Granulomatous Slack Skin With Lung and Esophagus Involvement: A Case Report and Molecular Analysis.

ABSTRACT: Granulomatous slack skin (GSS) is a rare subtype of mycosis fungoides, and few cases have been known to spread to the blood, lymph nodes, or viscera. We present a case with early dissemination to the lung. A 27-year-old woman, previously healthy, presented with scattered disseminated scaly patches, associated with vulvar and intergluteal firm swelling and groin-skin induration for 1 year. She also reported mild fatigue and breathlessness on moderate exertion. The patient underwent blood tests, skin biopsies, and computed tomography scan. The skin biopsy showed a mildly atypical T-cell lymphoid infiltrate involving the dermis/hypodermis, with focal epidermotropism, associated with a granulomatous infiltrate and elastophagocytosis. The computed tomography scan revealed bilateral ground-glass lung nodular opacities. Positron emission tomography showed an increased signal in the skin and subcutis around the buttocks, inguinal and mediastinal lymph nodes, and lungs. The lung biopsy confirmed a dense T-cell infiltrate with numerous multinucleated giant cells. Subsequently, esophageal involvement was also observed following biopsy. Molecular analyses demonstrated identical T-cell clones in the skin and lung. After 6 cycles of chemotherapy/localized external radiotherapy, the patient had a partial skin response and stable lung disease. A preferred diagnosis of GSS with systemic spread was made based on clinical/histologic/molecular findings, after considering granulomatous mycosis fungoides and peripheral T-cell lymphoma, not otherwise specified. This case highlights the frequent diagnostic difficulty in distinguishing GSS from an inflammatory granulomatous dermatitis. Pulmonary and esophageal involvements are rare in GSS, and the simultaneous presentation of characteristic cutaneous GSS with systemic disease poses an additional classification challenge.

Homozygous Loss of CDKN2 in Primary Cutaneous CD8(+) Lymphoma NOS.

ABSTRACT: Primary cutaneous acral CD8(+) lymphoma (AL) has been accepted as primary cutaneous acral CD8-positive T-cell lymphoproliferative disorder in the revised WHO and updated WHO-EORTC lymphoma classifications. Commonly arising on the ears and comprising a clonal cytotoxic CD8 + T-cell infiltrate, almost all cases follow an indolent clinical course. A single aggressive case reported in the literature had a deletion at the CDKN2 locus at 9p21. We report an atypical CD8 + T-cell proliferation arising on the chest of an elderly man who had some similarities to AL but with a very high proliferation rate, absent p16 protein expression, and homozygous loss of the CDKN2 locus using FISH analysis. A diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL NOS) was preferred. Analyses of 4 cases of AL demonstrated often low p16 protein expression but intact CDKN2 loci. This case raises the problems of the boundaries between AL and PTCL NOS, and a possible role in the loss of p16 function in pathogenesis.

Pigmented Epidermotropic Breast Carcinoma: A Diagnostic Pitfall Mimicking Melanoma A Case Report and Literature Review.

We report the clinical and pathologic features of a patient with breast carcinoma, who developed clinically visible pigmented skin lesions during the course of the disease. The combination of clinical pigmentation, histological pagetoid epidermal spread, and considerable melanin pigment within tumour cells lead to a misdiagnosis of melanoma. This case provides a striking example of the ability of epidermotropic breast carcinoma to mimic melanoma. A literature review is also reported.

Mycosis Fungoides and Granulomatous Slack Skin: A Single Entity With Distinct Clinical Phenotypes.

ABSTRACT: Granulomatous cutaneous T-cell lymphoma includes mycosis fungoides with significant granulomatous inflammation (GMF) and granulomatous slack skin (GSS), listed in the WHO classification as a subtype of mycosis fungoides (MFs). 1 These overlapping entities have shared clinical and histopathologic features which can present a diagnostic challenge. The dominance of the granulomatous infiltrate and the often sparse lymphocytic infiltrate frequently with minimal cytological atypia are features that distract from the correct diagnosis, even when raised by the clinician. We describe the clinical and histopathologic characteristics of 3 cases of granulomatous cutaneous T-cell lymphoma, illustrate the close clinical and pathologic relationship between GMF and GSS and emphasize the diagnostic difficulties that the granulomatous infiltrate can present. Furthermore, we demonstrate, for the first time, considerable elastolysis in a significant proportion of classical (Alibert-Bazin) MF lesions and therefore postulate that the differences observed between GMF and GSS are one of degree and secondary to their anatomic location rather than reflecting meaningful separate entities.

Creating evidence-based engaging online learning resources in neuroanatomy.

Online anatomical resources are rising in popularity since the COVID-19 pandemic, but the pedagogical principles and effectiveness of their use remain unclear. This article aims to demonstrate evidence-informed ways in which fellow educators can create engaging online learning resources in clinical neuroanatomy and compare the effectiveness of text-based and online learning resources. Data were analyzed from the Soton Brain Hub (SBH) YouTube page. Separately, a cross-sectional study comparing the learning gain of using text-based and video resources was done. The knowledge gain and retention were compared between groups using a pre-teaching and post-teaching multiple choice questions. YouTube analytics showed the average time a viewer spends on a video was found to be highly correlated to the length of the video, r = 0.77, p < 0.001 (0.69-0.82). The cross-sectional study indicated a significant difference in mean normalized learning gain of video resources 61.9% (n = 53, CI 56.0-67.7%) versus text resources 49.6% (n = 23, CI 39.1-60.1%) (p = 0.030). However, there was no difference in retained learning gain between video resources 39.1% (n = 29, CI 29.2-49.0%) versus text-based 40.0% (n = 13, CI 23.9-56.1%) (p = 0.919). Students engage most with short videos less than 5 min which reduces the intrinsic load of learning. Online resources are as effective as text-based resources in providing learning gain and retention. In the future, the continued rise in popularity of online learning resources may result in further reduction in traditional face-to-face teaching.

Assessing the Impact of Interactive Educational Videos and Screencasts Within Pre-clinical Microanatomy and Medical Physiology Teaching.

Modern medical curricula adopt the use self-directed learning approaches, which frequently include the use of technology enhanced learning resources. Often, students prefer those which are available via mobile devices because it can facilitate flexibility and autonomy with their learning, more so than with traditional modalities. Although the production value of resources may be appealing to users, those that work most effectively for education align well to existing pedagogies. One such pedagogy is the cognitive theory of multimedia learning. It is a framework that can be used to facilitate the construction of educational video, that can benefit learning gain through reducing the cognitive load.Although much research has been conducted on how information should be presented in video resources, there is very limited evidence within the subject of clinical anatomy and physiology or when applying different types of educational video, such as screencasts, or interactive video. In the field of anatomy education recent approaches have sought to standardize a robust methodology to evaluate digital resources. This procedure utilizes a combination of normalized learning gain and learner perceptions to gain an accurate picture of educational impact.The current study investigated the impact of both interactive educational videos and screencasts compared with traditional teaching techniques in the challenging subjects of histology and pain physiology. A quasi-randomized, cross-sectional study was conducted with 135 medical students enrolled at the University of Southampton. Sixty fourth- and fifth-year students assessed the histology resources, and 75 second-year students assessed the pain histology resources. Participants were randomly assigned to either a text-based resource, interactive video, or screencast group. Outcomes measured were: 1. Normalized knowledge gain (and retention) assessed using one-best-answer multiple choice question tests 2. Student perceptions using 1-10 Likert-scale style questionnaires. A significant improvement in mean normalized knowledge gain was observed for all teaching modalities. For pain physiology, the means were: Text-49.0% (n = 23), interactive video-70.1% (n = 26), and screencast-53.8% (n = 26). For all learning gains, P < 0.001. For histology, there was a mean normalized learning gain for text-80.0% (n = 20), interactive video-74.4% (n = 20), and screencast groups-68.3% (n = 20). For all learning gains, P < 0.001.For pain physiology resources, interactive videos significantly improved learning gain compared to the screencast (P < 0.05) and the text resource groups (P < 0.01). There was no significant difference between those who used the text or screencast resources. There was also no significant difference in knowledge retention between the different teaching methods for each subject.Following teaching, all three teaching modalities had similar effects on student confidence in the subjects, desire for educational channels dedicated to each topic, and preference for locally produced vs. externally produced videos. These findings have the potential to inform educators on which types of resources to create or to select for their students to have the best impact on learning.

Clinical, histopathological and prognostic features of primary cutaneous acral CD8+ T-cell lymphoma and other dermal CD8+ cutaneous lymphoproliferations: results of an EORTC Cutaneous Lymphoma Group workshop.

BACKGROUND: The differential diagnosis of atypical dermal nonepidermotropic CD8+ lymphocytic infiltrates includes a heterogeneous spectrum of lymphoproliferations with overlapping histological and phenotypic features, but divergent clinical manifestations and prognoses. As these neoplasms are rare, more data on their clinicopathological presentation and course are needed. OBJECTIVES: To assess the clinical, histological and immunophenotypic features; outcomes of; and differences between dermal CD8+ lymphoproliferations. METHODS: Retrospective analysis of a series of 46 patients and biopsies by the international EORTC Cutaneous Lymphoma Group. RESULTS: The dermal CD8+ lymphoproliferations (n = 46) could be assigned to one of three groups: (i) cutaneous acral CD8+ T-cell lymphoma (n = 31), characterized mostly by a solitary nodule arising at acral sites, a monotonous dermal infiltrate of small-to-medium-sized CD8+ lymphocytes with a characteristic dot-like pattern of CD68, a low proliferation rate and an excellent prognosis; (ii) primary cutaneous CD8+ peripheral T-cell lymphoma, unspecified/NOS (n = 11), presenting with one or multiple rapidly evolving tumours, mostly medium-sized pleomorphic CD8+ tumour cells with expression of several cytotoxic markers, and high proliferative activity; and (iii) cutaneous CD8+ lymphoproliferations (n = 4), associated with congenital immunodeficiency syndromes in two patients with persisting localized or disseminated violaceous to brownish plaques on the extremities, a histiocyte-rich infiltrate of mostly small CD8+ lymphocytes with subtle atypia and a protracted course; and papular CD8+ eruptions in two patients with acquired immunosuppression. CONCLUSIONS: A constellation of distinct clinical, histopathological and phenotypic features allows discrimination and assignment of dermal CD8+ infiltrates into distinct disease entities. Primary cutaneous acral CD8+ lymphoma, assigned a provisional category in current lymphoma classifications, is a distinct and reproducible entity. A correct diagnosis is essential to avoid unnecessarily aggressive treatment for indolent CD8+ lymphoproliferations and to identify cases with underlying immuno-deficiency or potential for dismal outcome.

Introduction of the Modified Neuroanatomy Motivation Questionnaire and Its Role in Comparing Medical Student Attitudes Towards Learning Neuroanatomy Between Neuro-enthusiasts and Standard Students.

BACKGROUND: Neurophobia has been identified as a potential barrier to adequate knowledge of neurology in the medical community, and therefore to patient safety. There is a drive to identify the source of neurophobia, in the hope of tackling it. Comparing the learning motivations of standard medical students with those who enjoy neuroanatomy may be a way of doing this. METHODS: The science motivation questionnaire (SMQ) was modified for neuroanatomy. It was distributed to three cohorts of second year medical students and students attending the extracurricular National Undergraduate Neuroanatomy Competition (NUNC). Cohen's D test for effect size was used to compare standard medical students and those attending the NUNC. RESULTS: Five hundred ninety-seven questionnaires were completed by second year students, and 320 by NUNC attendees. The differences in motivation to learn neuroanatomy between the 2 groups mainly fell into themes of career motivation, personal relevance, intrinsic motivation and assessment anxiety. CONCLUSION: This study has demonstrated the use of the SMQ in neuroanatomy, and found differences in motivators to learn neuroanatomy between self-selecting "neurophiles" and standard medical students, mainly relating to intrinsic motivation and its role in their lives. More research is needed to further explore these differences and how they might apply to interventions in medical school curricula.

Evaluating the Efficacy and Optimisation of the Peer-Led Flipped Model Using TEL Resources Within Neuroanatomy.

The flipped classroom (where students prepare before and then develop understanding during class) and technology-enhanced learning (audio-visual learning tools) are increasingly used to supplement anatomy teaching. However, the supporting literature lacks robust methodology and is conflicting in demonstrating efficacy outcomes. Contrastingly, near-peer teaching (where senior students teach juniors on the same academic programme) is well researched and reported to be both effective and versatile. This provides an ideal vehicle in which to investigate and potentially optimise these approaches.This study aims to assess educational impact of the peer-led flipped model and student engagement and perceptions regarding traditional and TEL resources.A quasi-randomised, cross-sectional study was conducted with 281 second-year University of Southampton medical students. Students were randomly allocated to 3 groups: traditional lecture (control), flipped text resource, or flipped video resource. The first group received no pre-teaching material, but the flipped groups received a text or video pre-teaching resource. Objective outcomes measured were: Knowledge gain and retention via multiple-choice questionnaires and formative exams Student perceptions and engagement using questionnaires and 2 focus groups All groups demonstrated significant knowledge gain post-teaching (p < 0.0001). However, regardless of engagement with pre-teaching material, no significant difference was found in knowledge gain or retention between the groups. Students engaged 21.1% more with the text rather than video resource (p = 0.0019), but spent equal time using both (p = 0.0948). All resources and teaching approaches were perceived 'very useful' with no significant differences found between groups. A qualitative approach utilising thematic analysis of focus groups identified 4 themes, including 'Attitudes towards flipped classroom', which revealed mixed reviews and perceptions from participants.This study has found the peer-led flipped model is of no detriment to educational impact compared to peer-led traditional approaches in a well-established peer teaching programme in undergraduate medicine at the University of Southampton. Students value traditional and video resources but engage with them differently. Additionally, it was reported that in this experiment, NPT did not seem well suited to the flipped classroom, suggesting a rare limitation of the utility of NPT application within an anatomy curriculum.

Cutaneous Squamous Cell Carcinoma in Epidermolysis Bullosa: a 28-year Retrospective Study.

Epidermolysis bullosa (EB), notably severe recessive dystrophic EB (RDEB-S), is associated with increased risk of aggressive mucocutaneous squamous cell carcinomas, the major cause of mortality in early adulthood. This observational, retrospective case review describes a series of EB patients with cutaneous squamous cell carcinomas over a 28-year period. Forty-four EB patients with squamous cell carcinomas were identified with a total of 221 primary tumours. They comprised: 31 (70%) with RDEB-S, 4 (9%) with other RDEB subtypes, 5 (11.4%) with dominant dystrophic EB, 3 (6.8%) with intermediate junctional EB and 1 (2.3%) with Kindler EB. Squamous cell carcinomas occurred earlier in RDEB-S (median age 29.5 years; age range 13-52 years) than other groups collectively (median age 47.1 years; age range 30-89 years) and most had multiple tumours (mean 5.8; range 1-44). Squamous cell carcinoma-associated mortality was high in RDEB-S (64.5%), with median survival after first squamous cell carcinoma of 2.4 years (range 0.5-12.6 years), significantly lower than previous reports, highlighting the need for early surveillance and better treatments.

Follicular T-Helper Cells in Marginal Zone Lymphoma: Evidence of an Organoid Immune Response.

INTRODUCTION: Primary cutaneous marginal zone B-cell lymphoma (MZL) follows an indolent clinical course. Histopathologically, there is a polymorphous infiltrate that includes small lymphocyte-like and centrocyte-like B cells and plasma cells usually with a substantial T-cell fraction. Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, in which the signature cells have a follicular T-helper (TFH) phenotype and are admixed with numerous B cells. Thus, both present histologies of combined B-cell and T-cell infiltrates and represent differential diagnoses. The presence of TFH in MZL has yet to be elucidated. METHODS: Forty-one biopsies from 40 cases of MZL and 7 cases of lymphoid hyperplasia cutis (LCH) were stained with antibodies to follicular T-helper cells, including Bcl-6, PD-1, ICOS, and CD10, as part of their diagnostic workup, were reviewed, and the stained slides were evaluated semiquantitively. Five reactive lymph nodes were also evaluated as controls. RESULTS: All cases of MZL and LCH contained TFH, albeit usually in low proportions. There were repeated differences in levels of expression between TFH markers, with PD1 and Bcl-6 being the most prevalent. The pattern of involvement in MZL and LCH closely mirrored that observed in the reactive lymph nodes. CONCLUSION: MZL includes TFH cells, similar to reactive lymph nodes, and a complexity of cell types. This provides evidence of an organoid immune response challenging its simple categorization as a malignancy.

Primary Cutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorder or Primary Cutaneous Marginal Zone B-Cell Lymphoma? Two Distinct Entities With Overlapping Histopathological Features.

ABSTRACT: Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder and primary cutaneous marginal zone B-cell lymphoma are 2 distinct entities with several overlapping features which can result in diagnostic uncertainty. Clinically, they both follow an indolent course and present with solitary or multiple papules or nodules. Histologically, they are characterized by polymorphous dermal infiltrates rich in mixed populations of B cells and T cells, often in similar proportions. The histological hallmark of primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder is the presence of follicular T-helper cells within the infiltrate and has historically been used as a marker for differentiating between the 2 conditions. However, there is now mounting evidence that follicular T-helper cells are also seen in primary cutaneous marginal zone B-cell lymphoma and nodal marginal zone lymphoma. The 2 cases presented herein caused diagnostic uncertainty because they displayed appreciable features of both conditions. We discuss the potential mechanisms behind these overlapping histopathological features and hypothesize a model that explores the idea of a collective organoid response to an antigenic stimulus.

Secondary skin involvement in classic Hodgkin lymphoma: Results of an international collaborative cutaneous lymphoma working group study of 25 patients.

BACKGROUND: Cutaneous involvement by classic Hodgkin lymphoma (CHL) is an extraordinarily rare phenomenon in the current era. To date, no single large case series of cutaneous involvement by Hodgkin lymphoma has ever been reported in the literature. METHODS: A comprehensive search for cases designated "skin" and "Hodgkin" was performed at different institutions between 1990 and 2020. Twenty-five cases were identified, and each case was independently reviewed by at least three board-certified dermatopathologists and/or hematopathologists. RESULTS: All cases represented examples of systemic CHL with secondary skin dissemination. A single lesion, usually a tumor, nodule or infiltrative plaque was observed in 56% of cases and multiple lesions were present in 28% of cases. Most patients (86%-12/14) had a diagnosis of stage IV disease at first diagnosis. The interval between the clinical (first) diagnosis of HL and the development of skin lesions ranged between 6 and 108 months (average 33.75 months). Comprehensive histopathologic evaluation of these cases (at the initial diagnosis) revealed a diagnosis of classic HL not otherwise specified (NOS) in 60% of cases (15/25), nodular sclerosis type in 24% (6/25), mixed cellularity in 12% (3/25), and lymphocyte depleted in 4% (1/25). CONCLUSIONS: We provide documentation of a large series of CHL with secondary skin involvement in association with CHL with additional clinical, morphologic, and immunophenotypic features.

A Problem of Classification: 2 Cases of Epstein-Barr Virus + Primary Cutaneous Plasmacytoma Arising in Immunocompetent Elderly Patients.

ABSTRACT: Primary extramedullary plasmacytoma is rare monoclonal proliferation of plasma cells, which arise in various nonosseous anatomic locations without detectable underlying systemic disease. Historically, cutaneous infiltrates rich in mature neoplastic plasma cells have fallen into one of the following categories, plasmacytoma, lymphoplasmacytic lymphoma, and marginal zone lymphoma, which included immunocytoma. Since 2005, each of these was subsumed under the marginal zone lymphoma umbrella, largely on the basis of acknowledged diagnostic difficulties in some of these cases. We describe 2 cases in which the cutaneous infiltrates consisted of a pure population of light chain-restricted mature plasma cells in the absence of any other evidence for a marginal zone proliferation, or evidence of extracutaneous involvement, including a paraprotein. We propose that primary cutaneous plasmacytoma is the accurate diagnosis and is consistent with wider nomenclature. The unusual observation of widespread Epstein-Barr virus expression in both tumors is also discussed.

Prominent Blasts in Primary Cutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorder. A Reconsideration of Diagnostic Criteria.

ABSTRACT: Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (PCSM-LPD), recently downgraded from a T-cell lymphoma, is a poorly characterized histopathological entity. Presenting as a solitary lesion that often grows rapidly, it may raise suspicion for a cutaneous B-cell lymphoma. However, classically, the dermal lymphoid proliferation is predominantly CD4+ with a follicular T-helper profile and a smaller B-cell fraction. Diagnostic uncertainty may arise when B cells are present in large numbers, a B-cell clone is present, or large cell populations are seen. To meet the diagnostic criterion of PCSM-LPD, large cells should not constitute more than 30% of the infiltrate. The 2 cases presented in this article caused diagnostic uncertainty owing to the observation of high numbers of large cells and in one case the presence of a B-cell clone, on the background of otherwise typical clinicopathological features of PCSM-LPD. We review the literature specifically regarding the prevalence of large cell populations and their immunophenotypic characteristics and in light of this discuss whether a current diagnostic criterion should be reconsidered.

Solitary CD8-Positive Primary Cutaneous Peripheral T-Cell Lymphoma: A Question of Classification.

ABSTRACT: Acral CD8(+) lymphoma is a provisional entity in the latest edition of the WHO Lymphoma Classification and is associated with a highly specific dot-like pattern of immunohistochemical expression of CD68. We report a case of an ulcerated solitary cutaneous lesion arising on the forehead of an adult man, which had a CD8(+) cytotoxic phenotype and areas of dot-like CD68 positivity, but with a number of features that significantly detracted from the classically described acral CD8(+) lymphoma. The nosological status of the lesion is discussed with respect to a preferred diagnosis of peripheral T-cell lymphoma, not otherwise specified.

Multiple-Choice versus Open-Ended Questions in Advanced Clinical Neuroanatomy: Using a National Neuroanatomy Assessment to Investigate Variability in Performance Using Different Question Types.

Methods of assessment in anatomy vary across medical schools in the United Kingdom (UK) and beyond; common methods include written, spotter, and oral assessment. However, there is limited research evaluating these methods in regards to student performance and perception. The National Undergraduate Neuroanatomy Competition (NUNC) is held annually for medical students throughout the UK. Prior to 2017, the competition asked open-ended questions (OEQ) in the anatomy spotter examination, and in subsequent years also asked single best answer (SBA) questions. The aim of this study is to assess medical students' performance on, and perception of, SBA and OEQ methods of assessment in a spotter style anatomy examination. Student examination performance was compared between OEQ (2013-2016) and SBA (2017-2020) for overall score and each neuroanatomical subtopic. Additionally, a questionnaire explored students' perceptions of SBAs. A total of 631 students attended the NUNC in the studied period. The average mark was significantly higher in SBAs compared to OEQs (60.6% vs. 43.1%, P < 0.0001)-this was true for all neuroanatomical subtopics except the cerebellum. Students felt that they performed better on SBA than OEQs, and diencephalon was felt to be the most difficult neuroanatomical subtopic (n = 38, 34.8%). Students perceived SBA questions to be easier than OEQs and performed significantly better on them in a neuroanatomical spotter examination. Further work is needed to ascertain whether this result is replicable throughout anatomy education.

Dermatofibrosarcoma protuberans (DFSP) in children: A combined multidisciplinary approach.

Dermatofibrosarcoma protuberans (DFSP) is rare, comprising (1%-6%) of all sarcomas. The incidence is less than one per million before the age of 20. It is a locally aggressive tumor with a low risk of metastasis. We share our experience in the management of three pediatric patients with complex cases of DFSP in a combined surgical approach involving plastic and dermatologic surgery, using the slow Mohs micrographic surgery technique.

Metastatic porocarcinoma achieving complete radiological and clinical response with pembrolizumab.

A 67-year-old woman presented in 2012 with a crusty nodule on the left lower limb. Histopathological examination at this time reported a poorly differentiated squamous cell carcinoma (SCC). Two years later, she underwent lymphadenectomy and radiotherapy due to unilateral inguinal and pelvic sidewall nodal metastases. The following year she required excision of two subcutaneous lesions, reported pathologically to be SCC metastases. Further imaging following cyberknife radiotherapy to new brain metastases demonstrated widespread metastatic visceral disease. Twelve cycles of carboplatin and capecitabine failed to halt disease progression. In February 2017, she commenced pembrolizumab, achieving an excellent response and currently has no clinical or radiological evidence of disease. Given the unusual behaviour of her cancer, a histopathological review was requested. The diagnosis was revised to that of porocarcinoma (PC). This represents the first documented case of PC treated with immunotherapy. As of March 2019, the patient remains free of disease.

Novel GPR34 and CCR6 mutation and distinct genetic profiles in MALT lymphomas of different sites.

Mucosa-associated lymphoid tissue (MALT) lymphoma originates from a background of diverse chronic inflammatory disorders at various anatomic sites. The genetics underlying its development, particularly in those associated with autoimmune disorders, is poorly characterized. By whole exome sequencing of 21 cases of MALT lymphomas of the salivary gland and thyroid, we have identified recurrent somatic mutations in 2 G-protein coupled receptors (GPR34 and CCR6) not previously reported in human malignancies, 3 genes (PIK3CD, TET2, TNFRSF14) not previously implicated in MALT lymphoma, and a further 2 genes (TBL1XR1, NOTCH1) recently described in MALT lymphoma. The majority of mutations in GPR34 and CCR6 were nonsense and frameshift changes clustered in the C-terminal cytoplasmic tail, and would result in truncated proteins that lack the phosphorylation motif important for ß-arrestin-mediated receptor desensitization and internalization. Screening of these newly identified mutations, together with previously defined genetic changes, revealed distinct mutation profiles in MALT lymphoma of various sites, with those of salivary gland characterized by frequent TBL1XR1 and GPR34 mutations, thyroid by frequent TET2, TNFRSF14 and PIK3CD mutations, and ocular adnexa by frequent TNFAIP3 mutation. Interestingly, in MALT lymphoma of the salivary gland, there was a significant positive association between TBL1XR1 mutation and GPR34 mutation/translocation (P=0.0002). In those of ocular adnexa, TBL1XR1 mutation was mutually exclusive from TNFAIP3 mutation (P=0.049), but significantly associated with IGHV3-23 usage (P=0.03) and PIK3CD mutation (P=0.009). These findings unravel novel insights into the molecular mechanisms of MALT lymphoma and provide further evidence for potential oncogenic co-operation between receptor signaling and genetic changes.