Mucoepidermoid carcinoma (MEC) and adenosquamous carcinoma (ASC), the same or different entities?

Mucoepidermoid carcinoma (MEC) and adenosquamous carcinoma (ASC) have overlapping histopathological appearances and sites of occurrence, which may cause diagnostic difficulty impacting subsequent treatment. We conducted a systematic review of the scientific literature to determine whether molecular alterations were sufficiently different in MEC and ASC to aid in classifying the two entities. We searched Medline, Embase and Web of Science for studies reporting molecular determinations of ASC and/or MEC and screened retrieved records for eligibility. Two independent researchers reviewed included studies, assessed methodological quality and extracted data. Of 8623 identified records, 128 articles were included for analysis: 5 which compared the two tumors in the same investigation using the same methods and 123 which examined the tumors separately. All articles, except one were case series of moderate to poor methodological quality. The 5 publications examining both tumors showed that 52/88 (59%) MEC and 0% of 110 ASC had rearrangement of the MAML2 gene as detected by FISH and/or RT-PCR, but did not investigate other genes. In the entire series MEC had MAML2 gene rearrangement in 1337/2009 (66.6%) of tumors studied. The articles examining tumors separately found that MEC had mutations in EGFR (11/329 cases, 3.3%), KRAS (11/266, 4.1%) and ERBB2 (9/126, 7.1%) compared with ASC that had mutations in EGFR (660/1705, 38.7%), KRAS (143/625, 22.9%) and ERBB2 (6/196, 3.1%). The highest level of recurrent mutations was in pancreatic ASC where (108/126, 85.7%) reported mutations in KRAS. The EGFR mutations in ASC were similar in number and kind to those in lung adenocarcinoma. By standards of systematic review methodology and despite the large number of retrieved studies, we did not find adequate evidence for a distinctive molecular profile of either MEC or ASC that could definitively aid in its classification, especially in histologically difficult cases that are negative for MAML2 rearrangement. The case series included in this review indicate the relevance of MAML2 rearrangement to support the diagnosis of MEC, findings that should be confirmed by additional research with adequate study design.

Diagnostic Value of MAML2 Rearrangements in Mucoepidermoid Carcinoma.

Mucoepidermoid carcinoma (MEC) is often seen in salivary glands and can harbor MAML2 translocations (MAML2+). The translocation status has diagnostic utility as an objective confirmation of the MEC diagnosis, for example, when distinction from the more aggressive adenosquamous carcinoma (ASC) is not straightforward. To assess the diagnostic relevance of MAML2, we examined our 5-year experience in prospective testing of 8106 solid tumors using RNA-seq panel testing in combinations with a two-round Delphi-based scenario survey. The prevalence of MAML2+ across all tumors was 0.28% (n = 23/8106) and the majority of MAML2+ cases were found in head and neck tumors (78.3%), where the overall prevalence was 5.9% (n = 18/307). The sensitivity of MAML2 for MEC was 60% and most cases (80%) were submitted for diagnostic confirmation; in 24% of cases, the MAML2 results changed the working diagnosis. An independent survey of 15 experts showed relative importance indexes of 0.8 and 0.65 for "confirmatory MAML2 testing" in suspected MEC and ASC, respectively. Real-world evidence confirmed that the added value of MAML2 is a composite of an imperfect confirmation test for MEC and a highly specific exclusion tool for the diagnosis of ASC. Real-world evidence can help move a rare molecular-genetic biomarker from an emerging tool to the clinic.

Clonality, Mutation and Kaposi Sarcoma: A Systematic Review.

BACKGROUND: It remains uncertain whether Kaposi sarcoma (KS) is a true neoplasm, in that it regresses after removal of the stimulus to growth (as HHV8) when immunosuppression is reduced. We aimed to summarize the available evidence on somatic mutations and clonality within KS to assess whether KS is a neoplasm or not. METHODS: Medline and Web of Science were searched until September 2020 for articles on clonality or mutation in KS. Search strings were supervised by expert librarians, and two researchers independently performed study selection and data extraction. An adapted version of the QUADAS2 tool was used for methodological quality appraisal. RESULTS: Of 3077 identified records, 20 publications reported on relevant outcomes and were eligible for qualitative synthesis. Five studies reported on clonality, 10 studies reported on various mutations, and 5 studies reported on chromosomal aberrations in KS. All studies were descriptive and were judged to have a high risk of bias. There was considerable heterogeneity of results with respect to clonality, mutation and cytogenetic abnormalities as well as in terms of types of lesions and patient characteristics. CONCLUSIONS: While KS certainly produces tumours, the knowledge is currently insufficient to determine whether KS is a clonal neoplasm (sarcoma), or simply an aggressive reactive virus-driven lesion.

How Does Blood-Retinal Barrier Breakdown Relate to Death and Disability in Pediatric Cerebral Malaria?

BACKGROUND: In cerebral malaria, the retina can be used to understand disease pathogenesis. The mechanisms linking sequestration, brain swelling, and death remain poorly understood. We hypothesized that retinal vascular leakage would be associated with brain swelling. METHODS: We used retinal angiography to study blood-retinal barrier integrity. We analyzed retinal leakage, histopathology, brain magnatic resonance imaging (MRI), and associations with death and neurological disability in prospective cohorts of Malawian children with cerebral malaria. RESULTS: Three types of retinal leakage were seen: large focal leak (LFL), punctate leak (PL), and vessel leak. The LFL and PL were associated with death (odds ratio [OR] = 13.20, 95% confidence interval [CI] = 5.21-33.78 and OR = 8.58, 95% CI = 2.56-29.08, respectively) and brain swelling (P < .05). Vessel leak and macular nonperfusion were associated with neurological disability (OR = 3.71, 95% CI = 1.26-11.02 and OR = 9.06, 95% CI = 1.79-45.90). Large focal leak was observed as an evolving retinal hemorrhage. A core of fibrinogen and monocytes was found in 39 (93%) white-centered hemorrhages. CONCLUSIONS: Blood-retina barrier breakdown occurs in 3 patterns in cerebral malaria. Associations between LFL, brain swelling, and death suggest that the rapid accumulation of cerebral hemorrhages, with accompanying fluid egress, may cause fatal brain swelling. Vessel leak, from barrier dysfunction, and nonperfusion were not associated with severe brain swelling but with neurological deficits, suggesting hypoxic injury in survivors.

Counting mitoses: SI(ze) matters!

Mitoses are often assessed by pathologists to assist the diagnosis of cancer, and to grade malignancy, informing prognosis. Historically, this has been done by expressing the number of mitoses per n high power fields (HPFs), ignoring the fact that microscope fields may differ substantially, even at the same high power (×400) magnification. Despite a requirement to define HPF size in scientific papers, many authors fail to address this issue adequately. The problem is compounded by the switch to digital pathology systems, where ×400 equivalent fields are rectangular and also vary in the area displayed. The potential for error is considerable, and at times this may affect patient care. This is easily solved by the use of standardized international (SI) units. We, therefore, recommend that features such as mitoses are always counted per mm2, with an indication of the area to be counted and the method used (usually "hotspot" or "average") to obtain the results.

Misleading terminology in pathology: lack of definitions hampers communication.

Accurate terminology is the basis for clear communication among specialists and relies upon precise definitions, indispensable for the WHO Classification of Tumours. We identified a number of potentially misleading terms in use in the recently published WHO Classification of Tumours, 5th edition. From a list of common sources that might be consulted by specialists in the pathology field, we searched for definitions of the terms. Where at least two sources provided definitions for a term, we assessed their level of agreement using an ad hoc developed scale. We identified 26 potentially misleading terms from the 5th edition Digestive System and Breast Tumour Books, and 16 sources. The number of definitions provided by the sources ranged from no definition (for four terms) to ten (for two terms). No source had definitions for all terms. We found only 111 (27%) of a possible 416 definitions. Where two or more definitions were present for a term, the level of agreement between them was judged to be high. There was a paucity of definitions for potentially misleading terms in the sources consulted, but there was a good agreement when two or more definitions were present. In a globalized world where healthcare workers and learners in many fields may access these sources to learn about terminology with which they are unfamiliar, the lack of definitions is a hindrance to a precise understanding of classification in the speciality of pathology and to clear communication between specialist groups.

Differences in 7th and 8th edition American Joint Committee on Cancer staging for periocular sebaceous carcinoma.

OBJECTIVE: To examine the clinicopathological features of periocular sebaceous carcinoma and describe the differences in T category between the seventh and eighth editions of the American Joint Committee on Cancer (AJCC) staging system for eyelid carcinoma in a Canadian population. METHODS: This study is a single-centre retrospective review of consecutive patients diagnosed with periocular sebaceous carcinoma at Vancouver General Hospital over a 24-year period. Medical records and pathological slides were reviewed. Clinicopathological features, management, and outcomes were recorded. Each carcinoma was staged as per both the seventh and eighth editions AJCC staging system for eyelid carcinoma. RESULTS: Forty-five patients (25 women, 20 men) were identified with a median age of 74 years (range 42-91 years). Tumour size was with a median of 4 mm (range 1-30 mm) and a mean of 6.7 mm. Using the seventh edition, patients were assigned the following T categories: Tis = 10, T1 = 9, T2 = 11, T3 = 8, T4 = 0. Under the eighth edition, 18 of 45 patients (40%) were restaged, with the majority of these (15 patients, 33%) being downstaged. The eighth edition categories were as follows: Tis = 10, T1 = 22, T2 = 3, T3 = 0, T4 = 3. Three patients developed disease recurrence, 2 of whom (staged T2c and T4b) died of disease. CONCLUSIONS: There were substantial differences in the seventh and eighth editions of AJCC for the staging of periocular sebaceous carcinoma. Our series had small tumours at presentation with infrequent recurrences or metastases. We found a high number of patients with in-situ-only disease.

cIMPACT-NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT-Utrecht meeting on future CNS tumor classification and grading.

cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to evaluate and make practical recommendations on recent advances in the field of CNS tumor classification, particularly in light of the rapid progress in molecular insights into these neoplasms. For Round 2 of its deliberations, cIMPACT-NOW Working Committee 3 was reconstituted and convened in Utrecht, The Netherlands, for a meeting designed to review putative new CNS tumor types in advance of any future World Health Organization meeting on CNS tumor classification. In preparatory activities for the meeting and at the actual meeting, a list of possible entities was assembled and each type and subtype debated. Working Committee 3 recommended that a substantial number of newly recognized types and subtypes should be considered for inclusion in future CNS tumor classifications. In addition, the group endorsed a number of principles-relating to classification categories, approaches to classification, nomenclature, and grading-that the group hopes will also inform the future classification of CNS neoplasms.

Revising the WHO classification: female genital tract tumours.

The upcoming revision of the World Health Organisation (WHO) classification of tumours of the female genital tract is scheduled for release in the second quarter of 2020. It will feature significant changes compared to earlier editions. In this review, we outline the process of revising this important reference source for those diagnosing tumours or engaged in cancer research and describe the significant changes. The WHO classification of tumours is increasingly evidence-based, with a clear update cycle, improved quality of illustrations and content, led by an editorial board comprised mainly of pathologists, but increasingly incorporating input from other disciplines. The advent of the new website allows the use of whole-slide images and hyperlinks to evidence or external bodies that produce guidance on staging or reporting.

Understanding and Classification of Ocular Lymphomas.

BACKGROUND: Lymphomas that involve the tissues of the ocular adnexae and the eye itself can be confusing for both the new and seasoned learner alike. In this review, I present a simple way of classifying these disorders that will help to facilitate understanding of these myriad entities. SUMMARY: Classifications of lymphomas have changed significantly over the last 40 years, but in recent decades, the basic structure of the WHO classification has remained the same, facilitating understanding. KEY MESSAGES: The ocular lymphomas can be divided into those that are external to the eye (ocular adnexae) and those that are internal (vitreoretinal and uveal). At each of these sites specific subtypes of lymphoma are common. Focusing on these common subtypes can aid the learner to create a scaffold that enables current understanding and upon which they can build for the future.

Primary Secretory Carcinoma of the Lacrimal Gland: Report of a New Entity.

PURPOSE: Secretory carcinoma has been described in the breast, salivary glands, skin, and other organs, but has not been reported in the lacrimal gland to date. Since lacrimal and salivary glands show similar tumors, we hypothesized that lacrimal secretory carcinoma may exist but has been misclassified in the past. DESIGN: We undertook a retrospective review of all lacrimal gland tumors at 2 tertiary institutions with centralized ocular pathology practices. METHODS: A total of 350 lacrimal tumors were reviewed by the authors. Candidate tumors were tested for ETV-NTRK rearrangement by fluorescence in situ hybridization and the presence of the translocation was confirmed by next-generation sequencing. RESULTS: We identified a single case of secretory carcinoma. The diagnosis was confirmed by demonstrating specific immunohistochemical profile and the presence of ETV6-NTRK3 gene fusion, which is characteristic of secretory carcinoma of other sites. The tumor occurred in a young man who was treated with surgery alone with no recurrence during 12 years of follow-up. CONCLUSION: Secretory carcinoma is a new lacrimal gland carcinoma type that should be added to the spectrum of low-grade lacrimal gland tumors.

Gene Expression Profiling and Heterogeneity of Nonspecific Orbital Inflammation Affecting the Lacrimal Gland.

Importance: Although a variety of well-characterized diseases, such as sarcoidosis and granulomatosis with polyangiitis, affect the lacrimal gland, many patients with dacryoadenitis are diagnosed as having nonspecific orbital inflammation (NSOI) on the basis of histology and systemic disease evaluation. The ability to further classify the disease in these patients should facilitate selection of effective therapies. Objective: To test the a priori hypothesis that gene expression profiles would complement clinical and histopathologic evaluations in identifying well-characterized diseases and in subdividing NSOI into clinically relevant groups. Design, Setting, and Participants: In this cohort study, gene expression levels in biopsy specimens of inflamed and control lacrimal glands were measured with microarrays. Stained sections of the same biopsy specimens were used for evaluation of histopathology. Tissue samples of patients were obtained from oculoplastic surgeons at 7 international centers representing 4 countries (United States, Saudi Arabia, Canada, and Taiwan). Gene expression analysis was done at Oregon Health & Science University. Participants were 48 patients, including 3 with granulomatosis with polyangiitis, 28 with NSOI, 7 with sarcoidosis, 4 with thyroid eye disease, and 6 healthy controls. The study dates were March 2012 to April 2017. Main Outcomes and Measures: The primary outcome was subdivision of biopsy specimens based on gene expression of a published list of approximately 40 differentially expressed transcripts in blood, lacrimal gland, and orbital adipose tissue from patients with sarcoidosis. Stained sections were evaluated for inflammation (none, mild, moderate, or marked), granulomas, nodules, or fibrosis by 2 independent ocular pathologists masked to the clinical diagnosis. Results: Among 48 patients (mean [SD] age, 41.6 [19.0] years; 32 [67%] female), the mclust algorithm segregated the biopsy specimens into 4 subsets, with the differences illustrated by a heat map and multidimensional scaling plots. Most of the sarcoidosis biopsy specimens were in subset 1, which had the highest granuloma score. Three NSOI biopsy specimens in subset 1 had no apparent granulomas. Thirty-two percent (9 of 28) of the NSOI biopsy specimens could not be distinguished from biopsy specimens of healthy controls in subset 4, while other examples of NSOI tended to group with gene expression resembling granulomatosis with polyangiitis or thyroid eye disease. The 4 subsets could also be partially differentiated by their fibrosis, granulomas, and inflammation pathology scores but not their lymphoid nodule scores. Conclusions and Relevance: Gene expression profiling discloses clear heterogeneity among patients with lacrimal inflammatory disease. Comparison of the expression profiles suggests that a subset of patients with nonspecific dacryoadenitis might have a limited form of sarcoidosis, while other patients with NSOI cannot be distinguished from healthy controls.

The role of biopsy in lacrimal gland inflammation: A clinicopathologic study.

PURPOSE: To determine the causes of lacrimal gland inflammation based on histopathology and systemic evaluation. METHODS: This is a retrospective case series study. From the University of British Columbia Orbit Clinic between January 1976 and December 2008, we reviewed the medical records of 60 patients who presented with inflammatory features of the lacrimal gland (i.e., erythema, edema, or tenderness) in which the diagnoses were not possible clinically and on imaging alone. As was our routine practice, all these patients underwent lacrimal gland biopsy before starting any treatment. RESULTS: The histopathologic findings of the 60 patients showed that 37 (61.7%) had identifiable types of lacrimal inflammation including 10 with Sjogren's syndrome, seven with sarcoidal reaction, six with feature of granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis), five with lymphoma, two with sclerosing inflammation, two with IgG4-related dacryoadenitis, and one patient each with infectious dacryoadenitis, myoepithelial carcinoma, xanthogranuloma, eosinophilic angiocentric fibrosis, and eosinophilic allergic granulomatous nodule. The histopathologic findings of the remaining 23 (38.3%) patients showed nonspecific inflammation of the lacrimal gland. 23 patients (38.3%) had associated systemic diseases. 48 patients (80%) were treated successfully and 10 (16.7%) had recurrence of inflammation. CONCLUSIONS: We recommend that in patients presenting with lacrimal gland inflammation (i.e., erythema, edema, tenderness) in which the specific diagnosis cannot be made clinically and on imaging, biopsy is warranted for accurate diagnosis and appropriate treatment. We found that the majority of these patients (61.7%) had specific histopathology, and 38% had systemic diseases.

LAMELLAR HOLE-ASSOCIATED EPIRETINAL PROLIFERATION: A Clinicopathologic Correlation.

PURPOSE: To correlate clinical and optical coherence tomographic features with histopathological and immunohistochemical findings in an eye undergoing surgical excision of lamellar hole-associated epiretinal proliferation (LHEP). METHODS: An eye with a lamellar macular hole and LHEP without a tractional epiretinal membrane component was identified with spectral-domain optical coherence tomographic imaging and underwent pars plana vitrectomy with LHEP and internal limiting membrane peeling and gas tamponade. The surgically excised LHEP specimen was analyzed with histopathological and immunohistochemical staining using flat-mount preparation techniques. Postsurgical outcomes including visual acuity and optical coherence tomographic imaging were reviewed. RESULTS: With spectral-domain optical coherence tomography, the lamellar macular hole was found to be closed with no residual LHEP after the surgery. Visual acuity improved from 20/200 preoperatively to 20/40 at 6 months after the surgery. Histopathological and immunohistochemical analyses of the LHEP specimen revealed retinal glial cells that reacted positively with anti-glial fibrillary acidic protein and anti-glutamine synthetase, a Müller cell-specific antibody. CONCLUSION: Lamellar macular hole with LHEP may demonstrate closure after pars plana vitrectomy with LHEP and internal limiting membrane peeling and gas tamponade. There was considerable improvement in visual acuity. It is possible that LHEP originates from middle retinal layers of the lamellar hole defect because it contains retinal glial cells, specifically Müller cells.

CFH Y402H polymorphism and the complement activation product C5a: effects on NF-κB activation and inflammasome gene regulation.

BACKGROUND/AIMS: The Y402H polymorphism in the complement factor H (CFH) gene is an important risk factor for age-related macular degeneration (AMD). Complement activation products and proinflammatory cytokines are associated with this polymorphism at the systemic level, but less is known of the associations in the outer retina of the genotyped eye. Here we investigate complement activation products and their role in nuclear factor (NF)-κB activation and gene expression of the NLRP3 inflammasome pathway. METHODS: Postmortem donor eyes were genotyped for the CFH Y402H polymorphism and assessed for complement C3a, C5a, interleukin (IL)-18 and tumour necrosis factor (TNF)-α. ARPE19 cells were stimulated basolaterally with C5a or TNF-α in polarised cultures. NF-κB activation was assessed with a reporter cell line. Gene expression of inflammasome-related (NLRP3, caspase-1, IL-1ß and IL-18) and classic inflammatory (IL-6 and IL-8) genes was studied. The distribution of inflammasome products, IL-1ß and IL-18, was studied in postmortem donor eyes with AMD pathologies. RESULTS: Eyes with the homozygous at-risk variant demonstrated higher levels of C5a, IL-18 and TNF-α in Bruch's membrane and choroid. C5a promoted NF-κB activation and upregulation of IL-18 in polarised ARPE19. TNF-α promoted NF-κB activation and gene expression of caspase-1, IL-1ß, IL-18, IL-6 and IL-8, but downregulated NLRP3. In eyes with geographic atrophy, strong immunoreactivity was observed for inflammasome products IL-1ß and IL-18 compared with age-matched controls. CONCLUSION: The at-risk polymorphism of the CFH Y402H may contribute to AMD disease process through increased complement and NF-κB activation, and the upregulation of IL-18, a product of inflammasome activation.

DEVELOPMENT OF EPSTEIN-BARR VIRUS UVEITIS AFTER REMISSION OF PRIMARY VITREORETINAL LYMPHOMA.

PURPOSE: To describe a case of Epstein-Barr virus (EBV) uveitis that occurred after the treatment and remission of primary vitreoretinal lymphoma (PVRL). METHODS: Descriptive case report. Complete ophthalmologic evaluation, cytology, polymerase chain reaction, cytokine analysis of aqueous humor, and diagnostic vitrectomy were performed. RESULTS: A 66-year-old Caucasian woman developed uveitis in the same eye 20 months after remission of PVRL. Empiric chemotherapy failed to treat the suspected PVRL recurrence, and aqueous humor cytology showed an absence of malignant cells. Qualitative polymerase chain reaction of aqueous humor confirmed the presence of EBV. Treatment for EBV resulted in remission of the uveitis. CONCLUSION: The authors describe a rare case of EBV uveitis that was preceded by PVRL. It is important to consider EBV in cases where suspected recurrence of PVRL does not respond to appropriate treatment.