Bronchioloalveolar carcinoma presenting with meningeal carcinomatosis. Cytologic diagnosis in cerebrospinal fluid

The cytologic findings in a 35-year-old patient with bronchioloalveolar carcinoma who initially presented with central nervous system involvement are reported. Following the cytologic diagnosis of carcinomatous meningitis (metastatic adenocarcinoma), an open lung biopsy was performed, which confirmed the presence of a primary pulmonary neoplasm (bronchioloalveolar carcinoma). This case illustrates the importance of the cytologic diagnosis of a clinically unsuspected primary neoplasm. Further, together with three earlier reported cases, it indicates that, in young patients, tumor cells shedding into the cerebrospinal fluid can be the first indication of bronchioloalveolar carcinoma.     

Cerebrospinal fluid cytology in immature teratoma of the central nervous system. A case report

The present case shows the usefulness of cerebrospinal fluid (CSF) cytology in the diagnosis of leptomeningeal dissemination by immature teratoma. The tumor arose in the thoracolumbar spinal cord of a 14-year-old male. The initial histopathologic diagnosis was made on the tumor tissue taken at laminectomy. Postoperatively, CSF cytology revealed epithelial cell clusters, scattered squamous epithelial cells and small bundles of striated muscle fibers in the background of many histiocytes and inflammatory cells. Although these cells showed only slight cytologic atypia, their presence in the subarachnoid space suggested the leptomeningeal spread of well-differentiated portions of the immature teratoma. The postmortem examination revealed the primary tumor in the spinal cord and multiple metastatic nodules in the brain.     

Sputum cytology for the diagnosis of carcinoma of the lung

Of 400 consecutive patients with histologically proven carcinoma of the lung, one to six sputum samples (mean, 2.8) were examined cytologically; 60% also had histologic examination of paraffin-embedded material. The overall sensitivity of sputum cytology was 0.58. The sensitivity increased from 0.37 to 0.57 when three samples rather than one were examined; it increased by only another 0.01 when four to six samples were studied. The examination of paraffin-embedded material yielded another 0.075 increase in sensitivity. A multiparametric study, including diameter, cavitation, site and histologic type of the pulmonary tumors, showed that sputum cytology was particularly significant for neoplasms of the left upper lobe and that the sensitivity related to the histologic type was not independent of the site, diameter and cavitation. The overall cytologic typing accuracy was 0.77, with a range from 0.20 to 0.96. The majority of the diagnoses at variance with histology and the unclassified malignant epithelial tumor cells were found to be associated predominantly with carcinoma of the large-cell type and with poorly differentiated adenocarcinomas.     

Immunocytologic diagnosis of small-cell lung cancer in imprint smears.

Imprints of histologic or autopsy specimens from 12 small-cell lung cancers (SCLCs), 82 non-SCLCs (50 adenocarcinomas, 25 squamous-cell carcinomas, 1 adenosquamous carcinoma and 6 large-cell carcinomas), 2 carcinoid tumors, 1 malignant lymphoma and 8 metastatic carcinomas were examined immunocytologically for the presence of cluster 1 SCLC antigen (neural-cell adhesion molecule: N-CAM), chromogranin A, Leu-7, neuron-specific enolase (NSE) and gastrin-releasing peptide (GRP). The monoclonal antibodies NCC-LU-243 and NCC-LU-246, which are reactive with cluster 1 SCLC antigen/N-CAM, diffusely stained the cell membranes of all SCLCs and carcinoid tumors (100%) and diffusely and focally stained those of two of the large-cell carcinomas, two of the adenocarcinomas, two of the squamous-cell carcinomas and the one adenosquamous carcinoma. Malignant lymphoma and metastatic carcinoma were negative for this antigen. A few cases of large-cell carcinoma, adenocarcinoma, squamous-cell carcinoma and adenosquamous carcinoma were also stained with these antibodies, which may indicate a neuroendocrine differentiation. However, these tumors were different from SCLCs in that their positive tumor cell population was definitely smaller than that in SCLC, in which almost all tumor cells were positive. This confirmed the usefulness of antibodies against cluster 1 SCLC antigen for the immunocytologic diagnosis of SCLC and carcinoid tumor in imprint smears. Chromogranin A, GRP, NSE and Leu-7 were not useful in immunocytologically differentiating the imprints from these cases since only a few tumor cells were reactive with these antibodies. The antibodies against cluster 1 SCLC antigen/N-CAM can also be applied to cytologic preparations of sputum, pleural fluid and fine needle aspirates stained routinely by the Papanicolaou method since the antigen is preserved in such alcohol-fixed smears.     

Intraobserver and interobserver variability in the diagnosis of epithelial abnormalities in cervical smears

In a study of variability in the diagnosis of epithelial abnormalities, cervical smears with abnormalities of different severity were rescreened twice by 19 observers with an interval of six months. The observers focused on grading atypicality of squamous, squamous metaplastic and endocervical columnar epithelial cells; their results were compared (1) for the two screenings to assess intraobserver variability and (2) to "review" (final) diagnoses to assess interobserver variability. When the same observer rescreened a smear, 83.3% of the diagnoses did not differ more than one grade between two screenings; however, average intraobserver variability differed considerably for individual observers. The intraobserver variability was only slightly (not significantly) influenced by the years of experience in cytopathology of the observers. Intraobserver variability proved to be an important factor in incorrect diagnoses: 49.1% of the smears with false-negative and 52.9% with false-positive diagnoses at the first rescreening were correctly assessed at the second rescreening. Of all diagnoses made at rescreening, 80.9% were in agreement with the review diagnosis. The interobserver variability also showed considerable differences between observers; however, there was a strong influence of the experience of the observer on the interobserver variability. Atypicality grading of endocervical columnar epithelium by the observers showed a low correlation with the review diagnoses. The relatively low accuracy in the evaluation of this kind of epithelial abnormality is likely to be attributable to the low incidence of abnormal changes of endocervical columnar epithelium. The results of this study point to intraobserver variability as the main cause of false diagnoses. When wrongly diagnosed, severe epithelial abnormalities are more often underestimated than completely overlooked. Apart from training in cytopathology, the establishment of laboratory protocols for multiple screening of even minor abnormalities seem to be the most effective means of reducing the number of false diagnoses.     

Sputum cytology of metastatic carcinoma of the lung.

The cytopathology of 47 cases of metastatic carcinoma of the lung and of 28 cases of recurrent or metastatic bronchogenic carcinoma is reviewed. The diagnostic yield was better for recurrent than for metastatic carcinoma but overall was comparable to that of primary bronchogenic carcinomas. The metastatic tumors were located in all areas of the lung and included single as well as multiple lesions. The positive yield did not differ significantly in relation to any of the pathologic features but was somewhat higher if the metastases were large and centrally located. A definite differentiation of the metastatic tumors, usually adenocarcinomas, from new primary bronchogenic carcinomas is often possible particularly if the cytopathology can be compared with that of the primary lesion. Specific cytologic features include the relative lack of cohesion and the formation of columns in metastatic breast carcinomas, the formation of larger cohesive well circumscribed nodules composed of tall columnar cells in metastatic colon carcinomas, clear cell features in some metastatic adenocarcinomas of the kidney, and the small cell size and uniform, regular nuclear features in the often cytologically well differentiated metastatic carcinomas of the prostate.     

Determining the optimal flexion-extension axis of the elbow in vivo - a study of interobserver and intraobserver reliability

In the current study the interobserver and intraobserver reliability of a recently developed method to obtain the position and orientation vectors of the flexion-extension axis of the elbow in vivo is determined. The method uses the Flock of Birds six degrees-of-freedom electromagnetic tracking device. Ten subjects performed three trials comprising five flexion and extension cycles. The movements of the forearm with respect to the upper arm were recorded. Observer A measured two trials and observer B measured one trial. Optimal instantaneous helical axes were calculated in a humeral coordinate system for each trial. Intraclass correlation coefficients and 99% confidence intervals were computed to compare the three measurements. Zero was in the range of all the narrow confidence intervals, which is strong indication for resemblance. Interobserver intraclass correlation coefficients values for orientation vectors were good to excellent and intraobserver values were fair to good. The intraclass correlation coefficients values for position vectors were lower, probably due to the lack of variance between subjects. It is concluded that the method is reliable and can be used in certain clinical settings.     

The cytopathology of cerebrospinal fluid. II. Metastatic cancer, meningeal carcinomatosis and primary central nervous system neoplasms

The evaluation of cerebrospinal fluid (CSF) requires adaption of basic cytopathologic principles to the specific neoplasms that involve the central nervous system (CNS). In this review, general criteria for detecting malignant cells in CSF are presented. The incidence and cytologic characteristics of specific metastatic tumors that involve CSF are reviewed, and the incidence, pathogenesis and natural history of meningeal carcinomatosis are discussed. The role of cytopathology in the detection and management of primary CNS tumors is presented. Emphasis is placed on the cytologic characteristics of individual types of primary brain tumors and the application of fine needle aspiration biopsy to intracranial lesions.     

Granulocytic sarcoma with meningeal leukemia but no bone marrow involvement at presentation. A report of two cases with characteristic cerebrospinal fluid cytology.

Two cases occurred of granulocytic sarcoma with cerebrospinal fluid involvement but no associated leukemia on presentation. Both cases were difficult to identify by histology and were initially misdiagnosed as malignant lymphoma. The characteristic cerebrospinal fluid cytologic picture allowed the diagnosis. These cases underscore the value of cytologic examination of tumor imprints and the use of myeloid markers in panels for immunophenotyping lymphomas.     

Peritoneal washing cytology on fluid hysteroscopy and after curettage in women with endometrial carcinoma.

OBJECTIVE: To assess the influence of fluid hysteroscopy with target biopsy of the endometrium and the influence of added curettage on the results of peritoneal washing cytology (PWC) in endometrial carcinoma. STUDY DESIGN: In 42 women at risk of endometrial carcinoma, we performed fluid hysteroscopy with target biopsy of the endometrium and curettage. Evaluation of PWC of the pouch of Douglas was performed three times during the procedure: prior to hysteroscopy, after fluid hysteroscopy with target biopsy and after curettage. RESULTS: On cytologic slides from peritoneal washings in 11 patients with carcinoma of the endometrium, malignant endometrial cells were found after curettage in 72.7%. There was no statistically significant difference in PWC prior to hysteroscopy (two women, 20%) or after hysteroscopy with target biopsy (three women, 30%). There was a statistically significant difference (.05 level) in positive PWC after hysteroscopy with target biopsy (three women, 33.3%) and after curettage (eight women, 88.9%). CONCLUSION: Slides from carcinoma of the endometrium in PWC do not deteriorate after hysteroscopy with target biopsy of the endometrium, but tumor cells will appear in the pouch of Douglas after curettage.     

Cerebrospinal fluid and metastasis of transitional cell carcinoma of the bladder

Two cases are presented of cerebrospinal fluid with tumor cells metastatic from transitional cell carcinomas of the bladder. They demonstrate that in spite of the rarity of transitional cell carcinoma's metastasizing to the central nervous system (0.4% to 0.6%), it is necessary to consider the bladder as the primary site and to obtain urinary cytology in such cases when the primary tumor is still unknown.     

Giant-cell carcinoma of the lung. A cytologic study

A case of giant-cell carcinoma of the lung, confirmed at autopsy, is presented. The cytologic features seen in sputum samples, bronchial washings and brushings and fine needle aspiration biopsy material as well as the histologic findings are described. The possible relationship to bronchioloalveolar carcinoma is discussed. The cytologic features of giant-cell carcinoma of the lung, when seen in the context of the clinical and radiologic setting, should allow the cytologic identification of the tumor prior to surgical intervention.     

Interobserver and intraobserver variability in the cytologic diagnosis of normal and abnormal metaplastic squamous cells in pap smears

OBJECTIVE: Interoberver variability has important implications for patient care, diagnostic error and medical litigation. In the management of any cervical epithelial abnormality, its biologic significance as well as diagnostic reproducibility is very important. Interobserver variability has not been measured adequately for metaplastic squamous lesions. We analyzed interobserver and intraobserver variability and diagnostic accuracy in the diagnosis of dysplastic metaplastic cells. STUDY DESIGN: Sixty Pap smears from patients with abnormalities of metaplastic squamous cells of varying severity were selected from the files of Lankenau Hospital, Wynnewood, Pennsylvania, U.S.A., diagnosed between 1990 and 1996. These were reviewed by four observers with different levels of cytology experience. Each of the observers blindly and independently reviewed all Pap smears. Tabulated results were analyzed to determine interobserver and intraobserver variability and diagnostic accuracy. RESULTS: Statistically significant interobserver reproducibility was found between both inexperienced observers as well as between observers 1 (experienced) and 3 (inexperienced) and between observers 2 (experienced) and 4 (inexperienced). The observed degree of agreement between both experienced observers (1 and 2) reflected random rating rather than reproducibility. There was no difference in interobserver reproducibility in low vs. high grade lesions. Intraobserver reproducibility had no significant correlation with experience of the observer. The sensitivity ranged from 0.69 to 0.97 (mean, 0.79), while the specificity ranged from 0.09 to 0.46 (mean, 0.30). Mean diagnostic accuracy was better in benign and low grade squamous intraepithelial lesions in comparison to high grade squamous intraepithelial lesions. CONCLUSION: There was good interobserver agreement in classifying squamous metaplastic lesions. The agreement did not correlate with grade of dysplasia or experience of the cytopathologists. These findings should be considered in making treatment, quality assurance and legal decisions. A larger study is indicated to study interobserver and intraobserver variability and define cytologic criteria for lesions of metaplastic squamous cells.     

Previous cytology in patients with invasive carcinoma of the cervix

The cytologic history of 346 patients presenting with invasive carcinoma of the cervix was reviewed. A total of 74 patients (21%) reported that cervical cytology had been performed in the five years prior to presentation; confirmation of the cytologic history was obtained in 65 cases. Smears were available for review in 34 cases; of 28 smears originally reported as negative, 20 were found to be abnormal on review. The possible reasons for the failure of cytologic detection in these patients are discussed.     

Neuronal autoantibody titers in the course of small-cell lung carcinoma and platinum-associated neuropathy

The aims of this study were to investigate, in patients with newly diagnosed small-cell lung carcinoma (SCLC), whether or not there may be a relationship between the presence, type or titer of circulating neuronal autoantibodies and (i) the extent of SCLC dissemination at presentation, (ii) the development of peripheral neuropathy during platinum chemotherapy, (iii) survival time. We studied stored serum from 58 patients with uncomplicated SCLC who had participated in two trials conducted by the North Central Cancer Treatment Group (NCCTG); 29 had extensive disease and 29 had limited disease. No patient had neuropathy or other neurological or paraneoplastic problems at the time of enrollment but each group included 14 or 15 patients respectively who developed peripheral neuropathy in the course of chemotherapy. We tested five consecutive serum specimens from each patient in blinded fashion by (i) an indirect immunofluorescence assay optimized to detect neuron-restricted nuclear and cytoplasmic antibodies (triple substrate of mouse cerebellum, gut and kidney), and (ii) immunoprecipitation assays to detect neuronal Ca²⁺-channel-binding antibodies (N-type and P/Q-type). Sera that were positive by immunofluorescence were analyzed further by Western blotting. Neuronal autoantibodies were significantly more frequent in patients who had limited SCLC at presentation (12/29 or 41% positive) than in those with extensive SCLC (5/29 or 17% positive, P = 0.02). Neuronal autoantibodies of nuclear or cytoplasmic specificity were found in 50% of the seropositive patients with limited SCLC (21% of the total group), but in no patient with extensive SCLC (P = 0.01). The frequency of neuronal autoantibodies did not differ significantly among patients who did and did not develop peripheral neuropathy. Titers fell progressively during chemotherapy and did not rise again when peripheral neuropathy became clinically evident. This argues against a synergism between drug toxicity and neuronal autoimmunity as the mechanism of platinum-associated peripheral neuropathy. Seropositivity for neuronal autoantibodies did not affect the survival of patients with either limited or extensive SCLC. It is conceivable that the immunosuppression attendant on combined cisplatin/etoposide therapy cancels a pre-existing protective antitumor immune response (presumably cytotoxic-T-cell-mediated) for which the nuclear and cytoplasmic paraneoplastic IgG autoantibodies serve as a surrogate marker. Testing of this hypothesis would require the survival of seropositive and seronegative patients to be compared in a larger trial, using a therapeutic modality that does not compromise immunocompetence. Received: 20 November 1998 / Accepted: 6 January 1999     

Expression of c-src in cultured human neuroblastoma and small-cell lung carcinoma cell lines correlates with neurocrine differentiation.

Human cell lines with neuronal and neuroendocrine features were examined for their expression of pp60c-src, the cellular homolog of the transforming gene product pp60v-src of Rous sarcoma virus. Four neuroblastoma (LA-N-5, SH-SY5Y, Paju, and SK-N-MC) and three small-cell lung carcinoma (U-2020, U-1690, and U-1285) cell lines were selected on the basis of their stage of neurocrine differentiation, as determined by the expression of neuron-specific enolase. In an immune complex protein kinase assay, all seven cell lines displayed c-src kinase activity which was considerably higher than that found in nonneurocrine cells (human diploid fibroblasts, glioma, and non-small cell lung carcinoma cell lines). Furthermore, the c-src kinase activity, as determined by autophosphorylation or phosphorylation of an exogenous substrate, enolase, correlated with the stage of neurocrine differentiation. There was an approximately 30-fold difference in c-src kinase autophosphorylation activity between the cell lines representing the highest and lowest stages of neurocrine differentiation. A similar variation was found in the steady-state levels of the c-src protein of these cell lines. Highly differentiated neuroblastoma cells expressed two forms of the src protein. Digestion by Staphylococcus aureus V8 protease did reveal structural diversity in the amino-terminal ends of these c-src molecules. In summary, we found a clear correlation between c-src kinase activity and the stage of neuronal and neuroendocrine differentiation. Thus, the phenotypic similarity between neurons and neuroendocrine cells includes high c-src expression.     

Conventional respiratory cytology versus fine needle aspiration cytology in the diagnosis of lung cancer

The results of 184 fine needle aspiration (FNA) cytologic examinations were compared with the findings of "conventional" respiratory cytology (on sputums, bronchial brushings and bronchial washings) and histology (on biopsy and autopsy samples) and with the medical records. Positive cytologic results were obtained in 6 (10%) of 60 sputums, 17 (21%) of 80 brushings, 16 (19%) of 84 washings and 82 (44%) of 184 aspirates. These positive results were confirmed by biopsy for 6 of 6 sputums, 16 of 17 brushings and 15 of 16 washings. Among the 82 patients with a positive FNA cytology, malignancy was confirmed by lung biopsy in 39 and by autopsy in 2; the cytologic diagnosis was supported by clinical and radiographic findings in all but 1 of the remaining 41 patients. Using transbronchial lung biopsy, autopsy and medical records as final standards, the positive predictive values were 100% for sputum, 94.1% for brushings, 93.0% for washings and 98.6% for FNA samples. The high positive predictive values of FNA and the other cytologic procedures indicate that these diagnostic modalities provide simple, rapid and reliable methods for the diagnosis of lung cancer.     

Cytogenetic features of the differential diagnosis of lymphoid thymomas, small-cell non-Hodgkin lymphomas and undifferentiated small cell lung carcinoma

The predominance of compact and nucleolonemic types of nucleoli in undifferentiated small cell carcinoma of lung, the prevalence of micronucleoli and ring-shaped types of nucleoli in lymphoid thymoma and the increase of the level of micronucleoli in small cell non-Hodgkin's lymphoma have been established.