Global and mitosis-specific interobserver variation in mitotic count scoring and implications for malignant melanoma staging.

AIMS: Staging is the gold standard for predicting malignant melanoma outcome but changes in its criteria over time indicate ongoing evolution. One notable recent change from the 8th edition of the American Joint Committee on Cancer (AJCC) staging manual was removal of mitotic count. We explore the extent to which this feature is limited by interobserver error in order to find ways to improve its fitness for use should it be revisited in future staging versions. METHODS AND RESULTS: In a cohort of 476 patients with melanoma ≤1.0 mm, a mitotic count of 0 versus 1 was significant for metastasis-free survival, but not melanoma-specific or overall survival. In 10 melanomas that were 0.9-1.0 mm thick, the mitotic count intraclass correlation coefficient for histopathologists was 0.58 (moderate agreement). Uniquely, we also assessed agreement for specific putative mitotic figures, identifying precise reasons why specific mitotic figures qualified for scoring or elimination. A kappa score was 0.54 (moderate agreement). We also gathered data on other staging features. Breslow thickness had an intraclass correlation coefficient of 0.41 (moderate agreement) and there was a systematic difference between histopathologists among cases (P = 0.04). Every case had a range that crossed the AJCC8 0.8-mm pT1a/pT1b staging boundary. Ulceration was only identified in two of the 10 cases. For ulceration, kappa agreement score was 0.31 (fair). CONCLUSION: This study supports the removal of mitotic count from staging, but shows that its scoring is substantially affected by interobserver variation, suggesting that more prescriptive guidelines might have a beneficial impact on its prognostic value.

Diagnostic performance of ultrasound vs. ultrasound-guided FNAc in thyroid nodules: data from the ElaTION trial.

INTRODUCTION: ElaTION is a large multi-centre pragmatic randomised controlled trial, performed in 18 secondary/tertiary hospitals across England, comparing elastography ultrasound-guided fine needle aspiration cytology (EUS-FNAC) with ultrasound-guided FNAC (US-FNAC) alone in the diagnostic assessment of thyroid nodules. Secondary trial outcomes, reported here, assessed the accuracy of ultrasound-alone (US) compared with US-guided FNAC to inform and update current practice guidelines. METHODS: Adults with single or multiple thyroid nodules who had not undergone previous FNAC were eligible. Radiologists assessed all thyroid nodules using US alone, thereby enabling assessment of its accuracy (sensitivity and specificity) versus US-FNAC. RESULTS: Of the 982 participants, a final definitive diagnosis was obtained in 688, who were included in the final analyses. The sensitivity of US-alone was the same as US-FNAC (0.91, [95% CI 0.85, 0.97] vs 0.87 [95%CI 0.80-0.95], p=0.37). US alone had statistically significant lower specificity than US-FNAC alone (0.48 vs 0.67 respectively, p<0.0001). The malignancy rate on histology in a nodule classified as benign on ultrasound (U2) was 9/263 (3.42%) and on cytology (Thy2) was 15/353 (4.25%), whereas the malignancy rate in a nodule that was benign on both (U2, Thy2) was 3/210 (1.43%). Malignancy risk for U3, U4, and U5 nodules was 68/304 (22.4%), 43/83 (51.8%), and 29/38 (76.3%) respectively (p<0.0001). Yet 80/982 (8%) patients were discharged despite having U3-U5 scans with Thy1 (non-diagnostic) FNAC and no definitive diagnosis.Malignancy risk was higher in smaller nodules: <10mm 23/60 (38.3%), 10-20mm 46/162 (28.4 %), and >20mm 80/466 (17.2%) (p<0.0001). Nodules with indeterminate cytology with atypical features (Thy3a) carried a similar malignancy risk to those with indeterminate cytology (Thy3/3f): 27/95 (28.4%) versus 42/113 (37.2%) respectively (p=0.18). CONCLUSION: Ultrasound alone appears to be an effective diagnostic modality in thyroid nodules, confirming the recommendations of recent guidelines and the BTA classification. However, findings also suggest caution regarding existing recommendations for conservative management of non-diagnostic (Thy1/Bethesda I) and atypical (Thy3a/Bethesda III) nodules. In those cases, ultrasound (U3-5) features may help identify high-risk subgroups for more proactive management.

NUT Carcinoma Arising from the Parotid Gland: A Case Report and Review of the Literature.

NUT carcinoma is an aggressive carcinoma with an overall poor survival outcome. The mediastinum and head and neck area, especially the sinonasal region, are among the common sites of disease. Histopathological diagnosis of NUT carcinoma is often very challenging due to its overlapping features with other poorly differentiated carcinomas. We report a case of NUT carcinoma arising from the parotid gland of a young female patient. Primary NUT carcinoma of salivary gland is very rare, with only 15 such cases reported in the literature to date. Our case highlights the diagnostic challenges associated with such lesions.

Microsecretory Adenocarcinoma of Salivary Glands: An Expanded Series of 24 Cases.

Microsecretory adenocarcinoma (MSA) is a recently described salivary gland tumor with a characteristic histologic and immunophenotypic profile and recurrent MEF2C-SS18 fusions. Because only six cases of MSA have been published, its complete clinicopathologic spectrum is unclear, and its biologic behavior has not been documented. Here, we present an updated and expanded experience of 24 MSA cases. All cases of MSA were obtained from the authors' files. Immunohistochemistry for S100, SOX10, p63, p40, SMA, calponin, and mammaglobin was performed. Molecular analysis was performed by targeted RNA sequencing, SS18 break apart fluorescence in situ hybridization, and/or reverse transcriptase polymerase chain reaction for MEF2C-SS18 fusion. Clinical follow-up was obtained from medical records. A total of 24 MSA cases were collected, from 13 women and 11 men, ranging from 17 to 83 years (mean 49.5 years). The vast majority (23 of 24) arose in the oral cavity, with the palate (n = 14) and buccal mucosa (n = 6) as the most frequent subsites. Tumors showed consistent histologic features including: (1) microcystic tubules, (2) flattened intercalated duct-like cells, (3) monotonous oval hyperchromatic nuclei, (4) abundant basophilic luminal secretions, (5) fibromyxoid stroma, and (6) circumscribed borders with subtle infiltration. The tumors were very consistently positive for S100 (24 of 24), p63 (24 of 24), and SOX10 (14 of 14) and negative for p40 (0 of 21), calponin (0 of 12) and mammaglobin (0 of 16), while SMA (4 of 20) was variable. MEF2C-SS18 fusion was demonstrated in 21 of 24 cases; in the remaining 3 cases with insufficient RNA, SS18 break apart FISH was positive. Treatment information was available in 17 cases, all of which were managed with surgery only. In 14 cases with follow-up (1-216 months, mean 30), no cases recurred or metastasized. MSA is a distinct salivary gland neoplasm with remarkably consistent clinical, histologic, immunophenotypic, and genetic features that generally behaves in an indolent manner following surgery alone. These observations solidify MSA as a unique, low-grade salivary gland carcinoma that warrants inclusion in the next version of the WHO classification of head and neck tumors.

Multiple Orthokeratinized Odontogenic Cysts: A Report of Two Cases and Review of the Literature.

Orthokeratinized odontogenic cysts (OOC) are developmental odontogenic cysts characterised by an orthokeratinized stratified squamous epithelial lining. They were originally believed to be part of the spectrum of Odontogenic Keratocyst, but are now considered to be a distinct entity. They are rare, making up approximately 1% of all odontogenic cysts and they usually occur singly. In this paper we present two new cases of multiple OOCs, and compare them to previous case reports of multiple lesions. The clinical and pathological features are discussed, along with possible diagnostic pitfalls.

WNT5A expression increases during melanoma progression and correlates with outcome.

PURPOSE: Wnt ligands play a major role in development and are important in cancer. Expression microarray analysis correlates one member of this family, WNT5A, to a subclass of melanomas with increased motility and invasion. There are no large studies of clinical samples primarily addressing the importance of WNT5A in melanoma progression or outcome. Therefore, this study aimed to assess the protein expression of WNT5A during melanoma progression and its effect on outcome. EXPERIMENTAL DESIGN: Expression of WNT5A was determined in a series of 59 primary melanomas with matched metastases. To provide a benchmark of progression against which to assess WNT5A, expression of p16(ink4a) was analyzed, as this has been previously well documented in melanoma. The effect of WNT5A protein expression on outcome was assessed in 102 melanomas. RESULTS: Cytoplasmic WNT5A showed a trend of increasing expression with melanoma progression (P = 0.013), whereas there was diminishing p16(ink4a) expression (P = 0.006). Nevi showed relatively strong WNT5A expression. Strong cytoplasmic WNT5A was an independent risk factor for reduced metastasis-free and overall survival in multivariate analysis (P = 0.001 and 0.003, respectively). CONCLUSION: Cytoplasmic WNT5A increases with melanoma progression and strong expression is associated with poor outcome.

A hairy situation.

A 2-day-old neonate was transferred to a specialist paediatric otolaryngology centre with stridor at rest, feeding difficulties and an apparent mass in the oropharynx. The newborn displayed evidence of respiratory distress, however, she remained self-ventilating. MRI highlighted a fat-containing lesion in the postnasal space with no intracranial extension. A CT scan under general anaesthesia showed no underlying bony abnormality, and hence an examination of the nasopharynx, oropharynx and microlaryngoscopy and bronchoscopy were performed. The macroscopically hairy lesion arising from the superior aspect of the soft palate was resected. Histology displayed a benign growth measuring 28×17×12 mm in keeping with a hairy polyp. This is one of very few cases, to the best of our knowledge, in which a hairy polyp (bigerminal choristomas) has resulted in stridor in the first few days of life. Nasal masses in neonates, although a rare phenomenon, remain clinically important as they are obligate nasal breathers.

Molecular aspects of melanoma.

Melanoma is the most serious type of skin cancer. Unfortunately, treatment has progressed little and advanced melanoma has appalling survival rates. A goal of molecular analysis is to fully describe the alterations that underpin melanoma's clinical phenotype so that diagnosis can be more accurate, outcome can be predicted with greater confidence, and treatment that is tailored to the patient can be given. This article describes the handful of "signature" changes that are known to occur, describes how some recent studies have shed light on changes beyond this signature, and finally discusses the impact of molecular pathology for practicing histopathologists.

Molecular Aspects of Melanoma.

Melanoma is the most serious type of skin cancer. Unfortunately, treatment has progressed little and advanced melanoma has appalling survival rates. A goal of molecular analysis is to fully describe the alterations that underpin melanoma's clinical phenotype so that diagnosis can be more accurate, outcome can be predicted with greater confidence, and treatment that is tailored to the patient can be given. This article describes the handful of "signature" changes that are known to occur, describes how some recent studies have shed light on changes beyond this signature, and finally discusses the impact of molecular pathology for practicing histopathologists.

Inclusion body myositis: an underdiagnosed myopathy of older people.

Inclusion body myositis (IBM), a condition characterised by progressive muscle weakness and inclusion bodies visible on muscle biopsy, is the most common type of myopathy in patients over 50 years of age. However, it is not only under diagnosed but frequently misdiagnosed as polymyositis and hence wrongly treated with steroids. In the evaluation of progressive weakness in older Caucasian males, IBM should be an important diagnostic consideration. Treatment-resistant 'polymyositis' in patients over 50 years of age is often IBM. If there is no histological confirmation, the diagnostic criteria allow for a category of 'possible IBM'. Sometimes, the diagnosis is missed because of the slow progression of the disease and a lack of suspicion on the part of physicians. The following case report and literature review will explore many of these issues.