Elizabeth M. Gillies

Cytologic and molecular diagnosis of thyroid cancers: is it time for routine reflex testing?

The Bethesda system for standardized reporting of thyroid fine needle aspiration (FNA) cytology has positively affected the clarity of communication of results and management of patients evaluated for thyroid nodules. Problematic areas still exist in the triage of some of these samples, particularly those in the categories of “follicular lesion with atypia of uncertain significance” and “follicular lesion.” The literature on molecular and genetic abnormalities in thyroid lesions is reviewed. Potentially useful markers for distinguishing currently problematic categories of FNA cytologic samples, especially nondiagnostic samples, atypia of uncertain significance, and follicular lesions, are discussed. The predictive value of the respective molecular analyses in these settings is examined. Evaluation of FNA samples with negative or suboptimal follicular cytology for Ras mutations may be useful in detecting potentially significant follicular lesions (carcinomas) but is quite low in overall yield. Cytologic samples with atypia of uncertain significance, which may include the possibility of papillary carcinomas, may be fruitfully evaluated using a panel of molecular tests for BRAF, RET/PTC, PAX8/PPARG1, and Ras. Other markers also have potential utility in the workup of thyroid lesions. An era of combined modality testing in thyroid cytology is emerging in which classical cytologic findings can be coupled with molecular data to increase the predictive power of diagnostic interpretations; however, there remains a group of atypical cytologic samples negative for known molecular markers in which the risk of malignancy is too high to simply follow expectantly. Cancer (Cancer Cytopathol) 2012.

Metastatic rhabdoid melanoma: report of a case with a comparative review of the literature

Melanoma has a propensity to mimic the morphologic appearances of a wide variety of epithelial and soft tissue neoplasms. Although rarely encountered, these unusual morphologic variants of melanoma are often treacherous and may be difficult and challenging to diagnose. Thus, recognition of these variants is of paramount importance in the evaluation of any kind of epithelial or soft tissue neoplasm. Rhabdoid melanoma is one such example of these melanoma variants. Very few cases of rhabdoid melanoma have been reported, most of which were found in metastatic lesions. We wish to expand this rather sparse body of literature by reporting a case of metastatic rhabdoid melanoma arising subcutaneously in the right thigh of a 64‐year‐old man with a remote history of primary toe melanoma. Moreover, we present a comparative review of the clinical, histologic, immunohistochemical and ultrastructural features of previously reported cases. We found significant heterogeneity in the extent of rhabdoid change, expression of melanocytic and non‐melanocytic markers and ultrastructural filamentous patterns in the cases we reviewed. It is our hope that this case report and literature review will help pathologists in the evaluation of neoplasms with rhabdoid morphology.

Tumor grade, microvessel density, and activities of malate dehydrogenase, lactate dehydrogenase, and hexokinase in squamous cell carcinoma.

Squamous cell carcinomas were evaluated with respect to tumor differentiation (through use of hematoxylin and eosin stain), microvessel density (through use of CD-34 immunocytochemical stain), and magnitudes of malate dehydrogenase (MDH), hexokinase, and lactate dehydrogenase (LDH) enzyme activities. Direct correlations were found between tumor grade, MDH activity, and microves-sel density. Direct correlations were also found between hexokinase activity and MDH activity and microvessel density. Inverse correlations were found between LDH activity and both tumor grade and MDH activity. These results suggest that the high rate of glucose utilization (indicated by hexokinase activity) found in more poorly differentiated tumors has a higher component of aerobic oxidative metabolism (indicated by MDH activity) and a relatively lower contribution from anaerobic metabolism (indicated by LDH activity) than do the rates found in more differentiated tumors. It is also suggested that as the glycolytic rate increases, more pyruvate goes into the Krebs cycle than into lactate. The availability of glucose-derived pyruvate for oxidative metabolism would mean less of a dependency on glutamine as a carbon source in squamous cell carcinoma.

HISTOLOGIC EVALUATION OF NECK DISSECTION SPECIMENS

Histologic evaluations of neck dissection specimens from carcinomas of the head and neck provide information required for disease staging, planning further treatment, and prognosis. Histologic evaluation performed adequately and accurately can and continues to provide a more accurate, meaningful, and promising means of formulating and predicting prognosis including risk of metastases. A multi-institutional study using comprehensive standardized histologic evaluation of histopathologic variables of primary tumor and cervical lymph nodes among homogenous patient groups receiving similar therapy is important. Histopathologic parameters remain an important adjunct parameter to clinical evaluation in guiding, planning treatment, and predicting prognosis for patients with head and neck cancers.

Comparison of molecular methods for detection of HPV in oral and oropharyngeal squamous cell carcinoma.

Substantial molecular evidence exists to implicate human papillomavirus (HPV) in the pathogenesis of a subset of oral and oropharyngeal squamous cell carcinomas. Several studies have shown that HPV-associated oral/oropharyngeal tumors differ etiologically, biologically, and clinically from those that lack the virus. HPV infection confers a significant survival benefit; therefore, HPV detection in tumors could be used to risk-stratify patients and drive optimum treatment strategies. We explored the clinical utility of 6 polymerase chain reaction (PCR)-based or signal amplification-based methods in the detection of HPV in 68 invasive oral/oropharyngeal SSCs and 10 reactive tonsil specimens. Agreement for HPV16 results among the 5 different assays capable of detecting this genotype was substantial (multirater &kgr;=0.72). Only moderate agreement was noted for the 3 assays capable of detecting HPV18 (multirater &kgr;=0.43). HPV results for each assay were evaluated relative to a “majority” HPV result derived from the results of all the detection methods. An HPV16 E6 PCR assay showed the highest concordance with adjudicated consensus HPV16 results (98.7%; &kgr;=0.97), followed by the TaqMan (93.4%; &kgr;=0.87), Linear Array (92.1%; &kgr;=0.84), and E7 PCR (92.1%; &kgr;=0.84) assays, all of which had agreements exceeding 90%, whereas the HPV16/18 Invader assay was lower (85.5%; &kgr;=0.71). The presence of high-risk HPV in a minority of “normal” tonsillar tissues may confound assessment of the virus in oral/oropharyngeal squamous cell carcinoma biopsies using in vitro amplification methods.

SINONASAL NEUROENDOCRINE CARCINOMA IN ASSOCIATION WITH SIADH

Background. Neuroendocrine carcinoma (NEC) is a rare malignancy of the nasal cavity or paranasal sinuses. The syndrome of inappropriate ADH secretion (SIADH) has not been previously reported in association with this cancer.

Communicating diagnostic uncertainty in surgical pathology reports: disparities between sender and receiver.

Surgical pathologists use a variety of phrases to communicate varying degrees of diagnostic certainty which have the potential to be interpreted differently than intended. This study sought to: (1) assess the setting, varieties and frequency of use of phrases of diagnostic uncertainty in the diagnostic line of surgical pathology reports, (2) evaluate use of uncertainty expressions by experience and gender, (3) determine how these phrases are interpreted by clinicians and pathologists, and (4) assess solutions to this communication problem. We evaluated 1500 surgical pathology reports to determine frequency of use of uncertainty terms, identified those most commonly used, and looked for variations in usage rates on the basis of case type, experience and gender. We surveyed 76 physicians at tumor boards who were asked to assign a percentage of certainty to diagnoses containing expressions of uncertainty. We found expressions of uncertainty in 35% of diagnostic reports, with no statistically significant difference in usage based on age or gender. We found wide variation in the percentage of certainty clinicians assigned to the phrases studied. We conclude that non-standardized language used in the communication of diagnostic uncertainty is a significant source of miscommunication, both amongst pathologists and between pathologists and clinicians.

Immunolabeling of gamma-glutamyl transferase 5 in normal human tissues reveals that expression and localization differ from gamma-glutamyl transferase 1

Abstract Gamma-glutamyl transferase (GGT5) was discovered due to its ability to convert leukotriene C4 (LTC4, a glutathione S-conjugate) to LTD4 and may have an important role in the immune system. However, it was not known which cells express the enzyme in humans. We have developed a sensitive and specific antibody that can be used to detect human GGT5 on Western blots and in fixed tissue sections. We localized GGT5 expression in normal human tissues. We observed GGT5 expressed by macrophages present in many tissues, including tissue-fixed macrophages such as Kupffer cells in the liver and dust cells in the lung. GGT5 was expressed in some of the same tissues that have been shown to express gamma-glutamyl transferase (GGT1), the only other enzymatically active protein in this family. But, the two enzymes were often expressed by different cell types within the tissue. For example, GGT5 was expressed by the interstitial cells of the kidney, whereas GGT1 is expressed on the apical surface of the renal proximal tubules. Other tissues with GGT5-positive cells included: adrenal gland, salivary gland, pituitary, thymus, spleen, liver, bone marrow, small intestine, stomach, testis, prostate and placenta. GGT5 and GGT1 are cell surface enzymes. The different pattern of expression results in their access to different extracellular fluids and therefore different substrates. GGT5 has access to substrates in blood and intercellular fluids, while GGT1 has access primarily to fluids in ducts and glands throughout the body. These data provide new insights into the different functions of these two related enzymes.

Comparison of 2 line blot assays for defining HPV genotypes in oral and oropharyngeal squamous cell carcinomas

Patients with invasive oral and oropharyngeal squamous cell carcinomas infected with human papillomaviruses (HPV) demonstrate improved survival. HPV detection in tumors may assist in risk stratification of patients and in guiding optimum treatment. Two reverse line blot assays [Linear Array (LA) and INNO-LiPA (LiPA)] were evaluated for detection of HPV genotypes in paraffin-embedded biopsies. Overall, 82.4% of 131 biopsies were HPV+ by LiPA versus 61.1% by LA (κ = 0.32). Completely concordant results were observed in 52.7% of cases: 18 negative and 51 with exactly the same genotype(s). An additional 13 cases had partial agreement. These 82 completely or partially concordant cases revealed a high rate of HPV positivity (78.0%), primarily involving HPV16 (90.6%). HPV+ tumors occurred preferentially in the oropharynx, especially tonsils, with trends for male patients and poor differentiation. Significant differences in these associations were found when LA and LiPA results were analyzed independently. No relationships were found between tumor HPV status and tobacco or alcohol use.

Improved Early Stage (T1/2) Oral Tongue Cancer MedialPathology Margins Using Horizontal Mattress SutureTechnique

The oral tongue is the most common site for oral cavity cancers. Squamous cell carcinoma (SCCa) is responsible for over 90% of cases with an estimated incidence of 3.0/100,000 in the United States [1,2]. Males with a history of tobacco and alcohol use are at greatest risk and commonly present with early stage lesions. Treatment involves wide local excision, neck dissection if indicated and possibly post-operative radiation therapy depending on pathological features. The 5 year survival is 75-89% for early stage disease [2].