Yannick Le Corre

Relationship between ankle brachial index and arterial remodeling in pseudoxanthoma elasticum

OBJECTIVES Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease characterized by elastic fiber fragmentation and calcification in the cutaneous, ophthalmologic, and vascular tissues. Cardiovascular manifestations such as peripheral arterial disease (PAD) are frequent in PXE. Because of the changes in the elastic properties and medial calcification of the arterial wall in PXE, the impact of the arterial remodeling on the ankle brachial index (ABI), a well-established diagnostic method for the detection and follow-up of PAD, remains to be determined in this disease. METHODS This was a cross-sectional, comparative, open study, which took place at the PXE Consultation Center, University Hospital of Angers. The subjects were 53 patients (mean age, 49 ± 14 years; 35 females) with PXE clinically proven on the basis of established criteria (skin changes, angioid streaks, and skin biopsy). The ABI at rest, symptoms of intermittent claudication (IC), carotid intima-media thickness (IMT), carotid-femoral pulse wave velocity (c-f PWV), compliance (CC), and β stiffness index were measured in a single-center cohort. RESULTS Forty-five percent of the PXE patients had an ABI ≤0.90, but only one patient had an ABI >1.40. IC was found in 23% of the patients with an ABI ≤0.90. There were no significant differences between the patients with a low and normal ABI in terms of IMT (P = .566) or β stiffness index (P = .194), but differences were significant for c-f PWV (P = .010) and CC (P = .011). Adjusted multivariate linear regression for the Framingham-Laurier score showed that patients with a low ABI had less compliant carotid arteries (B = 0.318, P = .039). CONCLUSIONS PAD detected by a low ABI is very frequent in PXE, although with limited prevalence of symptomatic claudication. Unexpectedly, ABI was low in such calcifying PAD and associated with lower CC, independently of atherosclerosis risk factors. These findings demonstrate that PXE represents a unique monogenic model of PAD in which the specific arterial wall remodeling could change the diagnostic value of the ABI to detect PAD.

Quantification of the Calcification Phenotype of Abcc6-Deficient Mice with Microcomputed Tomography

Pseudoxanthoma elasticum in humans and dystrophic cardiac calcification in mice are heritable disorders characterized by dystrophic calcification of soft connective tissues related to the defective function of the ABCC6 (human)/Abcc6 (mouse) transporter. Of particular interest is the finding of calcified vibrissae in Abcc6(-/-) mice, which facilitates the study of dystrophic calcification by histological techniques. We aimed to determine whether mice prone to dystrophic cardiac calcification (C3H/HeOuJ and DBA/2J strains) presented similar vibrissae changes and to evaluate the value of microcomputed tomography to quantify the extent of mystacial vibrissae calcifications. These calcifications were absent in DBA/2J and C57BL/6J control mice. In both Abcc6(-/-) and C3H/HeOuJ mice, calcifications progressed in a caudal-rostral direction with aging. However, the calcification process was delayed in C3H/HeOuJ mice, indicating an incomplete expression of the calcification phenotype. We also found that the calcification process in the cephalic region was not limited to mystacial vibrissae but was also present in other periorbital sensorial vibrissae. The vibrissae calcification was circular and encompassed the medial region of the vibrissae capsule, adjacent to the ring and cavernous sinuses (the areas adjacent to blood and lymphatic vessels). Collectively, our findings confirm that Abcc6 acts as an inhibitor of spontaneous chronic mineralization and that microcomputed tomography is a valuable noninvasive tool for the assessment of the calcification phenotype in Abcc6-deficient mice.

Pseudoxanthoma elasticum: cardiac findings in patients and Abcc6-deficient mouse model.

Background Pseudoxanthoma elasticum (PXE), caused by mutations in the ABCC6 gene, is a rare multiorgan disease characterized by the mineralization and fragmentation of elastic fibers in connective tissue. Cardiac complications reportedly associated with PXE are mainly based on case reports. Methods A cohort of 67 PXE patients was prospectively assessed. Patients underwent physical examination, electrocardiogram, transthoracic echocardiography, cardiac magnetic resonance imaging (CMR), treadmill testing, and perfusion myocardial scintigraphy (SPECT). Additionally, the hearts of a PXE mouse models (Abcc6−/−) and wild-type controls (WT) were analyzed. Results Three patients had a history of proven coronary artery disease. In total, 40 patients underwent exercise treadmill tests, and 28 SPECT. The treadmill tests were all negative. SPECT showed mild perfusion abnormalities in two patients. Mean left ventricular (LV) dimension and function values were within the normal range. LV hypertrophy was found in 7 (10.4%) patients, though the hypertrophy etiology was unknown for 3 of those patients. Echocardiography revealed frequent but insignificant mitral and tricuspid valvulopathies. Mitral valve prolapse was present in 3 patients (4.5%). Two patients exhibited significant aortic stenosis (3.0%). While none of the functional and histological parameters diverged significantly between the Abcc6−/− and WT mice groups at age of 6 and 12 months, the 24-month-old Abcc6−/− mice developed cardiac hypertrophy without contractile dysfunction. Conclusions Despite sporadic cases, PXE does not appear to be associated with frequent cardiac complications. However, the development of cardiac hypertrophy in the 24-month-old Abcc6−/− mice suggests that old PXE patients might be prone to developing late cardiopathy.

Hereditary leukonychia totalis, acanthosis-nigricans-like lesions and hair dysplasia: a new syndrome?

Leukonychia is an ungueal discoloration or dyschromia. The hereditary form is rare. In the observations reported in the literature, leukonychia was total or sub-total, and was sometimes associated to other various symptoms. We report an original observation of hereditary leukonychia totalis in a father and two of his children, associated with acanthosis-nigricans-like lesions and hair dysplasia. These symptoms were also present in eight other members of the same family.

Endocrine toxicity of immune checkpoint inhibitors: essential crosstalk between endocrinologists and oncologists

Two types of immune checkpoint inhibitors, both antibodies that target cytotoxic T‐lymphocyte antigen‐4 and those that target programmed cell death‐protein 1, have been approved for use in melanoma, non‐small‐cell lung cancer, and renal cell carcinoma as first‐line or second‐line therapy. Their adverse events are primarily regarded as immune‐related adverse events. We felt it was important to pinpoint and discuss certain preconceptions or misconceptions regarding thyroid dysfunction, hypophysitis, and diabetes induced by immune checkpoint inhibitors. We have identified areas of uncertainty and unmet requirements, including essential interaction between endocrinologists and oncologists. Five issues have been identified for discussion: (1) diagnosis of endocrine toxicity, (2) assessment of toxicity severity, (3) treatment of toxicity, (4) withdrawal or continuation of immunotherapy, (5) preventive action.

Clinical Features of Spontaneous Partial Healing During Mycobacterium ulcerans Infection.

Background. Buruli ulcer, caused by Mycobacterium ulcerans, is a necrotizing skin disease leading to extensive cutaneous and subcutaneous destruction and functional limitations. Spontaneous healing in the absence of medical treatment occurs in rare cases, but this has not been well described in the literature. Methods. In a retrospective case study in an area of Benin where this disease is highly endemic, we selected 26 Buruli ulcer patients presenting features of spontaneous healing from a cohort of 545 Buruli ulcer patients treated between 2010 and 2013. Results. The 26 patients studied had a median age of 13.5 years and were predominantly male (1.4:1). Three groups of patients were defined on the basis of their spontaneous healing characteristics. The first group (12 patients) consisted of patients with an ulcer of more than 1 year′s duration showing signs of healing. The second (13 patients) group contained patients with an active Buruli ulcer lesion some distance away from a first lesion that had healed spontaneously. Finally, the third group contained a single patient displaying complete healing of lesions from a nodule, without treatment and with no relapse. Conclusions. We defined several features of spontaneous healing in Buruli ulcer patients and highlighted the difficulties associated with diagnosis and medical management. Delays in consultation contributed to the high proportion of patients with permanent sequelae and a risk of squamous cell carcinoma. Early detection and antibiotic treatment are the best ways to reduce impairments.

Merkel cell carcinomas infiltrated with CD33+ myeloid cells and CD8+ T cells are associated with improved outcome

Background: Merkel cell carcinoma (MCC) is a rare tumor of the skin that has an aggressive behavior. Immunity is the main regulator of MCC development, and many interactions between lymphocytes and tumor cells have been proven. However, the impact of tumor‐infiltrating myeloid cells needs better characterization. Objective: To characterize tumor‐infiltrating myeloid cells in MCC and their association with other immune effectors and patient outcome. Methods: MCC cases were reviewed from an ongoing prospective cohort study. In all, 103 triplicate tumor samples were included in a tissue microarray. Macrophages, neutrophils, and myeloid‐derived suppressor cells were characterized by the following markers: CD68, CD33, CD163, CD15, CD33, and human leukocyte antigen‐DR. Associations of these cell populations with programmed cell death ligand 1 expression, CD8 infiltrates, and vascular density were assessed. Impact on survival was analyzed by log‐rank tests and a Cox multivariate model. Results: The median density of macrophages was 216 cells/mm2. CD68+ and CD33+ macrophage densities were associated with CD8+ T‐cell infiltrates and programmed cell death ligand 1 expression. In addition, MCC harboring CD8+ T cell infiltrates and brisk CD33+ myeloid cell infiltrates were significantly and independently associated with improved outcomes (recurrence‐free and overall survival). Limitations: Sampling bias and the retrospective design were potential study limitations. Conclusion: Infiltration of CD33+ myeloid cells and CD8+ T lymphocytes defines a subset of MCC associated with improved outcome.

Differentiating Merkel cell carcinoma of lymph nodes without a detectable primary skin tumor from other metastatic neuroendocrine carcinomas: The ELECTHIP criteria

Background: Merkel cell carcinoma (MCC) can present as a cutaneous tumor or a lymph node metastasis without a primary tumor. MCC presenting without a primary tumor (MCCWOPT) can be misinterpreted on histologic examination as lymph node metastasis (LNM) from another neuroendocrine carcinoma (LNMNEC). However, this distinction is crucial for therapeutic management. Objective: To determine the discriminative criteria for the differential diagnosis of MCCWOPT, LNM from cutaneous MCC, and LNMNECs. Methods: Clinical, morphologic, and immunohistochemical data (expression of cytokeratins AE1, AE3, 7, 19, and 20; chromogranin A, synaptophysin, thyroid transcription factor‐1 [TTF‐1]), as well as the presence of Merkel cell polyomavirus (by immunohistochemistry and PCR) were compared in patients with MCCWOPT (n = 17), LNM from a cutaneous MCC (n = 11), and LNMNEC (n = 20; 8 lung, 7 thyroid, 3 digestive tract, 2 other). Results: MCC (including MCCWOPT and LNM from a cutaneous MCC) differed from LNMNEC by 7 discriminative criteria: 1) elderly age, 2) location of the tumor, 3) extent of the disease, 4) cytokeratin expression, 5) TTF‐1 expression, 6) histologic type, and 7) Merkel cell polyomavirus detection, summarized under the acronym ELECTHIP. All MCC patients had ≥5 of the ELECTHIP criteria, whereas all patients with LNMNEC (except 1) had <3 criteria. Limitations: The discriminant ability of the ELECTHIP criteria should be validated in a second independent set. Conclusion: MCCWOPT can be distinguished from other LNMNEC by the ELECTHIP criteria.

Exemestane-induced radiation recall dermatitis and morbilliform rash.

Dear Editor, Radiation recall dermatitis (RRD) is an uncommon phenomenon defined by an acute inflammatory skin reaction within a previously irradiated area, triggered by the administration of systemic agents after radiotherapy or ultraviolet light. We report the first case of radiation recall dermatitis (RRD) induced by exemestane. A 74-year-old woman was diagnosed with grade II infiltrating ductal carcinoma of the right breast. She underwent tumorectomy with axillary sentinel lymph node biopsy, which was negative, and then received 66 Gy on her right breast. Irradiation induced grade I radiodermatitis. Anastrozole, an aromatase inhibitor indicated as adjuvant therapy in hormone-sensitive breast cancers, was instigated following radiation therapy. Because of severe polyarthralgia, anastrozole was withdrawn and exemestane, another aromatase inhibitor, was substituted after complete resolution of her symptoms. Three weeks later, she developed an erythematous and edematous plaque on her right breast, strictly limited to the previously irradiated skin (Fig. 1). The next day, a diffuse maculopapular eruption appeared on the trunk and upper extremities. Hypereosinophilia at 1400/mm was present. A skin biopsy of a papule was performed and demonstrated epidermal spongiosis, traversed by mononuclear cells and eosinophils in the superficial dermis compatible with a drug reaction. Hypereosinophilia and rash regressed a few days after withdrawal of exemestane without any medication. The patient refused skin tests, but the clinical presentation is compatible with RRD and drug eruption. Radiation recall dermatitis is an acute skin inflammatory reaction occurring on previously irradiated areas. The time interval between radiotherapy and administration of the imputed drug varies from a week to years. Classically, patients have a low reaction to radiation during radiotherapy. Modification of the dose and fractionation do not seem to influence the incidence. The skin is the major site of radiation recall toxicity but other organs have also been reported to be involved. It can range from mild rash to ulceration or skin necrosis. When not severe, it tends to resolve spontaneously and rapidly after withdrawal of the causal agent but close observation remains essential. Topical corticosteroids can be used and systemic corticosteroids are rarely necessary. Rechallenge is possible with reduced doses and does not always induce a reaction. Radiation recall dermatitis has been reported with several drugs, including anticancer agents, tamoxifen and vemurafenib, but never with exemestane. Remarkably, RRD has never been observed with a number of usual chemotherapy drugs, such as cyclophosphamide, suggesting that the phenomenon is very drug-specific. The originality of our observation is based on the association of both RRD and drug eruption in the same patient. The mechanism is probably based on idiosyncratic drug hypersensitivity reactions, probably with non-immune activation of inflammatory pathways, following cumulative DNA damage and oxidative stress. Radiation may cause heritable mutations within survival cells in the irradiated area, especially in the stem cells that are unable to tolerate subsequent chemotherapy because of a “remembered” reaction. Local vascular permeability may also affect the subsequent pharmacokinetics of certain drugs to provoke RRD. The occurrence of hypereosinophilia has never been described in this phenomenon. Here, it is probably related to the maculopapular rash.

Detection of the Merkel cell polyomavirus in the neuroendocrine component of combined Merkel cell carcinoma

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. The main etiological agent is Merkel cell polyomavirus (MCPyV), detected in 80% of cases. About 5% of cases, called combined MCC, feature an admixture of neuroendocrine and non-neuroendocrine tumor cells. Reports of the presence or absence of MCPyV in combined MCC are conflicting, most favoring the absence, which suggests that combined MCC might have independent etiological factors and pathogenesis. These discrepancies might occur with the use of different virus identification assays, with different sensitivities. In this study, we aimed to determine the viral status of combined MCC by a multimodal approach. We histologically reviewed 128 cases of MCC and sub-classified them as “combined” or “conventional.” Both groups were compared by clinical data (age, sex, site, American Joint Committee on Cancer [AJCC] stage, immunosuppression, risk of recurrence, and death during follow-up) and immunochemical features (cytokeratin 20 and 7, thyroid transcription factor 1 [TTF1], p53, large T antigen [CM2B4], CD8 infiltrates). After a first calibration step with 12 conventional MCCs and 12 cutaneous squamous cell carcinomas as controls, all eight cases of combined MCC were investigated for MCPyV viral status by combining two independent molecular procedures. Furthermore, on multiplex genotyping assay, the samples were examined for the presence of other polyoma- and papillomaviruses. Combined MCC differed from conventional MCC in earlier AJCC stage, increased risk of recurrence and death, decreased CD8 infiltrates, more frequent TTF1 positivity (5/8), abnormal p53 expression (8/8), and frequent lack of large T antigen expression (7/8). With the molecular procedure, half of the combined MCC cases were positive for MCPyV in the neuroendocrine component. Beta papillomaviruses were detected in 5/8 combined MCC cases and 9/12 conventional MCC cases. In conclusion, the detection of MCPyV DNA in half of the combined MCC cases suggests similar routes of carcinogenesis for combined and conventional MCC.