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Background: Mandatory review of outside pathologic material is intended to detect interpretive errors that may have a clinically significant impact on patient care. Prior to definitive treatment of referred patients, the University of Iowa Carver College of Medicine requires a review of pertinent pathologic material previously obtained at outside institutions. The aims of this study were to determine if this local standard of practice has a measurable impact on patient care., Methods: The pathologic diagnoses of 499 second opinion cytology cases seen at the University of Iowa Carver College of Medicine were studied. Each second opinion was classified as "no diagnostic disagreement", "minor disagreement", or "major disagreement" with respect to the originating institution's interpretation. The clinical impact of major disagreement cases was determined by pathologic and clinical follow-up via chart review., Results: Second opinion cytology resulted in 37 cases (7.4% of total cases) with major diagnostic disagreements. Clinical and pathologic follow-up was available in 30 of the major disagreement cases; second opinion diagnosis was better supported in 22 of these cases compared to the outside diagnosis. The second opinion in 6 major disagreement cases prompted changes in clinical management., Conclusions: Major disagreements in second opinion cytology are common, likely reflective of the challenges inherent in the interpretation of cytologic specimens. Although mandatory second opinion of outside cytologic material prompted changes in clinical management in only a small fraction of cases (1.2%), this rate was similar to those previously published for surgical pathology second opinion. These findings support the notion that mandatory second opinion policy as an important part of patient care., ((c) 2009 American Cancer Society.)

Background: Preclinical testing suggests the combination of carboplatin and irinotecan has at least additive antitumor activity. The primary objectives of the current study were to determine the maximum tolerated doses (MTDs) and recommended phase 2 doses of carboplatin administered with irinotecan to pediatric patients with refractory solid tumors., Methods: This was a multicenter, open-label, single-arm dose escalation study in which subjects with refractory solid tumors received 21-day treatment cycles of intravenous carboplatin on Day 1 followed by intravenous irinotecan administered daily for 10 days within 2 consecutive weeks. The plasma pharmacokinetics of ultrafiltrable platinum, irinotecan, and 2 irinotecan metabolites were determined during Cycle 1. The interpatient plan for dose escalation at study initiation was to increase irinotecan first followed by increases in carboplatin., Results: Twenty-eight patients with a median age of 8.5 years (range, 1-21 years) were enrolled with a variety of solid tumors. Two of 6 subjects at the first dose level (carboplatin target area under the curve [AUC], 4.0 mg/mL*min; irinotecan, 18 mg/m2/dose) experienced dose-limiting gastrointestinal toxicities requiring a dose de-escalation scheme (carboplatin AUC, 4.0 mg/mL*min; irinotecan, 15 mg/m2/dose). Three of 6 subjects at the second dose level experienced dose-limiting gastrointestinal complications and bone marrow suppression. A further dose de-escalation to carboplatin AUC of 4.0 mg/mL*min and irinotecan of 12 mg/m2/dose resulted in dose-limiting bone marrow suppression in 1 of 13 patients treated at that dose, and therefore was determined to be the MTD. One complete response (in a patient with medulloblastoma) and 3 partial responses (in patients with neuroblastoma, medulloblastoma, and lymphoendothelial carcinoma, respectively) were observed., Conclusions: The recommended phase 2 dose in heavily pretreated pediatric patients is carboplatin (AUC, 4 mg/mL*min on Day 1) and irinotecan (12 mg/m2/dayx10 days) given every 21 days., (Copyright (c) 2008 American Cancer Society.)

Background: Clear cell tumors (CCTs) occur as primary neoplasms in a number of anatomic sites. Due to their overlapping morphologic features, these tumors can be challenging for the cytologist, particularly when they present as metastatic lesions., Methods: Forty-nine fine-needle aspirations (FNA) of metastatic CCTs from 46 patients (age range, 29-87 years; mean, 64 years) were reviewed retrospectively. In addition to the routine smears and cell block preparations, ancillary studies were performed in selected cases. Clinical and/or histologic follow-up was obtained for all patients., Results: The sites of the 49 FNAs were the lung (12 cases), lymph nodes (9 cases), liver (7 cases), bone (7 cases), soft tissue (4 cases), pelvis (2 cases), adrenal gland (2 cases), pancreas (1 case), thyroid (2 cases), peritoneum (2 cases), and vagina (1 case). Twenty-seven patients had a previous history of a CCT and the FNA material in these cases was consistent with a metastasis. The primary anatomic sites in these cases were the kidney (20 cases), ovary (2 cases), salivary gland (1 case), and cervix (1 case). On light microscopy, these tumors had a similar appearance and often were indistinguishable. Nineteen patients did not have a prior history of malignancy; 12 of these patients had a concurrent renal mass and the diagnosis of metastatic renal cell carcinoma was made. The anatomic site of origin of seven of the ten remaining tumors (kidney [2 cases], lung [2 cases], ovary [1 case], germ cell [1 case], and endometrium [1 case]) was established through immunocytochemical studies of cytologic material and clinical follow-up., Conclusions: FNA plays an important role in the diagnosis of metastatic CCT. Cytologic examination, ancillary studies, and clinical information can establish the anatomic site of origin in the majority (95%) of cases, precluding the necessity of obtaining additional tissue. Cancer (Cancer Cytopathol), (Copyright 1999 American Cancer Society.)

Background: The cytologic diagnosis of gastric adenocarcinoma often is difficult, and the role of gastric brushing in the detection of gastric malignancy is controversial. The purpose of this study was to identify the key cytologic criteria that are most useful for establishing a diagnosis of adenocarcinoma in gastric brushing specimens., Methods: One hundred gastric brushings were reviewed retrospectively. Fifty of the specimens were obtained from patients with histologically confirmed benign lesions. The other 50 specimens were obtained from patients with histologically confirmed gastric adenocarcinoma. All 100 brushing specimens were reviewed without knowledge of the histologic diagnosis. Each specimen was assessed for the presence or absence of 16 different cytologic features that have been identified in the published literature as being useful for separating benign conditions from malignancy. A multiple logistic linear regression analysis was performed to determine which combination of criteria was the most useful for diagnosing gastric adenocarcinoma., Results: Three key cytologic criteria were identified as being the most useful for diagnosing gastric adenocarcinoma: single atypical cells with intact cytoplasm, eccentric nuclei, and atypical naked nuclei. When at least 2 of these cytologic criteria were present, the sensitivity and specificity for detecting adenocarcinoma were 88% and 100%, respectively. Two minor cytologic criteria also were identified: nuclear hyperchromasia and nuclear molding., Conclusions: Our statistical analysis demonstrates that gastric adenocarcinoma can be diagnosed with a high degree of accuracy using gastric brushing specimens when specific cytologic criteria are applied.

Background: The head and neck region is one of the most common locations of rhabdomyosarcoma. Salivary gland involvement is usually secondary to advanced disease, and presentation as a primary salivary gland tumor is very rare., Methods: Three cases of rhabdomyosarcoma presenting as parotid masses, in 2 boys (ages 3 and 7 years) and a girl (age 5 years), were retrieved from the files of 2 institutions., Results: The three patients presented with parotid gland enlargement. Clinically, the enlargements appeared to be inflammatory, and they were treated unsuccessfully with antibiotics. Fine-needle aspiration biopsy (FNAB) was performed on all three patients. The cytologic features varied from one case to another; one case had features of a small round cell tumor, another was composed of a monomorphic population of spindle cells in a metachromatic stroma, and the third case was composed mostly of spindle cells with moderate cellular pleomorphism. Immunohistochemical studies performed in two of the cases confirmed the diagnosis of rhabdomyosarcoma, and ultrastructural studies were confirmatory in the other case. The patients are alive; 2 of them have had no evidence of disease after 6 and 9 years of follow-up, and the third, the most recent patient, has just finished adjuvant chemotherapy., Conclusions: With the increased use of FNAB for the evaluation of salivary gland masses in children, the authors believe that it is important to recognize the occurrence of rhabdomyosarcoma in this location. Immunohistochemical studies have proved helpful in differentiating rhabdomyosarcoma from other parotid gland tumors and can be readily done on cytologic preparations.

Background: Although site-specific cancer frequencies and incidence rates for the United States are regularly reported by the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) program, they have not been reported by histologic type within a specific site. This report presents data for 76,303 cancers of the urinary tract by histologic type., Methods: Cancer data were obtained from the SEER program. Urinary tract cancers were eligible if they were histologically confirmed, in situ or invasive, and diagnosed between 1973 and 1987. The urinary tract was divided into the following sites: kidney and renal pelvis, ureter, urinary bladder, urethra, and other urinary. Histologic types were evaluated by site, age, sex, race, incidence, and survival., Results: Of the 76,303 cancers, 72.0% were transitional cell carcinomas and 22.0% were adenocarcinomas. Adenocarcinoma was the most common histologic type in the kidney and renal pelvis (also referred to as renal cell carcinoma), whereas transitional cell carcinoma was the most common histologic type in the remainder of the urinary tract. For the more common histologic types, age-adjusted incidence rates were always higher among males than females., Conclusions: Because adenocarcinomas represent most kidney and renal pelvis cancers and transitional cell carcinomas represent most urinary bladder cancers, these histologic types largely explain incidence and survival trends reported for these two common cancer sites. Future population-based cancer epidemiologic studies should try to focus more on specific histologic types within a cancer site to better clarify risk factors and incidence and survival trends for cancer.

Background: Bladder cytology is being used increasingly to detect and monitor early stage bladder cancer. Because of the lack of significant cytomorphologic atypia in low grade transitional cell carcinomas (TCCs), there often is great difficulty in separating these neoplastic cells from benign urothelial cells., Methods: In an attempt to increase diagnostic sensitivity, 82 bladder wash specimens, which included 33 low grade TCCs and 49 nonneoplastic lesions, were reviewed retrospectively. With a stepwise logistic regression analysis, three key cytomorphologic criteria useful in the separation of low grade TCC from benign urothelium were identified., Results: The key cytologic criteria were increased nuclear/cytoplasmic ratios, irregular nuclear borders, and cytoplasmic homogeneity. By using contingency tables, these three criteria combined had a sensitivity of 45% and a specificity of 98% in the diagnosis of low grade transitional cell carcinoma. If any two of the criteria were present, there was a sensitivity of 85% and a specificity of 96%., Conclusions: By using these three criteria, the diagnosis of TCC can be made with a high degree of accuracy in bladder wash specimens.

Background: Traditionally, open biopsy has been considered the optimal procedure for the diagnosis of breast nodules. Fine-needle aspiration biopsy (FNAB) has been proposed as an alternate method for the diagnosis of many palpable breast lesions., Methods: The authors compared the diagnostic utility of open biopsy and FNAB using decision tree and cost-effectiveness analyses., Results: When compared with two-step excisional biopsy, FNAB achieved a savings of over $700 at the cost of 0.1% decrease in 10-year overall survival., Conclusions: These data indicate FNAB to be a reasonable alternative to open biopsy for the diagnosis of palpable breast lesions in many patients.

Background: Alpha-fetoprotein (AFP) serum values after orchiectomy for testicular cancer can be used to predict the residual disease status. However, the optimal strategy for postorchiectomy marker analysis has not been studied. This article evaluated different analytic methods in an effort to identify the approach that provided the greatest sensitivity and specificity for occult residual disease., Methods: Statistical information on the AFP half-life (t1/2) derived from a clinical data set of 24 patients with AFP-secreting clinical Stage A testicular cancer and pathologically defined nodal status was incorporated into a mathematic model of postorchiectomy marker values as a function of residual tumor volume and time. The model was used to test the effect of various analytic strategies on detecting the residual tumor. The clinical data set then was analyzed to measure the effect of different analytic methods on the predictive value of the AFP t1/2., Results: In the model, the AFP t1/2 calculated from a single set of serum measurements obtained from the initial serum t1/2 was a poor predictor of disease status in patients with up to 40% residual tumor volume. Determined by the sequential addition of serum values obtained at normal t1/2 intervals, the AFP t1/2 improved in sensitivity but required up to seven serial values (35 days) to detect an abnormal t1/2 in patients with 10% residual tumor. By contrast, changes in the most recent interval t1/2 relative to the initial calculated t1/2 predicted the disease status in patients with 10% residual tumor after four t1/2 (20 days) and in patients with 1% residual volume after 35 days., Conclusions: The use of this last strategy in the clinical data set improved both the sensitivity and specificity of the AFP t1/2 in predicting residual tumor relative to the other methods.

To determine if in vivo binding specificities of monoclonal antibodies to tumor nodules would reflect in vitro antibody specificities as determined by radioimmunoassay, two monoclonal antibodies were selected for imaging of human tumor xenografts in nude mice. By in vitro radioimmunoassay, antibody 436 binds to the M20 melanoma cell line, but not to the P3 carcinoma cell line; antibody 44 binds to P3 but not to M20. Both antibodies are IgG1 isotypes. Nude mice bearing an M20 melanoma in one flank and a P3 carcinoma in the other were injected intravenously with 5 to 25 micrograms of each antibody labeled with either I-125 or I-131; in separate animals the labels were reversed. Animals were imaged daily with a scintillation camera equipped with a pinhole collimator. On day 6 the animals were sacrificed, and binding of the antibodies to the tumors and normal tissue were compared. Antibody 436 had up to a two-fold binding advantage in vivo for the melanoma, whereas antibody 44 had up to a two-fold binding advantage for the carcinoma, thus confirming the in vitro specificities of each. However, imaging on day 4 and computer analysis of percent radioactivity in the tumors showed that tumor images were related directly to tumor size and relatively uninfluenced by antibody specificity. Thus, even though antibody specificity can be demonstrated by differential tissue counting, imaging of tumor deposits appears to involve a nonspecific phenomenon that is largely dependent upon tumor weight.

Fine needle aspiration biopsy (FNAB) has become a popular method to diagnose mass lesions of the liver. Although several reports have listed FNAB criteria to be used to diagnose both primary and metastatic tumors of the liver, none have separated key cytologic criteria from secondary criteria. We reviewed the FNAB smears from 35 patients with proven hepatocellular carcinoma and 74 patients with proven metastatic tumors in the liver. All specimens were coded as to the presence or absence of the following variables: polygonal cells with centrally placed nuclei; well-defined, granular cytoplasm; large nucleoli; small cytoplasmic vacuoles; large cytoplasmic vacuoles; bile; polymorphonuclear leukocytes; malignant cells separated by sinusoidal vessels; endothelial cells surrounding tumor cell clusters; multinucleated tumor giant cells; basophilic intracytoplasmic inclusions; eosinophilic intracytoplasmic inclusions; and intranuclear cytoplasmic inclusions. A step-wise logistic regression analysis was performed on the data to determine the variables predictive of hepatocellular carcinoma. The statistical analysis selected polygonal cells with centrally placed nuclei, malignant cells separated by sinusoidal capillaries, and bile as the key cytologic criteria for hepatocellular carcinoma. Endothelial cells surrounding tumor cell clusters and intranuclear cytoplasmic inclusions were selected as secondary criteria by this analysis.

A 12-year-old girl was admitted to the hospital for evaluation of an abdominal mass. A preoperative computed tomography scan showed a large tumor in the pelvis. The serum alpha-fetoprotein level was 2,170,000 ng/ml. A 3000-g left ovarian neoplasm was resected. It was encapsulated and showed focal microcystic degeneration, necrosis, and hemorrhage. Microscopically, it was composed of gland-like spaces containing mucin-positive material and surrounded by scant fibrovascular tissue. The epithelial cells were low columnar with immature oval, basophilic nuclei. Immunoperoxidase staining for alpha-fetoprotein and alpha1-antitrypsin were positive. Enzyme histochemistry was negative for alkaline phosphatase and positive for alpha-naphthyl acetate esterase. Electron microscopy, including freeze-fracture analysis, showed desmosomes and tight junctions. No gap junctions were identified. Actin filaments, glycogen, and microvilli were abundant. This is the first case of an ovarian endodermal sinus tumor with exclusive enteric differentiation.