Genetics of adnexal tumors: An update.

Cutaneous adnexal tumors form a vast heterogeneous group that include frequent entities that are mostly benign, as well as rare tumors that are occasionally malignant. In contrast to cutaneous tumors arising from the interfollicular epidermis that develop as a result of accumulation of UV-induced DNA damage (basal cell carcinoma, squamous cell carcinoma), the oncogenesis of adnexal tumors is related to a broad spectrum of genetic mechanisms (e.g., point mutation, fusion genes, viral integration, etc.). In this setting, specific and recurrent genetic alterations have been progressively reported, and these allow better classification of these entities. For certain of them, immunohistochemical tools are now available, enabling precise integrated histological and molecular diagnosis since certain entities are linked to well-defined alterations. In this context, we aim in this review to summarize the main molecular tools currently available for the classification of adnexal tumors.

Post-traumatic ulcerated and chronic necrobiosis lipoidica of the elbow: A new entity?

BACKGROUND: Necrobiosis lipoidica (NL) is a chronic granulomatous dermatosis usually affecting the lower limbs, although less common sites have been described. Herein we report a series of cases of NL located on the elbow, with an unusual presentation and occurring after trauma or surgery. OBSERVATIONS: Our series includes three men and one woman, with a mean age of 64 years. Three had undergone surgery for elbow bursitis and one had had trauma after a fall from a horse, with exposure of subcutaneous tissue prior to healing. Within 5 years, they had all developed an atrophic erythematous annular plaque with papular and telangiectatic edges, with recurrent episodes of ulceration and scarring. Repeated tests for infectious agents were negative. Histological examinations showed granulomas and necrobiosis with palisading or early-stage palisading. Partial healing was achieved in two patients after 6 months of doxycycline. Treatment with adalimumab resulted in disappearance of the ulcers at 6 months in one patient. DISCUSSION: Unusual sites of NL impose consideration of other types of palisading granuloma or mycobacterial infections, which we were able to rule out. Two other cases of NL of the elbow similar to ours are reported in the literature. These cases, involving multiple ulcerations over a very long period of time, probably constitute a distinct entity because of the very distinct character of these 6 cases. Tetracyclines are partially active and tumour necrosis factor alpha (TNF)-alpha inhibitors may offer an option.

Dermatopathology in Strasbourg during the German Occupation (1940-1945).

INTRODUCTION: The activity of the Strasbourg Dermatology Clinic was interrupted in September 1939 by the outbreak of the Second World War and the evacuation of the hospital. After annexing Alsace to the Reich, the German authorities demanded that physicians return to work, which resumed at the Dermatology Clinic, and was now entirely Germanized, in particular the laboratory of dermatopathology. Our aim was to study activity in the histopathology laboratory between 1939 and 1945. MATERIAL AND METHODS: We studied all the histopathology reports contained in three registers written in German. We collected patient data, clinical elements and diagnoses by microscopy. There were a total of 1202 cases between September 1940 and March 1945. The records were in a good state of preservation, enabling exhaustive analysis. RESULTS: The number of cases peaked in 1941 and diminished thereafter. The average age of patients was 49 years, and the sex ratio was 0.77. Patients were referred from Alsace or other Reich territories; referrals from other regions of France or other countries had ceased. There were 655 cases in dermatopathology, with a predominance of tumor lesions, followed by infections and inflammatory dermatoses. We noted 547 cases of non-cutaneous diseases, mainly in gynecology, urology, and in ear, nose, throat and digestive surgery; their numbers peaked in 1940-41, then tapered off progressively. DISCUSSION: Thedisruptions associated with thewar were manifested by the use of German language and the cessation of scientific publications. The lack of general pathologists in the hospital resulted in numerous cases in general pathology. Skin biopsies were mainly diagnostic and focused on skin cancers, whereas inflammatory and infectious diseases predominated before the war. No traces of data related to unethical human experimentation were identified in these archives, in contrast to other institutes in Strasbourg that were truly Nazified. CONCLUSION: These data from the Strasbourg Dermatology Clinic contain valuable information for the history of medicine and provide an insight into the functioning of a laboratory under the Occupation.

Rosacea: Treatment targets based on new physiopathology data.

Over the past 15 years, numerous clinical, epidemiological and physiopathological articles have been published on rosacea. There is now increasing evidence that rosacea is an inflammatory disease characterised by abnormal innate immune response, major vascular changes, and increased colonisation by Demodex mites, along with a genetic predisposition and multiple external aggravating factors. It is thus possible to define treatment targets and possible treatments: 1) permanent vascular changes (medical and instrumental treatments); 2) flushing (betablockers, botulinum toxin); 3) innate immunity (antibiotics, nonspecific antioxidants and anti-inflammatory molecules); 4) a neurovascular component (analgesics, antidepressants); 5) Demodex (antiparasitic drugs); 6) microbiome; 7) skin barrier impairment (cosmetics and certain systemic drugs); 8) sebaceous glands (isotretinoin, surgery); 9) environmental factors (alcohol, coffee, UV exposure). Treatment recommendations are now available in many countries and benefit from the new phenotypic approach to rosacea, in which every sign or symptom is considered separately rather than having to deal with overlapping subtypes. Since the 2000s, many good quality clinical trials have been published in the field of rosacea and many others are still ongoing. Rosacea is a complex disease involving many different mechanisms and with numerous possible treatments, but there are still some important unmet needs with regard to optimal care.

Position paper on a simplified histopathological classification of basal cell carcinoma: results of the European Consensus Project.

BACKGROUND: Histopathological classification of basal cell carcinoma (BCC) has important prognostic and therapeutic implications, but reproducibility of BCC subtyping among dermatopathologists is poor. OBJECTIVES: To obtain a consensus paper on BCC classification and subtype definitions. METHODS: A panel of 12 recognized dermatopathologists (G12) from nine European countries used a modified Delphi method and evaluated 100 BCC cases uploaded to a website. The strategy involved five steps: (I) agreement on definitions for WHO 2018 BCC subtypes; (II) classification of 100 BCCs using the agreed definitions; (III) discussion on the weak points of the WHO classification and proposal of a new classification with clinical insights; (IV) re-evaluation of the 100 BCCs using the new classification; and (V) external independent evaluation by 10 experienced dermatopathologists (G10). RESULTS: A simplified classification unifying infiltrating, sclerosing, and micronodular BCCs into a single "infiltrative BCC" subtype improved reproducibility and was practical from a clinical standpoint. Fleiss' κ values increased for all subtypes, and the level of agreement improved from fair to moderate for the nodular and the unified infiltrative BCC groups, respectively. The agreement for basosquamous cell carcinoma remained fair, but κ values increased from 0.276 to 0.342. The results were similar for the G10 group. Delphi consensus was not achieved for the concept of trichoblastic carcinoma. In histopathological reports of BCC displaying multiple subtypes, only the most aggressive subtype should be mentioned, except superficial BCC involving margins. CONCLUSIONS: The three BCC subtypes with infiltrative growth pattern, characteristically associated with higher risk of deep involvement (infiltrating, sclerosing, and micronodular), should be unified in a single group. The concise and encompassing term "infiltrative BCCs" can be used for these tumors. A binary classification of BCC into low-risk and high-risk subtypes on histopathological grounds alone is questionable; correlation with clinical factors is necessary to determine BCC risk and therapeutic approach.

Bullous haemorrhagic dermatitis induced by heparins and other anticoagulants: 94 cases from French pharmacovigilance centres and a literature review.

BACKGROUND: Bullous haemorrhagic dermatitis (BHD) is an uncommon and highly particular side effect of various forms of heparins. METHODS: To better characterise the disease, we collected all cases from French Pharmacovigilance centres recorded over a 20-year period (37 cases) and performed a Medline literature search up to June 2020 (57 cases). RESULTS: In all, 94 patients were identified (male/female ratio: 2.2) of mean age 73.5±12.1 years (31-94). Patients were treated with enoxaparin (n=66), unfractionated heparin (n=11), fondaparinux (n=10), tinzaparin (n=4), bemiparin (n=1), reviparin (n=1), dalteparin (n=1), and 4 with other anticoagulants: warfarin (n=3) and rivaroxaban (n=1). All cases presented with 1 to more than 100 haemorrhagic vesicles and bullae, distant from the injection sites, located mainly on the lower (75%) or upper limbs (69%). The lesions were asymptomatic, except in 5 patients who had pruritic or painful lesions. The interval between treatment initiation and BHD ranged from 6 hours to 30 days (mean: 8.4±7 days). Biopsy (n=53) showed intraepidermal or subcorneal cavity with red cells (n=39) or junctional blisters (n=10), with eosinophilic infiltrate only rarely. Direct immuno-fluorescence was negative in 19/20 cases and indirect immunofluorescence was negative in 8/8. The outcome was favourable in all cases, including in 12 patients for whom heparin was maintained. A 93-year-old patient died of compressive haematomas unrelated to BHD. We found 5 cases similar to BHD due to other anticoagulants. DISCUSSION: This is the largest comprehensive series of this adverse effect due to heparins or, more rarely, to other anticoagulants. Dermatologists must be aware of BHD, since this benign side effect does not necessarily require interruption of treatment. It is rare, considering the large-scale prescription of heparins, and occurs mainly in male patients aged over 70. Although the presentation is highly typical, the physiopathology is difficult to understand, as coagulation parameters are usually normal. Aging, skin fragility or mechanical factors might play a role.

Clinicopathologic analysis of trichoblastoma and comparison with nodular basal cell carcinoma.

BACKGROUND: Trichoblastoma (TB) is an uncommon benign follicular tumour for which clinical data is limited since most reports originate from pathology studies. OBJECTIVE: To describe the clinical aspects of TB. METHODS: This is an ancillary study of a prospective multicentre cohort of 2710 clinically suspected basal cell carcinoma (BCC), including 935 nodular BCCs. Sixty-two cases were TB: they were analysed and compared to 935 nodular BCCs. RESULTS: TB mostly occurred in females (61% vs. 43% for BCC, P<0.01) of mean age 63 years. They were located on the head and neck, mainly on the nose and forehead, in 87% of cases. The mean size was 8.1mm, 77% were<10mm (55% of BCCs, P<0.001), 8% were ulcerated (vs. 21% of BCCs, P<0.02), and 47% persisted for more than 1 year (34% of BCCs, P<0.05). Most cases had a clinical presentation similar to nodular BCC, except for 5 small, flat, white papules and 1 anfractuous plaque. LIMITATIONS: Cases originated from a series of tumours clinically suspected as BCCs. DISCUSSION: Some 2.6% of tumours clinically diagnosed as BCC are in fact TB. TB occurs on the head, are more frequent in women, and are smaller and of longer duration than BCC. In most cases, clinical diagnosis on clinical grounds is difficult.

Androgen receptor expression in epidermal and adnexal tumours.

INTRODUCTION: Androgen receptor (AR) immunohistochemistry is used in general pathology and in dermatopathology, particularly for sebaceous tumours. The goal of this study was to quantify AR expression in benign and malignant epidermal tumours and adnexal tumours. METHODS: We studied AR expression in 301 skin lesions using standard immunohistochemistry and compared 10 trichoblastomas, 10 sebaceomas and 10 hidradenomas using 5 markers (cytokeratin 7 and 8, PHLDA1, BerEp4 and AR). RESULTS: The rates of AR expression were: 22% in basal cell carcinomas, 3% in squamous cell carcinomas, 92% in sebaceous tumours, 10% in follicular tumours and 22% in sweat gland tumours. Benign sebaceous tumours were AR+ in 97% of cases. Only 12% of sebaceous carcinomas showed no AR staining. The immunohistochemical profiles of the comparative study were as follows: sebaceoma: AR+, CK7-, CK8-, PHLDA1-, BerEp4-; hidradenoma: AR-, CK7+, CK8+, PHLDA1+, BerEp4+; trichoblastoma: AR-, CK7-, CK8-, PHLDA1+, BerEp4+. DISCUSSION: AR staining was positive in 92% of sebaceous tumours, including sebaceomas, in some cases indicative of Muir-Torre syndrome. AR staining is therefore highly sensitive for the diagnosis of sebaceous tumours, but it is non-specific and is best used in combination with other antibodies, notably anti-CK8 and PHLDA1, particularly to distinguish sebaceoma from hidradenoma or trichoblastoma.

Clinical factors predictive for histological aggressiveness of basal cell carcinoma: A prospective study of 2274 cases.

INTRODUCTION: Since surgery is the first-line treatment for basal cell carcinomas (BCC), the histological aggressiveness of the disease must be clinically predicted in order to apply optimal safety margins that ensure a high rate of complete resection while minimising the risk of recurrence. OBJECTIVES: To evaluate clinical predictive factors of histological aggressiveness of BCC, we conducted a national prospective multi-centre study. METHODS: All consecutive patients presenting for BCC surgery were included, and standardised clinical data collected, and slides were submitted for review. Trabecular, micronodular and morpheaform BCCs were classified as aggressive. RESULTS: Of the 2710 cases included, 2274 were histologically confirmed. Clinical subtyping was correct in 49.9% of superficial BCCs, 86.2% of nodular BCCs and only 22% of aggressive BCCs. By multivariate analysis, aggressive BCCs were more frequently ulcerated (45%), indurated (70%), showed adherence (8.6%), and were associated with high-risk anatomical zones (50.3%, P<0.0001). These predictive clinical features may be helpful for decision making.

[Anatomoclinical and immunohistochemical study of 8 cases of dermatomyofibroma]. / Étude anatomoclinique et immunohistochimique de 8 cas de dermatomyofibromes.

INTRODUCTION: Dermatomyofibroma (DMF) is a rare, benign tumour that is little-known among clinicians. However, it has typical clinical, histological and immunohistochemical features that distinguish it from other fibrous tumours. METHOD: We report herein on the clinical, histological and immunohistochemical aspects of eight cases of DMF identified between 2008 and 2019 at the dermatopathology laboratory of Strasbourg. RESULTS: Five men and three women of average age at diagnosis of 21 years and 9 months (range: 9 to 54 years) were included. Lesions ranged in size from 1 to 11cm. Most cases involved the upper body (6 cases), with one case on the abdomen and one on the side. The lesions presented as a solitary asymptomatic red or reddish brown nodule or plaque that gradually developed. The plaques were hard and caused functional discomfort on movement of the neck. Well-circumscribed spindle cell proliferation was noted in the reticular dermis parallel to the epidermis, without mitotic figures or cytological atypia. The subcutis was infiltrated in 5 cases. Expression of calponin was positive in all cases but one, while that of caldesmon, PS100 and desmin was negative. Expression of smooth muscle actin was positive in 2 cases, and both cases were also positive for stromylesin-3. CD34 was positive in 2 cases. DISCUSSION: DMF is an extensive tumour capable of attaining large diameters and must be completely excised. The main differential diagnoses of DMF are dermatofibrosarcoma protuberans, dermatofibroma, fibrous hamartoma, myofibromatosis and cheloid. It can be identified based on various factors, whether clinical (young age, extensive lesion), histological (horizontal proliferation in the reticular dermis) or immunohistochemical (positive expression of calponin).

[Clinical heterogeneity of poikilodermatous mycosis fungoides: A retrospective study of 12 cases]. / Hétérogénéité clinique du mycosis fongoïde poïkilodermique : étude rétrospective de 12 cas.

INTRODUCTION: Poikilodermatous mycosis fungoides is a rare and indolent clinical variant of mycosis fungoides (MF). It can be difficult to distinguish from poikilodermatous parapsoriasis, a group of chronical dermatoses that may sometimes progress to MF. We aimed to specify the clinical, histopathological and developmental features of these entities by means of a retrospective study of 12 cases followed in our center. PATIENTS AND METHODS: We identified cases of poikiloderma for which a diagnosis of MF or parapsoriasis was made by the physician. Photographs and histological slides were reviewed, and a final diagnosis of MF was made if the International Society for Cutaneous Lymphoma criteria for the diagnosis of early MF were fulfilled. RESULTS: Twelve patients were included, 10 of whom met of the MF criteria. 5 patients had large poikilodermatous patches or thin, well-defined plaques ; 3 patients had the same lesions associated with classical MF lesions ; finally, 4 patients had widespread ill-defined erythematous lesions in a net-like pattern, described as parakeratosis variegata, including 3 MF. 2 patients with well-defined lesions (one associated with classical MF lesions) progressed to the tumoral stage whereas none of the patients with parakeratosis variegata presented such progression. A total of 5 patients had a high skin phototype (IV and V). Two patients had squamous cell carcinoma on poikilodermatous lesions. DISCUSSION: Our study suggests that poikilodermatous MF covers a heterogeneous clinical spectrum comprising on one hand a presentation of delimited lesions sharing classical MF risk of progression, and on the other, an entity similar to parakeratosis variegata, an entity overlooked in the French nomenclature, which was particularly benign in our small series, raising the question of its affiliation to the MF group. This question merits further investigation in a larger-scale study.

[Generalized granuloma annulare: A clinicopathological study]. / Granulome annulaire généralisé : étude anatomoclinique.

BACKGROUND: Granuloma annulare (GA) is a benign granulomatous skin disorder that is generalized (GGA) in 15 % of cases. Although many case reports describe a relationship between GGA and systemic diseases, few large series have been published, and their association is debated. We present herein a series of GGA in order to describe their clinical and histological features. PATIENTS AND METHODS: We included all biopsy-proven cases of GA presenting at the dermatopathology laboratory of Strasbourg where generalized (i.e. over 10 lesions). Clinical features were obtained from patients' medical files. RESULTS: We included 35 GGA, with a sex ratio of 0.5. The mean age was 54 years. Lesions were annular or non-annular in equal measure and were symptomatic in 25 % of cases. Most patients (77 %) had an associated disease, already known in 60 % of cases, including dyslipidemia (27 %), diabetes mellitus (20 %), immunosuppressive drugs (17 %), atopy (17 %), auto-immune disease (17 %), hematological disease (14 %), and cancer (9 %). Histological analysis revealed the predominant pattern to be interstitial (54 %) rather than palisading (20 %), having no correlation with clinical type. Eosinophils were frequent (46 %) in GA but were not correlated with systemic disease or drug taking. Among the 40 % of patients treated, 50 % had a successful outcome on topical corticosteroids, doxycycline, antimalarial drugs or phototherapy. DISCUSSION: GGA differs from localized GA, which is mostly associated with an already known systemic disease, whether metabolic, infectious or neoplastic, uncorrelated with clinical or histological features, and screening is necessary.

[Anatomoclinical and dermatoscopic study of trichoadenoma]. / Trichoadénome : description anatomoclinique et dermatoscopique.

INTRODUCTION: Trichoadenoma is a very rare follicular tumour with a remarkable histopathological appearance. In this article we present a series of 12 cases of trichoadenoma, as well as the anatomoclinical and dermatoscopic findings in a typical case. We discuss these findings in the light of an extensive literature research. PATIENTS AND METHODS: We collated 12 cases of trichoadenoma of indisputable diagnosis made at the dermatopathology laboratory of the Dermatological Clinic of the University Hospitals of Strasbourg over a 30-year period (1989-2018). RESULTS: The 12 cases comprised 7 women and 5 men, of average age 58.9 years, the majority having lesions on the cephalic extremity followed by the buttocks and thighs. Histopathological examination, which was similar in all 12 cases, showed multiple epidermal cysts containing an eosinophil lamellar keratin with a stratified wall without any visible hair, located in the superficial and mid dermis and appearing to be stacked on top of one another. In immunohistochemistry, broad spectrum keratin markers were still positive, the follicular marker Ber-EP4 weakly expressed and PHLDA1 was negative. For the case examined using polarized-light dermatoscopy, small rounded white-yellow areas were observed corresponding to cystic structures surrounded by irregular linear vessels. DISCUSSION: Trichoadenoma is a rare tumour seen in middle-aged adults of mean age 45 years, and has no sexual predominance. It is asymptomatic, slow-growing, variable in colour, measures less than one centimeter and is most often located on the face or buttocks. In terms of histology, the juxtaposition of multiple small cystic structures suggests a follicular origin. Differential diagnosis is made with trichoblastomas, which always intensely express PHLDA1 and/or Ber-EP4, desmoplastic trichoepithelioma, which consists of multiple much thinner spans in a highly fibrous stroma with clearly visible arborescent vessels over a white-yellow ivory background at dermatoscopy, microcystic carcinoma, which has a deeper extension, and plaque milium, in which the cysts are larger.

[Acute localized exanthematous pustulosis following heparin calcium injections]. / Pustulose exanthématique aiguë localisée après injections d'héparine calcique.

BACKGROUND: Acute localized exanthematous pustulosis (ALEP) is a rare variant of acute generalized exanthematous pustulosis and is also defined by diagnostic criteria established by the EuroSCAR study group. Some twenty cases of ALEP have been described in the literature. PATIENTS AND METHODS: A 61-year-old woman suddenly developed erythematous and edematous lesions after subcutaneous heparin calcium injections in the thighs, with bullous detachment at the center of the lesions and multiple vesicles and non-follicular pustules on the edges. These lesions were centered around the injection points. There were no other skin lesions and no lesions on the oral mucosa, and the patient was apyrexial. The skin biopsy revealed an intracorneal pustule with spongiosis, as well as a prominent infiltrate of lymphocytes, neutrophils and eosinophils in the dermis, with no necrotic keratinocytes. We confirmed a definite diagnosis of ALEP, with a score of 10/12 according to the EuroSCAR criteria. A favorable outcome was quickly obtained after discontinuation of heparin injections, with only post-inflammatory pigmented macules. DISCUSSION: This case shows that heparin calcium can lead to ALEP, thus contraindicating further administration of this substance. Other causative factors consist chiefly of systemic antibiotics, spider bites and exposure to certain plants. This case is remarkable in terms of the limitation of lesions to heparin calcium injection sites.

[Ulceration of lymphomatous skin lesions in a patient with Sezary syndrome treated with brentuximab-vedotin]. / Ulcérations de lésions cutanées lymphomateuses sous brentuximab-védotin chez un patient atteint de syndrome de Sézary.

BACKGROUND: Brentuximab-vedotin (BV), an anti-CD30 agent combined with an anti-neoplastic agent, has recently yielded promising results in the treatment of cutaneous T-lymphomas such as Sezary syndrome. Surprisingly, these results are observed regardless of levels of CD30 expression by tumour cells. PATIENTS AND METHODS: Herein, we report the case of a 52-year-old man with Sézary syndrome (SS) with skin and lymph node involvement, and whose tumour cells were not expressing CD30 at the time of disease progression. His disease was refractory to several lines of treatment, and a partial response was obtained using BV therapy, with secondary ulceration of SS-specific skin lesions. DISCUSSION: Ulceration of our patient's skin lesions was concomitant with clinical improvement and the semiology was identical to cases of skin ulceration under methotrexate in patients with psoriasis or mycosis fungoides. The mechanism of action appears to be related to sudden interruption of the cell cycle in a context of rapid cell renewal, although the way in which the antibody acts on keratinocytes has not yet been fully elucidated.

[Acute generalized pustular bacterid followed by Sweet's syndrome and erythema nodosum]. / Pustulose aiguë généralisée post-streptococcique suivie d'un syndrome de Sweet et d'un érythème noueux.

INTRODUCTION: Streptococcal infections can cause various skin manifestations related to the direct action of the offending organism itself or to a reactional mechanism. Reactional manifestations are less well known and understood, and they include generalized acute pustulosis belonging to the spectrum of neutrophilic dermatoses. We report a case of generalized acute pustulosis followed by Sweet syndrome and erythema nodosum occurring after a streptococcal infection. PATIENTS AND METHODS: A 60-year-old woman was consulting for a diffuse pustular rash after a throat infection, with high levels of anti-streptolysin (337 U/L) and anti-streptodornase (2560 U/L). The biopsy showed folliculitis and a neutrophilic infiltrator of the dermis, and bacteriological and mycological cultures were sterile. The patient then developed papules evoking Sweet syndrome followed by nodules typical of erythema nodosum after 20 days. A favourable outcome was achieved under colchicine. DISCUSSION: Generalized acute pustulosis is a form of neutrophilic dermatosis whose mechanisms, area predilection and treatment are poorly known. The clinical presentation of this patient was initially typical and the secondary progression to lesions like those in Sweet syndrome is consistent with the pathophysiological continuity and overlap of these entities.