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Primary sinonasal neuroendocrine carcinoma (SNEC) is a rare aggressive sinonasal malignancy which typically occurs in the ethmoidal or maxillary sinuses, with or without nasal cavity involvement, of middle-aged patients (median age 53 years), with a slight male preponderance. No risk factors have been identified. Most patients present at advanced stages due to the lack of significant symptoms.1,4,5,8 Advanced tumours may invade the skull, orbit or brain. Staging is of limited value in predicting prognosis and recent literature clearly highlights the importance of histological diagnosis, particularly differentiation grade, in determining the prognosis and predicting treatment response. Nomenclature has been ambiguous, but broadly SNECs can be classified as well-, moderately- or poorly differentiated. The latter group includes sinonasal undifferentiated carcinoma and sinonasal small cell carcinoma. On histological examination, well-to-moderately differentiated tumours show medium-sized cells with large nuclei containing stippled or ‘salt/pepper’ chromatin and scant cytoplasm. Nuclear moulding, increased mitoses and apoptotic bodies are commonly seen. Immunohistochemistry reveals expression of neuroendocrine markers.1,4–7 Poorly-differentiated tumours may lose expression of neuroendocrine markers and differentiation from other poorly differentiated malignancies can be extremely difficult.1,4–7 Due to the limited number of reported cases, there is no clear consensus on management, although oncologists now advocate multimodal therapy. Combined surgery and radiotherapy is thought to beneficial in moderately and poorly-differentiated subtypes.1,4–8 We describe a classical case of SNEC with secondary orbital involvement, with a review of the current literature.

Hyperkeratosis lenticularis perstans (Flegel disease) is a rare, benign hyperkeratotic skin disorder which typically occurs in lower extremities of Caucasian middle-aged patients. Most cases are sporadic although familial cases with an autosomal dominant mode of inheritance have been reported.1–5 Clinically the condition mimics many other hyperkeratotic and inflammatory disorders and the diagnosis is only confirmed on histopathological and clinical correlation.2,5,6 The condition typically presents with asymptomatic keratotic/scaly red/brown papules which histomorphologically show lamellar hyperkeratosis with abrupt peripheral basket-weave orthokeratosis, irregular acanthosis and underlying lichenoid lymphocytic infiltrate.1–7 The pathogenesis remains unclear and thus various topical and/or systemic treatments have shown variable success rates. Herein we describe a classical case with review of the current literature.

Metastatic uveal melanoma (mUM) to the liver is incurable. Transcriptome profiling of 40 formalin-fixed paraffin-embedded mUM liver resections and 6 control liver specimens was undertaken. mUMs were assessed for morphology, nuclear BAP1 (nBAP1) expression, and their tumour microenvironments (TME) using an &ldquo, immunoscore&rdquo, (absent/altered/high) for tumour-infiltrating lymphocytes (TILs) and macrophages (TAMs). Transcriptomes were compared between mUM and control liver, intersegmental and intratumoural analyses were also undertaken. Most mUM were epithelioid cell-type (75%), amelanotic (55%), and nBAP1-ve (70%). They had intermediate (68%) or absent (15%) immunoscores for TILs and intermediate (53%) or high (45%) immunoscores for TAMs. M2-TAMs were dominant in the mUM-TME, with upregulated expression of ANXA1, CD74, CXCR4, MIF, STAT3, PLA2G6, and TGFB1. Compared to control liver, mUM showed significant (p &lt, 0.01) upregulation of 10 genes: DUSP4, PRAME, CD44, IRF4/MUM1, BCL2, CD146/MCAM/MUC18, IGF1R, PNMA1, MFGE8/lactadherin, and LGALS3/Galectin-3. Protein expression of DUSP4, CD44, IRF4, BCL-2, CD146, and IGF1R was validated in all mUMs, whereas protein expression of PRAME was validated in 10% cases, LGALS3 stained TAMs, and MFGEF8 highlighted bile ducts only. Intersegmental mUMs show differing transcriptomes, whereas those within a single mUM were similar. Our results show that M2-TAMs dominate mUM-TME with upregulation of genes contributing to immunosuppression. mUM significantly overexpress genes with targetable signalling pathways, and yet these may differ between intersegmental lesions.

Uveal melanoma (UM) is a rare aggressive intraocular tumour with a propensity for liver metastases, occurring in ∼50% of patients. The tumour suppressor BAP1 is considered to be key in UM progression. Herein, we present the largest study to date investigating cellular expression patterns of BAP1 protein in 165 UMs, correlating these patterns to prognosis. Full clinical, histological, genetic, and follow-up data were available for all patients. BAP1 gene sequencing was performed on a subset of 26 cases. An independent cohort of 14 UMs was examined for comparison. Loss of nuclear BAP1 (nBAP1) protein expression was observed in 54% (88/165) UMs. nBAP1 expression proved to be a significant independent prognostic parameter: it identified two subgroups within monosomy 3 (M3) UM, which are known to have a high risk of metastasis. Strikingly, nBAP1-positiveM3 UMs were associated with prolonged survival compared to nBAP1-negative M3 UMs (Log rank, p = 0.014). nBAP1 protein loss did not correlate with a BAP1 mutation in 23% (6/26) of the UMs analysed. Cytoplasmic BAP1 protein (cBAP1) expression was also observed in UM: although appearing 'predominantly diffuse' in most nBAP1-negative UM, a distinct 'focal perinuclear' expression pattern - localized immediately adjacent to the cis Golgi - was seen in 31% (18/59). These tumours tended to carry loss-of-function BAP1 mutations. Our study demonstrates loss of nBAP1 expression to be the strongest prognostic marker in UM, confirming its importance in UM progression. Our data suggest that non-genetic mechanisms account for nBAP1 loss in a small number of UMs. In addition, we describe a subset of nBAP1-negative UM, in which BAP1 is sequestered in perinuclear bodies, most likely within Golgi, warranting further mechanistic investigation.

Current treatments for metastatic uveal melanoma (mUM) are limited and rarely prolong patient survival. Immunotherapy trials for mUM are few and to date have demonstrated only marginal success. High densities of tumor-associated macrophages (TAMs) and infiltrating T lymphocytes (TILs) in primary UM are associated with poor prognosis. Little is known about the immune microenvironment of mUM. Our aim was to examine the presence and distribution of TAMs and TILs in mUM within the liver. Whole-tissue sections of liver mUM (n=35) were examined by immunohistochemistry. For TAMs, monoclonal antibodies against CD68 and CD163 were used. Macrophage density and morphology were scored using previous established systems. Density and spatial distribution of TILs were highlighted using antibodies against CD3 (pan-lymphocyte marker), CD4 (T-helper cells), and CD8 (T-cytotoxic cells). CD68+ and CD163+ TAMs were seen within the tumor in all 35 specimens; their density was "moderate" in 50% of cases and "few" in 43%, and the majority showed an "indeterminate" phenotype. CD3+ TILs were noted both within mUMs and surrounding the tumor. Of these, CD8+ TILs were "few" in number within mUM but were predominantly seen peritumorally at the tumor/normal liver interface, whereas CD4+ TILs showed a high perivascular density within mUM. CD68+ and CD163+ TAMs of "indeterminate" morphology were observed in mUM, suggesting a tendency toward the protumorigenic M2 phenotype. CD4+ TILs were seen within the mUM, whereas CD8+ TILs tended to be peritumoral. The biological and functional roles of inflammatory cells in mUM require further investigation to determine if they represent potential targets for future therapies in mUM.

Background/aims Iris melanomas (IM) are rare and have a lower mortality than posterior uveal melanomas (UM). Our aims were to determine the prevalence of genetic changes associated with prognosis of posterior UM, in both treated and non-treated IM. Methods Retrospective database review and molecular analysis of all patients diagnosed with IM at the Liverpool Ocular Oncology Centre (LOOC) between 1993 and 2015. Archival pathology specimens of confirmed IM cases were analysed for chromosomal alterations, using multiplex ligation-dependent probe amplification (MLPA) or microsatellite analysis (MSA) depending on DNA yield, and BRAF mutation status. Results 5189 patients were diagnosed with intraocular melanoma at LOOC from 1993 to 2015. Of these, 303 (5.8%) patients were diagnosed with IM. Tissue samples were available for 26 IM cases. Twelve of these cases had biopsies taken post-proton beam radiotherapy (PBR). Histological subtyping showed 14 IM being spindle, 2 epithelioid and 10 were of mixed cell type. Twenty of the 26 IM cases (77%) analysed genetically were classified as either disomy 3 (n=16) or monosomy 3 (n=4). Chromosome 6p gain was detected in 4/18 (22%) IM, and polysomy 8q in 6%. BRAF mutations were not detected in any of the four IM cases examined. One patient with IM died from metastatic disease: this tumour was disomy 3 with 6p and 8q gains. All other patients were alive with no evidence of metastases at study closure. Conclusions Chromosomal aberrations seen in posterior UM can also be demonstrated using MLPA or MSA in both treatment naive and PBR-treated IM. Most IM display a low-metastatic risk chromosomal profile.

Background: Lymphomas of the lacrimal sac are rare, accounting for less than 10% of lacrimal sac malignant tumours. They may present with symptoms typical of secondary acquired nasolacrimal duct obstruction and are thus often misdiagnosed. Methods: Case series and literature review. Results: Herein we describe 3 cases of chronic lymphocytic leukaemia (CLL)/small-cell lymphocytic lymphoma (SLL) of the lacrimal sac with immunohistochemical and in 1 case molecular confirmation. Conclusion: Lymphomas of the lacrimal sac should be suspected in patients with known CLL presenting with epiphora and dacryocystitis. During dacryocystorhinostomy, an incisional biopsy of the lacrimal sac is essential for confirming CLL/SLL involvement and may guide treatment.

Chondroid syringoma or mixed skin tumour is a rare, benign skin adnexal tumour which typically occurs in the head and neck region of middle-aged patients. Due to their rarity, they are often clinically misdiagnosed and with the diagnosis only confirmed on histological examination. They typically comprise sweat gland elements within a prominent ‘cartilage-like' stroma. Treatment involves total excision with clear surgical margins. Where excision is incomplete, routine follow up is required due to risk of recurrence or malignant transformation, though the latter is extremely rare. Herein we describe a classical case with review of the current literature.

Tumors of the lacrimal sac are rare but their recognition and early management are imperative, as they are locally invasive and potentially life-threatening. Because of their rarity, large clinical studies with statistically significant data on the natural course, management, and prognosis of these neoplasms are unavailable. Current practices are therefore based on a few case series and a small number of isolated case reports. Most tumors are primary and of epithelial origin (60-94%), of which 55% are malignant. Lacrimal sac tumors typically present with epiphora and a palpable mass over the medial canthus and are thus often erroneously diagnosed as chronic dacryocystitis. A full history with clinical and diagnostic workup is essential to plan treatment, which is often multi-disciplinary. Statistically significant associations have been shown with higher tumor staging and size with increased metastatic risk and lower survival rates. Management usually involves complete surgical resection with adjuvant radiotherapy and/or chemotherapy for malignant lesions. Long-term follow-up is required, as recurrences and metastases can occur many years after initial treatment.