SHP2 is up-regulated in breast cancer cells and in infiltrating ductal carcinoma of the breast, implying its involvement in breast oncogenesis.

AIMS: To determine whether Src homology phosphotyrosyl phosphatase 2 (SHP2) is up-regulated in breast cancer and, if so, to determine whether its up-regulation has any relationship with clinical variables of breast cancer. METHODS AND RESULTS: Immunoblotting, immunohistochemistry and immunofluorescence microscopy were used to assess the state of SHP2 expression in breast cancer cells and in infiltrating ductal carcinoma (IDC) of breast. The possible role of SHP2 in breast cancer cell transformation was determined by dominant-negative expression and anchorage-independent growth assays. All of the breast cancer cell lines tested and 72% of IDC breast tumours analysed had increased amounts of the SHP2 protein. In support of its positive role, dominant-negative SHP2 blocked anchorage-independent growth of breast cancer cells. Furthermore, overexpression of SHP2 seemed to have a positive relationship to HER2 overexpression, nuclear accumulation of hormone receptors, higher tumour grade and lymph node metastasis, but not to age of breast cancer patients. CONCLUSION: SHP2 is a widely overexpressed signalling protein in IDC breast tumours. Given SHP2's positive role in cell growth, transformation and stem cell survival, the positive relationship of its overexpression to lymph node metastasis, nuclear accumulation of hormone receptors and higher tumour grade suggests that SHP2 promotes breast oncogenesis.

Peritoneal washing cytology is unnecessary in gynecologic surgery for benign diseases.

BACKGROUND: The presence of tumor cells in peritoneal washing cytology specimens taken during surgery affects the staging of many gynecologic malignancies. Peritoneal washings are often collected routinely, even in cases of presumed benign disease. This study was designed to address whether evaluation of these specimens is justified. METHODS: We reviewed diagnostic reports from all peritoneal washings and the corresponding surgical pathology specimens from patients undergoing gynecologic surgery during a 1-year period in one institution and a 20-month period in the other. Cases were divided into benign and malignant categories based on the surgical pathology diagnosis. RESULTS: Three hundred forty-six patients had peritoneal washings collected during the study period. The proportion of cases with malignancy was 30% in one institution and 49% in the other. Of these, 119 had an endometrial or ovarian malignancy, including 16 ovarian tumors of low malignant potential. Malignant cells were detected in 19 cases. In 10 of these 19, grossly apparent peritoneal tumor implants were present at the time of surgery. The remaining 227 were found to have benign disease, and the peritoneal washing cytology diagnosis was negative in all cases. Potential savings of $13,000 to $17,000 based on current insurance reimbursement could have been realized for these 227 patients without compromising patient care. CONCLUSIONS: These data suggest that peritoneal washing cytology specimens collected at the time of gynecologic surgery for presumed benign disease can be held and processed later if an unsuspected malignancy is discovered. This practice can result in cost savings without compromising patient care. Cancer (Cancer Cytopathol)

Roles of epidemiology, pathology, molecular biology, and biomarkers in the investigation of occupational lung cancer.

The pathology and molecular biology of lung cancer demonstrate that these tumors evolve through a series of mutations, molecular changes, and corresponding morphologic changes. To elucidate how occupational and environmental factors influence lung cancer histogenesis it is important not only to understand epidemiology and the interactions between etiologic agents but also to integrate information from pathology, biochemistry and molecular biology. This review focuses on the range of techniques currently available for characterizing lung cancer and how their prudent use can be beneficial in the identification of occupational carcinogens. Because many occupational and environmental lung cancers are caused by multiple etiologic agents, the integration of histology with cellular, biochemical and molecular biomarker techniques may provide new approaches for understanding the disease process.

Fine needle aspiration of the breast. A probabilistic approach to diagnosis of carcinoma.

OBJECTIVE: To develop a classification scheme for reporting the results of fine needle aspiration (FNA) cytology of a breast lesion according to its likelihood of being a carcinoma. STUDY DESIGN: To verify the validity of this scheme, we studied a total of 267 FNAs that were prospectively classified according to predefined criteria as positive (76), suspicious (41), proliferative with atypia (66), proliferative without atypia (48) and unremarkable (36), and compared these results with the final histology. RESULTS: The percentages of patients who had carcinoma on histology were 100% (76), 93% (38), 35% (23), 6% (3) and 31% (11) of cases diagnosed as positive, suspicious, atypical proliferative, proliferative without atypia and unremarkable on cytology, respectively. However, if only invasive carcinoma is considered, then the percentage of carcinoma was 99% (75), 93% (38), 23% (15), 2% (1) and 11% (4), respectively. The only invasive carcinoma in the proliferative-without-atypia category was a tubular carcinoma and represented a false negative diagnosis. All four invasive carcinomas with an unremarkable cytologic diagnosis were due to sampling errors. Definitive surgery after FNA was common in cases with positive (65%) and suspicious (42%) cytologic diagnosis, whereas all but one patient with atypical, proliferative and unremarkable diagnoses had a biopsy initially. CONCLUSION: This scheme of reporting breast FNA results with defined criteria according to the probability of identifying carcinoma provides a rational basis for guidelines for the management of breast lesions.

Acute lung injury induced by a commercial leather conditioner.

Following a formulation change, a leather conditioner was involved in a 1992 nationwide outbreak of respiratory illness. We investigated the composition and toxicity of the conditioner produced before (previous product) and after (new product) the disease outbreak. The new product induced tachypnea, pulmonary edema, pulmonary hemorrhage, and sporadic deaths in exposed guinea pigs and rats. Ultrastructurally, these changes were associate with direct pulmonary cytotoxicity characterized by necrosis of alveolar type I cells and alveolar septal interstitial edema. Chemical analyses suggested major alterations in the fluorohydrocarbon constituents in the new formulation of the leather conditioner. While these alterations could not be specifically identified, they appeared to include changes from fluoralkanes to fluoroalkenes, fluorophenyl, and/or fluoroalcohol compounds. Changes in solvent composition were consistent with traces of 2-butoxyethanol and isomers of dipropylene glycol methyl ether, and additional C10-C12 alkanes. In this study, we demonstrated the toxicity of the new product in laboratory animals. Some of the altered constituents of the new product have been identified and are potential candidates for additional investigations to identify specific etiologic agents.

The value of multiple fluid specimens in the cytological diagnosis of malignancy.

Multiple fluid specimens of a patient are often received in the cytology laboratory. Both clinicians and pathologists question the optimal number of specimens required to detect a malignancy. We reviewed the computerized cytology files at Boston's Beth Israel Hospital from 1988 to 1991 to identify patients with two or more specimens from the same anatomic site. Two hundred and fifteen patients with a total of 570 specimens were identified. Before December 19, 1990, two direct smears were examined per fluid sample. After December 19, 1990, two direct smears and two cytospin preparations were examined. Medical records of patients without a positive diagnosis of cytology were reviewed. Overall, a cytological diagnosis of malignancy was made on at least one specimen for 55 patients (26%). The first positive diagnosis was made on the initial specimen in 36 patients (65%), on the second in 15 patients (27%), the third in three patients (5%), and the fifth in one patient (2%). For those specimens prepared with the two techniques described above (two direct and two concentrated smears), the first positive diagnosis was made on the initial specimen in 89% of the cases. Medical record review uncovered 55 additional patients who had clinical evidence of malignancy. Of these, 22 (40%) had at least one suspicious diagnosis of their fluid specimens. The first suspicious diagnosis was made with three or fewer specimens in all 22 patients. The majority of malignant effusions are detected with two specimens. Examination of more than three specimens is of little value. Multiple preparatory, especially concentration, techniques may increase the probability of detecting malignancy in one specimen.

Correlation of histologic grade of breast carcinoma with cytologic features on fine-needle aspiration of the breast.

Histologic grade is an important prognostic factor for breast carcinoma. To determine whether histologic grade could be reproduced on fine-needle aspiration of the breast, we analyzed 50 cases of histologically proven infiltrating ductal carcinomas that had a preoperative fine-needle aspiration. The histologic grade was based on tubule formation, nuclear pleomorphism, and mitotic frequency [a modified Bloom-Richardson (BR) grading system]. Fine-needle aspirations were analyzed for cellularity, cellular arrangements, percentage of single cells, nuclear pleomorphism, mitoses, hyperchromasia, chromatin pattern, nucleoli, and background. The cases in BR Grades 1 and 2 (n = 28) were combined into one category for comparison with those in BR 3 (n = 22). BR 3 was more likely than BR 1 and 2 to be associated with marked nuclear pleomorphism (59 versus 18%, P < 0.05) and vesicular or coarse chromatin (77 versus 43%, P < 0.05). Of the 18 cases that showed both marked nuclear pleomorphism and either coarsely granular or vesicular chromatin on fine-needle aspiration, 13 (72%) were BR Grade 3 on histology. These 13 cases represent 59% of the 22 cases of BR Grade 3 on histology. Aspiration cytology is of some, but limited, use in predicting BR grade. As expected, nuclear features are most easily translated from histology to cytology.

Fine-needle aspiration of Hürthle cell lesions. A cytomorphologic approach to diagnosis.

Hürthle cells may be found in fine-needle aspirates of the thyroid (FNATs) from Hürthle cell tumors (HCTs) and nonneoplastic Hürthle cell lesions, including Hashimoto's thyroiditis and goiter. To differentiate the characteristic cytomorphologic features from these lesions, the authors studied 38 surgically excised Hürthle cell lesions of the thyroid. Preoperative FNATs were reviewed for a number of architectural and cytologic features. The chi-squared and Fisher's exact tests were used for statistical analysis. There were many statistically significant cytologic differences between HCTs and nonneoplastic Hürthle cell lesions. Statistically significant features indicating an HCT versus nonneoplastic Hürthle cell lesion included the following: a high percentage (> 90%) of Hürthle cells, single Hürthle cells (> 10%), cellular dyshesion, large nucleoli, significant nuclear pleomorphism, significant nuclear enlargement, absence of macrophages, absence of plasma cells, and absence of or few lymphocytes. The architecture of cell groups, cellularity, amount of colloid, and multinucleation appeared to be of no value. The presence of a high percentage of dyshesive Hürthle cells with large nucleoli, with some cells showing significant nuclear enlargement and pleomorphism, associated with a lack of lymphoplasmacytic inflammatory cells, appears statistically predictive of an HCT and should enable the differentiation of an HCT from a nonneoplastic Hürthle cell lesion.

Predictive value of fine-needle aspiration of the thyroid in the classification of follicular lesions.

BACKGROUND: Fine-needle aspiration has been less valuable in the diagnosis of follicular lesions than for other neoplasms of the thyroid. It has been observed that follicular carcinoma is found in microfollicular, but not macrofollicular lesions, and this has served as a guide to management for many surgeons. The authors attempted to determine what cytologic parameters might usefully distinguish these types of follicular lesion. METHODS: The histologic findings and cytology of 56 thyroid lobectomies for follicular lesions that had adequate preoperative fine-needle aspiration of the thyroid (FNAT) were reviewed. Histologic specimens were classified into macrofollicular, mixed, and microfollicular groups. Cytologic features examined included the presence of colloid, irregularity of cell arrangements within groups, the presence and size of flat and folded cell sheets, three-dimensional clusters, and microfollicles and macrofollicles. RESULTS: Of the histologic specimens, 15 were preponderantly (> 70%) microfollicular, 19 were mixed, and 22 were predominantly (> 70%) macrofollicular. Three cytologic features were useful in their distinction: none of the predominantly microfollicular but 24% of the mixed and predominantly macrofollicular had abundant colloid (P = 0.048). Likewise, none of the predominantly microfollicular but 27% of the mixed and predominantly macrofollicular had large follicles (P = 0.026). Finally, 73% of the predominantly microfollicular but only 37% of the mixed and predominantly macrofollicular showed irregularity or crowding of cells in groups (P = 0.018). CONCLUSIONS: Used in combination, abundant colloid, regular spacing, and large follicles are helpful in distinguishing macrofollicular and mixed lesions from microfollicular ones, which have a higher malignant potential.

Tubal metaplasia: a cytologic study with comparison to other neoplastic and non-neoplastic conditions of the endocervix.

Tubal metaplasia of the endocervix (TME), a condition that may be confused morphologically with glandular neoplasia, is frequently found in cone or hysterectomy specimens. To determine the frequency of detecting TME in cytologic smears, we retrospectively reviewed 28 Papanicolaou (Pap) smears from 22 women (mean age 39.1 yr; range 25-60 yr) with histologically proven TME. Our criteria for TME were the presence of two cell types in addition to endocervical secretory cells, i.e., peg cells (cells with dark and granular cytoplasm and elongate nuclei) and ciliated cells. All women had cervical cytology specimens obtained with an endocervical brush shortly before the procedures in which TME was diagnosed, and five also had at least one post-procedure smear. Of 20 smears with an adequate, non-neoplastic endocervical component, TME was found in 2 (10%). In these two, TME cells constituted 10% and < 5% of all the glandular cells, respectively, and the percentage of ciliated cells in the TME was approximately 25% and 75%. In conclusion, TME was noted infrequently (10%) on the cervical cytosmears of women with histologically-proven TME. This result corresponds to the histologic finding that TME typically involves the upper endocervix and glandular epithelium, with only 13% of the women having TME on the surface of the lower endocervix. Atypical glandular cells on cervical cytology are a problem for clinicians and pathologists alike. The differential diagnosis of such atypia, including TME, cells of the lower uterine segment, squamous intraepithelial lesion in glands and glandular neoplasia, is discussed.

Cytologic diagnosis of cytomegaloviral esophagitis. A report of three acquired immunodeficiency syndrome-related cases.

Cytomegalovirus (CMV) is recognized as a common cause of infectious esophagitis in patients with the acquired immunodeficiency syndrome (AIDS). The radiographic and endoscopic findings are variable, and although some features are suggestive of CMV esophagitis, none is specific. The mainstay of the diagnosis of this disease has been histologic demonstration of the characteristic intranuclear and intracytoplasmic inclusions. We report three patients with AIDS-related CMV esophagitis in whom cytologic smears from esophageal brushings contained diagnostic cells characterized by nuclear and cytoplasmic enlargement; marginated chromatin; large, basophilic intranuclear inclusions surrounded by a clear halo; and granular, eosinophilic intracytoplasmic inclusions. In one case the initial diagnosis was made from the biopsies, and only after careful review were cells diagnostic of CMV infection identified in the cytologic smears. In that patient, numerous cells with herpes simplex virus-related changes were present and probably masked the presence of the CMV-infected cells. In contrast, the biopsies from another patient showed only necrotic debris and inflammatory cells, whereas the cytologic preparations revealed cells with the characteristic CMV inclusions. With improved therapy for this often-debilitating opportunistic infection, rapid and accurate diagnosis is imperative. Cytology complements histology, and concurrent use of these diagnostic modalities will detect CMV esophagitis more frequently than will either technique alone.

Comparison of different preparation techniques for fine needle aspiration specimens. A semiquantitative and statistical analysis.

Different options exist for preparing fine needle aspiration specimens (FNAS). To compare direct smears and cytocentrifugation specimens, we prospectively obtained FNAS from 38 operative cases, making alcohol-fixed (DIR) and air-dried (AIR) direct smears and collecting additional passes in 50% ethanol (ETH), Saccomanno's solution (SAC) and Hanks' Balanced Salt Solution (HBSS). All slides were stained with Papanicolaou stain except AIR, which were stained with Diff-Quik. We evaluated cellularity, nuclear and cytoplasmic preservation, percent single cells, background and degree of three-dimensionality on a 0-3+ scale and rendered an independent diagnosis for each medium. Statistical analysis of differences between techniques was performed utilizing the paired t test. Cellularity was significantly decreased for ETH, HBSS and SAC as compared to DIFF and DIR. Nuclear preservation was best for DIR and inferior for AIR, ETH, SAC and HBSS. Background was best seen in DIR and AIR as compared to ETH and SAC. HBSS was significantly inferior to DIR but not to AIR. There were no significant differences in cytoplasmic preservation and percent single cells. Three-dimensionality was increased for ETH and SAC but not for HBSS. The ability to make a definitive diagnosis was significantly inferior only for HBSS and SAC as compared to AIR. Direct smears made by cytotechnologists or pathologists are better than Cytospin specimens. However, despite their inherent disadvantages, rinse techniques may be advantageous when specimens are collected solely by clinicians.

Image-directed percutaneous biopsy. A comparison of cytologic and histologic findings.

BACKGROUND: Image-directed biopsies may be collected as histologic or cytologic specimens. METHODS: In 34 patients, the results of aspiration cytologic examination were compared prospectively with core tissue biopsy findings obtained and diagnosed independently using the same image-guided procedure. RESULTS: Cytologic examination disclosed 22 patients with positive or suspicious findings of malignancy; there was one false-suspicious result. Seventeen patients with such results were discovered by examining the core biopsy specimens. Cytologic findings also were more definitive in diagnosing malignancy. Those in whom an immediate interpretation could be done were more likely to have adequate cytologic specimens (88%) than those without (62%). One to five passes were done, but all 21 patients with definitive findings of either benign or malignant by cytologic examination underwent three or fewer passes. The three patients with positive biopsy results, but less definitive cytologic findings, all underwent only one cytologic pass. CONCLUSIONS: Therefore, it was concluded that cytologic examination is more sensitive and definitive than biopsy in diagnosing lesions using image guidance. Immediate interpretation and/or multiple passes increase the diagnostic yield. However, more than three aspiration cytologic passes appear to yield diminishing returns.

Comparative features of comedo and noncomedo ductal carcinoma in situ of the breast on fine-needle aspiration biopsy.

To determine whether fine-needle aspiration biopsy (FNAB) can differentiate between comedo (C-DCIS) and noncomedo ductal carcinoma in situ (NC-DCIS), we reviewed retrospectively the preoperative FNAB and surgical biopsy slides of 13 cases of DCIS with adequate cytologic material. Eight were NC-DCIS and 5 were C-DCIS. Three (60 percent) of the C-DCIS and 7 (88%) of the NC-DCIS were nonpalpable lesions biopsied under conventional mammographic guidance. Three (60%) of the C-DCIS but only 2 (25%) of the NC-DCIS were considered either suspicious or positive for malignancy on FNAB, the remainder in both groups being atypical. A statistically significant difference in marked nuclear pleomorphism (60% of C-DCIS vs. 0% of NC-DCIS, P = 0.04) and large nucleoli (60% of C-DCIS vs. 0% of NC-DCIS, P = 0.04) was observed between these 2 groups. DCIS is morphologically diverse, and it appears that the cytologic features of individual cells on FNAB may distinguish C-DCIS from NC-DCIS.

Tubal metaplasia of the uterine cervix: a prevalence study in patients with gynecologic pathologic findings.

Tubal metaplasia (TM) of endocervical epithelium may be confused with endocervical dysplasia or adenocarcinoma in histologic or cytologic specimens. However, the potential magnitude of this problem is unknown, because the prevalence of endocervical TM in routine surgical pathology material is undefined. To determine the prevalence, distribution, and associated features of endocervical TM, we retrospectively reviewed a consecutive series of cone biopsy specimens (n = 82) and hysterectomy specimens in which the entire cervix had been sectioned (n = 26), obtained over 28-months. Tubal metaplasia was defined as epithelium containing all three cell types (ciliated, secretory, and intercalary) found in the normal fallopian tube. The mean patient age was 41 years (range, 21-79). Endocervical TM was present in 33 of 108 patients (31%) and was evenly distributed among all age groups. Its prevalence was related to the number of sections examined (23% of cases with less than or equal to 12 blocks of the cervix; 52% of cases with greater than 12 blocks; p less than 0.01) and was greater in hysterectomy than in cone specimens (62 vs. 21%, p less than 0.001). Although most frequent in the upper endocervix and in deep portions of glands, TM involved the surface in 36%, the superficial parts of glands in 64%, and the lower endocervix in 30% of positive cases. There was no association with phase of the menstrual cycle, inflammatory changes, or low-grade cervical intraepithelial neoplasia (CIN), but TM was inversely related to high-grade CIN in glands, presumably due to replacement of metaplastic cells by neoplastic cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative features of carcinoma in situ and atypical ductal hyperplasia of the breast on fine-needle aspiration biopsy specimens.

With the use of fine-needle aspiration biopsy to evaluate non-palpable breast lesions, an increasing number of cases of ductal carcinoma in situ (DCIS) are encountered. The authors previously demonstrated that it is not possible to distinguish definitively between DCIS and invasive ductal carcinoma on fine-needle aspiration biopsy. To determine whether DCIS could be separated from atypical ductal hyperplasia (ADH), the authors identified all cases of exclusive DCIS or ADH with fine-needle aspiration biopsy before surgery. Sixteen cases of ADH and 19 cases of DCIS were identified. Of these, 12 in each category were sufficiently cellular to allow evaluation of architectural and cytologic features. Cases of ADH were more likely to be diagnosed as negative or atypical (11 of 12); in contrast, DCIS was more likely to be designated as suspicious or positive (9 of 12). Architectural and cytologic features characteristic of ADH included cells arranged in flat cohesive sheets, distinct cell borders, and myoepithelial cells. Those features characteristic of DCIS were single cells representing more than 10% of atypical cells, cellular dyshesion, and inflammatory background, coarsely granular chromatin, and nuclear pleomorphism. Many other features were not useful in separating ADH from DCIS. Based on this small series, it appears that the distinction between some cases of DCIS and ADH may be possible on fine-needle aspiration biopsy.