Pleural fluid secondary to pulmonary cryptococcal infection: a case report and review of the literature.

BACKGROUND: Pulmonary Cryptococcosis (PC) is diagnosed with increasing incidence in recent years, but it does not commonly involve the pleural space. Here, we report a HIV-negative case with advanced stage IIIB non-small cell lung cancer (NSCLC) treated with radiation therapy presented with dyspnea, a new PET-positive lung mass and bilateral pleural effusion suspecting progressive cancer. However, the patient has been diagnosed as pulmonary cryptococcal infection and successfully treated with oral fluconazole therapy. CASE PRESENTATION: A 77-year-old male with advanced stage non-small cell lung cancer treated with combined chemo-radiation therapy who presented with progressive dyspnea, a new PET-positive left lower lobe lung mass and bilateral pleural effusions. Initial diagnostic thoracentesis and bronchoscopy yielded no cancer, but instead found yeast forms consistent with cryptococcal organisms in the transbronchial biopsies of the left lower lobe lung mass. Subsequent to this, the previously collected pleural fluid culture showed growth of Cryptococcus neoformans. The same sample of pleural effusion was tested and was found to be positive for crytococcal antigen (CrAg) by a lateral flow assay (LFA). The patient has been treated with oral fluconazole therapy resulting in gradual resolution of the nodular infiltrates. CONCLUSION: PC should be considered in immunosuppressed cancer patients. Additionally, concomitant pleural involvement in pulmonary cryptococcal infections may occur. The incidence of false positive 18FDG-PET scans in granulomatous infections and the use of CrAg testing in pleural fluid to aid in diagnosis are reviewed.

Cytomorphology of non-small cell lung carcinoma with anaplastic lymphoma kinase gene rearrangement.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase demonstrating activating mutations in several malignancies including a subset (1-5%) of non-small cell lung carcinomas (NSCLC). Prior work examining, the histologic features of these tumors found a spectrum of findings, notably a solid/acinar pattern, as well as a mucinous cribriform pattern. We present the first study to date describing the cytomorphology of NSCLC harboring ALK rearrangements. A retrospective database search was conducted to identify cytologic specimens of NSCLC demonstrating ALK rearrangement. Cytogenetic analysis was performed with fluorescence in situ hybridization. A total of 12 patients were identified, 10 with available material. Cellular morphology and smear background was evaluated in the study group, as well as control cases lacking ALK rearrangement. A total of 25 specimens from 10 patients were obtained. Five patients never smoked, and four patients had a remote smoking history. ALK rearrangements were identified in cells with unique cytologic characteristics. All cases demonstrated moderate to poor differentiation with a predominance of single cells showing anisonucleosis and frequent intracytoplasmic neutrophils. The control cases showed cells with smaller, less pleomorphic nuclei, and smaller nucleoli with more clusters/tissue fragments. Several unique cytomorphologic features were consistently identified in the study population relative to the control population and include a prominence of single, markedly enlarged tumor cells with plasmacytoid features and anisonucleosis, as well as intracytoplasmic neutrophils. Larger studies are warranted to confirm our preliminary findings, as these features may help establish a more cost-effective means to select patients being tested for ALK mutational analysis.

Role of ancillary testing in thyroid fine needle aspiration: Review and update.

Thyroid nodules are common, and ultrasound-guided fine needle aspiration identifies 70-75% as benign, and 4% as malignant. The remainder falls into categories of "indeterminate" with a widely ranging malignancy rate from 10-75%. The diagnosis and clinical management of indeterminate lesions is evolving, and we will review ancillary testing as an aid to diagnosis.

Utility of P16 expression and Ki-67 proliferation index in ASCUS and ASC-H pap tests.

Current cervical screening uses a combination of cytology and high-risk human papillomavirus (HR-HPV) analysis in cases of atypical squamous cells of undetermined significance (ASCUS) and atypical squamous cells cannot exclude high-grade intraepithelial lesion (ASC-H). These diagnoses are subject to interobserver variability and HR-HPV analysis can be limited by sampling inadequacy. This study correlates immunoexpression of P16 and Ki-67 in residual cervicovaginal material against cytology category and HR-HPV status. Eighteen pap tests were selected: 8 ASCUS, 4 ASC-H, and 6 controls (2 LSIL and 4 HSIL). Digene Hybrid Capture II test was used to detect HR-HPV. The cytospins were stained for P16/Ki-67. Pap tests, P16, Ki-67, HR-HPV result and available biopsies were correlated. P16 expression correlated with HR-HPV status in 15/17 cases. Discordant cases (1 ASCUS and 1 ASC-H) were +P16/-HR-HPV. Ki-67 correlated with HR-HPV in 8/15 cases. Discordant cases were +HR-HPV/- Ki-67 (HSIL, LSIL, and ASC-H one each), and -HR-HPV/+Ki-67 (3 ASCUS, 1 LSIL, 1 ASC-H). Two cases were + P16/+ Ki-67/- HR-HPV. None were - P16/- Ki-67/+ HR-HPV. Histologic follow-up in 13 cases varied from benign to CIN III. Two cases of +P16/ - Ki-67/- HR-HPV had benign cervical biopcies. Although a small sample size, our findings show a utility for adjunct P16/ Ki-67 in addition to HR-HPV testing in cases of squamous atypia when HR-HPVs are non-detected due to low DNA copies, or missed lesions in cervical biopsies.

Urinary cytomorphology and clinical correlates of prostatic small cell neuroendocrine carcinoma.

BACKGROUND: Small cell carcinoma (SCC) of the prostate represents a rare form of prostatic carcinoma. While the tumor is often considered to arise from neuroendocrine proliferation or possibly dedifferentiation of an acinar carcinoma, the precise etiology remains uncertain. The diagnosis of prostatic SCC in urine has to date not been described. METHODS: A retrospective review was performed at a tertiary-care hospital, and 3 patients with prostatic SCC in voided urinary specimens were identified. The following clinical data were collected for each case: age, gender, treatment and follow-up information, when available. RESULTS: The patient age range was 70-86 years, all male. Two patients had known metastatic adenocarcinoma of the prostate, and 1 had recently presented with prostatic SCC. One patient with metastatic disease died shortly after diagnosis, the other was lost to follow-up. The third patient with a recent presentation has yet to have a treatment plan finalized. CONCLUSIONS: Our results highlight the importance of making this uncommon diagnosis as it may carry significant treatment and prognostic importance. Future work should hopefully clarify the role of ERG gene rearrangements in the pathogenesis of prostatic SCC, as there is a potential role here for targeted therapy.

Urinary cytopathology in primary bladder amyloidosis.

BACKGROUND: Amyloidosis results from the accumulation of unique extracellular proteins which are not able to be degraded via the usual mechanism of lysosomal proteolysis. Isolated collections of amyloid within the bladder are extremely uncommon, and a cytopathologic description in voided urine has not been described to date. METHODS: A retrospective review was performed at a tertiary-care hospital, and 3 patients with isolated bladder amyloidosis and corresponding voided urine specimens were identified. The following clinical data were collected for each case: age, gender, treatment and follow-up information. RESULTS: The patient age range was 76-84 years, with 2 males and 1 female. Amyloidosis was never clinically suspected. In 1 patient, a urinary amyloid manifested, which was thought to represent extraneous debris at the time of original diagnosis. Two patients never manifested signs of systemic amyloidosis or multiple myeloma, and the third was found to have a monoclonal gammopathy. CONCLUSIONS: Our results show the difficulty of diagnosing urinary amyloid in the absence of clinical suspicion. Further, the presence of urinary amyloid is unlikely in patients with bladder amyloidosis as the cohesive nature of the protein makes spontaneous shedding uncommon. Testing for systemic amyloidosis is warranted and if the disease is localized, a favorable outcome can be expected.

Acinar cell carcinoma of the pancreas: clinical and cytomorphologic characteristics.

Acinar cell carcinoma is a rare malignant epithelial neoplasm with predominantly exocrine acinar differentiation and is seen primarily in older men (mean age, 62 years). The presenting symptoms are usually non-specific, and jaundice is often not present. Symptoms relating to the overproduction and release of lipase into the circulation are present in 10-15% of patients. Characteristic cytomorphologic features include a population of cells with minimal pleomorphism, eccentrically placed nuclei with a single prominent nucleoli and moderate hyperchromasia. The cytoplasm is finely granular, and the background may contain granular debris secondary to cytolysis. A significant proportion of the cases also have a minor neuroendocrine component or scattered neuroendocrine cells. Approximately 50% of patients have metastatic disease at presentation, often restricted to the regional lymph nodes and liver. The prognosis is poor, only slightly better than that of pancreatic ductal adenocarcinoma.

Impact of Oncotype DX on treatment decisions in ER-positive, node-negative breast cancer with histologic correlation.

Oncotype DX, a gene-expression profiling assay, provides stratification of patients with estrogen-receptor positive, lymph-node-negative early breast cancer into risk groups based on recurrence score, which are associated with distant recurrence and response to chemotherapy. This study aims to determine whether Oncotype DX influences clinicians' treatment decisions, and whether assay results correlate with histologic assessment. Fifty patients with estrogen-receptor positive, node-negative early breast cancer analyzed by Oncotype DX and operated on by two breast surgeons were included. To assess effect on treatment decisions, clinical vignettes were created by retrospective chart review. Physicians were then presented with the clinical vignettes and instructed to make a treatment decisions (i.e., hormone therapy alone versus hormone therapy combined with chemotherapy) both before and after knowledge of the recurrence score. To assess correlation with histologic assessment, a prospective, blinded review of tumor slides was performed by two pathologists. Based on this review, tumors were placed into low, intermediate and high risk groups for comparison with Oncotype DX assay results. Treatment decisions were changed based on Oncotype DX results in 36 and 18% of cases by breast surgeons and medical oncologists, respectively. All tumors categorized as high risk by Oncotype DX were categorized as high risk based on histologic assessment, and 96% of cases categorized as low risk by recurrence score were categorized as low or intermediate risk by histologic assessment. Oncotype DX significantly influences management of estrogen-receptor positive, lymph-node-negative early breast cancer. Further studies are needed to assess association of histologic categorization to assay results.

Acral myxoinflammatory fibroblastic sarcoma: cytopathologic findings on fine-needle aspiration.

BACKGROUND: Acral myxoinflammatory fibroblastic sarcoma (AMFS) is a rare low-grade sarcoma with somewhat unique morphologic characteristics. While recurrences are relatively common, distant metastases are infrequent. Cytopathologic descriptions of AMFS are limited, prompting the current study. METHODS: A retrospective review was performed at two tertiary-care hospitals, and 3 patients with this diagnosis were identified. The cytopathologic and clinical features were reviewed. The following clinical data was collected for each case: age, gender, site of lesion, treatment, and follow-up information. RESULTS: Pertinent cytologic features included large atypical epithelioid cells with occasional macronucleoli and lipoblast-like features in a background of bland spindle cells, myxoid stroma, and inflammation. All patients presented with acral mass lesions. Metastatic disease to an inguinal lymph node was found in 1 patient. CONCLUSIONS: AMFS is a low-grade sarcoma which shows some characteristic cytologic features. However, due to the presence of occasional bizarre and pleomorphic giant cells, there can be overlap with higher-grade sarcomas, and correlation with histology, immunohistochemistry, and imaging are required to make this diagnosis.

Low prostate-specific antigen and no Gleason score upgrade despite more extensive cancer during active surveillance predicts insignificant prostate cancer at radical prostatectomy.

OBJECTIVE: To identify parameters that predict insignificant prostate cancer in 67 radical prostatectomies after biopsy reclassification to worse disease on active surveillance. METHODS: Parameters evaluated at diagnosis and at biopsy reclassification included serum prostate-specific antigen, prostate-specific antigen density, number of positive cores, maximum percent involvement of cancer per core, and any interval negative biopsies. Gleason upgrading at biopsy reclassification was also assessed to predict insignificant cancer. RESULTS: Mean time between diagnosis and radical prostatectomies was 30.3 months with a median of 3 biopsies (range 2-9). Nineteen of 67 (28.4%) had clinically insignificant cancer at radical prostatectomy. In the entire group, there were no variables significantly associated with insignificant cancer at radical prostatectomy. In a subgroup analysis of 37 patients without Gleason pattern 4/5 at biopsy reclassification, 16/37 (43.2%) showed insignificant cancer at radical prostatectomy. In this subgroup, prostate-specific antigen at diagnosis was significantly lower in men with insignificant cancer (3.7 ng/mL) vs significant cancer (5.4 ng/mL) (P = .0005). With prostate-specific antigen <4 ng/mL at diagnosis or at biopsy reclassification, 12/13 (92.3%) men showed insignificant cancer, whereas only 4/24 (16.7%) men with prostate-specific antigen >4 ng/mL both at diagnosis and at biopsy reclassification showed insignificant cancer. CONCLUSION: Most men with biopsy reclassification while on active surveillance have significant disease at radical prostatectomy, justifying their treatment. Low prostate-specific antigen at diagnosis or at biopsy reclassification can predict a high probability of insignificant cancer in the absence of Gleason pattern 4/5 on biopsy. These men may be candidates for continuing active surveillance.

Invasive low-grade papillary urothelial carcinoma: a clinicopathologic analysis of 41 cases.

Typically in invasive papillary urothelial carcinoma both the overlying papillary and the invasive components are high grade. We describe a series of patients with invasive low-grade papillary urothelial carcinoma (LPUC) in which both the noninvasive and invasive components are low grade. A retrospective search from The Johns Hopkins Surgical Pathology Database and consult cases from one of the author's files from 1998 to 2011 found 54 cases of invasive LPUC, excluding the more common, unique, and already well-characterized nested variant of urothelial carcinoma. Slides were available for 41 cases and formed the basis of the current study. The mean patient age was 68.4 years, with a male predominance. The specimens consisted of 37 bladder biopsies, 1 renal pelvis biopsy, 1 cystoprostatectomy specimen, 1 nephrectomy specimen, and 1 nephroureterectomy specimen. In all cases, invasion was limited to the superficial lamina propria above the muscularis mucosae. None of the histologic features correlated with tumor recurrence. Follow-up information was available for 73% of cases, with an average time interval of 49 months. Recurrent tumor was identified in 10/29 (34%) cases; however, 34% of cases without recurrence had limited follow-up (<24 mo). Three patients showed progression in tumor grade, and 3 additional patients progressed in both grade and stage (60% stage/grade progression). Four patients developed recurrence with ureteral noninvasive LPUC (2 in the bladder and 2 in the ureter). All are alive without disease. As this lesion is being increasingly recognized, larger studies are needed to determine whether invasion arising in LPUC is a significant risk factor for future disease.

Dysplastic lesions in inflammatory bowel disease show increased positivity for the stem cell marker aldehyde dehydrogenase.

The chronic inflammatory state in patients with inflammatory bowel disease places them at a substantially elevated risk for developing colorectal carcinoma. Moreover, distinguishing an inflammatory phenotype from dysplasia in inflammatory bowel disease can be difficult and has significant patient management implications. To this end, we studied the expression of the cancer stem cell marker aldehyde dehydrogenase to determine whether expression is increased in dysplastic lesions arising in inflammatory bowel disease. We studied 54 patients with inflammatory bowel disease who underwent surgical resection. Of the 54 patients, 13 exhibited high-grade dysplasia or adenocarcinoma, 19 exhibited low-grade dysplasia, and 22 displayed only inflammatory atypia. Staining for aldehyde dehydrogenase was evaluated in the cytoplasm of epithelial and stromal cells. We determined the intensity of staining (0 to 3+) and the percentage of cells staining positively. Positive staining for aldehyde dehydrogenase was observed in 92% (12/13) of cases with high-grade dysplasia/adenocarcinoma and in 95% (18/19) of cases with low-grade dysplasia. Cases with inflammatory atypia showed positive staining in 45% (10/22) of cases. The sensitivity for aldehyde dehydrogenase in epithelial cells as a marker for dysplasia was 95%; specificity was 55%. For stromal cells adjacent to dysplasia, sensitivity was 44%; and specificity was 68%. Although the sensitivity of aldehyde dehydrogenase for dysplasia was excellent, specificity was less than ideal. Our findings support the hypothesis that dysplasia in inflammatory bowel disease is associated with increased aldehyde dehydrogenase positivity, which supports the cancer stem cell hypothesis.

Does routine repeat testing of critical values offer any advantage over single testing?

CONTEXT: Before being communicated to the caregiver, critical laboratory values are verified by repeat testing to ensure their accuracy and to avoid reporting false or erroneous results. OBJECTIVE: To determine whether 2 testing runs offered any advantage over a single testing run in ensuring accuracy or in avoiding the reporting of false or erroneous results. DESIGN: Within the hematology laboratory, 5 tests were selected: hemoglobin level, white blood cell count, platelet count, prothrombin time, and activated partial thromboplastin time. A minimum of 500 consecutive critical laboratory test values were collected retrospectively for each test category. The absolute value and the percentage of change between the 2 testing runs for each critical value were calculated and averaged for each test category and then compared with our laboratory's preset, acceptable tolerance limits for reruns. RESULTS: The mean results obtained for the absolute value and the percentage of change between the testing runs were 0.08 g/dL (1.4%) for hemoglobin levels, 50 cells/µL (10.2%) for white blood cell counts, 1500 cells/µL (9.9%) for platelet counts, 0.7 seconds (1.4%) for prothrombin time, and 5.1 seconds (4.4%) for activated partial thromboplastin time (all within our laboratory's acceptable tolerance limits for reruns). The percentage of specimens with an absolute value or a mean percentage of change outside our laboratory's acceptable tolerance limits for reruns ranged between 0% and 2.2% among the test categories. No false or erroneous results were identified between the 2 testing runs in any category. CONCLUSIONS: Routine, repeat testing of critical hemoglobin level, platelet count, white blood cell count, prothrombin time, and activated partial thromboplastin time results did not offer any advantage over a single run.

Acinar cell carcinoma with prominent intraductal growth pattern: case report and review of the literature.

Acinar cell carcinoma of the pancreas is rare, accounting for less than 1% of carcinomas arising in the exocrine pancreas. Patients are typically between the fifth and seventh decade of life and show a 2:1 male predominance. Symptoms tend to be nonspecific, and approximately 50% of the patients have metastases at the time of presentation. There have been recent case reports of acinar cell carcinoma showing both intraductal and/or papillary patterns of growth that could potentially be mistaken for intraductal neoplasia. The cases reported up to date presented as solitary nodules. The authors describe the first case of acinar cell carcinoma with both intraductal and tubuloglandular growth diffusely involving the pancreas. In addition, the authors review the published cases reporting acinar cell carcinoma with intraductal and/or papillary growth patterns.

The added value of molecular testing in small pancreatic cysts.

CONTEXT: Recent studies have shown high amplitude K-ras gene mutation and allelic imbalances are predictive of malignancy in pancreatic cysts. OBJECTIVE: Our purpose is to determine the added benefit of molecular testing in diagnosing small pancreatic cysts. DESIGN: Retrospective, single-institution study. PATIENTS: Patients with pancreatic cysts (less than, or equal to, 3 cm) who presented for EUS evaluation. INTERVENTION: EUS-guided pancreatic cyst aspiration cytology, carcinoembryonic antigen (CEA) level determination, and detailed DNA analysis including K-ras gene mutation and allelic imbalance. MAIN OUTCOME MEASUREMENTS: Ability of cyst fluid DNA analysis to render a diagnosis compared with cytology and CEA level determination. RESULTS: Diagnostic agreement was seen in 55.6% (35/63) of cases. In 10 cases (15.9%), there was disagreement between cytology and molecular. Molecular testing provided a diagnosis in 20 cases (31.7%) when either cytology was unsatisfactory, or CEA not elevated (less than 192 ng/mL). Elevated CEA levels were seen in 16 cases (25.4%), each diagnosed as a mucinous lesion with molecular analysis. CONCLUSIONS: Molecular analysis of pancreatic cyst fluid adds diagnostic value in scant specimens when cytology may be unsatisfactory and CEA unreliable.

Implications of enhancer of zeste homologue 2 expression in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer deaths in the United States. Single-agent gemcitabine remains the standard treatment of advanced pancreatic adenocarcinoma. A recently discovered histone methyltransferase termed enhancer of zeste homologue 2 (EZH2) was found to be overexpressed in a variety of carcinomas including pancreatic adenocarcinoma. Silencing of E-cadherin was proposed as a mechanism by which enhancer of zeste homologue 2 mediates tumor aggressiveness, and enhancer of zeste homologue 2 depletion has been found to sensitize pancreatic cancer cells to gemcitabine. In this study, we correlated enhancer of zeste homologue 2 with E-cadherin expression in pancreatic adenocarcinoma and evaluated response to gemcitabine in relation to enhancer of zeste homologue 2 expression in tumor cells. Fifty-four pancreatic adenocarcinomas, 13 intraductal papillary mucinous neoplasms, and 6 chronic pancreatitis cases were stained with antibodies against enhancer of zeste homologue 2 and E-cadherin. Enhancer of zeste homologue 2 staining was scored from 1 to 4+ and classified as either low (1-2+ in <25% of tumor nuclei) or high (3-4+ in >25% of tumor nuclei). E-cadherin expression was scored on membrane positivity as follows: 0 (0%-10%), 1 (10%-25%), 2 (25%-75%), and 3 (>75%). High enhancer of zeste homologue 2 expression in pancreatic adenocarcinoma was significantly associated with decreased E-cadherin expression and more aggressive disease. There was significantly longer survival in gemcitabine-treated patients with low versus high enhancer of zeste homologue 2 expression. High enhancer of zeste homologue 2 expression was detected in intraductal papillary mucinous neoplasms with moderate to severe dysplasia, but not in chronic pancreatitis. Our study suggests that E-cadherin down-regulation may lead to enhancer of zeste homologue 2-mediated invasion and metastasis.

Identification of gastrointestinal contamination in endoscopic ultrasound-guided pancreatic fine needle aspiration.

OBJECTIVE: To evaluate whether B72.3 and CEA could identify duodenal and gastric contamination in cell blocks of clinically proven cases of pancreatic ductal carcinoma, intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN). STUDY DESIGN: Cell blocks of pancreatic fine needle aspirates from 19 ductal adenocarcinomas, 9 IPMNs, 5 MCNs, and 22 cases containing gastrointestinal epithelial contamination (GIC) (7 gastric, 15 duodenal) were stained with antibody to carcinoembryonic antigen (CEA) and B72.3. RESULTS: CEA was positive in 89% of adenocarcinomas and 92% of mucinous lesions. It was never expressed in gastric contamination and was positive in 2/15 (13%) duodenal contaminants. B72.3 was positive in 95% of adenocarcinomas and 85% of mucinous lesions. It was positive in 2/7 (28%) gastric and 7/15 (47%) duodenal contaminants. CONCLUSION: In contrast to previous work, our preliminary results indicate that B72.3 expression cannot be reliably used to identify GIC. A lack of CEA expression, however, can be used to identify both gastric and duodenal contamination. This represents an important diagnostic aid in the evaluation of suspected low grade mucinous lesions.

Post-traumatic fungal keratitis caused by Carpoligna sp.

PURPOSE: To report the first case of fungal keratitis caused by presumed Carpoligna species. METHODS: A 37-year-old gardener sustained a full-thickness, stellate corneal laceration while cutting wood outdoors with a circular saw. Two months after surgical repair, he developed a severe infectious keratitis with descemetocoele at the apex of the original stellate laceration. RESULTS: Culture results confirmed fungal elements without evidence of bacteria. Oral and topical voriconazole were initiated. Due to compliance and cost issues, voriconazole was replaced with natamycin 5% prior to discharge from hospital. The patient improved and healed without perforation. The patient was left with a central stromal scar. DNA extraction from the fungal colony allowed PCR amplification of the 28s ribosomal RNA region of the fungus that led to the diagnosis of Carpoligna pleurothecii. Corticosteroids were never used during the patient's treatment. CONCLUSION: This is the first reported case of infectious keratitis caused by presumed Carpoligna species. The treatment for Carpoligna pleurothecii keratitis includes voriconazole, natamycin, and possibly amphotericin B.