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Background In March 2020, a directive to halt all elective and non-urgent procedures was issued in Ontario, Canada because of COVID-19. The directive caused a temporary slowdown of screening programs including surveillance colonoscopies for colorectal cancer (CRC). Our goal was to determine if there was a difference in patient and tumour characteristics between CRC patients treated surgically prior to the COVID-19 directive compared to CRC patients treated after the slowdown. Methods CRC resections collected within the Champlain catchment area of eastern Ontario in the 6 months prior to COVID-19 (August 1, 2019–January 31, 2020) were compared to CRC resections collected in the 6 months post-COVID-19 slowdown (August 1, 2020–January 31, 2021). Clinical (e.g., gender, patient age, tumour site, and clinical presentation) and pathological (tumour size, tumour stage, nodal stage, and lymphovascular invasion) features were evaluated using chi-square tests, T-tests, and Mann–Whitney tests where appropriate. Results Three hundred and thirty-eight CRC specimens were identified (173 pre-COVID-19, 165 post-COVID-19 slowdown). CRC patients treated surgically post-COVID-19 slowdown had larger tumours (44 mm vs. 35 mm; P = 0.0048) and were more likely to have presented emergently (24% vs. 10%; P < 0.001). Although there was a trend towards higher tumour stage, nodal stage, and clinical stage, these differences did not reach statistical significance. Other demographic and pathologic variables including patient gender, age, and tumour site were similar between the two cohorts. Interpretation The COVID-19 slowdown resulted in a shift in the severity of disease experienced by CRC patients in Ontario. Pandemic planning in the future should consider the long-term consequences to cancer diagnosis and management.

Pleomorphic adenoma (PA) is the most common biphasic type of salivary gland tumour to arise in adults. It is a biphasic tumour composed of both luminal (ductal) cells and abluminal (basal and myoepithelial) cells. Other biphasic salivary gland type tumours, both benign and malignant, can mimic PA, especially on small biopsies. Previous studies have shown that glial fibrillary acidic protein (GFAP) is preferentially expressed in PA and can be useful in the distinction from other salivary gland tumours. However, most of these studies were performed on a small subset of tumour types at a time when the classification of salivary gland type tumours was less refined. The purpose of this study was to assess the expression of glial fibrillary acidic protein (GFAP) in a broad group of both benign and malignant salivary gland tumours. The expression of GFAP was assessed in 99 tumours including 54 PAs, 5 basal cell adenomas, 1 myoepitheliomas, 5 adenoid cystic carcinomas, 6 epithelial-myoepithelial carcinomas (EMCA), 6 mucoepidermoid carcinomas, 7 salivary duct carcinomas, 1 adenocarcinomas NOS, 2 myoepithelial carcinomas, 4 basal cell adenocarcinomas, 5 acinic cell carcinomas and 3 polymorphous adenocarcinomas. Of the malignant cases, 8 were classified as carcinomas ex PA. GFAP was also assessed in 19 concurrent biopsy specimens. GFAP was expressed in the resections of 51 PAs examined (94%). Expression was predominantly strong and diffusely seen in myoepithelial cells. Strong and diffuse GFAP expression was also seen in two EMCAs (33%) and one myoepithelial carcinoma (50%). On biopsy specimens, 100% of PAs and basal cell adenomas expressed GFAP. GFAP was also seen in 1 out of 3 carcinomas ex PAs on biopsies. Almost all PAs show strong and diffuse expression of GFAP. In contrast, most malignant neoplasms that can mimic PA on biopsies show only rare, focal expression. Other benign tumours composed of abluminal/myoepithelial cells also show focal expression of GFAP, highlighting the spectrum these tumours share with PA. Overall, the presence of strong and diffuse GFAP expression can favour a benign neoplasm, specifically a PA, on limited biopsy specimens.

BackgroundIn March 2020, a directive to halt all elective and non-urgent procedures was issued in Ontario, Canada because of COVID-19. The directive caused a temporary slowdown of screening programs including surveillance colonoscopies for colorectal cancer (CRC). Our goal was to determine if there was a difference in patient and tumour characteristics between CRC patients treated surgically prior to the COVID-19 directive compared to CRC patients treated after the slowdown.MethodsCRC resections collected within the Champlain catchment area of eastern Ontario in the six months prior to COVID-19 (August 1, 2019-January 31, 2020) were compared to CRC resections collected in the six months post-COVID-19 slowdown (August 1, 2020-January 31, 2021). Clinical (e.g. gender, patient age, tumour site, clinical presentation) and pathological (tumour size, tumour stage, nodal stage, lymphovascular invasion) features were evaluated using chi square tests, T-tests and Mann-Whitney tests where appropriate.Results343 CRC specimens were identified (175 pre-COVID-19, 168 post-COVID-19 slowdown). CRC patients treated surgically post-COVID-19 slowdown had larger tumours (44 mm vs. 35 mm; p = 0.0048) and were more likely to have presented emergently (24% vs .10%; p < 0.001). While there was a trend towards higher tumour stage, nodal stage, and clinical stage, these differences did not reach statistical significance. Other demographic and pathologic variables including patient gender, age, and tumour site were similar between the two cohorts.InterpretationThe COVID-19 slowdown resulted in a shift in the severity of disease experienced by CRC patients in Ontario. Pandemic planning in the future should consider the long-term consequences to cancer diagnosis and management.

Neuroendocrine carcinomas of the head and neck are rare and are classified as well differentiated, moderately differentiated, and poorly differentiated carcinomas with the latter category being subdivided into small cell and large cell neuroendocrine carcinoma (LCNEC). While most carcinomas in the nasopharynx are associated with Epstein-Barr virus (EBV), there has been only one previous report demonstrating a link between EBV and LCNEC of the nasopharynx. In this report we describe a second case of EBV-positive LCNEC arising in the nasopharynx with bilateral cervical metastases. The patient was treated with a combination of radiation and chemotherapy which resulted in a complete clinical and radiological response. The patient is still disease free 3 years after presentation. The results of this case suggest that EBV-positive LCNEC is sensitive to chemoradiotherapy and as a result may have better prognosis than EBV-negative LCNEC arising in the nasopharynx or other sites.

In many centres, patients now have access to their electronic medical record (EMR) and laboratory results, including pathology reports, are amongst the most frequently accessed pieces of information. The pathology report is an important but highly technical medical document that can be difficult for patient and clinicians alike to interpret. To improve communication and patient safety, pathologists are being called upon to play a more direct role in patient care. Novel approaches have been undertaken by pathologists to address this need, including the addition of patient-friendly summaries at the beginning of pathology reports and the development of patient education tools. MyPathologyReport.ca is a novel website exclusively providing pathology education to patients. It has been designed to help patients understand the language of pathology and to effectively navigate their pathology report. At present, the website includes over 150 diagnostic articles and over 125 pathology dictionary definitions. The diagnostic articles span all body sites and include a variety of malignant, benign and non-neoplastic conditions. Since its creation, this website has been visited over 14 000 times, with cancer-related diagnoses and definitions representing the most commonly accessed articles. This website has been embedded in patient accessible EMRs and shared through partnerships with patients, caregivers and their respective advocacy groups. Our next steps involve longitudinal assessment of MyPathologyReport.ca from non-medical community members, evaluation of patient satisfaction and understanding and further collaboration with hospitals and care-providers to increase patient access to this resource.

Clinically, radiologically, and pathologically, chondroid neoplasms of the skull can be diagnostically challenging due to overlapping features in each of these domains. Compounding the problem for the pathologist, there is also significant morphologic, immunophenotypic, and molecular genetic overlap between benign and malignant cartilaginous lesions, and the majority of these lesions are encountered quite rarely in routine surgical pathology practice. Each of these factors contribute to the diagnostic difficulty posed by these lesions, highlighting the importance of radiologic-pathologic correlation in the diagnosis. This review is intended to provide an update for surgical pathologists on some of the most commonly encountered chondroid neoplasms in the skull, and includes the following lesions: chondromyxoid fibroma, synovial chondromatosis, chondrosarcoma and variants, and chordoma and variants. For each of these lesions, the differential diagnosis and useful ancillary tests will be discussed in the context of a broad range of additional primary and secondary lesions.

Pleomorphic adenoma (PA) is the most common salivary gland neoplasm. On a molecular level PA is characterized by a translocation involving PLAG1 or HMGA2. PA is considered to be a benign tumor although it can undergo malignant transformation. Alternatively, cases of histologically benign PA "metastasizing" to lymph nodes or distant body sites are well documented. Several theories have been proposed to explain this behavior. However, there is a lack of molecular data available to assess the relationship of metastasizing PA (MPA) and their benign counterparts. In this study we describe 4 cases of MPAs and perform the first molecular study linking them to conventional PA. The index case was identified in the course of routine clinical practice, while the other cases were retrieved from the archives of the authors. Slides were reviewed to confirm the diagnosis of both the primary/recurrent tumor and the metastasis. Fluorescence in situ hybridization (FISH) was performed in all cases and RNA sequencing was performed on the index case. In all cases there was a history of recurrent PA involving the parotid. Lymph node metastases were identified in 2 cases; non-lymph node metastases were identified in 3 cases. All the metastases were histologically benign. RNA sequencing performed on the index case demonstrated a novel HMGA2-TMTC2 translocation, which was confirmed by separate FISH break-apart assays for both genes. FISH performed on the remaining cases demonstrated rearrangement of PLAG1 in all 3 cases. This study demonstrates that MPA harbors the same disease-defining molecular hallmark as their benign counterparts.

Objective The prognosis for patients with triple negative breast cancer (TNBC) is poor, however, a subset will demonstrate complete pathological response (pCR) to chemotherapy. GATA-3 and AR may be a negative predictors for pCR although it is unclear if these results apply to TNBC. Methods Patients diagnosed with TNBC and treated with neoadjuvant chemotherapy were identified. Immunohistochemistry was performed for GATA-3 and AR. Both were scored using a composite of staining intensity and percentage cells stained. The primary outcome was pCR. Results Twenty-four patients were included and 7 achieved pCR. There was no difference in the pre-chemotherapy tumor size (44 ± 28 mm vs. 54 ± 30 mm; p = 0.764) or lymph node status (86% vs. 71%; p = 0.629) between patients with and without pCR. GATA-3 expression was present in 20 cases (83%) while AR was present in 6 cases (25%). No AR expression was seen in 15 cases (63%) with GATA-3 positivity. There was no difference in either GATA-3 (4.3 ± 2.7 vs. 3.6 ± 2.5; p = 0.549) or AR (1.4 ± 2.5 vs. 1.1 ± 2.4; p = 0.778) expression between patients with and without pCR. Conclusions GATA-3 expression is frequent in TNBC even in the absence of AR. However, neither GATA-3 nor AR are associated with pCR after neoadjuvant chemotherapy.

Neuroendocrine carcinomas (NECs) are epithelial neoplasms showing morphologic, immunophenotypic or ultrastructural evidence of neuroendocrine differentiation. The 2017 WHO Classification of Head and Neck Tumours classifies NECs into well, moderately and poorly differentiated NECs according to light microscopic features, mitotic rate and presence of tumour necrosis. In this study, we performed next generation sequencing (NGS) using a targeted 161 cancer gene panel on a poorly differentiated NEC of the nasal cavity. The tumour was composed of large cells arranged in poorly formed glands and solid nests. The mitotic count rate was 30/10 HPFs and p53 protein was strongly expressed in all tumour cells. NGS identified a missense mutation, c.764T > G (p.Ile255Ser) in the TP53 gene with an allele frequency of 85%. This mutation results in an isoleucine to serine substitution and a non-functional protein. No other mutations were identified. These results suggest that TP53 mutations may drive oncogenesis in poorly differentiated NECs of the head and neck.

Primary cutaneous adenoid cystic carcinoma (ACC) is a rare skin tumor that is unlikely to metastasize. We present a case of primary cutaneous ACC in a 67-year-old male with axillary lymph node, pulmonary and brain metastases. To the best of our knowledge, this is the first reported case of cutaneous ACC with distant metastases to the brain.

BackgroundIntraductal papillary neoplasms of the biliary tract (IPNB) and intracholecystic papillary neoplasms (ICPN) are rare tumours characterized by intraluminal papillary growth that can be associated with invasive carcinoma. Their natural history remains poorly understood. This study examines clinicopathological features and outcomes.MethodsPatients who underwent surgery for IPNB/ICPN (2008–2014) were identified. Descriptive statistics and survival data were generated.ResultsOf 23 patients with IPNB/ICPN, 10 were male, and the mean age was 68 years. The most common presentations were abdominal pain (n = 10) and jaundice (n = 9). Tumour locations were: intrahepatic (n = 5), hilar (n = 3), the extrahepatic bile duct (n = 8) and the gallbladder (n = 7). Invasive cancer was found in 20/23 patients. Epithelial subtypes included pancreatobiliary (n = 15), intestinal (n = 7) and gastric (n = 1). The median follow‐up was 30 months. The 5‐year overall (OS) and disease‐free survivals (DFS) were 51% and 57%, respectively. Decreased OS (P = 0.09) and DFS (P = 0.05) were seen in patients with tumours expressing MUC1 on immunohistochemistry (IHC).ConclusionIPNB/ICPN are rare precursor lesions that can affect the entire biliary epithelium. At pathology, the majority of patients have invasive carcinoma, thus warranting a radical resection. Patients with tumours expressing MUC1 appear to have worse OS and DFSs.

Objectives High-grade ductal carcinoma in situ (HG-DCIS) of the breast often shows tumor attenuation and reactive fibrosis. These changes, previously described as “regressive,” have been paradoxically associated with an increased risk of invasive carcinoma. We aimed to further characterize the spectrum of the so-called regressive changes (RCs) in HG-DCIS. Methods We reviewed 52 consecutive cases of HG-DCIS on biopsy specimens followed by excision. RCs were divided into early (stage 1) and advanced (stages 2 and 3) stages according to the degree of ductal fibrosis and tumor effacement. The presence of inflammation, hormone receptor status, and diagnosis on excision were recorded. Results RCs were seen in 51 (98%) cases: 96%, 76.4%, and 39.2% cases showed stages 1, 2, and 3, respectively. Periductal T cells with a normal CD4/CD8 ratio were constantly seen. Advanced RCs and inflammation were more frequent in estrogen and progesterone receptor–negative tumors. RCs were not associated with invasion but correlated with a larger residual HG-DCIS volume on excision. Conclusions Regression in HG-DCIS is frequent. It may reflect a targeted immune response to certain phenotypes, mainly hormone receptor–negative lesions. Nonetheless, RCs do not lead to complete tumor obliteration but correlate with aggressive tumor characteristics instead.

Osteoclast-like giant cells are frequently encountered in nonskeletal malignancies; however, the evidence to date suggests that they represent a tissue response to the lesion rather than neoplastic differentiation. We describe a case of metastatic melanoma demonstrating osteoclast-like differentiation in the lung. The lung nodule was diagnosed as a metastatic melanoma by histological features and confirmed by immunohistochemistry. Resection specimen showed numerous multinucleated giant cells exhibiting osteoclast-like morphology dispersed throughout the lesion. Both the neoplastic melanocytes and giant cells were reactive for HMB-45, Melan-A, and S100. In addition, the multinucleated neoplastic giant cells were also reactive for the monocyte/macrophage lineage markers CD68 and CD163, and alkaline phosphatase, an enzyme present in normal osteoclasts. The neoplastic melanocytes and the multinucleated neoplastic giant cells were also reactive for microphthalmia-associated transcription factor, a protein required for the development of both melanocytes and osteoclasts. Collectively, a co-expression of monocyte/macrophage markers along with melanocytic markers and alkaline phosphatase in the multinucleated neoplastic giant cells in metastatic melanoma suggest that malignant melanocytes are capable of differentiating into osteoclast-like cells and consequently aid invasion into various structures and eliciting the aggressive behavior.

Background and Purpose— Ischemia on computed tomography (CT) is associated with subsequent stroke after transient ischemic attack. This study assessed CT findings of acute ischemia, chronic ischemia, or microangiopathy for predicting subsequent stroke after transient ischemic attack. Methods— This prospective cohort study enrolled patients with transient ischemic attack or nondisabling stroke that had CT scanning within 24 hours. Primary outcome was subsequent stroke within 90 days. Secondary outcomes were stroke at ≤2 or >2 days. CT findings were classified as ischemia present or absent and acute or chronic or microangiopathy. Analysis used Fisher exact test and multivariate logistic regression. Results— A total of 2028 patients were included; 814 had ischemic changes on CT. Subsequent stroke rate was 3.4% at 90 days and 1.5% at ≤2 days. Stroke risk was greater if baseline CT showed acute ischemia alone (10.6%; P =0.002), acute+chronic ischemia (17.4%; P =0.007), acute ischemia+microangiopathy (17.6%; P =0.019), or acute+chronic ischemia+microangiopathy (25.0%; P =0.029). Logistic regression found acute ischemia alone (odds ratio [OR], 2.61; 95% confidence interval [CI[, 1.22–5.57), acute+chronic ischemia (OR, 5.35; 95% CI, 1.71–16.70), acute ischemia+microangiopathy (OR, 4.90; 95% CI, 1.33–18.07), or acute+chronic ischemia+microangiopathy (OR, 8.04; 95% CI, 1.52–42.63) was associated with a greater risk at 90 days, whereas acute+chronic ischemia (OR, 10.78; 95% CI, 2.93–36.68), acute ischemia+microangiopathy (OR, 8.90; 95% CI, 1.90–41.60), and acute+chronic ischemia+microangiopathy (OR, 23.66; 95% CI, 4.34–129.03) had greater risk at ≤2 days. Only acute ischemia (OR, 2.70; 95% CI, 1.01–7.18; P =0.047) was associated with a greater risk at >2 days. Conclusions— In patients with transient ischemic attack/nondisabling stroke, CT evidence of acute ischemia alone or acute ischemia with chronic ischemia or microangiopathy was associated with increased subsequent stroke risk within 90 days.

Neural, sclerosing, and myofibroblastic lesions of the ear and temporal bone present diagnostic challenges for both clinicians and pathologists due to significant overlap in their clinical presentations, histologic appearances, and immunohistochemical profiles. While some of these lesions, such as schwannomas, are relatively common, others are rendered even more difficult because they are encountered very rarely in routine surgical pathology practice. This review is intended to provide an update on the pathology of some of the most commonly encountered primary diagnostic entities for the ear and temporal bone, and includes the following neural lesions: schwannoma, meningioma, and encephalocele/meningocele. Sclerosing lesions that will be discussed include spindle cell and sclerosing rhabdomyosarcoma, sclerosing epithelioid fibrosarcoma, and sclerosing paraganglioma. Finally, myofibroblastic lesions that will be reviewed are nodular fasciitis, IgG4-related disease, and solitary fibrous tumor. For each of these lesions, the differential diagnosis and useful ancillary tests will be discussed in the context of a broad range of additional primary and secondary lesions.

Chordoma is a rare malignant bone tumor that can arise anywhere along the central neural axis and many involve head and neck sites, most commonly the skull base. The relative rarity of these tumors, combined with the complex anatomy of the head and neck, pose diagnostic challenges to pathologists. This article describes the pertinent clinical, pathologic, and molecular features of chordomas and describes how these features can be used to aid in formulating a differential diagnosis. Emphasis is placed on key diagnostic pitfalls and the importance of incorporating immunohistochemical information into the diagnosis.

Background: Isolated dysarthria is an uncommon presentation of transient ischemic attack (TIA)/minor stroke and has a broad differential diagnosis. There is little information in the literature about how often this presentation is confirmed to be a TIA/stroke, and therefore there is debate about the risk of subsequent vascular events. Given the uncertain prognosis, it is unclear how to best manage patients presenting to the emergency department (ED) with isolated dysarthria. The objective of this study was to prospectively identify and follow a cohort of patients presenting to EDs with isolated dysarthria in order to explore their natural history and risk of recurrent cerebrovascular events. Specifically, we sought to determine early outcomes of individuals with this nonspecific and atypical presentation in order to appropriately expedite their management. Methods: Patients with isolated dysarthria having presented to 8 Canadian EDs between October 2006 and April 2009 were analyzed as part of a prospective multicenter cohort study of patients with acute neurological symptoms as assessed by emergency physicians. The study inclusion criteria were age ≥18 years, a normal level of consciousness, and a symptom onset Results: Between 2006 and 2009, 1,528 patients were enrolled and had a 90-day follow-up. Of these, 43 patients presented with isolated acute-onset dysarthria (2.8%). Recurrent stroke occurred in 6/43 (14.0%) within 90 days of enrollment. The predicted maximal 90-day stroke rate was 9.8% (based on a median ABCD2 score of 5 for the isolated dysarthria cohort). After adjusting for covariates, isolated dysarthria independently predicted stroke within 90 days (aOR: 3.96; 95% CI: 1.3-11.9; p = 0.014). Conclusions: The isolated dysarthria cohort carried a recurrent stroke risk comparable to that predicted by the median ABCD2 scores. Although isolated dysarthria is a nonspecific and uncommon clinical presentation of TIA, these findings support the need to view it first and foremost as a vascular presentation until proven otherwise and to manage such patients as if they were at high risk of stroke in accordance with established high-risk TIA guidelines.

Background and Purpose— CT angiography spot sign predicts hematoma expansion in patients with acute intracerebral hemorrhage (ICH). The spot sign may represent a site of active extravasation, a locus of arrested hemorrhage forming fibrin globes, or represent associated epiphenomena such as hypertensive microaneurysms. We sought to describe the evolution of spot signs over 60 seconds in acute ICH using dynamic CT angiography and determine whether they grow and diffuse into the hematoma as would be expected with active extravasation. Methods— We prospectively identified consecutive patients presenting with spontaneous ICH Results— We collected data on 35 patients; 13 of 35 (37%) patients were spot-positive. Spot-positive patients had larger median ICH volume compared with spot-negative patients (median 10.7 versus 49.2 mL; P =0.007). Maximal spot sign volumes ranged from 0.02 to 2.8 mL (median 0.17 mL). Spot sign volumes increased significantly with time ( P Conclusions— In this dynamic CT angiography study of ICH, spot signs evolve consistent with sites of active extravasation.

Background: Warfarin-associated intracerebral hemorrhage (WAICH) is a devastating disease with increasing incidence. In this setting, treatment with prothrombin complex concentrates (PCC) is essential to correct coagulopathy. Yet despite the availability of coagulopathy correction strategies, significant treatment delays can occur in emergency departments (EDs), which may be overcome using stroke prenotification strategies. To explore this, we compared arrival-to-treatment times with PCC for WAICH between two different stroke response systems that used the same international normalized ratio (INR) correction protocol. Methods: We established a registry of consecutive patients presenting with WAICH and treated with PCC presenting to two Canadian tertiary-care academic stroke centers: one with a stroke prenotification system, and one with a traditional ED assessment, treatment and referral system. In this comparative cohort design, we defined the WAICH diagnosis time as the earliest time point where both INR and CT were available. We compared median times from arrival to treatment, as well as arrival to diagnosis, and diagnosis to treatment. Results: Between 2008 and 2010, we collected data from 123 consecutive patients with intracranial hemorrhage who received PCC for INR correction (79 from ED referral, and 44 prenotification). Onset-to-arrival times, demographics, Glasgow Coma Scale scores, and baseline INR were similar between the two systems. Arrival-to-treatment times were significantly shorter in the prenotification system as compared to the traditional ED referral system (135 vs. 267 min; p = 0.001), which was driven by both decreased arrival-to-diagnosis time (49 vs. 117 min; p = 0.006), as well as decreased diagnosis-to-treatment time (56 vs. 112 min; p < 0.001). Arrival-to-scan times and arrival-to-INR times were similarly shorter in the prenotification system (68 vs. 118 min and 20.5 vs. 47 min, respectively). Conclusion: Stroke prenotification was associated with shorter arrival-to-treatment times for emergent INR correction in patients with WAICH, which was driven by both faster diagnosis and treatment. Our results are consistent with those seen in ischemic stroke, suggesting that prenotification systems present an opportunity to optimize acute intracerebral hemorrhage therapy.

BACKGROUND Differentiated squamous intraepithelial neoplasia (dSIN) is a pathway in the development of invasive squamous cell carcinoma (SCC) distinct from the usual-type squamous intraepithelial neoplasia (uSIN) and has not been described in the larynx. MATERIALS AND METHODS Sixty-nine consecutive cases of SCC were identified which included 25 dSIN, 13 uSIN, and 31 mixed dSIN+usual-like SIN (u-like SIN) cases. RESULTS dSIN was characterized by atypical squamous cells limited to the basal/parabasal layers and u-like SIN was characterized by cytologic atypia limited to less than full thickness. Despite the lack of neoplastic involvement of the full thickness of the epithelium, these types of SIN were commonly connected with invasive carcinoma. Prior biopsies demonstrating only dSIN, without the underlying invasive SCC, were underdiagnosed in 2 cases. Because of the frequent keratinization, u-like SIN likely represents the "keratinized dysplasia" and shows changes suggestive of dSIN with upward spread of neoplastic cells into the upper layer of the epithelium. CONCLUSIONS Laryngeal dSIN represents an important but under recognized pathway of invasive SCC development. As moderate dysplasia of uSIN type are not associated with invasive SCC, labeling u-like SIN as dysplasia of grade 2 or 3 likely leads to the controversies in the current grading systems in the upper aerodigestive system and causes confusion for clinicians.

Poorly differentiated sinonasal malignancies are amongst the hardest differential diagnoses in pathology, owing to the large number of rare entities that arise there. Complicating the matter is that most pathologists, including those with experience in head and neck pathology, have little experience in any one of these rare entities. Most patients with sinonasal carcinoma present with locally advanced disease and in the past a combination of chemotherapy, radiotherapy, and surgery would usually be recommended without the specific disease subtype playing a large part of the decision making. However, in the era of “precision medicine” and targeted therapies, the specific tumour subtype and an accurate diagnosis will become increasingly important even for the so-called “undifferentiated carcinoma”. Specific entities that tend to enter into the differential diagnosis include olfactory neuroblastoma, sinonasal undifferentiated carcinoma (SNUC), and non-keratinizing squamous cell carcinoma (viral and non-viral). However, recent new entities, such as NUT-midline carcinoma also have to be considered. Recently it was found that a subset of tumours originally diagnosed as one of the aforementioned entities all demonstrated loss of the ubiquitously expressed protein Integrase Interactor 1 (INI1; SMARCB1). These tumours were often basaloid with at least partial rhabdoid differentiation and most were considered a part of the SNUC spectrum. In this report, we describe two additional cases of INI1-deficient sinonasal carcinoma prospectively identified, both of which appeared to have a marked response to neo-adjuvant chemoradiation, a finding not previously described.

Background and Purpose— Transient ischemic attack (TIA) is a marker for early risk of stroke. No previous studies have assessed the use of urgent stroke prevention clinics for emergency department (ED) patients with TIA. We hypothesized that an ABCD2-based ED triaging tool for TIA with outpatient management would be associated with lower 90-day stroke rate than that predicted by ABCD2. Methods— A cohort of prospectively identified patients presenting with symptoms suggestive of TIA seen in 2 tertiary-care EDs. These patients were divided into 3 strata based on their ACBD2 score, and triage targets were set for each stratum. All patients received the same standard of care in the Stroke Clinic regardless of their risk score. Primary outcome was stroke by 90 days of index TIA. Secondary outcomes were subsequent TIA, myocardial infarction, or death. Results— One-thousand ninety-three patients met the inclusion criteria; 982 patients completed 90-day follow-up and comprised the final cohort. After stratification, 32%, 49%, and 19% of patients were categorized as low-, moderate-, or high-risk, respectively. The overall 90-day risk of stroke in all patients was 3.2%, compared with the ABCD2-predicted risk of 9.2%. Only 1.6% of patients with TIA/minor stroke were admitted from the ED. The risk of subsequent TIA, myocardial infarction, or death by 90 days was 5.5%, 0.1%, and 1.7%, respectively. Conclusion— Outpatient care in a rapid-access stroke prevention clinic using the ABCD2 score for triage resulted in a low 90-day stroke rate for patients in the ED with TIA. Benefit occurred without requiring admission for most patients.

Experimental studies of intracerebral hemorrhage (ICH) have focused on neuron death, with little or no information on axonal and myelin damage outside the hematoma. Because development of effective therapies will require an understanding of white matter injury, we examined white matter injury and its spatial and temporal relationship with microglial/macrophage activation in a collagenase model of rat striatal ICH. The hematoma and parenchyma surrounding the hematoma were assessed in young and aged animals at 6 h, 1, 3 and 28 days after ICH onset. Demyelination occurred inside and at the edge of the hematoma; regions where we have shown substantial neuron death. In contrast, there was axonal damage without demyelination at the edge of the hematoma, and by 3 days this damage had spread to the surrounding parenchyma, a region where we have shown there is no neuron death. Because the axonal damage preceded infiltration of activated microglia into the white matter tracts (seen at 3 days), our results support the hypothesis that these cells respond to, rather than perpetrate the damage. Importantly, axonal damage was worse in aged animals, which provides a plausible explanation for the poorer functional recovery of older animals after ICH, despite a similar loss of grey matter. Our findings support strategies that target white matter injury to reduce neurological impairment after ICH.

Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm; however, it is the most common cause of tumor-induced osteomalacia (TIO), a paraneoplastic syndrome characterized by renal phosphate wasting and hypophosphatemia. A subset of PMTs harbours an FGFR1 translocation although this alteration has not been demonstrated in PMT involving a head and neck site. We present a series of five PMTs involving the head and neck and demonstrate the diagnostic utility of fluorescence in situ hybridization (FISH) for detecting FGFR1 translocations. Patients’ age and sex, tumor location, original diagnosis, the duration of symptoms, the presence of TIO, biochemical results, and medical management were reviewed. The median age at presentation was 45 (range, 24–58 years) and TIO was present in three cases. Four tumors involved soft tissue and one involved bone. Four out of the five tumors in our series were initially misdiagnosed. Three tumors were ultimately categorized as malignant PMT (two patients developed metastatic disease). FGFR1 translocation was present in two out of four cases and remained unknown in one case. In summary, we report on five cases of PMTs arising in the head and neck and confirm utility of FGFR1 FISH in the diagnosis of a subset of PMT.

There are no effective treatments for intracerebral hemorrhage (ICH). Although inflammation is a potential therapeutic target, there is a dearth of information about time-dependent and cell-specific changes in the expression of inflammation-related genes. Using the collagenase-induced ICH model in rats and real-time quantitative RT-PCR we monitored mRNA levels of markers of glial activation, pro- and anti-inflammatory cytokines, enzymes responsible for cytokine activation and several matrix metalloproteases at 6 h and 1, 3 and 7 days after ICH onset. For the most highly up-regulated genes, immunohistochemistry was then used to identify cell-specific protein expression. Finally, minocycline, a drug widely reported to reduce damage in several models of brain injury, was used to test the hypothesis that it can reduce up-regulation of inflammation-related genes when administered using a clinically relevant dosing regime: intraperitoneal injection beginning 6 h after ICH. Our results show a complex inflammatory response, with different brain cell types producing several pro- and anti-inflammatory molecules for at least 7 days after ICH onset. Included is the first demonstration that astrocytes are an important source of interleukin-1beta (IL-1beta), interleukin-1 receptor antagonist (IL-1ra), interleukin-6 (IL-6) and MMP-12. Importantly, our results demonstrate that while delayed minocycline treatment effectively reduces early up-regulation of TNFalpha and MMP-12, its efficacy is lost when treatment is extended for up to a week, and it does not reduce several other genes associated with microglia activation. These results suggest caution in extrapolating to ICH the promising results of minocycline treatment in other models of brain injury.

Immunohistochemistry is frequently used to identify ovarian mucinous neoplasms as primary or metastatic; however, there is significant overlap in expression patterns. We compared traditional markers (CK7, CK20, CDX2, PAX8, estrogen receptor, β-catenin, MUC1, MUC2, and MUC5AC) to 2 novel proteins identified through mining of the Human Protein Atlas expression database: SATB2 and POF1B. The study cohort included 49 primary gastrointestinal (GI) mucinous adenocarcinomas (19 colorectal, 15 gastric, 15 pancreatobiliary), 60 primary ovarian mucinous neoplasms (19 cystadenomas, 21 borderline tumors, 20 adenocarcinomas), and 19 metastatic carcinomas to the ovary (14 lower and 5 upper GI primaries). Immunohistochemistry was performed on tissue microarrays, scored and interpreted as negative (absent or focal/weak) or positive. Metastatic tumors were frequently unilateral (42.8% of tumors from lower and 40% of tumors from upper tract) and ≥10 cm (85.7% of tumors from lower and 80% of tumors from upper tract). CK7 was positive in 88.5% upper GI and 88.3% primary ovarian compared with 24.3% lower GI neoplasms. CK20 and CDX2 were positive in 84.8% and 100% of lower GI tumors, respectively; however, expression was also common in upper GI (CK20 42.8%, CDX2 50%) and primary ovarian neoplasms (CK20 65.7%, CDX2 38.3%). Conversely, SATB2 was more specific for lower GI origin, being positive in 78.8% lower GI but only 11.5% upper GI and 1.7% primary ovarian neoplasms. PAX8 expression was common in primary ovarian neoplasms (75% of all neoplasms, 65% of carcinomas); only 1 (1.5%) GI tumor was positive. MUC2 and β-catenin were frequently positive in lower GI tumors (96.9% and 51.5%, respectively). Estrogen receptor expression was only seen in primary ovarian neoplasms (13.3%). Nuclear premature ovarian failure 1B (POF1B) expression was seen in malignant tumors regardless of their origin. A panel including CK7, SATB2, and PAX8 separated primary from secondary GI neoplasms with up to 77.1% sensitivity and 99% specificity, outperforming tumor laterality and size. Second-line markers such as CDX2, MUC2, estrogen receptor, MUC1, and β-catenin increased the sensitivity of immunohistochemistry in excluding lower GI origin. Biomarker search using proteomic databases has a value in diagnostic pathology, as shown with SATB2; however, as seen with POF1B, expression profiles in these databases are not always reproduced in larger cohorts.

The NUT midline carcinoma (NMC) is a recently described and highly aggressive tumor that usually involves the head and neck and anterior mediastinum. Most patients with NMC present with metastases and are often treated with neoadjuvant chemotherapy and/or radiation therapy. As a consequence, surgical specimens are often piecemeal excisions demonstrating treatment effect. In this report, we provide what is to the best of our knowledge the first complete gross description of NMC resected in toto and without prior treatment. The patient in this case underwent a pneumonectomy for a lung mass with curative intent. On gross examination, the tumor was found to be arising from the mediastinum with a smooth border, and demonstrated only minimal invasion of the surrounding structures. However, lymphovascular invasion was present throughout and there was extensive involvement of surrounding lymph nodes. The gross appearance of the tumor in this case reaffirms that NMC is an aggressive malignancy that usually metastasizes before it invades locally.

Aims Differentiated squamous intraepithelial neoplasia (DSIN) has been described in several sites, including the upper aerodigestive tract and vulva, so this study investigated whether it also occurred in the anal canal. Methods and results All cases of squamous cell carcinoma (SCC) involving the anal canal diagnosed between 2009 and 2015 at our institution were reviewed. Eighty-six cases were included, and 13 (15%) showed features consistent with DSIN: 10 were ‘pure’ DSIN, and three were ‘mixed’ DSIN and squamous intraepithelial lesion. DSIN was characterized by atypical keratinocytes limited to the basal/parabasal layers, acanthosis, and a ‘cobblestone’ appearance. Among specimens with pure DSIN, the surface was flat in eight cases. In five cases, the DSIN was extensive, and associated with deeply invasive SCC requiring radical surgical resection. Immunohistochemically, the epithelia showing changes consistent with DSIN were p16-negative, whereas the invasive component was p16-positive in 12 cases. Both Ki67 and p53 showed strong nuclear positivity in the basal/parabasal layers of DSIN. Conclusions Invasive SCC associated with DSIN often presents at an advanced stage of disease, requiring radical surgical treatment. The neoplastic changes in DSIN are limited to the basal/parabasal layers, which may account for the negative diagnoses by anal cytopathology and late clinical diagnosis. The recognition of anal DSIN is important in order to avoid underdiagnosis in superficial biopsies.

ObjectiveA cardiac source is often implicated in strokes where the deficit includes aphasia. However, less is known about the etiology of isolated aphasia during transient ischemic attack (TIA). Our objective was to determine whether patients with isolated aphasia are likely to have a cardioembolic etiology for their TIA.MethodsWe prospectively studied a cohort of TIA patients in eight tertiary-care emergency departments. Patients with isolated aphasia were identified by the treating physician at the time of emergency department presentation. Patients with dysarthria (i.e., a phonation disturbance) were not included. Potential cardiac sources for embolism were defined as atrial fibrillation on history, electrocardiogram, Holter monitor, atrial fibrillation on echocardiography, or thrombus on echocardiography.ResultsOf the 2,360 TIA patients identified, 1,155 had neurological deficits at the time of the emergency physician assessment and were included in this analysis, and 41 had isolated aphasia as their only neurological deficit. Patients with isolated aphasia were older (73.9±10.0 v. 67.2±14.5 years; p=0.003), more likely to have a history of heart failure (9.8% v. 2.6%; p=0.027), and were twice as likely to have any cardiac source of embolism (22.0% v. 10.6%; p=0.037).ConclusionsIsolated aphasia is associated with a high rate of cardioembolic sources of embolism after TIA. Emergency patients with isolated aphasia diagnosed with a TIA warrant a rapid and thorough assessment for a cardioembolic source.

Primary cutaneous adenoid cystic carcinoma (ACC) is a rare skin tumor that is unlikely to metastasize. We present a case of primary cutaneous ACC in a 67-year-old male with axillary lymph node, pulmonary and brain metastases. To the best of our knowledge, this is the first reported case of cutaneous ACC with distant metastases to the brain.

Peripheral nerve tumors are soft-tissue tumors that can occur in any nerve throughout the body. The majority of peripheral nerve tumors arise from elements of the nerve sheath with the two most common being neurofibromas and schwannomas. More than 90% of all peripheral nerve tumors are benign. When there is peripheral nerve involvement in metastatic carcinoma, it is often via contiguous spread from the primary mass; hematogenous seeding to a peripheral nerve is seldom seen. In this report the authors describe the even rarer case of metastatic renal cell carcinoma mimicking a schwannoma in a dorsal root ganglion. Cases from the literature show the rarity of this finding and its late clinical appearance. Given that survival in patients with metastatic carcinoma continues to increase, dorsal root ganglion metastasis may become more common over time.

Background and Purpose Anticoagulant-associated intracranial hemorrhage (aaICH) presents with larger hematoma volumes, higher risk of hematoma expansion, and worse outcome than spontaneous intracranial hemorrhage. Prothrombin complex concentrates (PCCs) are indicated for urgent reversal of anticoagulation after aaICH. Given the lack of randomized controlled trial evidence of efficacy, and the potential for thrombotic complications, we aimed to determine outcomes in patients with aaICH treated with PCC. Methods We conducted a prospective multicenter registry of patients treated with PCC for aaICH in Canada. Patients were identified by local blood banks after the release of PCC. A chart review abstracted clinical, imaging, and laboratory data, including thrombotic events after therapy. Hematoma volumes were measured on brain CT scans and primary outcomes were modified Rankin Scale at discharge and in-hospital mortality. Results Between 2008 and 2010, 141 patients received PCC for aaICH (71 intraparenchymal hemorrhages). The median age was 78 years (interquartile range, 14), 59.6% were male, and median Glasgow Coma Scale was 14. Median international normalized ratio was 2.6 (interquartile range, 2.0) and median parenchymal hematoma volume was 15.8 mL (interquartile range, 31.8). Median post-PCC therapy international normalized ratio was 1.4: 79.5% of patients had international normalized ratio correction ( Conclusions PCC therapy rapidly corrected international normalized ratio in the majority of patients, yet mortality and morbidity rates remained high. Rapid international normalized ratio correction alone may not be sufficient to alter prognosis after aaICH.

Intracerebral hemorrhage (ICH) usually affects older humans but almost no experimental studies have assessed aged animals. We address how aging alters inflammation, neuron death and lesion resolution after a hemorrhage in the rat striatum. In the normal aged brain, microglia displayed a 'dystrophic' phenotype, with shorter cellular processes and large gaps between adjacent cells, and there was more astrocyte reactivity. The ICH injury was monitored as hematoma volume and number of dying neurons at 1 and 3 days, and the volume of the residual lesion, ventricles and lost tissue at 28 days. Inflammation at 1 and 3 days was assessed from densities of microglia with resting vs. activated morphologies, or expressing the lysosomal marker ED1. Despite an initial delay in neuron death in aged animals, by 28 days, there was no difference in neuron density or volume of tissue lost. However, lesion resolution was impaired in aged animals and there was less compensatory ventricular expansion. At 1 day after ICH, there were fewer activated microglia/macrophages in the aged brain, but by 3 days there were more of these cells at the edge of the hematoma and in the surrounding parenchyma. In both age groups a glial limitans had developed by 3 days, but astrocyte reactivity and the spread of activated microglia/macrophages into the surrounding parenchyma was greater in the aged. These findings have important implications for efforts to reduce secondary injury after ICH and to develop anti-inflammatory therapies to treat ICH in aged humans.

Intracerebral hemorrhage (ICH) results from rupture of a blood vessel in the brain. After ICH, the blood-brain barrier (BBB) surrounding the hematoma is disrupted, leading to cerebral edema. In both animals and humans, edema coincides with inflammation, which is characterized by production of pro-inflammatory cytokines, activation of resident brain microglia and migration of peripheral immune cells into the brain. Accordingly, inflammation is an attractive target for reducing edema following ICH. In the present study, BBB damage was assessed by quantifying intact microvessels surrounding the hematoma, monitoring extravasation of IgG and measuring brain water content 3 days after ICH induced by collagenase injection into the rat striatum. In the injured brain, the water content increased in both ipsilateral and contralateral hemispheres compared with the normal brain. Quantitative real-time RT-PCR revealed an up-regulation of inflammatory genes associated with BBB damage; IL1beta, TNFalpha and most notably, MMP-12. Immunostaining showed MMP-12 in damaged microvessels and their subsequent loss from tissue surrounding the hematoma. MMP-12 was also observed for the first time in neurons. Dual-antibody labeling demonstrated that neutrophils were the predominant source of TNFalpha protein. Intraperitoneal injection of the tetracycline derivative, minocycline, beginning 6 h after ICH ameliorated the damage by reducing microvessel loss, extravasation of plasma proteins and edema; decreasing TNFalpha and MMP-12 expression; and reducing the numbers of TNFalpha-positive cells and neutrophils in the brain. Thus, minocycline, administered at a clinically relevant time, appears to target the inflammatory processes involved in edema development after ICH.

After intracerebral hemorrhage (ICH), blood entry is followed by neuron death and an inflammatory response, but development of pharmacological therapies has been hampered by an inadequate understanding of the spatial and temporal relationship between neuron death and inflammation. Using a rat model of ICH, we first investigated these relationships at 6 h, and 1, 3 and 7 days. At the edge of the hematoma, no degenerating neurons were observed at 6 h; however, dying neurons were present between 1 and 3 days, with peak neuron death occurring at 1 day. This is apparently the first report of ongoing neuron death at the edge of the hematoma during a time window that is appropriate for human therapy. Neuron death was limited to the edge of the hematoma, with no degenerating neurons in the striatum surrounding the hematoma, despite robust and prolonged microglia activation. Importantly, neuron loss at the edge of the hematoma was spatially and temporally associated with accumulation and activation of microglia/macrophages. We then tested the hypothesis that treatment with the tetracycline derivative, minocycline, after the hematoma had reached a maximal size, will reduce inflammation and neuron damage. Minocycline injection (45 mg/kg i.v. at 6 h, and i.p. at 24, 48 and 72 h) failed to reduce neuron loss outside the hematoma or striatal tissue loss (assessed at 7 days), despite reducing the number of neutrophils and activated microglia/macrophages. Thus, minocycline does not appear to target the mechanisms responsible for cell death in this model of ICH.