Karen E. Schoedel

Contribution of Molecular Testing to Thyroid Fine-Needle Aspiration Cytology of Follicular Lesion of Undetermined Significance/Atypia of Undetermined Significance

“Follicular lesion of undetermined significance/atypia of undetermined significance” is a heterogeneous category of cases that cannot be classified into 1 of the other established categories. The use of ancillary molecular studies has not been widely explored for this diagnosis.

Variability in the Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance Diagnosis in the Bethesda System for Reporting Thyroid Cytopathology: Sources and Recommendations

Objective: Of the 6 categories in the Bethesda System for Reporting Thyroid Cytopathology (BSRTC), the atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) category has received the most attention. The objectives of this study were to review the use of the AUS/FLUS category in recent studies, to search for likely sources of the variability in its use, and to address possible methods for improvement. Study Design: A PubMed search was performed to retrieve peer-reviewed articles that have comprehensively detailed the incidence and outcome of AUS/FLUS and other BSRTC categories. Related thyroid cytology articles on the BSRTC were also included. Results: Recent series that reported experiences with the BSRTC categories showed that the AUS/FLUS category exhibited a marked variability in incidence (0.7–18%) and malignant outcome (6–48%) in resection specimens. Review of the literature revealed institutional differences in technical aspects, interpretation and application of criteria, analysis of outcome data, and clinicopathologic interactions. Conclusions: A heightened awareness of technical issues, diagnostic borders of AUS/FLUS, and clinical management may aid in diagnostic refinement and help avoid overuse of this category.

Integration of KRAS testing in the diagnosis of pancreatic cystic lesions: a clinical experience of 618 pancreatic cysts.

With improvements in abdominal imaging, detection of incidental pancreatic cysts are becoming increasingly common. Analysis of pancreatic cyst fluid from fine-needle aspiration is particularly important in identifying intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs), which have significant implications in clinical intervention and follow-up. Previous controlled studies have shown that KRAS mutations in cyst fluid are highly specific for mucinous differentiation in pancreatic cysts; however, this has not been examined in the clinical setting. Over a 6-year study period, 618 pancreatic cyst fluids obtained by fine-needle aspiration at the time of endoscopic ultrasound were tested for KRAS mutations as part of routine evaluation for a cystic neoplasm. Of the 618 specimens, 603 (98%) from 546 patients were satisfactory for molecular analysis. Patients ranged in age from 17 to 90 years (mean, 63.9 years) and were predominantly female (68%). Pancreatic cysts were relatively evenly distributed throughout the pancreas and ranged in size from 0.6 to 11.0 cm (mean, 2.3 cm). Mutations in KRAS were detected in 232 of 603 (38%) aspirates. Although sufficient for molecular analysis, 320 of 603 (53%) specimens were either less than optimal (38%) or unsatisfactory (15%) for cytopathologic diagnosis. Surgical follow-up information was available for 142 (26%) patients and consisted of 53 KRAS-mutated and 89 KRAS-wild-type cysts. Overall, KRAS mutations had a specificity of 100%, but a sensitivity of 54% for mucinous differentiation. When stratified by cyst type, KRAS had a sensitivity of 67% and 14% for IPMNs and MCNs, respectively. In summary, KRAS mutations were highly specific for mucinous differentiation, but were inadequate in identifying MCNs. Future molecular studies and the combination of other fluid markers are required to improve the detection and classification of pancreatic mucinous neoplasms by endoscopic ultrasound fine-needle aspiration.

BRAF mutation detection in indeterminate thyroid cytology specimens

BRAF mutations are highly specific for papillary thyroid carcinoma (PTC) and many cytology specimens with BRAF mutations are expected to demonstrate cytologic features typical of PTC. However, indeterminate thyroid cytology cases are inevitable and understanding the significance of the BRAF mutation within the context of the Bethesda System for Reporting Thyroid Cytopathology would be valuable.

Expression of metalloproteinases and tissue inhibitors of metalloproteinases in giant cell tumor of bone: An immunohistochemical study with clinical correlation

The clinical behavior of giant cell tumors (GCTs) is unpredictable. To gain insight into this tumors biological behavior, matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were studied. These substances play essential roles in wound healing and neoplastic invasion and metastasis. Paraffin-embedded tissue was collected from 18 cases of histologically benign GCT, with 17 treated by curettage and 1 by resection. Eight cases showed no recurrence after a minimum of 2.5 years, and 10 had local recurrence. One showed metastasis. Antibodies to MMP-9, MMP-2, TIMP-1, and TIMP-2 were applied by immunohistochemical methods. In all cases, MMP-9 was strongly expressed in giant cells predominantly in a diffuse pattern and was strong but focal in stromal cells. MMP-2 decorated stromal cells and giant cells heterogeneously. TIMP-1 was variably expressed in giant cells of the nonrecurrent cases and was strongly present in a diffuse or patchy distribution in the stromal cells in 6 of 8 cases. However, in 9 of 10 recurrent cases, TIMP-1 was expressed weakly by both giant and stromal cells. TIMP-2 was variably expressed in the giant cells of the nonrecurrent cases, but 6 of 8 nonrecurrent cases showed strong stromal cell positivity for TIMP-2. Weak staining for TIMP-2 was observed in 7 of 10 recurrent cases in the stromal cells and 9 of 10 recurrent cases in the giant cells. These results indicate that expression of MMPs and TIMPs differs in giant cells and stromal cells in the same tumor. More significantly, in contrast to the nonrecurrent giant cell tumors, there is an imbalance in the MMPs and TIMPs in the recurrent tumors with a net excess of MMPs. This unopposed expression of MMPs in GCTs may play a role in breakdown of extracellular matrix and tissue invasion. Finally, these markers may prove useful in predicting behavior in these tumors.

Thyroid nodules with KRAS mutations are different from nodules with NRAS and HRAS mutations with regard to cytopathologic and histopathologic outcome characteristics

Mutations in the RAS gene in the thyroid gland result in the activation of signaling pathways and are associated with a follicular growth pattern and the probability of a carcinoma outcome ranging from 74% to 87%. In the current study, the authors investigated the cytopathologic and histopathologic features of common RAS mutation subtypes.

An S100 negative granular cell tumor with malignant potential: Report of a case☆☆☆★★★

Malignant granular cell tumors are rare, but exhibit typical histologic, immunohistochemical, and electron microscopic features that also characterize their benign counterparts. Although most granular cell tumors are S100 protein positive, we report an S100 negative granular cell tumor with histopathologic evidence supporting malignancy. This tumor is best categorized as a malignant granular cell tumor rather than a granular cell variant of a malignant histiocytic, mesenchymal, or epithelial neoplasm. A multidisciplinary approach is essential to diagnosis.

Colloid-rich follicular neoplasm/suspicious for follicular neoplasm thyroid fine-needle aspiration specimens: cytologic, histologic, and molecular basis for considering an alternate view.

Typically, thyroid follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) cases show moderate to marked cellularity and scant or absent colloid. Recently, cases have been noted with microfollicular cellularity in the background of moderate to abundant amount of colloid. The purpose of this study was to compare these “colloid‐rich” FN/SFN cases to the typical FN/SFN cases.

Clonorchis sinensis-associated cholangiocarcinoma: a case report and review of the literature.

Clonorchis sinensis is a flat, leaf-shaped hermaphroditic trematode endemic throughout Southeast Asia. It belongs to the group of liver flukes, along with Opisthorchis viverrini and Opisthorchis felineus. According to the 1994 report of the World Health Organization and the International Agency for Research on Cancer (IARC), the global number of Clonorchis sinensis infestations is estimated as 7 million, found predominantly in southern China, Korea, Taiwan, and Vietnam (1). The common practice of eating raw freshwater fish contributes to the high incidence of infection in these regions. Infestation with liver flukes occurs when humans ingest raw fish containing the infective cysts (metacercariae) present in their muscles and connective tissues. The metacercariae are excysted in the human duodenum and migrate through the ampulla of Vater along the epithelial lining of the common bile duct. Within 30 days, they mature into adult worms within the intrahepatic bile ducts and, occasionally, in the gallbladder, common bile duct, and pancreatic duct (2). The adult fluke attaches to the bile ducts with a pair of large suckers (3) and lays eggs that are excreted in the feces. Subsequently, the ova are ingested by snails of the Bithynia species, which are the first intermediate hosts. The eggs mature and eventually leave the snails in the form of freely swimming cercariae that penetrate cyprinoid fish, the second intermediate hosts. Within the muscle and connective tissues of this fish, the cercariae

Hemoperitoneum in the setting of metastatic cancer to the liver. A report of two cases with review of the literature.

SummaryTwo cases of hemoperitoneum occurring as a result of hepatic rupture due to metastatic neoplasms are presented. They represent examples of a striking and devastating but fortunately uncommon entity. The variety of primary neoplastic sites is diverse. Several possible mechanisms have been put forward to explain the event of hepatic rupture itself. Finally, it is important to note the uniformly poor survival rates following hepatic rupture despite therapy.