Biological implications of tumor cells in blood and bone marrow of pancreatic cancer patients.

BACKGROUND: Patients with pancreatic cancer often have tumor recurrence despite curative resection. Cancer cells detected in blood or bone marrow at the time of diagnosis may relate to tumor stage and to prognosis. Recent research emphasis has centered on tumor cells in bone marrow aspirates, but whether these represent early micrometastases or blood-borne cells in transit is unknown. PATIENTS AND METHODS: We developed a specific immunocytochemical assay that evaluated more than 5.3 x 10(6) extracted mononuclear cells per sample of blood and bone marrow and that could identify a single tumor cell in that population. The assay was applied to samples of blood and bone marrow from 105 patients with pancreatic cancer and 66 controls. The prevalence of isolated tumor cells was compared with Union Internationale Contre le Cancer (UICC) stage. A multivariate Cox regression analysis for survival was performed. RESULTS: Pancreatic cancer cells were detected in 26% of blood samples and in 24% of bone marrow specimens. Specificity for cancer was 96%. The prevalence of isolated tumor cells in patients with proven resectable cancer was 9% in blood and 13% in bone marrow. The prevalence increased with UICC tumor stage in blood (P =.04) but not in bone marrow (P =.52) and correlated in blood with resectability (P =.02), progression of disease (P=.08), and peritoneal dissemination (P =.003). While survival correlated significantly with tumor stage (P <.001) and isolated tumor cells in blood correlated with tumor stage, the finding of cancer cells in blood or bone marrow, or both, was not independently associated with survival in patients with pancreatic cancer. CONCLUSIONS: Isolated tumor cells in blood but not bone marrow reflect the stage of growth and spread of pancreatic cancer, particularly in the peritoneal cavity. The findings are consistent with cells in bone marrow aspirates being in transit, not implanted. These disseminated cancer cells may be the consequence, rather than the cause, of progression.

Detection and tumor staging of malignancy in cystic, intraductal, and solid tumors of the pancreas by EUS.

BACKGROUND: EUS can provide detailed imaging of pancreatic malignancies and direct fine needle aspiration (FNA) of pancreatic masses. The ability of EUS to detect and stage malignancy in cystic and intraductal lesions has not been investigated. Our aim was to determine the sensitivity and specificity of EUS imaging and FNA in detecting and staging of malignancy in solid, cystic, and intraductal lesions of the pancreas. METHODS: The records of 96 patients (46 solid, 26 cystic, 24 intraductal lesions) who underwent EUS followed by surgical exploration over a 3-year period were reviewed. The accuracy of EUS for detecting and staging malignancy was calculated based on the results of surgery and histology. RESULTS: EUS-guided FNA provided evidence of malignancy in solid, cystic, and ductal lesions with sensitivities of 59.5%, 50%, and 60%, respectively. The accuracy of staging by EUS was significantly less for intraductal lesions (47%), compared with cystic (100%) and solid lesions (85%) (p < 0. 05). CONCLUSIONS: EUS can be used to detect malignancy in cystic and intraductal tumors of the pancreas.

Significance of histiocytes in cervical smears from peri/postmenopausal women.

Histiocytes in cervicovaginal smears from peri- or postmenopausal women have been viewed as a potential indicator of endometrial neoplasia, but recent studies have refuted that view. This study further defines the clinical significance of such findings. All cervical smears were selected from women (< or = 50 yr) in whom the presence of histiocytes was mentioned; pertinent clinical history, follow-up information, and selected slides were reviewed. Among 105,225 total cervicovaginal smears from a 3.5-yr period, 106 smears from 103 women were identified. Forty-two patients (41%) were on hormone replacement therapy (2 on tamoxifen), and 23 (22.3%) patients experienced vaginal bleeding, all of whom had biopsy or cytology follow-up. Ten (9.6%) patients had no follow-up, 35 (32%) had repeat smears only, and 58 (56.3%) had endometrial/endocervical sampling. In 28 patients, the index smear was categorized as other than within normal limits or benign cellular changes; of these, 24 had subsequent tissue sampling and 4 had cytology follow-up. Of the patients with tissue sampling, 51 (84%) had benign findings (including polyps), 2 (3.5%) had hyperplasia, and 5 (10%) had adenocarcinoma. All 5 patients with adenocarcinoma had endometrial glandular cells on the smear, and 4 had vaginal bleeding. One patient with hyperplasia had vaginal bleeding, and the other was on tamoxifen and had endometrial glandular cells on the smear. None of the patients having only histiocytes on their smears and no clinical symptoms or risk factors had endometrial adenocarcinoma or hyperplasia. These findings support the conclusion that the presence of histiocytes alone on cervicovaginal smears from peri- or postmenopausal women is nonspecific and of no major clinical significance in the absence of other clinical or cytologic findings.

Cyst fluid cytology and chemical features in a case of lymphoepithelial cyst of the pancreas: A rare and difficult preoperative diagnosis.

Most pancreatic cysts (90%) are inflammatory pseudocysts. Approximately 10% of pancreatic cysts are neoplasms, including serous cystadenomas, and mucinous tumors, some of which are malignant. Analysis of pancreatic cyst fluid obtained by percutaneous or endoscopic fine-needle aspiration is increasingly being used for the preoperative diagnosis of pancreatic or peripancreatic cysts. However, cyst fluid chemical and cytologic features in less common types of pancreatic cysts have not been reported. Lymphoepithelial cyst of the pancreas is exceedingly rare, and only occasional individual reports have described cyst fluid findings. We report on a case of lymphoepithelial cyst of the pancreas developing in a middle-aged man. Cyst fluid aspirated under radiological guidance showed elevated levels of carcinoembryonic antigen (CEA), CA19-9, CA 125, and amylase, and a viscosity greater than that of serum. A cell block preparation of a fine-needle aspiration showed tissue fragments with a keratinized squamous lining and a lymphocytic infiltrate in the wall, and abundant background keratinous debris. The cytologic and biochemical findings in this case exhibit similarities to the findings reported in other reports, and may represent a recognizable pattern on cyst fluid analysis.

Fine needle aspiration biopsy of the pancreas.

This article covers basic topics such as indications, contraindications, techniques and complications. Individual sections focus on the differential diagnosis between adenocarcinoma and benign or reactive processes, diagnosis of pancreatic endocrine tumors, and the diagnosis of cystic lesions using pancreatic cyst fluid analysis including cytopathology.

Implications of peritoneal cytology for pancreatic cancer management.

OBJECTIVE: To assess the implications of positive cytology for malignant cells (positive results) from peritoneal washings in the management of patients with pancreatic cancer. DESIGN: Retrospective cohort study. SETTING: Referral practice in a university hospital. PATIENTS: A total of 32 consecutive pancreatic cancer patients with positive results from peritoneal washings during a 4-year period, 17 with visible biopsy-proven intraabdominal metastases at the time of laparoscopy or laparotomy and 15 without visible metastases. A treatment-matched control group of 30 patients was randomly selected from a group of 105 patients with negative cytology for malignant cells (negative results) from peritoneal-fluid cytology. INTERVENTIONS: Eight of 17 patients with visible metastases underwent treatment with chemotherapy, radiation, or both; 13 of the 15 patients with no visible metastases underwent further treatment, including pancreatic resection in 2 patients and external beam radiation in 13 patients (3 with intraoperative radiation therapy). MAIN OUTCOME MEASURES: Time to metastases and mortality. RESULTS: Median survival among patients with and without visible metastasis was 7.8 months and 8.6 months, respectively (P=.95), despite the fact that patients without visible metastases received more treatment. Patients without visible metastases at presentation were found to have metastatic disease as documented by computed tomographic scan or subsequent laparotomy at a median time of 2.9 months. The survival of treatment-matched patients with negative cytology was significantly longer (median, 13.5 months; P=.04). CONCLUSIONS: Pancreatic cancer patients with peritoneal micrometastases have a dismal outcome even without macroscopic metastases. Since these patients do not benefit from local therapy, the finding of a positive result from peritoneal-fluid cytologic testing contraindicates further irradiation or surgery, except for specific complications.

Cytological features of malignant metastatic ameloblastoma: a case report and differential diagnosis.

In this report, the cytological features and differential diagnosis of the metastasis from and subsequent local recurrence of an unusual case of malignant (metastatic) ameloblastoma are described, with histological confirmation. Characteristic cytological findings included fibrovascular central cores surrounded by palisading crowded basaloid or columnar cells or both and rosette-like structures of tumor cells with central fibrillary material. Keratin debris in the background and cystic cavities were prominent components of the metastatic ameloblastoma. The basaloid cells showed scant-to-absent cytoplasm, round-to-oval to tear-shaped nuclei, rare longitudinal nuclear grooves, single or multiple nucleoli, and smooth-to-clefted nuclear contours. No features to predict malignant behavior were identified (abundant mitotic activity, necrosis, nuclear pleomorphism). The cytological features of ameloblastoma appear to be characteristic enough to allow definitive diagnosis. However, since the cytology of this tumor is underreported in the literature, the unwary observer could easily misdiagnose it, especially at metastatic sites.

Cytologic diagnosis of pancreatic cystic lesions. A prospective study of 28 percutaneous aspirates.

PURPOSE: To prospectively evaluate fine needle aspiration biopsy (FNAB) of pancreatic cystic lesions. STUDY DESIGN: We performed a blind, prospective study on percutaneous aspirates from 28 radiographically identified cysts, including 6 inflammatory cysts (5 pseudocysts and 1 abscess), 4 serous cystadenomas, 1 cystic islet cell tumor, 5 mucinous cystic neoplasms, 6 mucinous cystadenocarcinomas and 6 nonpancreatic cysts. RESULTS: Four of six (67%) cystadenocarcinomas were identified as malignant, and the other two, which lacked sufficient morphologic criteria for malignancy, as consistent with mucinous cystic neoplasm. Two of five mucinous cystic neoplasms were correctly classified. One, which contained atypical cells, did not appear to be mucinous on the ThinPrep, and one, which lacked an epithelial component, was suggested because of the presence of mucin in the background. The fifth one contained inflammatory cells only. One of four serous cystadenomas produced a diagnostic specimen. FNAB of the cystic islet cell tumor was nondiagnostic. Five of six inflammatory cysts (83%) were correctly diagnosed, whereas one case produced an acellular, nondiagnostic specimen. Six of 28 (23%) cases were nonpancreatic cysts, aspirated under the presumption that they were pancreatic cysts based on radiologic studies: only one case, a papillary cystadenocarcinoma of the stomach, was correctly diagnosed; the other five cases were nondiagnostic, and in two of these the assumption that the cysts were pancreatic in origin precluded an accurate classification. CONCLUSION: FNAB of pancreatic cystic lesions can differentiate mucinous from nonmucinous pancreatic cysts and provide definitive evidence of malignancy. In some cases, serous cystadenomas can be diagnosed. Pseudocysts can be suspected on the basis of an inflammatory smear lacking both epithelial cells and background mucin, but this finding is not specific. Nonpancreatic lesions constitute a significant percentage of cases aspirated as pancreatic cysts and present a major pitfall in cytologic interpretation.

Fine needle aspiration biopsy of the thyroid gland in patients with prior Graves' disease treated with radioactive iodine. Morphologic findings and potential pitfalls.

OBJECTIVE: To evaluate the morphologic findings and their potential pitfalls in fine needle aspiration biopsies (FNAB) of thyroid glands obtained following radioactive iodine (RaI) (131I) treatment for Graves' disease. STUDY DESIGN: Study of thyroid FNAB specimens from six patients with prior Graves' disease treated with RaI who developed palpable nodules and had subsequent thyroid resections. RESULTS: The cytologic changes attributed to radiation were quite variable among the six cases and were so pronounced in one case that a false positive diagnosis of papillary carcinoma was made even though a history of RaI had been provided. The FNAB specimen from the second case, submitted without a history of RaI treatment, was diagnosed as suspicious for papillary carcinoma. The smears from patient 3 were signed out descriptively because the pertinent clinical history had not been provided. The FNAB specimens from the last three patients were correctly interpreted because of the history of RaI therapy provided. All six thyroid surgical specimens showed changes consistent with radiation injury, and none contained evidence of malignancy. CONCLUSION: The study's findings demonstrate that the atypia produced by RaI may be severe, leading to an erroneous diagnosis of malignancy. Provision of the appropriate clinical history of Graves' disease treated with RaI may prevent this pitfall.

Peritoneal fluid cytology in advanced mucinous cystadenocarcinoma of the pancreas.

OBJECTIVE: To assess the role of peritoneal cytology in the management of mucinous cystadenocarcinoma. STUDY DESIGN: A review of the peritoneal fluid cytologic findings in eight selected cases of pancreatic mucinous cystadenocarcinomas. RESULTS: Four of eight cases (50%) were positive for malignant cells. All four patients with positive peritoneal cytology had unresectable tumors and extensive intraabdominal metastases. Of the four patients with negative cytology, three had unresectable, locally invasive tumors without metastases, and one had a resectable tumor confined to the pancreas. CONCLUSION: Peritoneal cytology is frequently positive in unresectable mucinous cystadenocarcinomas with intraabdominal metastases, but cytology may often be negative in unresectable cases. Therefore, negative cytologic findings in these cases do not reliably ensure resectability, while positive findings clearly correlate with the presence of intraabdominal metastases. A larger study of unselected patients, including more with resectable tumors, will be required to define the full utility of this technique in preoperative assessment.

Peritoneal exfoliative cytology and Ki-ras mutational analysis in patients with pancreatic adenocarcinoma.

This is the first description of the detection of pancreatic adenocarcinoma peritoneal metastasis by established radiolabeled polymerase chain reaction (PCR) based Ki-ras mutational analysis. The present study evaluates both routine cytology and Ki-ras mutational analysis in the detection of peritoneal micrometastases in 24 subjects with pancreatic adenocarcinoma compared to seven control cases of chronic pancreatitis and seven control cases of cholecystitis. Locoregional extension, vascular invasion, and distal metastases were confirmed in 21/24 (88%) of the subjects with pancreatic adenocarcinoma by compute tomography, angiography, endosonography, or laparoscopy. The most common site of histologically confirmed extrapancreatic involvement was the vasculature (29%), followed by the liver (25%), duodenum (17%), peritoneum (17%), and lymph nodes (12%). Peritoneal lavage cytology was positive in 3/24 (12%) cases of pancreatic carcinoma while Ki-ras codon 12 mutational analysis was positive in 2/24 (8%). Two histologically confirmed cases of peritoneal metastases were not detected by either methodology, while peritoneal lavage cytology detected malignant cells in one case with histologically confirmed lymph node metastasis.

Flow cytometric analysis of DNA ploidy, percent S-phase fraction, and total proliferative fraction as prognostic indicators of local control and survival following radiation therapy for prostate carcinoma.

PURPOSE: Treatment recommendations for localized prostate cancer may be improved by the identification of tumor factors prognostic for local control and survival. In this retrospective study, flow cytometric deoxyribonucleic acid (DNA) ploidy analysis and cell cycle analysis were performed on paraffin-embedded biopsy material to determine if additional prognostic factors could be identified in patients treated with radiation therapy. METHODS AND MATERIALS: Seventy patients with T1-4NxM0 tumors were identified in whom the primary treatment had been radical radiation therapy with no prior or concurrent endocrine therapy and in whom sufficient prostatic tissue was available for flow cytometric analysis. There were 40 diploid, 26 aneuploid, and 4 multiploid cases. Aneuploid and multiploid cases were combined for analysis. Cell cycle data were obtained on all diploid and 10 aneuploid cases. RESULTS: The histologic differentiation of the tumor (well or moderate vs. poor) was an independent predictor of overall survival and disease-free survival (p = 0.05 and 0.01, respectively). Local control was worse in the poorly differentiated patients, although this was not statistically significant in a multivariate analysis (p = 0.08). Neither T-stage, deoxyribonucleic acid ploidy (diploid vs. nondiploid), percent S-phase fraction, nor total proliferative fraction (S-phase fraction + G2M) significantly predicted for any of these endpoints. Within the diploid and well or moderately differentiated subgroup (n = 25), S-phase (< 4.2 vs. > or = 4.2) was a significant predictor of local control (100% vs. 51%, p = 0.03). A comparable distinction could be made using total proliferative fraction (< 10% vs. > or = 10%) with local control rates of 100% vs. 56% (p = 0.05). Among the poorly differentiated tumors, no similarly favorable subgroup was identified. CONCLUSIONS: This retrospective and multivariate analysis identifies both histology and percent S-phase or total proliferative fraction as predictors of local control following irradiation, and confirms that histology, but not DNA ploidy, is significant for overall survival. If these previously unreported findings are confirmed by prospective studies, S-phase should be added to histology as a parameter in the evaluation of clinical trials.

Cyst fluid cytologic analysis in the differential diagnosis of pancreatic cystic lesions.

Pancreatic cystic lesions include inflammatory pseudocysts, benign serous cystadenomas, and mucinous neoplasms, some of which are malignant. Cytologic analysis of cyst fluid has been proposed to diagnose pancreatic cysts before definitive therapy. The authors report an analysis of 31 pancreatic cyst aspirates: 9 pseudocysts, 5 serous cystadenomas, 8 mucinous cystic neoplasms, 4 mucinous cystadenocarcinomas, 2 papillary cystadenocarcinomas, 1 mucinous ductal adenocarcinoma with cystic degeneration, and 2 cystic islet cell tumors. All pseudocysts were correctly classified as probable inflammatory lesions, because of the presence of abundant acute inflammation and histiocytes and the absence of glandular epithelium. Three of five serous cystadenomas were correctly classified, based on the presence of small cuboidal cells in clusters with microvesicular cytoplasm containing glycogen. Eleven of 12 mucinous tumors contained round cells with large cytoplasmic mucin vacuoles or columnar cells containing cytoplasmic mucin. Malignancy was diagnosed in 5 of 7 carcinomas, 1 case was classified as suspicious for malignancy, and 1 case was nondiagnostic because of the absence of a cellular component. The authors concluded that pancreatic cyst fluid cytologic analysis is useful in differentiating mucinous from nonmucinous pancreatic cysts and may provide definitive evidence of malignancy. In some cases, serous cystadenoma can be diagnosed based on cytologic analysis. An inflammatory smear without epithelial cells suggests a pseudocyst, but these findings are nonspecific, as a similar pattern may occur when a cystic neoplasm undergoes degenerative changes. Therefore, pseudocyst remains a diagnosis of exclusion.

The AgNOR technique, PCNA immunohistochemistry, and DNA ploidy in the evaluation of choroid plexus biopsy specimens.

The histologic distinctions between normal choroid plexus and choroid plexus papilloma and between choroid plexus papilloma and choroid plexus carcinoma are sometimes difficult. The authors performed the silver nucleolar organizer region (AgNOR) technique, immunohistochemistry for proliferating cell nuclear antigen (PCNA), and DNA ploidy analysis by flow cytometry on 9 samples of normal choroid plexus, 8 papillomas, and 13 carcinomas to evaluate whether these techniques can aid in these differential diagnoses. Significant differences were found in the mean AgNOR count between normal choroid plexus (1.35 +/- 0.11) and choroid plexus papillomas (2.42 +/- 0.81) (P < 0.001), but not between choroid plexus papillomas and carcinomas. In the normal choroid plexus, AgNORs were smooth and round; in the papillomas and carcinomas, however, they varied in size and shape. Compound AgNORs were commonly present in the tumors but were essentially absent in controls. Antibody to PCNA did not stain normal choroid plexus cells (except for focal staining in one sample of normal choroid plexus adjacent to a carcinoma) but stained many papilloma and carcinoma cells. DNA ploidy analysis demonstrated aneuploidy in some papillomas and carcinomas but could not be used for the distinction of normal choroid plexus from papillomas. These results suggested that the AgNOR technique and PCNA immunohistochemistry could be used to distinguish normal choroid plexus from choroid plexus papilloma in small, diagnostically difficult biopsy specimens.