Midline carcinoma expressing NUT in malignant effusion cytology.

Nuclear protein in testis (NUT) midline carcinoma (NMC) is a rare and aggressive subset of poorly differentiated squamous cell carcinoma that is defined by t(15,19) and typically presents in the midline structures of the head, neck, and mediastinum. We report two cases of NMC that presented uniquely with malignant pleural and pericardial effusions including one with cardiac tamponade at presentation. The first case is of a 25-year-old male patient who presented with progressive dyspnea associated with palpitations and dizziness on standing, found to have large bilateral pleural effusions. The second case is of a previously healthy 29-year-old male patient who presented with progressive dyspnea, cough with expectoration, and a large right lower neck mass of 3 months onset, and a large left pleural effusion and left lung infiltrate on imaging studies. Both cases showed malignant cells on cytology suggestive of poorly differentiated carcinoma. Subsequent histopathological and immunochemistry studies were consistent with the diagnosis of NMC. Both patients had a rapid decline in status and suffered comorbidities secondary to their carcinoma, inevitably leading to their death. It is important to consider NUT midline carcinomas can present in a variety of clinical scenarios, and it is important to consider in the differential diagnoses when evaluating malignant effusion cytology. Utilization of ancillary testing with a broad immunostain profile including NUT studies, as well as fluorescent in-situ hydridization (FISH) studies are helpful and necessary in making the appropriate diagnosis.

Post-irradiation pericardial malignant mesothelioma with deletion of p16: a case report.

Malignant mesotheliomas are rather uncommon neoplasms associated primarily with asbestos exposure; however, they may also arise as second primary malignancies after radiation therapy, with a latency period of 15-25 years. Numerous studies have reported an association between pleural malignant mesothelioma and chest radiation performed for other malignancies; on the other hand, post-irradiation mesotheliomas of the pericardium have been reported in only a few published cases to date, and no homozygous deletion of 9p21 has been described in such cases. We report the case of a 48-year-old man with a history of Hodgkin's lymphoma and no prior asbestos exposure who developed pericardial malignant epithelioid mesothelioma. We further discuss the cytologic, histologic, immunophenotypic, and fluorescence in situ hybridization findings in this case. To our knowledge, this is the first well-documented case of post-radiation pericardial malignant mesothelioma showing homozygous deletion of 9p21. Homozygous deletion of 9p21, the locus harboring the p16 gene, is present in post-irradiation pericardial malignant mesothelioma.

The impact of atypia/follicular lesion of undetermined significance and repeat fine-needle aspiration: 5 years before and after implementation of the Bethesda System.

BACKGROUND: Limited studies have examined the impact of the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) and specifically the category of atypia or follicular lesion of undetermined significance (AUS/FLUS). We studied their effects on reporting rates, subsequent management, and surgical outcome over a 10-year period, 5 years before and after implementation of the BSRTC. METHODS: A retrospective review of thyroid fine-needle aspiration (FNA) reports from 2003 to 2012 was performed. Diagnoses made before BSRTC were reclassified into the most appropriate category. Repeat FNA results for all AUS/FLUS cases were recorded. Surgical follow-up results were matched by side and size of the targeted nodule. Incidental microcarcinomas were not considered "malignant" on excision. Malignancy rates were calculated based on excision and by all aspirated specimens. RESULTS: Initial AUS/FLUS cases increased from 3% to 7% (P = .001) with implementation of the BSRTC. The nondiagnostic rate decreased from 19% to 10% (P = .026). Differences in malignancy rates before and after implementation of the BSRTC were not significant for all diagnostic categories. More repeat FNAs and fewer surgical excisions were performed after an initial AUS/FLUS diagnosis. Repeat FNA reclassified 56% of AUS/FLUS cases into a definitive category. The malignancy risks for AUS/FLUS plus benign and AUS/FLUS plus AUS/FLUS repeat FNAs were elevated compared with single benign and AUS/FLUS diagnoses. CONCLUSIONS: AUS/FLUS cases are increasing with the implementation of the BSRTC. Given the potential increase in repeat FNAs as a result, it may be important to alert the clinician regarding the elevated malignancy risk of a benign or AUS/FLUS diagnosis associated with a prior AUS/FLUS finding.

Pleural fluid metastases of salivary duct carcinoma: A case report and review of the literature.

Salivary duct carcinoma (SDC) comprises a small proportion of salivary gland tumors; however, it is known to be aggressive with a high rate of metastasis. Although frequent references are made to pulmonary dissemination, metastases in the pleural fluid have not been described. In this article, we report the cytologic features of metastatic SDC in the pleural fluid. The clinical history, cytomorphology and immunohistochemical features used for diagnosis are described. To the best of our knowledge, this is the first case of pleural fluid involvement by salivary duct carcinoma reported in the literature.

Significance of the diagnostic categories "atypical" and "suspicious for malignancy" in the cytologic diagnosis of solid pancreatic masses.

Endoscopic ultrasound guided (EUS) fine-needle aspiration (FNA) investigation of solid pancreatic lesions has been shown to have good sensitivity and specificity. Many lesions can be definitely classified as benign or malignant but some can only be cytologically classified as "atypical" or "suspicious for malignancy". Risk for malignancy in these indeterminate categories has not been well categorized. The cytology records of four University Medical centers were searched for all EUS guided FNAs of solid pancreatic lesions. All cases with a diagnosis of "atypical", or "suspicious for malignancy" were selected for analysis when histologic biopsy or over 18 months clinical follow-up was available. Two hundred and ninety-two cases with a diagnosis of "atypical" or "suspicious for malignancy" and adequate follow-up were obtained from the combined data of the four institutions. The percentage malignant for the categories "atypical" and "suspicious for malignancy" were 79.2 and 96.3%, respectively. If the category "atypical" was classified as benign and "suspicious for malignancy" was classified as malignant, the resulting positive predictive value was 96.3 (95% CI: 92.6-98.5) and the negative predictive value 20.8 (95% CI: 13.4-30.0). The categories of "atypical" and "suspicious for malignancy" stratify risk for malignancy in a fashion, which may aid in patient counseling and selection of follow-up protocols. Classification of "suspicious for malignancy" as malignant optimizes diagnostic sensitivity and specificity.

Juvenile granulosa cell tumors: immunoreactivity for CD99 and Fli-1 and EWSR1 translocation status: a study of 11 cases.

The accurate diagnosis of a juvenile granulosa cell tumor (JGCT) can be challenging, as these neoplasms often exhibit morphologic features that overlap other ovarian neoplasms. In addition, the immunohistochemical profile exhibited by JGCT is fairly nonspecific and typically includes reactivity for CD99. Recently, we noted that JGCTs can show immunohistochemical expression of Fli-1, a transcription factor expressed by Ewing sarcoma, a neoplasm that is occasionally in the differential diagnosis of JGCT. We evaluated a series of JGCTs to determine whether Fli-1 is commonly expressed by these tumors and whether they demonstrate chromosomal arrangements in EWSR1. Cases diagnosed as JGCT (n=11) were immunohistochemically evaluated for expression of Fli-1 and CD99. Fluorescence in situ hybridization was performed on all cases to search for chromosomal rearrangements in EWSR1. All 11 of our cases exhibited positive immunohistochemical staining for Fli-1 and CD99. None of the cases demonstrated rearrangement in EWSR1 by fluorescence in situ hybridization. In cases of JGCT that cannot be reliably distinguished from Ewing sarcoma based on morphology and immunohistochemistry alone, fluorescence in situ hybridization testing for EWSR1 rearrangements seems to be a useful diagnostic adjunct for their separation.

Hints to the diagnosis of mixed acinar-endocrine carcinoma on pancreatic fine-needle aspiration: avoiding a potential diagnostic pitfall.

BACKGROUND: Mixed acinar-endocrine carcinoma (MAEC) is a rare mixed tumor of the pancreas defined by both acinar and endocrine cell differentiation. CASE: We present 2 cases of MAEC initially diagnosed as pancreatic endocrine neoplasm on fine-needle aspiration. Both patients were male, aged 51 and 75 years, and presented with 16-mm and 6-mm pancreatic masses, respectively. Aspirates showed loose aggregates and dispersed single plasmacytoid cells with moderate nuclear size variation, slightly irregular nuclear contours, fine to coarsely granular chromatin, occasional prominent nucleoli, and scant to moderate finely granular cytoplasm. Rare mitotic figures and pyknotic forms were noted in one of the cases. Endocrine differentiation was confirmed by immunocytochemistry which led to an initial diagnosis of pancreatic endocrine neoplasm. Trypsin and lipase immunocytochemistry were later obtained, confirming a component of acinar cell differentiation. Findings were confirmed on surgical excision. CONCLUSION: Because of their potentially more aggressive clinical course and different therapeutic implications, MAECs are an important consideration in the differential diagnosis of pancreatic neoplasms. Certain cytomorphologic features and immunocytochemical markers of acinar cell differentiation may be helpful in raising the possibility of MAEC on cytology.

Respiratory cytology in the era of molecular diagnostics: a review.

Carcinoma of the lungs remains one of the primary causes of cancer mortality in the United States and represents a significant diagnostic challenge. Current diagnostic protocols depend substantially on cytology as an initial diagnostic modality. Pulmonary cytology can be diagnostically challenging with false positive and false negative diagnoses being relatively frequent. False positive diagnoses remain a significant problem for the cytologist with benign conditions including reactive atypia of type II pneumocytes, reactive bronchial respiratory epithelium, basal cell hyperplasia, and reactive metaplastic squamous cells being potentially misinterpreted as carcinoma. False negative diagnoses also occur usually attributable to sampling. Traditionally, cytopathologists were expected to recognize carcinoma when present and subdivide it into small cell or nonsmall cell varieties. With the advent of targeted therapy, expectations now include separation of adenocarcinoma from squamous cell carcinoma. Additionally, molecular testing for EGFR mutations and ALK rearrangements is now required as an accompaniment to morphologic diagnosis. This review summarizes the morphologic appearances of the common and diagnostically important carcinomas of the lung and discusses diagnostic pitfalls responsible for false positive and false negative diagnoses. Molecular testing for selection of targeted therapy is also reviewed.

Metastatic disease to the pancreas documented by endoscopic ultrasound guided fine-needle aspiration: a seven-year experience.

The study was performed to determine the frequency and origin for metastatic disease to the pancreas as found in an endoscopic ultrasound directed fine-needle aspiration series. The records of the Departments of Pathology at the University of Utah School of Medicine and the David Geffen School of Medicine were electronically searched for all fine-needle aspirates obtained from pancreatic masses between January 1, 2002 and March 31, 2010. All cases with a diagnosis of metastatic disease were reviewed and whenever possible correlated with subsequent resection specimens. A total of 17 metastatic malignancies to the pancreas were detected in pancreatic FNAs representing 0.73% of all cases. Primaries included eight renal cell carcinomas, one medullary carcinoma of the thyroid, four lymphomas, one alveolar rhabdomyosarcoma, one squamous cell carcinoma derived from the esophagus, and a second squamous cell carcinoma originating from a lung primary and a small cell carcinoma of the lung. Metastatic renal cell carcinoma was the most frequent metastasis to the pancreas representing 47% of metastatic lesions detected by FNA. The metastatic deposits could be detected in the pancreas as many as 10 years following the original diagnosis and resection of the renal cell carcinoma.

Fine-needle aspiration of primary osseous lesions: A cost effectiveness study.

Fine-needle aspiration (FNA) is not widely used in the work-up of osseous lesions because of concerns regarding its high incidence of nondiagnostic specimens. Although several studies have shown that FNA is less expensive than surgical biopsy, the authors are aware of only one prior study evaluating the cost effectiveness of FNA, which includes the cost of incisional or core needle biopsies necessary to establish a diagnosis when the initial FNA was noncontributory. A computerized search of the pathology records of three medical centers was performed to obtain all FNAs of primary osseous lesions. For each FNA case, all subsequent core needle, incisional or excisional biopsies were recorded as was the result of the definitive operative procedure. The cost of obtaining the definitive diagnosis was calculated for each case including the cost of FNA, imaging guidance utilized, and cost of subsequent surgical biopsy when necessary. The cost of an alternate approach using only surgical biopsy was calculated. The average per patient costs of these two protocols were compared.A total of 165 primary bone tumors underwent FNA. One hundred six of these yielded a definitive cytologic diagnosis. In 59 cases, FNA yielded a result insufficient for definitive therapy necessitating surgical biopsy. FNA investigation of the 165 bone lesions cost 575,932 (average of 3,490 per patient). Surgical biopsy alone would have cost 5,760 per patient. FNA resulted in a cost savings of 2,215 per patient.

Implications of the proposed thyroid fine-needle aspiration category of "follicular lesion of undetermined significance": A five-year multi-institutional analysis.

National Cancer Institute State of the Science Conference on thyroid fine-needle aspiration (FNA) summarized diagnostic terminology. Six diagnostic categories were proposed including "follicular lesion of undetermined significance" (FLUS). FLUS was defined as findings neither convincingly benign nor sufficiently atypical for a diagnosis of "follicular neoplasm" or "suspicious for malignancy." It was proposed that this category represent less than 7% of thyroid FNAs. A search of the cytology records at three University Hospitals was performed for the term FLUS or older equivalent terms. Usage of FLUS was compared between institutions and among pathologists. Surgical pathology outcome for FLUS cases was determined. Twenty-eight pathologists evaluated 6,872 cases at the three institutions. Use of FLUS varied among pathologists (2.5 to 28.6%). Frequency of use of FLUS among institutions varied from 3.3 to 14.9%. FLUS cases [127 of 673 (18.9%)] underwent surgical exploration with malignancy identified in 36 cases (28.3%) undergoing resection. Use of FLUS varied substantially among pathologists and institutions. FLUS category requires more rigorously defined morphologic criteria for it to become a useful guide in clinical management.

Comparison of ImmunoCyt, UroVysion, and urine cytology in detection of recurrent urothelial carcinoma: a "split-sample" study.

BACKGROUND: ImmunoCyt (uCyt) and UroVysion are ancillary studies that may aid in the detection of urothelial carcinoma in urine specimens. We compared ImmunoCyt and UroVysion to urine cytology in the ability to detect recurrent urothelial carcinoma. METHODS: Single voided urine samples were obtained from 100 patients who had a previous history of bladder cancer. All patients underwent cystoscopy immediately after urine sample collection. Forty-one cystoscopically suspicious lesions were biopsied. Urine samples were divided and processed blindly and independently in 3 different laboratories for ImmunoCyt, UroVysion, and urine cytology (ThinPrep method). RESULTS: Of the 41 cystoscopically positive cases, most cystoscopy findings showed multiple tumors that were papillary and less than 1 cm. Biopsies showed many low-grade tumors (54%). Overall sensitivity of cytology for low- and high-grade urothelial cell carcinoma was 15% and 27%, whereas ImmunoCyt was 62% and 91% and UroVysion was 8% and 18%, respectively. Overall specificity of cytology was 97%, whereas ImmunoCyt was 63% and UroVysion was 90%. CONCLUSIONS: ImmunoCyt is more sensitive than either cytology or UroVysion in detecting low-grade tumors. Both cytology and UroVysion have comparable specificity in cystoscopically negative cases. Whereas ImmunoCyt may improve the cytological detection of recurrent bladder cancer, UroVysion may be used as a confirmatory test for either cytology or ImmunoCyt.

Histologic, immunohistochemical, and molecular classification of 52 IPMNs of the pancreas.

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas account for approximately 5% of pancreatic neoplasms. Prognosis is superior to that of pancreatic invasive ductal carcinoma. IPMNs reveal a variety of epithelial linings expressing different mucin staining patterns and may progress along different oncogenic pathways. MATERIALS AND METHODS: Fifty-two IPMNs were studied for expression of MUC1, MUC2, p16, p21, HER2, cyclin D1, and p53 protein and for mutations in K-ras, HER2, p53, EGFR, and BRAF genes. The cases were evaluated for dysplasia, presence of invasion, and morphology of lining epithelium. RESULTS: Twenty-six IPMNs appeared intestinal (IN). Five were low, 12 moderate, and 9 high grade. K-ras mutations were found in 15, EGFR mutations in 2, and BRAF mutation in 1. Seven cases were pancreaticobiliary (PB) and all showed moderate to high-grade dysplasia. Six K-ras mutations and 2 p53 mutations were found in PB tumors. p53 mutations were in cases with high-grade dysplasia. Nineteen IPMNs demonstrated a gastric foveolar (GF) pattern. The majority of GF cases had low or moderate dysplasia. Sixteen revealed K-ras mutations and 1 case each demonstrated a HER2 or p53 mutation. Five IPMNs revealed invasive adenocarcinoma, including a colloid carcinoma from an IN type epithelium. CONCLUSIONS: IN pattern IPMNs were the most common. Mixed histology was common. K-ras mutations were most common, but did not correlate with dysplasia. p53 mutations were seen in 6% of cases (only in GF and PB subtypes). A HER2 mutation was found in a GF IPMN. EGFR and BRAF mutations were restricted to IN IPMNs. These findings suggest the possibility of alternate pathways for carcinogenesis between epithelial subtypes of IPMNs.

In vivo analysis of fracture toughness of thyroid gland tumors.

BACKGROUND: Human solid tumors that are hard or firm on physical palpation are likely to be cancerous, a clinical maxim that has been successfully applied to cancer screening programs, such as breast self-examination. However, the biological relevance or prognostic significance of tumor hardness remains poorly understood. Here we present a fracture mechanics based in vivo approach for characterizing the fracture toughness of biological tissue of human thyroid gland tumors. METHODS: In a prospective study, 609 solid thyroid gland tumors were percutaneously probed using standard 25 gauge fine needles, their tissue toughness ranked on the basis of the nature and strength of the haptic force feedback cues, and subjected to standard fine needle biopsy. The tumors' toughness rankings and final cytological diagnoses were combined and analyzed. The interpreting cytopathologist was blinded to the tumors' toughness rankings. RESULTS: Our data showed that cancerous and noncancerous tumors displayed remarkable haptically distinguishable differences in their material toughness. CONCLUSION: The qualitative method described here, though subject to some operator bias, identifies a previously unreported in vivo approach to classify fracture toughness of a solid tumor that can be correlated with malignancy, and paves the way for the development of a mechanical device that can accurately quantify the tissue toughness of a human tumor.

Cost efficiency analysis for fine-needle aspiration in the workup of parotid and submandibular gland nodules.

The utility and cost effectiveness of salivary gland fine-needle aspiration (FNA) is controversial. Some authorities argue FNA has no added value over clinical-radiographic study because most salivary gland nodules occur in the parotid and the tumor's relationship to the facial nerve determines the operative procedure rather than the histology. Other experts contend FNA is of value by reducing the overall number of operative procedures performed. We studied 306 salivary gland nodules (214 parotid and 92 submandibular gland) undergoing FNA. One hundred and seventy one were subsequently surgically resected and the remaining 135 followed clinically. A 16% error rate was associated with the nonoperative group, necessitating later surgical resection. The cost of the FNAs and surgical resections (when performed) was calculated based on Medicare reimbursement rates. Costs were based on all cases undergoing initial FNA. The expense of initial resection was based on the observed percentage of patients undergoing resection in our series. The costs of resections related to erroneous FNA diagnoses were based on the error rate associated with FNA diagnoses clinically followed (i.e., chronic sialadenitis). Costs of FNAs, initial resections, and subsequent resections related to FNA errors were summed and compared with the cost which would have occurred if all nodules had been primarily resected.FNA reduced the number of operative procedures by approximately 65% for submandibular nodules and 35% for parotid nodules. Diagnoses which resulted in nonsurgical management included chronic radiation-induced sialadenitis, intraparotid lymph node, recurrent lymphoma, and accessory nodules or lobes of the parotid gland. Pure surgical management was associated with a cost of $275,750.00 per 100 patients. FNA management was associated with an expenditure of $206,632.00 per 100 patients, representing a savings of $69,118.00 (33% savings over surgical management alone). Based on these data, FNA appears to be cost effective in addition to supplying preoperative diagnoses helpful in counseling, operative planning, and allaying patient anxiety.