Philip T. Cagle

Overexpression of Glut1 and Glut3 in stage I nonsmall cell lung carcinoma is associated with poor survival.

Increased expression of Glut1 and Glut3 has been reported in many human cancers, including nonsmall cell lung carcinoma (NSCLC). The aim of this study was to determine the biologic significance of Glut1 and Glut3 overexpression in Stage I NSCLC.

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(+)).

Localized malignant mesothelioma

Localized malignant mesotheliomas are uncommon sharply circumscribed tumors of the serosal membranes with the microscopic appearance of diffuse malignant mesothelioma but without any evidence of diffuse spread. Little is known about their behavior. We report 23 new cases. The mean age at presentation was 63 years, and the sex ratio was approximately 2:1 (male/female). Twenty-one tumors were pleural and 2 were peritoneal. Sixteen tumors reproduced microscopic patterns of diffuse epithelial mesotheliomas, 6 had mixed epithelial and sarcomatous patterns, and 1 was purely sarcomatous. After surgical excision of the tumor, 10 of 21 patients with follow-up data were alive without evidence of disease from 18 months to 11 years after diagnosis. Patients who died had developed local recurrences and metastases, but none had diffuse pleural spread. Localized malignant mesotheliomas should be separated from diffuse malignant mesotheliomas because of their localized presentation, quite different biologic behavior, and far better prognosis.

Serous surface carcinoma of the peritoneum: a clinicopathologic study of 22 cases.

Serous surface carcinoma (SSC) of the peritoneum is defined as a primary tumor histologically indistinguishable from serous carcinoma of the ovary, diffusely involving the peritoneal surface but sparing or only superficially invading the ovaries. In this study of 22 cases of SSC, it was found that the main clinical manifestations of SSC were abdominal pain and enlargement. In most cases, SSC evenly involved the entire mesothelial surface but rarely was predominant in or even limited to the pelvis. It frequently invaded the submesothelium, but deep invasion into abdominal and pelvic organs or local metastasis was rare, and distant metastasis was not seen at presentation. Microscopically, SSC was a high-grade tumor frequently showing high mitotic rate, psammomas bodies, and necrosis. The tumor was usually contiguous with hyperplastic mesothelium on either ovarian surface or other locations. Tumor cells in all cases except one showed cytoplasmic or surface neutral or acidic mucin or both. Tumor cells stained positive for keratin (100% of cases), epithelial membrane antigen (100%), Leu-M1 (45%), B72.3 (85%), vimentin (35%), and carcinoembryonic antigen (25%). Electron microscopic studies of six cases showed epithelial differentiation in each. Seven patients (32%) were alive with no clinical disease at 3 to 31 months, one patient (4%) was alive with extensive local disease at 24 months, 11 patients (50%) died almost exclusively of local recurrence at 1 to 70 months, and three patients (14%) died of operative complications. It is concluded that SSC arises from peritoneal mesothelium but has epithelial phenotype. It can be morphologically differentiated from other conditions with similar laparotomy findings, such as malignant mesothelioma, benign papillary mesothelioma, cystic mesothelioma, and benign or borderline peritoneal serous tumors. The prognosis of SSC is poor, and most patients die of uncontrollable local disease.

Comparison of adrenal cortical tumors in children and adults

Morphologic features (abnormal mitoses, necrosis, vascular and capsular invasion, broad fibrous bands, cellular pleomorphism, size) previously suggested to be predictors of malignant behavior in adrenal cortical tumors were assessed individually in 23 (17 benign, 6 malignant) pediatric and 42 (29 benign, 13 malignant) adult tumors. Of these features, size was the only predictor of malignancy in pediatric tumors. All pediatric tumors weighing more than 500 g were malignant and all but one weighing less than 500 g were benign. The remaining features were present in both benign and malignant pediatric tumors, and pediatric benign tumors were significantly more likely to have mitoses (P <0.01), necrosis (P <0.001), broad fibrous bands (P <0.005), and moderate to severe pleomorphism (P <0.01) than were adult benign tumors. The authors conclude that pediatric tumors are more likely to be benign than previously thought, and that size is the only morphologic predictor of their biologic behavior.

Distinction of pulmonary small cell carcinoma from poorly differentiated squamous cell carcinoma: An immunohistochemical approach

Accurate morphologic distinction between small cell carcinoma and poorly differentiated squamous cell carcinoma has critical therapeutic significance, but can be limited by crush artifact, tumor necrosis, limited tumor representation, and overlapping morphologic features. We evaluated a panel of antibodies for their efficacy in distinguishing between these neoplasms. Formalin-fixed paraffin-embedded tissue sections of small cell carcinomas and poorly differentiated squamous cell carcinomas underwent immunohistochemical staining with antibodies to thyroid transcription factor-1, p63, high molecular weight keratin, and p16(INK4A). Of 28 small cell carcinomas, 26 (93%) small cell carcinomas showed diffuse moderate or strong staining for thyroid transcription factor-1 with no staining for high molecular weight keratin and p63. In contrast, 27/28 (96%) poorly differentiated squamous cell carcinomas manifested opposite immunoreactivities, with diffuse moderate or strong staining for high molecular weight keratin and p63, and no or minimal staining for thyroid transcription factor-1. In two additional cases originally interpreted as small cell carcinoma, high molecular weight keratin highlighted small numbers of neoplastic large cells, leading to reclassification as combined small cell and non-small cell carcinomas. p16(INK4A) expression varied widely in poorly differentiated squamous cell carcinomas, but was consistently moderate or strong and diffuse in small cell carcinomas, and proved helpful in the two thyroid transcription factor-1-negative small cell carcinomas. This study demonstrates that a panel consisting of antibodies to thyroid transcription factor-1, p63, high molecular weight keratin, and p16(INK4A) is highly effective for distinguishing between small cell carcinoma and poorly differentiated squamous cell carcinoma. This panel also facilitates diagnosis of combined small cell and non-small cell carcinomas.

Pulmonary histopathology in cocaine abusers

Lung histopathology was reviewed from 52 autopsies with positive toxicologic tests for cocaine from the medical examiners offices in Dallas and Austin, TX. The median patient age was 34.7 years, and the male to female ratio was 2:1. Twelve individuals primarily used the drug intravenously and six primarily smoked it, but in most patients usage history was not known. The most frequent manner of death was accidental, consisting predominantly of cocaine overdoses. Other frequent manners of death included both natural causes and homicides. Subjects with chest trauma were excluded from the study. Twenty-three age-matched control cases with negative cocaine histories and toxicologic tests also were obtained from medical examiner autopsies. Histopathologic findings in the cocaine abuse group included acute hemorrhage, 58% (P = .05); chronic hemorrhage, 40% (P < .01), interstitial pneumonitis/fibrosis, 38% (P < 0.01); congestion, 88% (P < .01); and intra-alveolar edema, 77% (P < .01). These changes were remarkably consistent regardless of locale or method of use. Our findings demonstrate that pulmonary hemorrhage is more frequent than suggested by clinical hemoptysis and that chronic pulmonary diseases such as interstitial fibrosis may develop in long-term users.

Growth Factor Independence-1 Is Expressed in Primary Human Neuroendocrine Lung Carcinomas and Mediates the Differentiation of Murine Pulmonary Neuroendocrine Cells

Human small cell lung cancers might be derived from pulmonary cells with a neuroendocrine phenotype. They are driven to proliferate by autocrine and paracrine neuropeptide growth factor stimulation. The molecular basis of the neuroendocrine phenotype of lung carcinomas is relatively unknown. The Achaete-Scute Homologue-1 (ASH1) transcription factor is critically required for the formation of pulmonary neuroendocrine cells and is a marker for human small cell lung cancers. The Drosophila orthologues of ASH1 (Achaete and Scute) and the growth factor independence-1 (GFI1) oncoprotein (Senseless) genetically interact to inhibit Notch signaling and specify fly sensory organ development. Here, we show that GFI1, as with ASH1, is expressed in neuroendocrine lung cancer cell lines and that GFI1 in lung cancer cell lines functions as a DNA-binding transcriptional repressor protein. Forced expression of GFI1 potentiates tumor formation of small-cell lung carcinoma cells. In primary human lung cancer specimens, GFI1 expression strongly correlates with expression of ASH1, the neuroendocrine growth factor gastrin-releasing peptide, and neuroendocrine markers synaptophysin and chromogranin A (P < 0.0000001). GFI1 colocalizes with chromogranin A and calcitonin-gene–related peptide in embryonic and adult murine pulmonary neuroendocrine cells. In addition, mice with a mutation in GFI1 display abnormal development of pulmonary neuroendocrine cells, indicating that GFI1 is important for neuroendocrine differentiation.

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.

Natural history of pulmonary scar cancers. Clinical and pathologic implications.

Twenty‐two cases of resected pulmonary scar cancers in which 10 year or greater follow‐up could be obtained were evaluated to determine morphologic and clinical criteria which would predict long‐term survival and elucidate the cause and effect relationship of the scar to the cancer. Maturity of the scar was found to be an important criterion in predicting long‐term survival. Of patients with tumors > 3 cm, only one of six with an early scar died with cancer, whereas four of eight patients with advanced scars died with cancer. All tumor > 3 cm had advanced scars and five of eight patients in this category died with cancer. These findings support the concept that the scar develops secondary to the cancer and that the maturity of the scar can be used as a prognostic criterion in resected tumors. Cancer 56: 2031‐2035, 1985.