Carcinoembryonic antigen content in fine needle aspirates of the lung. A diagnostic adjunct to cytology.

Carcinoembryonic Antigen (CEA) was measured in 59 consecutive fine needle aspirates (FNAs) of the lung from 58 patients to determine if the CEA content would enhance the sensitivity of the cytologic diagnosis. Twenty-eight males and 30 females with tumors 1-40 cm in diameter were studied. Final diagnoses were correlated with the clinical history, radiologic studies, tissue (when available) and follow-up. Image-guided FNAs were performed by radiologists using a 22-gauge Chiba needle and 20-mL syringe with one to four passes per specimen. Cytologic examination included rapid assessment in the radiology suite and a final diagnosis in 24 hours. CEA was measured by enzyme immunoassay using monoclonal antibody. Nine benign aspirates and 50 malignant aspirates were diagnosed. The sensitivity of cytology was 86% and specificity, 100%. Using 5 ng/mL as the cutoff, the sensitivity of CEA for malignant aspirates was 50% and specificity, 90%. The combined sensitivity of CEA and cytology was 95%. The mean CEA in malignant aspirates was 131 ng/mL and in benign aspirates, 2.41. The highest mean CEA was seen in adenocarcinoma, 402.6 ng/mL. Lower CEA content was seen in epidermoid carcinoma (58.6 ng/mL), large cell carcinoma (8.09), oat cell carcinoma, metastatic carcinoma of the kidney and breast, thymoma and lymphoma (each less than 1 ng/mL). Elevated CEA alone was diagnostic in two aspirates of bronchioloalveolar carcinoma; carcinoma with an unknown primary source, three; and large cell carcinoma, one. The adjunctive use of CEA in FNAs of the lung enhances the sensitivity of the cytologic diagnosis.     

Specific tumor markers in diagnostic cytology. Immunoperoxidase studies of carcinoembryonic antigen, lysozyme and other tissue antigens in effusions, washes and aspirates

The immunoperoxidase technique was used to identify specific tumor markers in exfoliated cells in fine needle aspirates and body fluids. Carcinoembryonic antigen (CEA) and lysozyme staining was evaluated in cytocentrifuge preparations from 42 malignant effusions and aspirates and 16 benign effusions. Reactive mesothelial cells were negative for CEA and lysozyme or showed faint peripheral cytoplasmic staining. Malignant cells from 50% of the adenocarcinomas studied were positive for CEA. All tumors studied were negative for lysozyme. These staining patterns are helpful in the differential diagnosis of reactive mesothelial and adenocarcinoma cells, a frequent diagnostic dilemma. Moreover, demonstration of specific tumor antigens (e.g., prostatic acid phosphatase, calcitonin and immunoglobulin) helped define the origin of metastatic malignancy in selected cases. Estrogen receptor activity was also identified in tumor cells using this technique. Immunoperoxidase was helpful in the evaluation of malignant cytologic specimens from patients with more than one tumor. Interpretation of staining patterns is discussed, with reference to the limitations of the technique. Immunoperoxidase methods maintain cytologic detail, are readily adaptable to diagnostic cytology and increase the specificity of cytologic diagnosis.     

Carcinoembryonic antigen levels in germ cell tumours

Elevated serum carcinoembryonic antigen (CEA) prior to specific treatment was noted in 3% (7/258) of assessable patients with testicular, extragonadal or ovarian germ cell tumours (GCT). In addition, persistently raised CEA was documented in 7% (26/385) of patients during or after cisplatin-based chemotherapy for metastatic GCT. Raised CEA did not appear associated with adverse prognosis. Among patients undergoing resection of residual tumour masses post-chemotherapy, 8 of 36 with mature differentiated teratoma excised had raised CEA compared with only one of 39 patients where no mature teratoma was found. However, CEA levels remained elevated in 6 of the 8 cases despite apparent complete resection of mature teratoma. Elevated CEA in treated GCT patients may be caused by hepatotoxicity from chemotherapy, intercurrent diseases, or other unknown factors. History of cisplatin-based chemotherapy may be a confounding factor in interpreting raised CEA levels. CEA measurements do not help in the management of patients with germ cell tumours.     

Carcinoembryonic antigen in breast-cancer tissue: a useful prognostic indicator.

Sections of breast carcinomas removed from 69 patients six to 13 years previously were examined using an immunoperoxidase technique to determine whether carcinoembryonic antigen (CEA) was present. Patients who had CEA-negative tumours had significantly higher five- and 10-year survival rates. The difference was not related to the stage of the disease, postoperative treatment, or histological type of tumour. These results suggest that immunohistological assessment of CEA in breast-cancer tissue may provide more precise prognostic information.     

Carcinoembryonic antigen: 3 years' experience in a cancer clinic.

Long-term studies on multiple plasma samples of 988 patients with carcinoma of entodermal origin indicate that, especially for patients with colorectal cancer, repeatedly elevated or rising carcinoembryonic antigen (CEA) values are a sign of poor prognosis when found preoperatively, postoperatively or during chemotherapy. Persistently elevated CEA values in postoperative patients apparently free of disease are a useful marker for early detection of recurrence or metastases. Normal CEA values are of little or no prognostic value.     

An alternative to the diagnostic dilatation and curettage--endometrial cytology.

Endometrial aspiration cytology has been shown by multicentre prospective studies to be an acceptable and valuable method of assessing the endometrium. A retrospective study was undertaken over three years'' routine use of the Isaacs cell sampler. In 86% of the cases suitable endometrium was obtained, with experience of the technique being the important factor. When compared with histological findings, all 11 cases of malignancy were confirmed, including one ovarian adenocarcinoma. Of the cytological reports of endometrial hyperplasia, 78% were confirmed by the histological findings, with the remainder showing minor degrees of cystic hyperplasia or normal endometrium. In no case was a more abnormal lesion present on histological examination than had been suggested by cytological findings. The use of progestogens in reversing hyperplasia is seen to be effective, though the long term benefit remains uncertain. It is concluded that with an experienced cytologist, Isaacs endometrial aspiration should be used routinely for the primary investigation of dysfunctional uterine bleeding and postmenopausal bleeding.     

Carcinoembryonic antigen gene and carcinoembryonic antigen expression in the liver metastasis of colorectal carcinoma.

The presence of the carcinoembryonic antigen (CEA) gene and CEA expression in the liver was tested to identify their possible roles in the liver metastasis of colorectal carcinoma. The CEA gene in the liver was identified by amplifying the CEA-specific N-terminal domain exon with digoxigenin-dUTP labeling in 16 colorectal carcinomas with liver metastases. Next, CEA expression was tested by immunostaining using the anti-CEA monoclonal antibody (T84.66, ATCC). Liver tissues from 13 stomach cancer patients and 12 colorectal cancer patients without liver metastasis were also tested as control groups. Three grades (<25%, 25-50%, and 50%< or =) were given according to the proportion of positive cells. The CEA gene was amplified in the metastatic tumor cells of the liver (2.6 +/- 0.2, mean grade +/- SEM) and their surrounding hepatocytes (1.5 +/- 0.2) in all cases. CEA expression was found in all metastatic tumor cells and 14 cases of the surrounding hepatocytes. Among the control groups, the CEA gene of the hepatocytes was found in 9 cases each of the colorectal and the stomach cancers that did not exhibit CEA expression. The level of serum CEA was related with the numbers and volume of liver metastases, but not with CEA expression in tumor cells and surrounding hepatocytes. The CEA gene in the metastatic tumor cells, not in the hepatocytes, was closely associated with CEA expression in the surrounding hepatocytes (p<0.01). Although the precise mechanism of CEA gene regulation in hepatocytes remains to be proven, the CEA gene in the metastatic tumor of the liver seems to affect CEA expression in the surrounding hepatocytes facilitating liver metastasis in colorectal carcinoma.     

P16INK4A as an adjunct test in liquid-based cytology

OBJECTIVE: To assess the utility of P16INK4A as an adjunct test in liquid-based cytology in cases with equivocal morphologic changes of high grade squamous intraepithelial lesion (HSIL). STUDY DESIGN: P16INK4A immunoreactivity was investigated in residual ThinPrep material (Cytyc Corp., Boxborough, Massachusetts, U.S.A.) from 30 cases with equivocal diagnoses of HSIL that had corresponding follow-up biopsies. Two control ThinPrep cases were included: 1 HSIL with biopsy-confirmed cervical intraepithelial neoplasia (CIN) 3 and a negative specimen with a corresponding biopsy of squamous metaplasia. The expression of P16INK4A in ThinPrep specimens and corresponding biopsies was scored as previously described. A ThinPrep case was scored positive if it contained > 10 abnormal cells with nuclear and cytoplasmic immunocytochemical staining. Corresponding biopsies were scored as having negative, sporadic, focal or diffuse staining. RESULTS: The P16INK4A antibody assay was positive in 19 of 30 ThinPrep cases (63.3%). Seventeen of the 19 (89.4%) biopsies corresponding to the positively stained ThinPreps also were positive, with a score of at least focal positivity in the dysplastic regions (2 CIN 1, 4 CIN 2, 11 CIN 3; 2 lesions lost in the tissue recut). The assay was negative in 11 ThinPreps (36.6%) and 10 biopsies (33.3%) with tissue confirmation of chronic cervicitis (5), squamous metaplasia (2), CIN 1 (3) and 1 lesion lost in the tissue recut. Seventeen of 18 (94.4%) ThinPreps confirmed as high grade lesions upon biopsy showed P16INK4A positivity. The control HSIL case with a CIN 3 biopsy was diffusely positive for P16INK4A, and the control negative case with biopsy diagnosis of squamous metaplasia was negative. Nondysplastic squamous and metaplastic epithelium in 7 biopsies and nondysplastic squamous or metaplastic cells in ThinPrep cases were negative. Sporadic staining of bacteria, inflammatory cells and endocervical cells was noted. CONCLUSION: ThinPrep cases in the equivocal cytologic category with the corresponding tissue biopsy assayed for P16INK4A expression showed that there was utility for this type of testing. A larger series comparing corresponding ThinPrep and tissue biopsies will be undertaken. The role of HPV infection in these cases will also be explored.     

Information, discrimination and divergence in cytology. IV. Quality control in diagnostic cytology

The performance of diagnostic cytology on Papanicolaou smears can be periodically monitored by calculating the total discrimination or the total divergence of the cytologic diagnoses against the histologic diagnoses on samples obtained by colposcope-directed biopsies. Using these measures, the annual performances of the Gynecologic Cytology Laboratory of the University of Minnesota between 1980 and 1988 were retrospectively analyzed. For those years, the total discrimination and total divergence behaved similarly and were sensitive to the performance of the total system, including specimen sampling errors and laboratory precision. The lowest limits of the permissible range of the total discrimination and total divergence were 0.15 and -1.21 decits, respectively, for a single-slide Papanicolaou test if an 80% "hit" rate was accepted as the lowest threshold for each category. The optimal numbers of category-states were not a sensitive indicator of the quality of a laboratory; i.e., the optimal number of diagnostic categories remained at three throughout the period studied.     

Carcinoembryonic antigen in cytological specimens of urothelial carcinoma

A peroxidase-antiperoxidase (PAP) technique was developed for the detection of carcinoembryonic antigen (CEA) in urothelial transitional cells of 52 bladder cancer patients. The percentage of CEA-containing malignant cells varied from 10% to 100%. As a mean, 65% of the malignant cells stained for CEA, while the corresponding figure for benign-looking cells was 24%. The results were compared with cytological evaluations, flow cytophotometric results, and immunofluorescent (IF) staining for CEA. With increasing malignancy, more CEA was detected with the PAP technique, whereas the IF technique failed to show this trend. 18 of 20 malignant-tumors had an aneuploid DNA pattern. The two diploid cases were moderately well differentiated. Samples from bladders with heavy inflammation should be avoided in the PAP technique, since the unspecific staining of granulocytes disturbed a correct evaluation of the transitional cells. The PAP technique used on cytological material is recommended for antigen determinations, since good morphology is obtained.     

Diagnostic accuracy of cytology and immunocytology in carcinomatous effusions

Background: Immunocytology substantially improves the diagnostic accuracy of conventional cytology in the diagnosis of carcinomatous effusions. Due to the unequivocal characterization of the various cell populations, a sensitivity of 92% and specificity of 100% was achieved by immunocytology, examining samples of 1234 serous effusions. Objective: Cytology plays a central role in the aetiological clarification of serous effusions. The sensitivity of this method for the diagnosis of carcinomatous effusions varies between 40% and 80%. The aim of the present study was to investigate whether immunocytology substantially improves the diagnostic quality of the cytological examination in the diagnosis of carcinomatous effusions. Method: Consecutive serous effusions were examined by conventional cytology and by immunocytology. The immunocytological examination was performed on smears, using a standard panel of three antibodies against pancytokeratin, human epithelial antigen 125 and calretinin. Results: Altogether, 1234 effusion samples were examined. A total of 603 effusions were caused by carcinomas, five by malignant mesotheliomas, 11 by malignant lymphomas and 615 by non‐malignant disorders. In conventional cytology, carcinomatous effusions were correctly diagnosed in 314 samples, corresponding to a sensitivity of 52%. In 31 specimens (5%) tumour cells without further specification were described and in 161 samples (27%) the presence of tumour cells was suspected (84% overall sensitivity). A total of 97 carcinomatous effusions (16%) were diagnosed false‐negatively and 50 (8%) of the 615 non‐malignant effusions false‐positively (92% specificity). In immunocytology, 561 carcinomatous samples were correctly diagnosed, representing a sensitivity of 93%. In six cases (1%) the presence of tumour cells was suspected. A total of 36 carcinomatous effusions (6%) were diagnosed false‐negatively (94% over‐all sensitivity). Out of the 615 non‐malignant specimens, there were no false‐positive diagnoses (100% specificity). Conclusion: Immunocytology is a simple, cost‐effective, routinely practicable method which substantially improves the diagnostic accuracy of conventional cytology in the diagnosis of carcinomatous effusions. Therefore, we recommend the use of immunocytology in all those cases where cytology on its own is not completely unequivocal.     

Fine needle aspiration cytology of mucoepidermoid carcinoma. A diagnostic problem

The cytomorphologic findings in fine needle aspirates from 18 cases of histologically confirmed primary mucoepidermoid carcinoma of the salivary gland were reviewed and correlated with the findings on the tissue sections. An accurate diagnosis of these tumors in fine needle aspirates was possible when all three components (i.e., epidermoid cells, intermediate cells and mucus-producing cells) were identified. The pitfalls in the cytologic diagnosis of this tumor are discussed.     

DNA ploidy in seminal vesicle cells. A potential diagnostic pitfall in urine cytology

OBJECTIVE: To verify that abnormal DNA ploidy in urine cytology can occasionally be attributed to contamination by seminal vesicle cells. STUDY DESIGN: In the first part of this study, we analyzed the DNA content of six urine cytology specimens containing seminal vesicle cells. In the second part, we evaluated 21 Feulgen-stained prostate core biopsies containing seminal vesicle-type epithelium using a CAS-200 system. DNA index, proliferative activity (S + G2M) and degree of hyperploidy (> 5C) were determined in each case. RESULTS: All six urine cytology specimens were diploid, with all but one containing hyperploid cells (range, 0-16%; mean, 6.3%). Seminal vesicle cells from prostate biopsies showed a broad range of ploidy abnormalities. Ten cases (48%) showed an aneuploid peak, two cases (9%) showed a tetraploid peak, and nine cases (43%) showed only a diploid peak. All but one case showed both an elevation in proliferative activity (mean S + G2M, 24.2%) and some hyperploid cells (mean, > 5C; 4.5%). CONCLUSION: Seminal vesicle cells, although rarely seen in urine cytology, can cause abnormal DNA ploidy measurements. Morphologic criteria remain vital to an accurate cytologic diagnosis.