Identification of Glandular (Acinar)/Tubule Formation in Invasive Carcinoma of the Breast: A Study to Determine Concordance Using the World Health Organization Definition.

CONTEXT.­: The Nottingham Grading System (NGS) developed by Elston and Ellis is used to grade invasive breast cancer (IBC). Glandular (acinar)/tubule formation is a component of NGS. OBJECTIVE.­: To investigate the ability of pathologists to identify individual structures that should be classified as glandular (acinar)/tubule formation. DESIGN.­: A total of 58 hematoxylin-eosin photographic images of IBC with 1 structure circled were classified as tubules (41 cases) or nontubules (17 cases) by Professor Ellis. Images were sent as a PowerPoint (Microsoft) file to breast pathologists, who were provided with the World Health Organization definition of a tubule and asked to determine if a circled structure represented a tubule. RESULTS.­: Among 35 pathologists, the κ statistic for assessing agreement in evaluating the 58 images was 0.324 (95% CI, 0.314-0.335). The median concordance rate between a participating pathologist and Professor Ellis was 94.1% for evaluating 17 nontubule cases and 53.7% for 41 tubule cases. A total of 41% of the tubule cases were classified correctly by less than 50% of pathologists. Structures classified as tubules by Professor Ellis but often not recognized as tubules by pathologists included glands with complex architecture, mucinous carcinoma, and the "inverted tubule" pattern of micropapillary carcinoma. A total of 80% of participants reported that they did not have clarity on what represented a tubule. CONCLUSIONS.­: We identified structures that should be included as tubules but that were not readily identified by pathologists. Greater concordance for identification of tubules might be obtained by providing more detailed images and descriptions of the types of structures included as tubules.

PIK3CA-related overgrowth spectrum (PROS) presenting as isolated macrodactyly.

PIK3CA-related overgrowth spectrum (PROS) is a heterogeneous group of diseases, with varied clinical presentations ranging from isolated segmental overgrowths to megalencephaly and vascular malformations, all resulting from post-zygotic activating mutations in PIK3CA. Isolated macrodactyly of upper limb is extremely rare, accounting only for 0.9%-1% of all congenital anomalies of the upper limb. This report describes a case of congenital, isolated, nonprogressive macrodactyly of the right index finger and thumb, in an adult patient that was treated with debulking surgery. The microscopic features were compatible with lipomatosis of nerve. Due to the prompt and pertinent molecular testing, which identified a somatic PIK3CA variant, c.3140A > G, p.H1047R., the case was classified as a PROS. The availability of mTOR inhibitors offers additional treatment possibilities in cases with progressive disease. This case report highlights the importance of molecular testing to identify PROS, to further the knowledge of this continually expanding entity.

Inflammatory myofibroblastic tumor of the larynx: Case report.

Inflammatory myofibroblastic tumor is usually a benign tumor of mesenchymal origin that is rarely found in the larynx. This case explores the unique laryngeal location and presentation of this tumor as well as the challenging radiographic and histologic findings.

Prognostic Assessment of BRAF Mutation in Preoperative Thyroid Fine-Needle Aspiration Specimens.

OBJECTIVES: We investigate the potential role of BRAF testing in guiding surgical intervention in papillary thyroid carcinoma (PTC). METHODS: Thyroid fine-needle aspiration (FNA) cases with available BRAF result and follow-up thyroidectomy for PTC were included in the study. Cytology and surgical diagnoses were correlated with BRAF status. RESULTS: There were 151 cases of thyroid FNA specimens with BRAF testing (70 mutant and 81 wild-type BRAF) and histologically confirmed unilateral, unifocal PTCs. There were no differences in age, sex, tumor size, or lymphovascular invasion on thyroidectomy specimens between mutant and wild-type BRAF cases. BRAF mutation was significantly associated with cytology diagnosis (P < .001), PTC subtype (P < .001), extrathyroidal extension (ETE) (P = .006), and higher tumor (T) stage (P = .04). However, an analysis within the histologic subtypes of PTC revealed no significant association between BRAF mutation and ETE or higher T stage. There was also no difference in central (P = .847) or lateral (p = 1) neck lymph node (LN) metastasis. CONCLUSIONS: BRAF mutation identified in thyroid FNA specimens correlates with histologic subtypes but is not an independent factor for predicting PTC biological behavior and should not be used to guide the extent of LN dissection.

Apolipoprotein E Promotes Invasion in Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) patients generally have a poor prognosis, because of the invasive nature of these tumors. In comparing transcription profiles between OSCC tumors with a more invasive (worst pattern of tumor invasion 5) versus a less invasive (worst pattern of tumor invasion 3) pattern of invasion, we identified a total of 97 genes that were overexpressed at least 1.5-fold in the more invasive tumor subtype. The most functionally relevant genes were assessed using in vitro invasion assays with an OSCC cell line (UM-SCC-1). Individual siRNA knockdown of 15 of these 45 genes resulted in significant reductions in tumor cell invasion compared to a nontargeting siRNA control. One gene whose knockdown had a strong effect on invasion corresponded to apolipoprotein E (APOE). Both matrix degradation and the number of mature invadopodia were significantly decreased with APOE knockdown. APOE knockdown also resulted in increased cellular cholesterol, consistent with APOE's role in regulating cholesterol efflux. APOE knockdown resulted in decreased levels of phospho-extracellular signal-regulated kinase 1/2, phospho-c-Jun N-terminal kinase, and phospho-cJun, as well as decreased activator protein 1 (AP-1) activity. Expression of matrix metalloproteinase 7 (MMP7), an AP-1 target, was also significantly decreased. Our findings suggest that APOE protein plays a significant role in OSCC tumor invasion because of its effects on cellular cholesterol and subsequent effects on cell signaling and AP-1 activity, leading to changes in the expression of invasion-related proteins, including MMP7.

Preoperative 18F-FDG-PET/CT vs Contrast-Enhanced CT to Identify Regional Nodal Metastasis among Patients with Head and Neck Squamous Cell Carcinoma.

Objective Our objective was to compare the accuracy of preoperative positron emission tomography (PET)/computed tomography (CT) and contrast-enhanced CT (CECT) in detecting cervical nodal metastases in patients treated with neck dissection and to scrutinize the ability of each modality to determine nodal stage. Study Design Case series with chart review. Setting Montefiore Medical Center, Bronx, New York. Subjects and Methods Patients who underwent neck dissection at our institution for primary treatment of head and neck squamous cell carcinoma (HNSCC) and had received preoperative PET/CT and CECT were included in this study. Imaging studies were reinterpreted by 3 specialists within the field and compared for interreader agreement. Concordance between radiology and histopathology was measured using neck levels and sides, along with patient nodal stage. Sensitivity, specificity, accuracy, positive predictive value, negative predictive value, and agreement coefficients were calculated. Results Seventy-three patients were included in the study. Sensitivity was 0.69 and 0.94 (level and side) for PET/CT vs 0.53 and 0.66 for CECT ( P = .056, P = .001). Specificity was 0.86 and 0.56 for PET/CT vs 0.91 and 0.76 for CECT ( P = .014, P = .024). No significant difference was found in overall accuracy ( P = .33, P = .88). The overall agreement percentages between N stage called by imaging modality and pathology were 52% and 55% for PET/CT and CECT, respectively. Conclusion No significant difference in sensitivity was found between PET/CT and CECT. CECT was found to have superior specificity compared with PET/CT. The information gleaned from each modality in the pretreatment evaluation of HNSCC appears to be complementary.

Endoscopic ultrasound-guided fine-needle aspiration diagnosis of secondary tumors involving the pancreas: An institution's experience.

BACKGROUND: Pancreatic masses may seldom represent a metastasis or secondary involvement by lymphoproliferative disorders. Recognition of this uncommon occurrence may help render an accurate diagnosis and avoid diagnostic pitfalls during endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). In this study, we review our experience in diagnosing secondary tumors involving the pancreas. MATERIALS AND METHODS: The electronic database of cytopathology archives was searched for cases of secondary tumors involving the pancreas at our institution and a total of 31 cases were identified. The corresponding clinical presentations, imaging study findings, cytological diagnoses, the results of ancillary studies, and surgical follow-up, if available, were reviewed. RESULTS: Nineteen of the patients were male and 12 female, with a mean age of 66 years. Twenty-three patients (74%) had a prior history of malignancy, with the latency ranging from 6 months to 19 years. The secondary tumors involving the pancreas included metastatic carcinoma (24 cases), metastatic sarcoma (3 cases), diffuse large B-cell lymphoma (2 cases), and plasma cell neoplasm (2 cases). The most common metastatic tumors were renal cell carcinoma (8 cases) and lung carcinoma (7 cases). Correct diagnoses were rendered in 29 cases (94%). The remaining two cases were misclassified as primary pancreatic carcinoma. In both cases, the patients had no known history of malignancy, and no ancillary studies were performed. CONCLUSIONS: Secondary tumors involving the pancreas can be accurately diagnosed by EUS-FNA. Recognizing uncommon cytomorphologic features, knowing prior history of malignancy, and performing ancillary studies are the keys to improve diagnostic performance and avoid diagnostic pitfalls.

Follicular variant of papillary thyroid carcinoma: accuracy of FNA diagnosis and implications for patient management.

Follicular variant of papillary thyroid carcinoma (FVPTC) creates a continuous diagnostic dilemma among pathologists because of the paucity of nuclear changes of papillary carcinoma and overlapping features with benign and other neoplastic follicular lesions. Current guidelines for the management of thyroid nodules recommend surgery for confirmed PTC, suspicious for PTC, and follicular neoplasm cases, while further immediate diagnostic studies or treatment are not routinely required if the nodule is benign on cytology. This study is designed to determine the accuracy of cytology in the diagnosis of FVPTC, based on the Bethesda classification system, and determine the implications for patient management based on the current recommendation. Based on a retrospective review of cytologic diagnoses between January 2008 and December 2011, thyroid fine needle aspiration (FNA) cytology specimens with subsequent surgical intervention and a final diagnosis of FVPTC were selected. The cytologic diagnoses were compared with the final diagnoses, and the percentage of cases contributing to the final diagnosis of FVPTC was calculated for each diagnostic category. Triage efficiency and diagnostic accuracy were calculated. One hundred and fifty-two cases with histologic confirmation of FVPTC were identified (representing 128 patients-101 female, 27 male). All patients had undergone either lobectomy with completion thyroidectomy or total thyroidectomy. The cytologic diagnosis of "positive for malignancy" accounted for only 27 % of the final histologic diagnosis of FVPTC, while suspicious for carcinoma, follicular neoplasm, follicular lesion of undetermined significance, and benign accounted for 11, 23, 23, and 16 % of the final diagnosis of FVPTC, respectively. Only 18 % of the 55 cases tested were positive for BRAF mutation. The subtle nuclear features of FVPTC pose challenges for an accurate diagnosis. Therefore, a better approach is to triage these cases for surgical intervention and/or further evaluation of the particular nodule. Our triage efficacy for FVPTC was 84 %; however, the diagnostic accuracy of PTC was 38 %. A negative diagnosis on FNA has diagnostic and management implications for up to 16 % of cases because they may have no further immediate diagnostic studies or treatment. BRAF mutation analysis provides minimal effect on diagnostic accuracy.

Risk stratification in follicular neoplasm: a cytological assessment using the modified Bethesda classification.

BACKGROUND: The 2007 Bethesda classification for thyroid cytology defines follicular neoplasm as a category of cases with cellular specimens demonstrating abundant follicular cells arranged in a microfollicular pattern with little or no colloid. The current recommendation for the management of these cases is diagnostic lobectomy. There has been great difficulty and variability in triaging and reporting follicular neoplasm. To increase diagnostic accuracy, at the study institution, this category is subclassified further into 3 categories: 1) microfollicular-patterned neoplasm (MN); 2) Hürthle cell neoplasm (HN); and 3) follicular lesion with some features suggestive of but not diagnostic of the follicular variant of papillary thyroid carcinoma (FL). The authors reviewed the cases of follicular neoplasm observed over a period of 5 years to document the follow-up trend using this modified classification. METHODS: A search of the cytology records was performed for the period between January 2008 and December 2012. All thyroid fine-needle aspiration cases were reviewed and those with a diagnosis of follicular neoplasm (including Hürthle cell neoplasm) were identified. Correlating follow-up surgical pathology reports were reviewed. RESULTS: A total of 399 cases of follicular neoplasm with surgical follow-up were identified. Malignancy was identified in 32% of all cases of follicular neoplasm and was found to be disproportionately higher in the FL category (73%). A cytological diagnosis of FL is more likely to be called malignant (73%) than benign neoplastic (9%) or benign nonneoplastic (18%). A cytological diagnosis of MN or HN is more likely to be benign neoplastic (46% and 46%, respectively) than malignant (29% and 26%, respectively) or benign nonneoplastic (25% and 28%, respectively). Of the cytological features examined, 2 (nuclear enlargement and nuclear grooves) were significantly associated with the follicular variant of papillary thyroid carcinoma. CONCLUSIONS: The results of the current study clearly indicate that follicular lesions with even subtle nuclear atypia have a high positive predictive value for malignancy and therefore should be distinguished from other follicular lesions because these cases require more aggressive surgical management. The current study also raises an important issue concerning the current thyroid classification based on the 2007 Bethesda classification for thyroid cytology. Future thyroid fine-needle aspiration classification schemes should consider subclassifying follicular neoplasms for the purpose of risk stratification.

Endoscopic ultrasound-guided fine-needle aspiration diagnosis of Merkel cell carcinoma metastatic to the pancreas.

Merkel cell carcinoma (MCC) is a rare and highly aggressive primary neuroendocrine carcinoma of the skin with a high propensity for local, regional, and distant spread. Distant metastasis of MCC to the pancreas is uncommonly seen and may impose a diagnostic challenge cytologically. Here we report a case of MCC with pancreatic metastasis, which was diagnosed by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). The aspirates revealed both single and clustered epithelial cells with scant cytoplasm and round nuclei with stippled chromatin and inconspicuous nucleoli. Immunocytochemically, the tumor cells were positive for CK20, synaptophysin, CD56, and CD117. The neoplastic cells were also identified by flow cytometry as non-hematopoietic cells which were positive for CD56 and negative for CD45. To our knowledge, this is only the second case report of MCC metastatic to the pancreas diagnosed by EUS-FNA. There have been several reports of MCC metastatic to the pancreas diagnosed only at the time of surgical resection. However, a preoperative diagnosis allows for appropriate management while sparing a patient the morbidity of unnecessary procedures.

Performance of endoscopic ultrasound-guided fine needle aspiration in diagnosing pancreatic neuroendocrine tumors.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) are rare tumors of the pancreas, which are increasingly diagnosed by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). In this retrospective study, we assessed the performance of EUS-FNA in diagnosing PNETs. MATERIALS AND METHODS: We identified 48 cases of surgically resected PNETs in which pre-operative EUS-FNA was performed. The clinical features, cytological diagnoses, and surgical follow-up were retrospectively reviewed. The diagnostic performance of EUS-FNA was analyzed as compared to the diagnosis in the follow-up. The cases with discrepancies between cytological diagnosis and surgical follow-up were analyzed and diagnostic pitfalls in discrepant cases were discussed. RESULTS: The patients were 20 male and 28 female with ages ranging from 15 years to 81 years (mean 57 years). The tumors were solid and cystic in 41 and 7 cases, respectively, with sizes ranging from 0.5 cm to 11 cm (mean 2.7 cm). Based on cytomorphologic features and adjunct immunocytochemistry results, when performed, 38 patients (79%) were diagnosed with PNET, while a diagnosis of suspicious for PNET or a diagnosis of neoplasm with differential diagnosis including PNET was rendered in the 3 patients (6%). One case was diagnosed as mucinous cystic neoplasm (2%). The remaining 6 patients (13%) had non-diagnostic, negative or atypical diagnosis. CONCLUSIONS: Our data demonstrated that EUS-FNA has a relatively high sensitivity for diagnosing PNETs. Lack of additional materials for immunocytochemical studies could lead to a less definite diagnosis. Non-diagnostic or false negative FNA diagnosis can be seen in a limited number of cases, especially in those small sized tumors.

Radiologic and clinical predictors of malignancy in the follicular lesion of undetermined significance of the thyroid.

Various ultrasonographic characteristics of thyroid nodules have been associated with a higher likelihood of malignancy, and certain clinical features may also increase the likelihood of malignancy in patients. This study is designed to determine the ultrasonographic and clinical predictors of malignancy in the atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) category. A search through the cytology files at our institution was made for cases with diagnosis of AUS/FLUS. The clinical and radiologic findings were correlated with the final surgical pathology diagnosis. A total of 140 cases of AUS/FLUS with corresponding surgical intervention were identified (112 females and 28 males). There was a 79 % malignancy rate in nodules with irregular contours, compared to 51 % in nodules with regular outlines. Nodules demonstrating calcifications showed a 57 % malignancy rate, compared to 50 % in nodules without calcifications. Sixty-one percent of cases with an ultrasonographic diagnosis of indeterminate to suspicious were malignant following surgical resection. The rates of malignancy in patients with radiation exposure, symptomatic nodules, and positive family history of thyroid cancer were 22, 59, and 33 %, respectively. BRAF mutation was demonstrated in 57 % of malignant cases and in none of benign cases. No single clinical or ultrasonographic feature or combination of features is adequately sensitive or specific to identify all malignant nodules. However, a combination of solid nodules, nodules with irregular contours, symptomatic nodules, and positive BRAF mutation has high predictive value for malignancy in patients with a cytologic diagnosis of AUS/FLUS.

Renal biopsy: comparative yield of cranial versus caudal needle trajectory. An ex vivo analysis.

AIM: To compare the diagnostic quality of tissue cores obtained using cranial and caudal angulation of the renal biopsy needle. Comparison was made in terms of the number of glomeruli and proportion of renal cortex with medulla on pathological analysis. METHODS: A total of 40 desktop, renal biopsies were performed on 10 ex vivo porcine kidneys using two different targeting angles. Biopsies were obtained from the 'lower pole' of each kidney using both cephalad and caudad angulations of the biopsy needle. Ten 18-gauge semi-automated cutting needles were used during twenty biopsies obtained per each angle; two biopsies were made using each needle. The resulting samples were collected in 40 separate and labelled formalin containers according to the used targeting angle. Two pathologists blinded to the corresponding biopsy angles reviewed the samples in consensus. RESULTS: Samples with a cephalad targeting angle had a mean length of 14.5 mm with mean number of 9.6 glomeruli and average 82% cortex and 18% medulla. Samples obtained using a caudad needle angulation had a mean length of 14.1 mm with mean number of 11.6 glomeruli and on the average 99% cortex. The P-values comparing the two samples were as follows: 0.63 comparing the mean length of cores, 0.08 for number of glomeruli and 0.002 comparing the proportion of cortex. CONCLUSION: The proportion of cortical tissue in the core biopsy specimen using the caudad angle approach was statistically significantly higher, compared with the cephalad needle trajectory.

Molecular characterization of pediatric gastrointestinal stromal tumors.

PURPOSE: Pediatric gastrointestinal stromal tumors (GIST) are rare and occur preferentially in females as multifocal gastric tumors, typically lacking mutations in KIT and PDGFRA. As KIT oncoprotein is consistently overexpressed in pediatric GIST, we sought to investigate the activation of KIT downstream targets and alterations of KIT/PDGFRA gene copy number, mine novel therapeutic targets by gene expression, and test tyrosine kinase receptor activation by proteomic profiling. EXPERIMENTAL DESIGN: Seventeen pediatric GISTs were investigated for KIT/PDGFRA genotype and biochemical activation of KIT downstream targets. The transcriptional profile of 13 nodules from 8 pediatric patients was compared with 8 adult wild-type (WT) GISTs, including 3 young adults. The drug sensitivity of second-generation kinase inhibitors was tested in murine Ba/F3 cells expressing human WT KIT, as well as in short-term culture of explants of WT GIST cells. RESULTS: A KIT/PDGFRA WT genotype was identified in all 12 female patients, whereas two of five males had either a KIT exon 11 or PDGFRA exon 18 mutation. KIT downstream targets were consistently activated. Pediatric GISTs showed a distinct transcriptional signature, with overexpression of BAALC, PLAG1, IGF1R, FGF4, and NELL1. In vitro studies showed that nilotinib, sunitinib, dasatinib, and sorafenib are more effective than imatinib against WT KIT. CONCLUSIONS: Rare cases of pediatric GIST may occur in male patients and harbor activating KIT/PDGFRA mutations. Pediatric GISTs show distinct transcriptional signature, suggesting a different biology than WT GIST in adults. In vitro drug screening showed that second-generation kinase inhibitors may provide greater clinical benefit in pediatric GIST.