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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.

Initially described, in 1948, as a tumor that could be mistaken with chondrosarcoma at histopathology, chondromyxoid fibroma is now a well-recognized entity. Surface-type chondromyxoid fibroma, however, remains an extremely rare occurrence. We present a case of a 55-year-old woman, who experienced right arm pain for 5 years. After unsuccessful treatment for presumed thoracic outlet syndrome, MRI revealed a large mass abutting the anteromedial cortex of the distal humeral diaphysis in a subperiosteal location. Further characterization was made with radiography, CT, and bone scan, which were followed by ultrasound-guided biopsy. Although histopathologic features were suggestive of chondromyxoid fibroma, the diagnosis remained somewhat uncertain initially due to the very unusual location involving the diaphysis of the humerus. Surgical resection was performed, and subsequent histopathologic analysis confirmed the diagnosis of chondromyxoid fibroma. Despite being a rare entity, surface-type chondromyxoid fibroma would need to be considered in the differential when dealing with expansile surface diaphyseal lesions.

Polymorphous adenocarcinoma (PAC) shows histologic diversity with streaming and targetoid features whereas cribriform adenocarcinoma of salivary gland (CASG) demonstrates predominantly cribriform and solid patterns with glomeruloid structures and optically clear nuclei. Opinions diverge on whether CASG represents a separate entity or a variant of PAC. We aimed to assess the level of agreement among 25 expert Head and Neck pathologists in classifying these tumors. Digital slides of 48 cases were reviewed and classified as: PAC, CASG, tumors with ≥50% of papillary architecture (PAP), and tumors with indeterminate features (IND). The consensus diagnoses were correlated with a previously reported molecular alteration. The consensus diagnoses were PAC in 18/48, CASG in16/48, PAP in 3/48, and IND in 11/48. There was a fair interobserver agreement in classifying the tumors (κ= 0.370). The full consensus was achieved in 3 (6%) cases, all of which were classified as PAC. A moderate agreement was reached for PAC (κ= 0.504) and PAP (κ= 0.561), and a fair agreement was reached for CASG (κ= 0.390). IND had only slight diagnostic concordance (κ= 0.091). PAC predominantly harbored PRKD1 hotspot mutation, whereas CASG was associated with fusion involving PRKD1, PRKD2, or PRKD3. However, such molecular events were not exclusive as 7% of PAC had fusion and 13% of CASG had mutation. In conclusion, a fair to moderate interobserver agreement can be achieved in classifying PAC and CASG. However, a subset (23%) showed indeterminate features and was difficult to place along the morphologic spectrum of PAC/CASG among expert pathologists. This may explain the controversy in classifying these tumors.

The hyalinizing trabecular adenoma/tumor is a rare and poorly characterized follicular-derived thyroid neoplasm recently shown to harbor recurrent PAX8-GLIS1 or PAX8-GLIS3 gene fusions. Here we sought to define the repertoire of genetic alterations of hyalinizing trabecular tumors, and whether PAX8-GLIS3 fusions are pathognomonic for hyalinizing trabecular tumors. A discovery series of eight hyalinizing trabecular tumors was subjected to RNA-sequencing (n = 8), whole-exome sequencing (n = 3) or targeted massively parallel sequencing (n = 5). No recurrent somatic mutations or copy number alterations were identified in hyalinizing trabecular tumor, whereas RNA-sequencing revealed the presence of a recurrent genetic rearrangement involving PAX8 (2q14.1) and GLIS3 (9p24.2) genes in all cases. In this in-frame fusion gene, which comprised exons 1-2 of PAX8 and exons 3-11 of GLIS3, GLIS3 is likely placed under the regulation of PAX8. Reverse transcription RT-PCR and/or fluorescence in situ hybridization analyses of a validation series of 26 hyalinizing trabecular tumors revealed that the PAX8-GLIS3 gene fusion was present in all hyalinizing trabecular tumors (100%). No GLIS1 rearrangements were identified. Conversely, no PAX8-GLIS3 gene fusions were detected in a cohort of 237 control thyroid neoplasms, including 15 trabecular thyroid lesions highly resembling hyalinizing trabecular tumor from a morphological standpoint, as well as trabecular/solid follicular adenomas, solid/trabecular variants of papillary carcinoma, and Hurthle cell adenomas or carcinomas. Our data provide evidence to suggest that the PAX8-GLIS3 fusion is pathognomonic for hyalinizing trabecular tumors, and that the presence of the PAX8-GLIS3 fusion in thyroid neoplasms may be used as an ancillary marker for the diagnosis of hyalinizing trabecular tumor, thereby avoiding overtreatment in case of misdiagnoses with apparently similar malignant tumors.

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.

Myofibroblastoma is a rare tumor that was originally described in the breast but has since been found in extra-mammary locations, where it been renamed mammary-type myofibroblastoma (MTM). We describe a case of MTM occurring in the anterior compartment of the thigh, which was initially interpreted as a possible a liposarcoma on MRI. Two subsequent biopsy samples and eventual excision revealed the tumor to have the characteristic pathology of MTM. This benign tumor, albeit rare, needs to be considered in the imaging differential diagnosis of fat containing deep soft tissue masses of the extremity.

The many diverse terms used to describe the wide spectrum of changes seen in proliferative verrucous leukoplakia (PVL) have resulted in disparate clinical management. The objective of this study was to produce an expert consensus guideline for standardized assessment and reporting by pathologists diagnosing PVL related lesions. 299 biopsies from 84 PVL patients from six institutions were selected from patients who had multifocal oral leukoplakic lesions identified over several years (a minimum follow-up period of 36 months). The lesions demonstrated the spectrum of histologic features described in PVL, and in some cases, patients developed oral cavity squamous cell carcinoma (SCC). An expert working group of oral and maxillofacial and head and neck pathologists reviewed microscopic features in a rigorous fashion, in combination with review of clinical photographs when available. The working group then selected 43 single slide biopsy cases for whole slide digital imaging (WSI) review by members of the consensus conference. The digital images were then reviewed in two surveys separated by a washout period of at least 90 days. Five non-PVL histologic mimics were included as controls. Cases were re-evaluated during a consensus conference with 19 members reporting on the cases. The best inter-observer diagnostic agreement relative to PVL lesions were classified as “corrugated ortho(para)hyperkeratotic lesion, not reactive” and “SCC” (chi-square p = 0.015). There was less than moderate agreement (kappa 0.41 kappa) for 35 of 48 cases. This expert consensus guideline has been developed with support and endorsement from the leadership of the American Academy of Oral and Maxillofacial Pathology and the North American Society of Head and Neck Pathologists to recommend the use of standardized histopathologic criteria and descriptive terminology to indicate three categories of lesions within PVL: (1) “corrugated ortho(para)hyperkeratotic lesion, not reactive;” (2) “bulky hyperkeratotic epithelial proliferation, not reactive;” and (3) “suspicious for,” or “squamous cell carcinoma.” Classification of PVL lesions based on a combination of clinical findings and these histologic descriptive categories is encouraged in order to standardize reporting, aid in future research and potentially guide clinical management.

Initially described, in 1948, as a tumor that could be mistaken with chondrosarcoma at histopathology, chondromyxoid fibroma is now a well-recognized entity. Surface-type chondromyxoid fibroma, however, remains an extremely rare occurrence. We present a case of a 55-year-old woman, who experienced right arm pain for 5 years. After unsuccessful treatment for presumed thoracic outlet syndrome, MRI revealed a large mass abutting the anteromedial cortex of the distal humeral diaphysis in a subperiosteal location. Further characterization was made with radiography, CT, and bone scan, which were followed by ultrasound-guided biopsy. Although histopathologic features were suggestive of chondromyxoid fibroma, the diagnosis remained somewhat uncertain initially due to the very unusual location involving the diaphysis of the humerus. Surgical resection was performed, and subsequent histopathologic analysis confirmed the diagnosis of chondromyxoid fibroma. Despite being a rare entity, surface-type chondromyxoid fibroma would need to be considered in the differential when dealing with expansile surface diaphyseal lesions.

The 8th edition of American Joint Committee on Cancer (AJCC 8th) staging manual incorporated depth of invasion (DOI) into pT stage of oral cavity cancer. The aim of this study was to characterize several histological findings that may complicate measurement of DOI in early conventional squamous cell carcinomas (SCC) of the oral tongue: (1) lack of or minimal residual carcinoma following biopsy; (2) positive deep margin; (3) extratumoral perineural invasion (PNI); and (4) lymphatic or vascular invasion. Conventional SCC of the oral tongue (n = 407) with the largest dimension of ≤ 4 cm and with a negative elective cervical lymph node dissection (pN0) were reviewed. A clear plastic ruler was used to measure DOI by dropping a “plumb line” to the deepest point of the invasive tumor from the level of the basement membrane of the normal mucosa closest to the invasive tumor. Examples of identifying reference point on the mucosal surface of oral tongue from which to measure the DOI are illustrated. In the experience of one contributing institution, the residual carcinoma was absent in 14.2% of glossectomies (34/239), while in 4.8% of cases (10/205) there was only minimal residual carcinoma. In 11.5% (21/183) of pT2 cases the deep margin was positive and thus DOI and pT may be underestimated. Of all cases with PNI, extratumoral PNI was identified in 23.1% (31/134) of cases, but represented the deepest point of invasion in only two cases. In one case, lymphatic invasion represented the deepest point of invasion and could have led to upstaging from pT1 to pT2. In conclusion, DOI measurement for SCC of the oral tongue may require re-examination of the diagnostic biopsy in up to 20% of cases due to the absence or only minimal residual carcinoma in glossectomy specimens. In 11.5% of apparently pT2 cases, DOI may be underestimated due to the positive deep margin. Rarely, extratumoral PNI or lymphatic invasion may be the deepest point of invasion. Overall, two issues (absent or minimal residual disease and positive deep margin) may confound DOI measurement in early SCCs of oral tongue.

Objective: To report a rare case of a male patient with primary hyperparathyroidism due to a parathyroid hormone (PTH)-secreting, intrathymic, cystic, parathyroid adenoma.Methods: The pertinent clinical features, laboratory data, radiologic and pathologic findings are reported, along with a brief literature review.Results: A 69-year-old male was followed for asymptomatic hypercalcemia secondary to primary hyperparathyroidism since 2013. He was also incidentally found to have an anterior mediastinal mass on a chest X-ray which remained stable on annual follow-up. He was monitored regularly with serial calcium and renal function tests, with no indication for surgical intervention. Dual-phase 99mTc-Sestamibi scan did not localize a culprit parathyroid gland in the neck or upper chest. He presented in 2015 with renal failure and hypovolemic shock secondary to severe hypercalcemia (calcium 17.20 mg/dL, PTH 3,452 pg/mL) requiring intensive care unit admission. Treatment with aggressive hydration, diuresis and pamidronate failed to lower calcium levels. Patient underwent emergent surgical exploration with combined resection of 2 enlarged, eutopic parathyroid glands suspicious for adenoma and the cystic mediastinal mass. PTH levels from fluid within the cystic mediastinal mass were elevated at 1,290,000 pg/mL. Immediate postoperative PTH and calcium levels dropped to 58 pg/mL and 10.80 mg/dL, respectively. Pathology of the mediastinal mass was consistent with ectopic, intrathymic, parathyroid adenoma.Conclusion: Anterior mediastinal mass in the setting of hypercalcemia should be considered as a possible source of ectopic PTH production in the setting of an otherwise negative 99mTc-Sestamibi parathyroid scan. Definitive treatment by resection of the mass is potentially curative.Abbreviations: PHPT primary hyperparathyroidism; PTH parathyroid hormone

Diabetic lumbosacral radiculoplexus neuropathy (DLRPN), or diabetic amyotrophy, is an infrequent neurovascular complication of diabetes thought to result from immune-mediated infarction of peripheral nerve branches (1). DLRPN has not previously been reported in association with infarction of the vertebral bone, which itself is a rare occurrence, typically in the setting of aortic surgery and spinal cord infarction (2). We report a case of simultaneous DLRPN and vertebral bony infarction in a patient with type 2 diabetes, highlighting the unifying vascular etiology responsible for both these uncommon pathologies. A 47-year-old man of Nepalese origin presented to hospital with a 2-week history of relatively acute-onset left lumbar pain, numbness and paresthesia in the left obturator and saphenous nerve distributions, and marked proximal left leg weakness. His past health was notable for a 4-year history of type 2 diabetes, well controlled with sitagliptin, canagliflozin, and metformin. On examination, there was Medical Research Council (MRC) grade 2/5 paresis of the left hip flexor and hip adductor muscles, with grade 1/5 power of knee extension. The left patellar reflex was absent. Electrodiagnostic studies showed a reduced left femoral motor potential and denervation at the …

High-risk human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas have a more favorable prognosis than HPV-negative ones. p16 immunohistochemistry has been recommended as a prognostic test in clinical practice. Several p16 antibodies are available, and their performance has not been directly compared. We evaluated three commercially available p16 antibody clones (E6H4, JC8 and G175-405) utilizing 199 cases of oropharyngeal squamous cell carcinoma from a tissue microarray, read by three pathologists with three different cutoffs for positivity: any staining, >50% and >75%. Positive predictive values for high-risk HPV status by RNA in situ hybridization for the E6H4, JC8 and G175-405 clones were 98%, 100% and 99% at the 75% cutoff, but negative predictive values were much more variable at 86%, 69% and 56%, respectively. These improved using the 50% cutoff, becoming similar for all three antibodies. Intensity varied substantially, with 85% of E6H4, 72% of JC8 and 67% of G175-405 showing strong (3+) intensity. With Kaplan-Meier survival plots at the 75% cutoff, the E6H4 clone showed the largest differential in disease specific and overall survival between p16-positive and -negative results. Decreasing the cutoff to 50% increased correlation with HPV in situ hybridization and improved the survival differential for the JC8 and G175-405 clones without worsening of performance for the E6H4 clone. Interobserver agreement was also assessed by kappa scores and was highest for the E6H4 clone. Overall, these study results show modest but important performance differences between the three different p16 antibody clones, suggesting that the E6H4 clone performs best because of strongest staining intensity, greatest differential in outcomes between positive and negative results, lowest interobserver variability, and lowest background, nonspecific staining. The results also suggest that a 75% cutoff is very functional but that, in this patient population with high HPV incidence, 50% and any staining cutoffs may be more effective, particularly for the non-E6H4 clones.

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.

Background The eighth edition of the American Joint Committee on Cancer staging manual (AJCC8) added depth of invasion to the definition of pathologic T stage (pT). In the current study, the authors assess pT stage migration and the prognostic performance of the updated pT stage and compare it with other clinicopathologic variables in patients with early squamous cell carcinoma of the oral tongue (OTSCC; tumors measuring ≤4 cm) with histologically benign lymph nodes (pN0). Methods A multi-institutional cohort of patients with early OTSCC was restaged as per AJCC8. Primary endpoints were local recurrence (LR) and locoregional recurrence (LRR). Influential variables were identified and an LR/LRR prediction model was developed. Results There were a total of 494 patients, with 49 LR and 73 LRR. AJCC8 pT criteria resulted in upstaging of 37.9% of patients (187 of 494 patients), including 34.5% (64 of 185 patients) from pT2 to pT3, without improving the prognostication for LR or LRR. Both LR and LRR were found to be similar for patients with AJCC8 pT2 and pT3 disease. On multivariate analysis, LR was only found to be associated with distance to the closest margin (hazard ratio, 0.36; 95% CI, 0.20-0.64 [P = .0007]) and perineural invasion (hazard ratio, 1.92; 95% CI, 1.10-0.64 [P = .046]). Based on these 2 predictors, a final proportional hazards regression model (which may be used similar to a nomogram) was developed. The proposed model appeared to be superior to AJCC pT stage for estimating the probability of LR and LRR for individual patients with early OTSCC. Conclusions AJCC8 pT criteria resulted in pT upstaging of patients with pN0 disease without improved LR or LRR prognostication. The proposed model based on distance to the closest margin and perineural invasion, status outperformed pT as a predictor of LR and LRR in patients with early OTSCC.

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.

Concern persists regarding percutaneous core needle biopsy (CNB) of a potentially malignant lesion of the retroperitoneum due to the perceived risk of immediate complications and adverse oncologic outcomes, including needle tract seeding (NTS). The aim of this study was to evaluate the incidence of (1) early complications and (2) NTS following CNB of suspected retroperitoneal sarcoma (RPS). Patients who underwent CNB of an RP mass with pre-biopsy suspicion of sarcoma were identified from a prospective database at two centers: (1) Princess Margaret Cancer Centre/Mount Sinai Hospital, Toronto (2009–2015); and (2) The Ottawa Hospital (1999–2015). Early complications, including bleeding, pain, infection, and organ injury, were recorded. Instances of NTS were identified from long-term follow-up of patients who underwent resection of primary RPS at these two centers after initial CNB (1996–2013). Of 358 percutaneous CNBs of suspected RPS performed over the study period, 7 (2.0%) resulted in minor bleeding with no transfusion, 3 (0.8%) resulted in significant pain, 1 (0.3%) resulted in unplanned admission to hospital for observation, and 1 (0.3%) resulted in a pneumothorax. There were no infections. In 203 patients who underwent resection of RPS following CNB, crude cumulative local recurrence was 24% at 5 years. At a median follow-up of 44 months, there was one case of NTS (approximately 0.5%). This large bi-institutional experience with CNB of an RP mass demonstrates that both the early complication rate and the incidence of NTS are very low. Physicians and patients can be reassured that the benefits of CNB in diagnosing sarcoma and determining its histologic subtype and grade far outweigh the risks.

T cell based immunotherapies targeting tumor antigens are a promising alternative to traditional cancer treatments due to their ability to eliminate malignant cells, but require highly immunogenic tumor-associated proteins as targets for CD8+ T cell recognition. Additional parameters to consider in a T cell based immunotherapy include tumor T cell infiltration and expression of HLA-peptide complexes on the surface of cancer cells. The goal of this study is to identify targetable immunogenic tumor antigens and to characterize the immune profile of human dedifferentiated liposarcoma (DDLPS) and osteosarcoma (OS) sarcoma subtypes by screening for cancer-testis antigen (CTA) expression, HLA expression, and tumor T cell infiltration by immunohistochemistry (IHC). Human tissue micro-arrays composed of 80 cores of OS and 49 cores of DDLPS were obtained and stained by IHC for selected CTAs (MAGE-A3, NY-ESO-1 and SSX2) and various immune markers. In DDLPS, 11% of samples express MAGE-A3 and 2% express SSX2 and NY-ESO-1 in low percentages of tumor cells. In OS, 100% of samples express MAGE-A3 and 89% express SSX2, both with >80% of positive cases showing moderate to high expression. NY-ESO-1 is expressed in 78% of OS samples, predominantly at low levels. Brisk infiltration of CD8+ T cells is observed in over 70% of both sarcoma types. Furthermore, all sarcoma samples tested are positive for HLA expression. These results show promising expression of CTAs MAGE-A3 and SSX2 in OS, which may be used as targets for immunotherapy for OS. The data generated throughout this study will provide insight into the immune profile of these sarcomas - information that is critical for immunotherapy design.

Salivary gland cancers are an uncommon and heterogenous group of malignancies, accounting for approximately 3% of head and neck tumors. We describe a case of a patient who presented with paraneoplastic Cushing’s syndrome secondary to metastatic salivary ductal carcinoma (SDC). Paraneoplastic ACTH secretion initially responded to chemotherapy with complete resolution of clinical symptoms. To our knowledge, this is the first described case of an ACTH-secreting SDC. We also review other paraneoplastic syndromes (PNS) that have been reported in association with salivary gland cancers.

Ectomesenchymal chondromyxoid tumor is a rare and benign neoplasm with a predilection for the anterior dorsal tongue. Despite morphologic heterogeneity, most cases are characterized by a proliferation of bland spindle cells with a distinctive reticular growth pattern and myxoid stroma. The immunophenotype of these neoplasms is likewise variable; most cases express glial fibrillary acid protein and S100 protein, with inconsistent reports of keratin and myoid marker expression. The molecular pathogenesis is poorly understood; however, a subset of cases has been reported to harbor EWSR1 gene rearrangement. Following identification of an RREB1-MKL2 fusion gene by RNA Sequencing in an index patient, a retrospective review of additional cases of ectomesenchymal chondromyxoid tumors was performed to better characterize the clinical, immunohistochemical, and molecular attributes of this neoplasm. A total of 21 cases were included in this series. A marked predisposition for the dorsal tongue was confirmed. Most cases conformed to prior morphologic descriptions; however, hypercellularity, hyalinized stroma, and necrosis were rare attributes not previously emphasized. The neoplastic cells frequently coexpressed glial fibrillary acid protein, S100 protein, keratin, smooth muscle actin, and/or desmin; a single case was found to contain significant myogenin expression. An RREB1-MKL2 fusion product was identified in 19 tumors (90%), a single tumor (5%) had an EWSR1-CREM fusion product, and the remaining case lacked any known fusion gene by RNA Sequencing. The latter 2 cases subtly differed morphologically from many in the cohort. This series illustrates that recurrent RREB1-MKL2 fusions occur in most, perhaps all, cases of ectomesenchymal chondromyxoid tumor.

Following publication of the original article [1], the authors reported an error in one of the author names. In this Correction the incorrect and correct author names are listed.

Aims To make recommendations on the indications for molecular testing regarding the diagnosis, prediction of prognosis, and treatment selection in adult patients with s oft tissue sarcomas (STS) excluding gastrointestinal stromal tumour. Materials and methods This guideline was developed by the Cancer Care Ontario’s Program in Evidence-Based Care (PEBC) and the Sarcoma Disease Site Group (DSG). The medline, embase, and Cochrane Library databases, main guideline websites, abstracts of relevant annual meetings, and PROSPERO databases were searched (January 2005 to October 2016). Internal and external reviews were conducted, with final approval by the PEBC and the Sarcoma DSG. Results Based on the available evidence, we made three S trong Recommendations, 14 Recommendations, 9 Qualified Statements, and seven No Recommendations. The three Strong Recommendations include: i) MDM2 amplification by fluorescence in situ hybridization (FISH) is recommended as a sensitive and specific test to differentiate patients with atypical lipomatous tumour/well-differentiated liposarcoma, or dedifferentiated liposarcoma from lipoma or other STS in the differential diagnosis; ii) SS18 (SYT) break-apart by FISH or SS18-SSX (SYT-SSX) fusion by reverse transcription-polymerase chain reaction is recommended as a sensitive and specific test to differentiate patients with synovial sarcoma from other sarcomas; iii) CTNNB1 S45F mutation by polymerase chain reaction is recommended as a prognostic factor for poor recurrence-free survival in patients with desmoid tumours. Conclusion This guideline may serve as a framework for the thoughtful implementation of molecular studies at cancer centres and other jurisdictions. Some of the recommendations may need to be updated when new evidence appears in the future.

INTRODUCTION: Retroperitoneal sarcoma (RPS) is a rare disease accounting for 0.1%–0.2% of all malignancies. Management of RPS is complex and requires multidisciplinary, tailored treatment strategies at all stages, but especially in the context of metastatic or multifocal recurrent disease. Due to the rarity and heterogeneity of this family of diseases, the literature to guide management is limited. METHODS: The Trans-Atlantic Retroperitoneal Sarcoma Working Group (TARPSWG) is an international collaboration of sarcoma experts from all disciplines convened in an effort to overcome these limitations. The TARPSWG has compiled the available evidence surrounding metastatic and multifocally recurrent RPS along with expert opinion in an iterative process to generate a consensus document regarding the complex management of this disease. The objective of this document is to guide sarcoma specialists from all disciplines in the diagnosis and treatment of multifocal recurrent or metastatic RPS. RESULTS: All aspects of patient assessment, diagnostic processes, local and systemic treatments, and palliation are reviewed in this document, and consensus recommendations provided accordingly. Recommendations were guided by available evidence, in conjunction with expert opinion where evidence was lacking. CONCLUSIONS: This consensus document combines the available literature regarding the management of multifocally recurrent or metastastic RPS with the practical expertise of high-volume sarcoma centers from multiple countries. It is designed as a tool for decision making in the complex multidisciplinary management of this condition and is expected to standardize management across centers, thereby ensuring that patients receive the highest quality care.

Background The molecular pathogenesis of many forms of soft tissue sarcomas (STS) have been rigorously characterized in the medical literature, which may be particularly important for the diagnosis and prediction of prognosis in STS. Methods Electronic databases (2005 to October 2016) were searched. Gastrointestinal stromal tumor and pediatric sarcomas were excluded. The eligible individual study’s risk of bias and the quality of aggregate evidence were assessed. Meta-analyses were performed. Results Of 6674 identified articles, 70 were eligible and analyzed, covering 13 types of STS. Meta-analyses showed that the test of detecting MDM2 amplification by fluorescence in situ hybridization was accurate in differentiating atypical lipomatous tumor/well-differentiated liposarcoma/dedifferentiated liposarcoma from benign tumors (N = 971; sensitivity = 95%, 95% confidence interval [CI] 89–98; specificity = 100%, CI 89–100) or from other STS (N = 347; sensitivity = 99%, CI 72–100; specificity = 90%, CI 78–95); that the test of detecting SS18-SSX fusion by reverse transcription polymerase chain reaction (PCR) was accurate in differentiating synovial sarcoma from other STS (N = 532; sensitivity = 93%, CI 85–96; specificity = 99%, CI 96–100). The presence of a CTNNB1 S45F mutation detected by PCR was a risk factor for decreased recurrence-free survival in desmoid tumors (N = 418; hazard ratio from 3.50 [CI 1.51–8.14] to 6.20 [CI 2.24–17.15]). Conclusions Sarcomas are rare cancers whose molecular pathogenesis is becoming increasingly understood. The current evidence demonstrates that molecular analyses are useful in the diagnosis and prediction of prognosis in some STS.

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.

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.

We hypothesize that cystic structures in metastatic papillary thyroid carcinoma (PTC) develop along the framework of lymphatic channels. To investigate this phenomenon, different categories of PTC were immunostained for D2-40 and TTF1. In this study, reactivity for D2-40 was considered as positive when there is membranous staining as often seen in lymphatic endothelial cells. Thirty cases of PTC with lymph node metastasis or with potential for lymphatic invasion and 20 cases metastatic PTC in lymph nodes were reviewed and found to show double/mosaic immunoreactivity for TTF1/D2-40 in 40-100% of cases. PTC metastasis in lymph nodes with cysts and some branching lymphatic-like channels lined by follicular cells with or without nuclear features of PTC were diffusely reactive to TTF1, and focally to D2-40. For primary and metastatic PTC, focal membranous D2-40 reactivity was also demonstrated in cysts or cleft linings. For25 thyroid neoplasms with no known potential for lymphatic invasion, there was no such immunoreactivity. The mosaic or double immunoreactivity for TTF1/D2-40 suggests lymphatic cancerization and possible endothelial mimicry of follicular cells. Mosaic/double immunoreactivity is helpful to detect the hidden pattern of lymphatic invasion masquerading as 'benign-appearing' follicles and supports our hypothesis of malignant cells developing along the lymphatic framework.

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.

To improve margin revision, this study characterizes the number, fragmentation, and orientation of tumor bed margins (TBM) in patients with pT1-2 pN0 squamous cell carcinoma (SCC) of the oral tongue.Pathology reports (n=346) were reviewed. TBM parameters were indexed. In Group 1 patients all margins were obtained from the glossectomy specimen and there were no TBM. In Revision Group/Group 2 (n=103), tumor bed was sampled to revise suboptimal margins identified by examination of the glossectomy specimen. In Group 3 (n=124), TBM were obtained before examination of the glossectomy specimen.Fewer TBMs were obtained per patient in Group 2 compared to Group 3 (57/103, 55% of patients with3 vs. 117/124, 94%, ≥3 TBMs, respectively). The new margin surface was more frequently indicated in Group 2 compared to Group 3 (59/103, 57%, vs. 19/124, 15%, p.001). If glossectomy specimen margins are accepted as the reference standard, then the TBM was 15% sensitive in Group 2 (95% confidence interval [CI], 7-29) and 32% sensitive in Group 3 (95% CI, 15-55). TBM fragmentation (23/103, 22% vs. 42/124, 34%) and frozen vs. permanent discrepancies (8/103, 3% vs. 3/124, 2%) were similar between Groups 2 and 3. The new margin surface was not indicated in 6 of 11 cases with discrepant frozen vs. permanent pathology findings, precluding judgment on final margin status. To facilitate the assessment of final margins, TBM should be represented by one tissue fragment with a marked new margin surface.

Benign and malignant primary bone and soft tissue lesions of the head and neck are rare. The uncommon nature of these tumors, combined with the complex anatomy of the head and neck, pose diagnostic challenges to pathologists. This article describes the pertinent clinical, radiographic, and pathologic features of selected bone and soft tissue tumors involving the head and neck region, including angiofibroma, glomangiopericytoma, rhabdomyosarcoma, biphenotypic sinonasal sarcoma, chordoma, chondrosarcoma, and osteosarcoma. Emphasis is placed on key diagnostic pitfalls, differential diagnosis, and the importance of correlating clinical and radiographic information, particularly for tumors involving bone.

Aims The data on the histological type of carcinomatous component and the extent of extracapsular invasion for salivary carcinomas ex pleomorphic adenoma (PA) are conflicting. We aimed to determine the prognostic value of extracapsular invasion in salivary duct carcinomas (SDC) ex PA. Methods and results A total of 117 patients with SDC were identified retrospectively; 44 cases involving major salivary glands had pre-existing PA (44 of 117, 37%). The morphological spectrum of SDC ex PA was characterized. The primary endpoint was overall survival (OS). Most SDC ex PA were widely invasive at presentation (27 of 44; 61%). Five patients with intracapsular SDC ex PA experienced no disease progression. The assessment of extracapsular invasion was precluded in eight cases (e.g. positive margins of resection). The rate of lymph node involvement was similar in cases with extracapsular invasion of ≤2 mm (two of three) and >7 mm (22 of 26). Only pT correlated with OS [116 months, 95% confidence interval (CI) 22-210 months for pT1 versus 20 months (95% CI 6-34) for pT4; P = 0.013]. Conclusions Intracapsular SDC ex PA are potentially indolent. SDC ex PA with extracapsular invasion of ≤2 mm are rare, and appear to be clinically aggressive. Several histological parameters preclude assessment of extracapsular invasion.

Objective Sinonasal cellular schwannoma represents

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.

Spindle cell (sarcomatoid) carcinoma of the larynx is a rare subtype of squamous cell carcinoma that shows a prominent spindle cell component with a mesenchymal phenotype. Heterologous elements may be seen in these spindled areas and usually consist of osteosarcomatous or chondrosarcomatous differentiation. We describe an unusual spindle cell carcinoma of the vocal cord in a 68-year-old male which demonstrated rhabdomyosarcomatous differentiation as confirmed by desmin and myogenin immunoreactivity. Thus rhabdomyosarcomatous differentiation adds to the phenotypic spectrum of spindle cell carcinomas of the larynx and should be considered before invoking a diagnosis of true rhabdomyosarcoma of the larynx.

The majority of malignancies arising in the head and neck among patients with AIDS are Kaposi sarcoma and non-Hodgkin lymphoma. Patients with HIV/AIDS are also at increased risk of developing several carcinomas of the head and neck. This paper focuses on these less common, albeit important, carcinomas. An English language literature search identified numerous population-based studies evaluating carcinomas in the head and neck of HIV-positive patients. Published results indicate that patients with HIV/AIDS are at an increased risk of developing mucosal squamous cell carcinoma, nasopharyngeal carcinoma, lymphoepithelial carcinoma of the salivary gland, and Merkel cell carcinoma in this anatomic region. Data also suggest that HIV-positive patients with these cancers present at a younger age, with more aggressive disease and worse prognosis compared to HIV-negative patients. Treatment involves surgical resection with or without radiation therapy and chemotherapy for locally advanced and metastatic disease. AIDS patients, however, are more likely to suffer radiation treatment complications. Highly active antiretroviral therapy (HAART) has not altered the incidence of these malignancies.

Bizarre parosteal osteochondromatous proliferation, also known as Nora lesion, is a rare benign surface lesion of the bone commonly affecting the hands and feet. It has an aggressive local growth pattern and high rate of recurrence post-excision. The authors report a case of recurred Nora lesion involving thumb metacarpal neck. En bloc resection with immediate reconstruction using distal radius bone graft was provided as a treatment with no clinical or radiological recurrence at 2-year follow-up.

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.

Objectives Epidermal growth factor receptor (EGFR) and c-MET are tyrosine kinase growth factor receptors implicated in gastric cancer (GC), and their pathways appear to be interdependent. The aim of this study was to investigate the prognostic value of EGFR and c-MET protein overexpression by immunohistochemistry in Canadian patients with resected GC and correlate it with clinicopathologic characteristics and overall survival (OS). Materials and methods Tissue microarray blocks were constructed from 120 resected GCs stained with EGFR and c-MET and scored semiquantitatively (0 to 3+). Each receptor's expression was compared with clinicopathologic characteristics and survival. Descriptive statistics, Kaplan-Meyer, and Cox regression were used for statistical analyses. Results Of the 113 interpretable cases, overexpression of EGFR and c-MET was noted in 17 (15%) and 65 (57%), respectively; coexpression of EGFR and c-MET was observed in 12 (10%) of GC. EGFR and c-MET overexpression correlated with poor OS: median 13 versus 30 months in EGFR positive versus negative GC (hazard ratio [HR]=1.67, P=0.11); 27 versus 49 months in c-MET positive versus negative GC (HR=1.17, P=0.49), respectively. GC coexpressing EGFR and c-MET was significantly correlated with poor survival: 12 versus 29 months in double-positive versus rest of tumors both in univariate (HR=2.62, P=0.003) and multivariate analyses (HR=2.58, P=0.01). Conclusions This study describes the prevalence and prognostic value of EGFR and c-MET in a Canadian population of patients undergoing curative intent resection for GC. Both c-MET and EGFR overexpression trended toward poor OS, but only the group with EGFR+/c-MET+ GC reached statistical significance on multivariate analysis.

Salivary duct carcinoma (SDC) is a prototypic aggressive salivary gland carcinoma. Our aim is to determine the prevalence of histologic variants (micropapillary, basal-like) and androgen receptor (AR) expression in a large multi-institutional series of SDC. AR status was determined by immunohistochemistry (IHC). Most SDCs were characterized by an apocrine phenotype and AR expression. Cases with a nonapocrine phenotype and AR-negative status were studied by additional IHC and fluorescence in situ hybridization for ETV6 or MYB/NFIB. The diagnosis of SDC was confirmed in 187 of 199 (94%) cases. Variant morphologies were identified in 12 cases: micropapillary (n=6), sarcomatoid (n=3), mucinous (n=2), and basal-like (n=1). AR IHC was performed in 183 cases, of which 179 (97.8%) showed AR expression. On the basis of morphologic appearance and results of additional studies, 12 cases were reclassified as squamous cell carcinoma (SCC) (n=4), epithelial-myoepithelial carcinoma with high-grade transformation (HGT) (n=2), myoepithelial carcinoma (n=2), mammary analogue secretory carcinoma, high grade (ETV6 translocated; n=1), adenoid cystic carcinoma with HGT (n=1), acinic cell carcinoma with HGT (n=1), and adenosquamous carcinoma (n=1). AR-negative SDC is extremely rare, and the majority of such cases are more accurately classified as other entities. HGTs of other salivary carcinomas and squamous cell carcinoma are the most common mimics of SDC. SDCs with variant morphologies still show at least a minor component of conventional apocrine appearance. Thus, apocrine morphology defines SDC.

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.

While sinonasal intestinal type adenocarcinoma (ITAC) is defined by an intestinal phenotype, non-intestinal type adenocarcinoma (non-ITAC) is traditionally viewed as a diagnosis of exclusion, despite previous implication of a seromucinous phenotype and similarity to sinonasal seromucinous hamartomas (SSH). We performed a comparison of clinicopathologic and immunophenotypic features of ITAC, non-ITAC and SSH using traditional discriminatory markers and new markers of seromucinous differentiation. Twenty-three non-ITAC, 17 ITAC, and 5 SSH were retrieved (1987–2014). As expected, ITAC occurred predominantly in the nasal cavity in elderly patients (mean age 65 years) with a striking male predilection (15:2). Regardless of grade/subtype, all ITAC were invariably CK20 and CDX2 positive, and many (11/15) showed some CK7 positivity. Non-ITAC occurred in younger individuals (mean age 51 years) with a slight female predilection (male to female ratio: 10:13) and showed diverse morphologic patterns and grades, some with morphologic similarity to SSH. SSH occurred in younger individuals (mean age 33 years). Non-ITAC and SSH were invariably CK7 positive and CK20 negative, however, 4/22 non-ITAC and 2/5 SSH showed squamoid morular metaplasia that aberrantly expressed CDX2 and co-expressed nuclear β-catenin. Markers of seromucinous differentiation (S100, DOG1, and SOX10) were essentially absent in ITAC, but present to varying degrees in the majority of non-ITAC and all SSH. Thus, the term ‘seromucinous adenocarcinoma’ is the more appropriate designation for non-ITAC. Squamoid morules in non-ITAC and SSH may be an immunophenotypic pitfall given the aberrant CDX2 expression.