Redefining WILD syndrome: a primary lymphatic dysplasia with congenital multisegmental lymphoedema, cutaneous lymphovascular malformation, CD4 lymphopaenia and warts.

BACKGROUND: Primary lymphoedema (PL) syndromes are increasingly recognised as presentations of complex genetic disease, with at least 20 identified causative genes. Recognition of clinical patterns is key to diagnosis, research and therapeutics. The defining criteria for one such clinical syndrome, 'WILD syndrome' (Warts, Immunodeficiency, Lymphoedema and anogenital Dysplasia), have previously depended on a single case report. METHODS AND RESULTS: We present 21 patients (including the first described case) with similar clinical and immunological phenotypes. All had PL affecting multiple segments, with systemic involvement (intestinal lymphangiectasia/pleural or pericardial effusions) in 70% (n=14/20). Most (n=20, 95%) had a distinctive cutaneous lymphovascular malformation on the upper anterior chest wall. Some (n=10, 48%) also had hyperpigmented lesions resembling epidermal naevi (but probably lymphatic in origin). Warts were common (n=17, 81%) and often refractory. In contrast to the previous case report, anogenital dysplasia was uncommon-only found in two further cases (total n=3, 14%). Low CD4 counts and CD4:CD8 ratios typified the syndrome (17 of 19, 89%), but monocyte counts were universally normal, unlike GATA2 deficiency. CONCLUSION: WILD syndrome is a previously unrecognised, underdiagnosed generalised PL syndrome. Based on this case series, we redefine WILD as 'Warts, Immunodeficiency, andLymphatic Dysplasia' and suggest specific diagnostic criteria. The essential criterion is congenital multisegmental PL in a 'mosaic' distribution. The major diagnostic features are recurrent warts, cutaneous lymphovascular malformations, systemic involvement (lymphatic dysplasia), genital swelling and CD4 lymphopaenia with normal monocyte counts. The absence of family history suggests a sporadic condition, and the random distribution of swelling implicates mosaic postzygotic mutation as the cause.

Disseminated Bisifusarium infection following toxic epidermal necrolysis in a child with B-cell acute lymphoblastic leukemia.

Fusarium is a polyphyletic genus of plant pathogens, members of which can cause opportunistic human infections with varying superficial and systemic presentations, including disseminated infections which typically occur in immunocompromised patients and have a poor prognosis. Treatment is challenging due to intrinsic resistance to many antifungal agents, and antifungal susceptibility testing is therefore essential. Early suspicion, isolation of the organism, and prompt initiation of management are crucial to improving survival. We present a case of disseminated Bisifusarium infection following toxic epidermal necrolysis in a child with B-cell acute lymphoblastic leukemia, successfully treated with liposomal amphotericin B, voriconazole, flucytosine, and terbinafine.

Capillaritis as a Skin Manifestation of Hepatosplenic Gamma-Delta T-Cell Lymphoma.

We present the case of a 10-year-old boy who was admitted with 3 months of episodic febrile neutropenia and a new petechial rash. Routine bloods identified neutropenia, thrombocytopenia, and a raised alanine aminotransferase. The dermatology team was consulted in light of the symmetrical petechial eruption of the upper torso. A punch biopsy of the lesion was consistent with early capillaritis. The results showed superficial dermal red blood cell extravasation with mild perivascular lymphohistiocytic inflammatory infiltrate. There was no evidence of an atypical lymphoid infiltrate in the skin biopsy. An initial bone marrow aspirate showed an abnormal mature T-cell population consisting of CD4 and CD8 T cells with gamma-delta positivity. Karyotyping was also done, which demonstrated isochromosome 7q. These findings were consistent with a diagnosis of hepatosplenic T-cell lymphoma (HSTL). The patient underwent fourth-line chemotherapy due to refractory relapsing disease but sadly passed away within 12 months of diagnosis. HSTL is a rare and aggressive subset of peripheral T-cell lymphoma. Prognosis is poor with a median survival of <1 year from diagnosis. However, reports suggest improved outcomes if intensive, early, high-dose chemotherapy is used alongside hematopoietic stem cell transplantation. Therefore, there is an impetus to attain early diagnosis for aggressive early treatment and improved patient outcomes. Capillaritis, presenting as asymptomatic nonpalpable purpura, can be a rare presenting feature of HSTL. Dermatologists could play a pivotal role in the early recognition of this rare but aggressive hematological malignancy and promote prompt treatment resulting in better patient outcomes.

Small Incidental Pheochromocytoma Presenting With Normal or Borderline High 24-hour Urine Fractionated Metanephrines.

A 73-year-old man was found to have a 2-cm lipid-poor right adrenal incidentaloma on computed tomography imaging for hematuria. Twenty-four-hour urine metanephrine was 1.1-fold elevated, then normal on repeat measurement. Paired with the second urine collection, plasma metanephrine measured by liquid chromatography tandem mass spectrometry after a 30-minute supine rest was 3.3-fold elevated. Plasma normetanephrine was 1.2-fold elevated. The 24-hour urine catecholamines and normetanephrine, measured twice, were normal. He received low-dose phenoxybenzamine and underwent successful resection of right pheochromocytoma. Postoperatively, both plasma metanephrine and normetanephrine levels normalized, using an age-appropriate upper reference limit for plasma normetanephrine. Patients who harbor small lipid-poor adrenal incidentalomas have a relatively high risk (>5%) of having pheochromocytoma, indistinguishable from adenomas or carcinomas on computed tomography scan. In such cases when 24-hour urine fractionated metanephrines are normal, plasma free metanephrines measured by liquid chromatography tandem mass spectrometry under optimal sampling conditions that are 2-fold or more elevated confirm the diagnosis of pheochromocytoma. Preoperative alpha blockade followed by surgical resection is then appropriate, rather than continued monitoring with repeat urine measurements.

Magnetic resonance lymphangiography: Establishing normal.

BACKGROUND: Despite an increased interest in visualizing the lymphatic vessels with magnetic resonance lymphangiography (MRL), little literature is available describing their appearance in nonlymphedematous individuals. To determine lymphatic abnormalities, an understanding of how healthy lymphatic vessels appear and behave needs to be established. Therefore, in this study, MRL of individuals without a history of lymphatic disease was performed. METHODS: A total of 25 individuals (15 women) underwent MRL of their lower limbs using a 3.0 T Philips magnetic resonance imaging scanner (Philips Medical Systems). The first nine participants were recruited to establish the concentration of gadolinium-based contrast agent (GBCA) to administer, with the remainder imaged before and after interdigital forefoot GBCA injections at the optimized dose. Outcomes, including lymphatic vessel diameter, tortuosity, and frequency of drainage via particular drainage routes, were recorded. RESULTS: Healthy lymphatic vessels following the anteromedial pathway were routinely observed in post-contrast T1-weighted images (average tortuosity, 1.09 ± 0.03), with an average of 2.16 ± 0.93 lymphatic vessels with a diameter of 2.47 ± 0.50 mm crossing the anterior ankle. In six limbs, vessels following the anterolateral pathways were observed. No vessels traversing the posterior of the legs were seen. In a subset of 10 vessels, the lymphatic signal, measured at the ankle, peaked 29 minutes, 50 seconds ± 9 minutes, 29 seconds after GBCA administration. No lymphatic vessels were observed in T2-weighted images. CONCLUSIONS: Contrast-enhanced MRL reliably depicts the lymphatic vessels in the legs of healthy controls. Following interdigital contrast injection, anteromedial drainage appears dominant. Quantitative measures related to lymphatic vessel size, tortuosity, and drainage rate are readily obtainable and could be beneficial for detecting even subtle lymphatic impairment.

Do family medicine residents optimally prescribe antibiotics for common infectious conditions seen in a primary care setting?

Background: Antimicrobial resistance is a worldwide phenomenon that leads to a significant number of unnecessary deaths and costly hospital admissions. More than 90% of antibiotic use happens in the community and of this, family physicians account for two-thirds of these prescriptions. Our study aims to determine whether family medicine residents are optimally trained in antibiotic prescribing for common infectious conditions seen in a primary care setting. Methods: This study is a secondary analysis of a prior study of antimicrobial stewardship in two urban primary care clinics in central Toronto, Ontario. A total of 1099 adult patient visits were included that involved family medicine resident trainees, seen between 2015 and 2016. The main outcome measures were resident antibiotic prescription rates for each condition and expert-recommended prescribing practices, the rate prescriptions were issued as delayed prescriptions, and the use of first-line recommended narrow-spectrum antibiotics. Results: Compared to expert-recommended prescribing rates, family medicine residents overprescribed for uncomplicated upper respiratory tract infections (URI) (5.0% [95% CI 2.2% to 9.7%] versus 0% expert recommended) and sinusitis (44.2% [95% CI 32.8% to 55.9%] versus 11%-18% expert range), and under prescribed for pneumonia (53.5% [95% CI 37.7% to 68.8%] versus 100% expert range]). Prescribing rates were within expert recommended ranges for pharyngitis (28.6% [95% CI 16.6% to 43.3%]), bronchitis (3.6% [95% CI 0% to 18.4%]), and cystitis (79.4% [95% CI 70.6% to 86.6%]). Conclusions: The antibiotic prescribing practices of family medicine residents during their training programs indicated overprescribing of antibiotics for some common infection presentations. Further study of antibiotic prescribing in primary care training programs across Canada is recommended to determine if future family physicians are learning appropriate antibiotic prescribing practices.

Historique: La résistance antimicrobienne est un phénomène mondial responsable d'un grand nombre de décès inutiles et d'hospitalisations coûteuses. Plus de 90 % des antibiotiques sont utilisés en milieu communautaire, et les deux tiers de ces prescriptions proviennent de médecins de famille. Par la présente étude, les auteurs visent à déterminer si les résidents en médecine de famille reçoivent la formation optimale pour prescrire des antibiotiques en vue du traitement des affections infectieuses courantes en soins primaires. Méthodologie: La présente étude est l'analyse secondaire d'une étude antérieure de la gouvernance antimicrobienne dans deux cliniques de soins primaires urbaines du centre de Toronto, en Ontario. Au total, 1 099 consultations de patients adultes effectuées en 2015 et 2016, auxquelles ont participé des résidents en médecine de famille, ont été incluses. Les principales mesures de résultats étaient le taux de prescription d'antibiotiques pour chaque affection et les pratiques de prescription recommandées par les experts, le rythme d'émission d'ordonnances tardives et l'utilisation d'antibiotiques à spectre étroit recommandés en première ligne. Résultats: Par rapport aux taux de prescription recommandés par les experts, les résidents en médecine de famille surprescrivaient en cas d'infections des voies respiratoires supérieures (IVRS) (5,0 % [intervalle de confiance (IC) à 95 % = 2,2 % à 9,7 %] par rapport à 0 % recommandé par les experts) et de sinusite (44,2 % [IC à 95 % = 32,8 % à 55,9 %] par rapport à une plage de 11 % à 18 % chez les experts), et sous-prescrivaient en cas de pneumonie (53,5 % [IC à 95 % = 37,7 % à 68,8 %] par rapport à 100 % chez les experts]). Les taux de prescription se situaient dans les plages recommandées par les experts dans les cas de pharyngite (28,6 % [IC à 95 % = 16,6 % à 43,3 %]), de bronchite (3,6 % [IC à 95 % = 0 % à 18,4 %]) et de cystite (79,4 % [IC à 95 % = 70,6 % à 86,6 %]). Conclusions: Les pratiques de prescription d'antibiotiques des résidents en médecine de famille pendant leur programme de formation démontrent une surprescription d'antibiotiques lors de présentations infectieuses courantes. Il est recommandé de poursuivre l'étude des prescriptions d'antibiotiques en soins primaires au Canada pour déterminer si les futurs médecins de famille assimilent les pratiques appropriées de prescription d'antibiotiques.

Erythematous capillary-lymphatic malformations mimicking blood vascular anomalies.

Superficial erythematous cutaneous vascular malformations are assumed to be blood vascular in origin, but cutaneous lymphatic malformations can contain blood and appear red. Management may be different and so an accurate diagnosis is important. Cutaneous malformations were investigated through 2D histology and 3D whole-mount histology. Two lesions were clinically considered as port-wine birthmarks and another 3 lesions as erythematous telangiectasias. The aims were (i) to demonstrate that cutaneous erythematous malformations including telangiectasia can represent a lymphatic phenotype, (ii) to determine if lesions represent expanded but otherwise normal or malformed lymphatics, and (iii) to determine if the presence of erythrocytes explained the red color. Microscopy revealed all lesions as lymphatic structures. Port-wine birthmarks proved to be cystic lesions, with nonuniform lymphatic marker expression and a disconnected lymphatic network suggesting a lymphatic malformation. Erythematous telangiectasias represented expanded but nonmalformed lymphatics. Blood within lymphatics appeared to explain the color. Blood-lymphatic shunts could be detected in the erythematous telangiectasia. In conclusion, erythematous cutaneous capillary lesions may be lymphatic in origin but clinically indistinguishable from blood vascular malformations. Biopsy is advised for correct phenotyping and management. Erythrocytes are the likely explanation for color accessing lymphatics through lympho-venous shunts.

Objective assessment of blood and lymphatic vessel invasion and association with macrophage infiltration in cutaneous melanoma.

The aims of this study were to investigate the role of vascular invasion (blood and lymphatic), vessel density and the presence of tumour-associated macrophages as prognostic markers in 202 cutaneous melanoma patients. Sections of primary melanoma were stained with lymphatic-specific antibody D2-40 to assess lymphatic vessel invasion and density in intratumoural and peritumoural areas; an antibody against endothelial marker CD34 was used to determine blood vessel invasion and density, and an antibody against CD68 was used to determine macrophage counts. Immunohistochemically determined vascular invasion (combined blood and lymphatic) was compared with that determined using haematoxylin and eosin (H&E) staining. The use of immunohistochemistry increased detection of vascular invasion from 8-30% of patients, and histological exam of H&E-stained tissue was associated with a false positive rate of 64%. Lymphatic vessel invasion occurred at a much higher frequency than blood vessel invasion (27 and 4% of patients, respectively). Although immunohistochemically detected vessel invasion was significantly associated with histological markers of adverse prognosis, such as increased Breslow thickness, ulceration and mitotic rate (all P<0.001), no associations with relapse-free or overall survival were observed. High macrophage counts were significantly associated with markers of aggressive disease, such as Breslow thickness, ulceration and mitotic rate (P<0.001, P<0.001, P=0.005, respectively), and lymphatic vessel invasion and high microvessel density (P=0.002 and P=0.003, respectively). These results suggest that vascular invasion is more accurately detected using immunohistochemistry and occurs predominantly via lymphatic vessels. The association of vessel characteristics with histological characteristics of the primary melanoma provides evidence for their biological importance in melanoma, but that they were not associated with clinical outcome attests to the value of existing histological prognostic biomarkers. We note that a high macrophage count may be associated with neovascularisation and primary tumour growth, and may also promote invasion through lymphatic vessels.

Outcome of breast lesions diagnosed as lesion of uncertain malignant potential (B3) or suspicious of malignancy (B4) on needle core biopsy, including detailed review of epithelial atypia.

AIMS: To provide updated evidence of the outcome of breast lesions of uncertain malignant potential (B3) and suspicious of malignancy (B4) diagnosed on needle core biopsy (NCB) and analyse the outcome of the different types of intraductal epithelial atypia. METHODS AND RESULTS: One-hundred and forty-nine B3 and 26 B4 NCBs diagnosed over a 2-year period (2007-2008) were compared with those diagnosed over a previous 2-year period (1998-2000). The proportion of B3 diagnoses increased from 3.1% to 4.5%, and the positive predictive value (PPV) of malignancy of a B3 core decreased from 25% to 10%. Increased diagnosis of radial scar and reductions in the PPV of lobular neoplasia and of atypical intraductal proliferation may explain the reduction in the PPV of the B3 group as a whole. There were no significant changes in the proportion of B4 diagnosis (1.1% and 0.8%) or the PPV of B4 (83% and 88%). Review of cores with intraductal atypia showed a wide range of PPVs, from 100% for suspicious of ductal carcinoma in situ, to 40% for atypical ductal hyperplasia categorized as B3, and 14% for isolated flat epithelial atypia. CONCLUSION: The study has found a decrease in the PPV for a B3 diagnosis and suggests possible explanations.

Checkpoint Inhibitor-associated Cutaneous Small Vessel Vasculitis: A Review of the Literature.

Checkpoint inhibitor therapy is an established cancer treatment option often complicated by the development of immune-related adverse events. Vasculitis has been reported with a broad spectrum of both cutaneous and systemic manifestations and can be complicated by delayed diagnosis. The authors report 2 histologically proven cases of cutaneous leucocytoclastic vasculitis induced by programmed cell-death 1 inhibitor inhibitor nivolumab. As physicians, including medical oncologists and dermatologists, we need to be aware of this clinical entity and the importance of clinicopathological confirmation in this setting to confirm the diagnosis to help guide the management of these complex patients.

A pilot study of estrogen receptor (ER) expression in pancreatic ductal adenocarcinoma (PDAC).

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic neoplasm with 5-year survival as low as 6%. It is therefore imperative to explore potential treatment avenues to improve survival in these groups of patients. Anti-estrogenic hormone therapy (AEHT) is well-tolerated and has been used in estrogen receptor (ER) subgroups of breast cancer. ER is a type of sex hormone receptor which have been reported to be expressed inconsistently in pancreatic cancer. This study aims to identify the presence of ER in PDAC specimens to guide potential use of AEHT in the management of unresectable PDAC. METHODS: This is a retrospective case control study of 10 patients (5 males, 5 females) who underwent pancreatic resections for PDAC from 2011 to 2012. Sections of the post-operative specimens were prepared and sent for ER staining. Pancreatic tissue specimens that were analysed included (I) ductal epithelial cells; (II) acinar cells; (III) islet cells; (IV) intralobular stromal cells; and (V) adenocarcinoma cells. RESULTS: Intralobular stromal cells were positively stained for ER in 7/10 (70%) of the cases, but were of weak intensity and patchy in distribution. Islet cells (<1%) stained for ER in 3/10 (30%) of the cases. Ductal epithelial cells, acinar cells and adenocarcinoma cells stained negative for ER in all of the cases. CONCLUSIONS: This pilot study did not detect the presence of ER expression in PDAC. ER expression in intralobular stromal and islet cells which was previously unreported, were noted in our study. The role of AEHT in pancreatic cancer remains uncertain and does not appear to be of value at present.

Histological features of medullary carcinoma and prognosis in triple-negative basal-like carcinomas of the breast.

Medullary carcinomas have a better prognosis than other grade 3 mammary carcinomas, but they typically show basal-like biological features, which are associated with a poor prognosis. In this study we examined the associations and prognostic relevance of medullary histological features in a series of 165 invasive carcinomas with a basal-like phenotype: triple-negative (oestrogen receptor, progesterone receptor, HER2) and expressing at least one basal marker (CK5/6, CK14, CK17 or EGFR). The following histological features were associated with each other: prominent inflammation, anastomosing sheets, absence of fibrosis, absence of infiltrative margin and absence of gland formation. Prominent inflammation and anastomosing sheets in at least 30% of the tumour were associated with a better prognosis on univariate analysis. The combination of these two features (a simplified definition of medullary-like type) was present in 17% of tumours and was an independent prognostic factor on multivariate analysis. This simplified definition had good inter-observer reproducibility (κ=0.61) and is worthy of more detailed assessment in an unselected group of mammary carcinomas. A fibrotic focus was present in 36% of carcinomas. Only 3% of tumours with a fibrotic focus had features of medullary-like carcinomas. Fibrotic focus of greater than 30% of the tumour was associated with a poor prognosis. This study emphasizes the heterogeneity of morphology and behaviour of triple-negative basal-like carcinomas.

Diffuse large B-cell lymphoma associated with chronic inflammation as an incidental finding and new clinical scenarios.

Diffuse large B-cell lymphoma that develops in the setting of long-standing chronic inflammation is typically associated with Epstein-Barr virus, and usually presents as tumor mass involving body cavities, as in pyothorax-associated lymphoma. It is listed as a distinct entity in the latest World Health Organization lymphoma classification. We report four cases that were incidentally discovered on histologic examination, one each in a splenic false cyst, a long-standing hydrocele, an atrial myxoma, and metallic-implant wear debris. Microscopic foci of atypical (neoplastic) large lymphoid cells were found within the contents of the cysts or curettage material, or within the stroma of the atrial myxoma. Despite the diverse clinical scenarios, all cases showed a homogeneous phenotype: positivity for B-lineage markers (CD20+, CD79a+, PAX5+), non-germinal center immunophenotype (CD10-, BCL6-/+, MUM-1+), and positivity for Epstein-Barr virus with type III latency (LMP1+, EBNA2+). The last feature supports the hypothesis that the lymphoma has arisen in a setting of 'local immunodeficiency' as a result of long-standing chronic inflammation in an enclosed space, a characteristic pathogenetic mechanism of diffuse large B-cell lymphoma associated with chronic inflammation. These cases therefore expand the spectrum of this entity to include new clinical scenarios for the development of this lymphoma type.

A case for palliative dermatology: COVID-19-related dermatoses.

The unprecedented coronavirus disease 2019 (COVID-19) pandemic has challenged health care systems in different ways. In the United Kingdom, various subspecialties are deployed to the wards to help medical workforce in the frontlines, with dermatologists helping with general medical wards and on-calls. We present a case of COVID-19-related urticaria manifesting in a palliative setting and responding well to systemic antihistamine. This pandemic has highlighted a new subspecialty that should be explored and researched-palliative dermatology-bridging elements of dermatology with the concepts of palliative medicine. As dermatologists, we should be in the position to help with the last stages of a patient's journey.

Pyogenic granuloma-like Kaposi sarcoma presenting in an HIV-negative man who has sex with men.

A 36-year-old immunocompetent man who have sex with men first presented to the plastics team with an ulcerating lesion on his left first toe. The lesion was suggestive of pyogenic granuloma (PG) clinically and histologically. Two years later, the same patient presented to the dermatology clinic with a new erythematous lesion with intermittent bleeding on the left second toe. Clinically, this lesion was suggestive of another PG. However, the histology of the skin curettage revealed part of a PG merging with an atypical spindle cell proliferation with characteristic 'sieve-like' appearance in keeping with Kaposi sarcoma. This was confirmed with human herpesvirus-8 immunohistochemistry staining. PG-like Kaposi sarcoma is an uncommon variant of Kaposi sarcoma. Often not considered clinically or histologically, a deep skin biopsy is essential to establish the right diagnosis. Our case highlights the need to consider Kaposi sarcoma as a differential diagnosis in all patients, including HIV-negative individuals, presenting with PG-like lesions.