedded cell blocks from 14 lung FNAs, 6 liver FNAs, 3 bronchial washings, 1 subcarinal lymph node FNA, 1 iliac lymph node FNA, 1 pelvic mass FNA, 1 neck lymph node FNA, 1 adrenal FNA, and 1 pleural effusion were deparaffinized and stained with monoclonal antibodies reactive to p63 (1:800, Santa Cruz Biotechnology) and TTF-1 (1:50, Dako). Slides were stained for p63 using a streptavidin-biotin kit (BioGenex) and diaminobenzidine as chromagen, and counterstained with hematoxylin. Slides were stained for TTF-1 using a Dako Autostainer. Thirty cases were examined, including 8 primary SCLCs, 8 extra-pulmonary metastases of lung SCLCs, 4 PDSCCs and 4 primary pulmonary adenocarcinomas, and 6 nonpulmonary adenocarcinomas metastatic to lung or other sites. Fifteen out of 16 (94%) SCLC cases were p63-/TTF-1+, ranging in intensity from focal-weak to diffuse-strong; 1/16 SCLCs from a bronchial washing was p63-/TTF-1- but synaptophysin was positive. All 4 primary lung adenocarcinoma cases were p63-/TTF-1+; contrasting with nonpulmonary adenocarcinomas that were all p63-/TTF-1-. All 4 PDSCC cases were p63+/TTF-1-. The panel of p63 and TTF-1 appears to be useful in the diagnostic evaluation of cytologic cell-block samples of pulmonary malignancy.

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The p53 homologous squamous stem-cell regulatory protein p63 is expressed in squamous carcinomas but is not characteristically detected in small-cell carcinomas (SCCs). A panel of thyroid transcription factor (TTF) 1 and p63 has been shown to be useful in distinguishing SCCs from poorly differentiated squamous carcinoma of the lung (PDSLC) in small biopsies and cytological cell blocks. Because tumor samples frequently are limited to cytological smears, we attempted to detect p63 in destained slides from a spectrum of pulmonary malignancies. Archival alcohol-fixed smears from 60 cases of cytologically diagnosed malignancies in bronchoscopically (n = 59) or fine-needle aspiration-obtained specimens (n = 1) were destained in acid alcohol, postfixed in 10% formalin, subjected to citrate-based antigen retrieval, and immunostained by exposure to anti-p63 monoclonal antibody 4A4, followed by reagents from a streptavidin-biotin immunoperoxidase kit, and diaminobenzidine as the chromogen. Postfixation in 10% formalin was found to be necessary for immunostaining. Normal ciliated and goblet cells were p63 negative, but reserve cells were p63 positive. All cases of squamous-cell carcinoma were positive for p63. Of 10 tumor samples originally diagnosed as SCC, only 6 samples were p63 negative and 4 samples exhibited positive staining. However, proper interpretation of the immunohistochemical (IHC) staining pattern and careful scrutiny of the cytological features and biopsy specimens in three of four cases led us to reclassify three cases into PDSLC. All adenocarcinomas (ACAs; n = 12), large-cell carcinomas (n = 4), and metastatic ACAs (n = 5) were p63 negative. Positive staining was seen in 9/16 tumors designated as non-SCCs; these tumors were not classified further into distinct histological categories.p63 staining in destained slides may be of value in facilitating the differential diagnosis between PDSLC and SCC. Criteria for conservative interpretation of results are discussed and include examination of reserve cells and ciliated cells on the same slide as internal positive and negative controls.

Body cavity effusions may be the first manifestation of malignancy or of recurrence or relapse. We surveyed effusions and washes for expression of X-linked inhibitor of apoptosis (XIAP), a potent constituent of the inhibitor of apoptosis (IAP) family of proteins. IAPs prevent apoptosis by blocking the activation of caspases, thereby preventing caspase-mediated cell degradation. Elevated expression of XIAP could be an underpinning of relapse and/or resistance to apoptosis-inducing cancer therapy. We performed an immunocytochemical survey of XIAP expression in cell blocks from benign and malignant body cavity effusions and washes. In all, 116 alcohol-fixed, formalin postfixed paraffin-embedded cell block specimens from 82 pleural effusions, 22 ascites, 11 pelvic/peritoneal washes and one pericardial effusion were evaluated immunocytochemically with monoclonal anti-XIAP (#610763, BD Biosciences, San Jose, USA) 1:250, 41C Â 72 h, and developed using EnVision-Plus reagents (Dako) and diaminobenzidine as chromagen. Particulate cytoplasmic staining was considered positive. The prevalence of staining for specific malignancies varied with the tissue of origin as follows: ovarian (13/13, 100%); lung (9/11, 82%), breast (6/13, 46%); gastric (4/7, 57%), colon (0/4, 0%), pancreas (2/3, 67%), gallbladder (1/1, 100%), fallopian tube (1/3, 33%), endometrial (6/7, 86%), mesothelioma (4/5, 80%), carcinoma of unknown primary (5/5, 100%) and hematopoietic malignancies (3/9, 33%). Overall, 54 out of 81 (67%) malignant effusions displayed XIAP positivity. Benign effusions (n ¼ 35) were virtually XIAP-negative except for two cases (6%) in which histiocytes showed moderate staining. Weak nonspecific staining was sometimes noted in inflammatory cells or histiocytes. XIAP immunostaining, when strong, allows for ready distinction of malignant from benign and reactive cell populations. Strong XIAP staining was most prevalent in ovarian carcinomas and less prevalent in mammary carcinomas. The degree of XIAP staining of tumor cells may be a means of identifying the most therapy-resistant cases (ie, those with strong XIAP expression), and allow additional triaging to XIAP-blocking drugs presently being developed and clinically tested.

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BackgroundMutations in LYST, a gene encoding a putative lysosomal trafficking protein, cause Chédiak-Higashi syndrome (CHS), an autosomal recessive disorder typically characterized by infantile-onset hemophagocytic syndrome and immunodeficiency, and oculocutaneous albinism. A small number of reports of rare, attenuated forms of CHS exist, with affected individuals exhibiting progressive neurodegenerative disease beginning in early adulthood with cognitive decline, parkinsonism, features of spinocerebellar degeneration, and peripheral neuropathy, as well as subtle pigmentary abnormalities and subclinical or absent immune dysfunction.MethodsIn a consanguineous Pakistani kindred with clinical phenotypes consistent with attenuated CHS, we performed SNP array-based homozygosity mapping and whole gene sequencing of LYST.ResultsWe identified three individuals homozygous for a novel six base pair in-frame deletion in LYST (c.9827_9832ATACAA), predicting the loss of asparagine and threonine residues from the LYST transcript (p.Asn3276_Thr3277del), and segregating with the phenotype in this family.ConclusionsWe further characterize the neurologic features of the attenuated form of CHS, and discuss pathophysiologic mechanisms underlying the neurodegenerative components of CHS. Attenuated CHS is phenotypically heterogenous and should be considered when young adults develop neurodegenerative disease and have pigmentary abnormalities. We briefly discuss surveillance and management of patients with CHS-related neurodegeneration.

No single cytologic feature is specifically diagnostic for papillary thyroid carcinoma. We report herein the presence of swirl-like cellular aggregates in fine needle aspirates of papillary thyroid carcinoma but not in other thyroid entities. Cellular swirls are defined as concentrically organized aggregates of tumor cells in which many of the most peripherally situated cells have ovoid rather than round nuclei that are oriented perpendicular to the radius of the swirl. One hundred Papanicolaou- and/or Diff-Quik-stained FNAs of the thyroid diagnosed as papillary carcinoma, including seven fine needle aspirates of cervical lymph nodes showing metastatic papillary carcinoma, with or without cell blocks, were reviewed for the presence of cellular swirls. An additional 100 thyroid FNAs, similarly stained and prepared, diagnosed as nodular goiter, Hashimoto's thyroiditis and follicular neoplasm were also reviewed for the presence of cellular swirls. Cellular swirls were easily observed at screening magnification and confirmed at high magnification. Seventeen of 100 FNAs (17%) of papillary carcinoma contained cellular swirls. No cases diagnosed as nodular goiter, Hashimoto's thyroiditis or follicular neoplasm contained these structures. Thirteen cases with swirls had histologic follow-up. These comprised seven papillary carcinomas with classical histopathology, two designated 'differentiated papillary carcinoma,' two with follicular variant histopathology; one with a minor component of follicular variant histopathology; one papillary carcinoma metastatic to a cervical lymph node with classic histopathology. Swirls occurred in cases with relatively little pleomorphism, or in well-differentiated regions of papillary carcinoma that also displayed less well-differentiated components. Cellular swirls are a finding that is highly specific to papillary thyroid carcinoma. They are easily seen at screening magnification. Their presence in a FNA specimen may be helpful in cases where classic criteria for papillary thyroid carcinoma are scarce, particularly in well-differentiated papillary thyroid carcinoma. While the size and scope of this study are insufficient to conclude that cellular swirls alone are diagnostic of papillary thyroid carcinoma in the absence of other criteria, we believe these structures should be added to the list of diagnostic criteria.