[Penile intraepithelial neoplasia]. / Les néoplasies intraépithéliales peniennes.

Penile carcinogenesis can be superposed on vulvar carcinogenesis, with two pathways : with or without a link to HPV. Penile squamous cell carcinomas arise from precursor lesions: penile intraepithelial neoplasia (PeIN) defined by the presence of intraepithelial atypia, which can progress to invasive squamous cell carcinoma. Differentiated PeINs not linked to HPV, affect elderly men with inflammatory lesions, most often lichen sclerosus. PeINs linked to HPV, basaloid, condylomatous or condylomatous-basaloid growth affect younger men. Although clinically similar, their distinction is important, because the treatment differs with a greater risk of invasion for forms unrelated to HPV.

[The malignant epithelial carcinomas of the penis: A review of the different histological types]. / Les carcinomes du pénis : une revue des différents types histologiques.

The most frequent cancer of the penis is the squamous cell carcinoma. Several variants of squamous cell carcinoma exist. It is important to make a difference between squamous cell carcinomas with and without a HPV infection. Furthermore, it is extremely important to recognize the different variants as their prognosis differs. These tumors are rare therefore classifying them can be challenging. This review is supposed to give an overview on the existing entities since 2016, but also allows a glimpse into the future with some comments on the upcoming WHO classification 2021.

[Lesions of the penis, the anatomy, epidemiology and carcinogenesis]. / Lésions du pénis, l'anatomie, l'épidémiologie et la cancérogenèse.

The penile carcinoma is rare, but many items playing a role are complex and it is important to know as well the anatomy, but also the carcinogenesis for a perfect patient's management.

[Penile carcinoma: Practical issues, from the biopsy to surgery]. / Cancer du pénis : problèmes pratiques du quotidien, de la biopsie à la chirurgie.

The management of a penile carcinoma is complex, a collaboration between radiologist, pathologist and urologist is necessary to obtain a correct staging. In this review we try to demonstrate step by step how to achieve a complete pathology report, how to manage the patient (imaging, biopsy, fresh frozen section and surgery).

[Vulvar intraepithelial neoplasias]. / Les néoplasies intraépithéliales vulvaires.

Vulvar squamous cell carcinoma arises from precursor lesions: vulvar intraepithelial neoplasias (VIN). Most of them are caused by the human papillomavirus (HPV), and the precursor lesion for this group is VIN usual type/high grade squamous intraepithelial lesion (uVIN/HSIL) of variable clinical presentation and having a light invasive potential. Some VIN are HPV-independent and arise in older women against the background of chronic dermatoses, mostly lichen sclerosus. Their histological diagnosis is more subtle. They have a higher invasive potential. A third precursor, leading to well-differentiated, or even verrucous, carcinomas, is still ill-defined to this day. We detail these lesions' clinics, histology, and biomarkers (immunohistochemical and molecular).

[CAD/CAM assisted facial epithesis: Clinical and technical aspects]. / Épithèse faciale par CFAO : aspects cliniques et techniques.

The face is an important part of the human body from an anatomical, functional, aesthetic and psychosocial point of view. It can be the site of several mutilations resulting from trauma, treatment of neoplasms and congenital malformations. The plastic facial prosthesis is therefore indicated to restore these facial deformities and to compensate for the various consequences. Recently, digital technologies have shown an increasing impact on the future of maxillofacial rehabilitation. Computer-aided design and manufacturing technique enabled practitioners to acquire numerical data, perform three-dimensional reconstructions, and then materialize and manufacture the facial epithesis through various manufacturing processes, by addition or subtraction. The aim of this article is to describe, through a clinical case, the steps of realization of a nasal epithesis by CAD/CAM, in a patient who underwent a surgical exeresis of the nasal pyramid following a squamous cell carcinoma. Thus, the clinical and technical aspects are highlighted, as follows, the taking of the impression, the materials used, the set-up and the make-up, as well as the software and the useful concepts for the computer-assisted realization of a facial plastic prosthesis of the nasal epithesis type. Our therapy will also focus on the interest of the multidisciplinary approach in Maxillofacial Prosthodontics.

Dlx5 promotes cancer progression through regulation of CCND1 in oral squamous cell carcinoma (OSCC).

Genetic studies have revealed a critical role of the distal-less homeobox gene 5 (Dlx5) in the pathogenesis of ovarian cancer, lung cancer, and T-cell lymphoma; however, the role and underlying mechanisms of Dlx5 in oral squamous cell carcinoma (OSCC) are largely unknown. In this study, we demonstrated that Dlx5 is up-regulated in OSCC tissues and cell lines, compared with their control groups. The results from our immunohistochemistry (IHC) analyses show that high expression levels of Dlx5 correlated with advanced TNM stages (P = 0.0001), lymph node metastasis (P = 0.0049), poor cellular differentiation (P = 0.0491), location of the tumors (P = 0.0132), and poor prognosis for the patient. We also demonstrated that knockdown of Dlx5 inhibited the viability, proliferation, and colony formation of OSCC cell lines CAL-27 and WSU-HN6 cells, probably by blocking cell cycle in the G1 phase. Furthermore, we revealed that Dlx5 exerts its biological functions via direct regulation of CCND1 in CAL-27 and WSU-HN6 cells. Ultimately, we have demonstrated that silencing of Dlx5 inhibits the growth of xenograft tumors in vivo, and that Dlx5 affects the progression of OSCC both in vitro and in vivo via directly regulating CCND1, providing a potential diagnostic biomarker and therapeutic target for OSCC.

[Diagnostic pitfall: Early arising, multiple and recurrent Marjolin's ulcer. About 8 patients (16 tumors) and literature review]. / Piège diagnostique : l'ulcère de Marjolin d'apparition précoce, multiple ou récidivant. À propos d'une série de 8 patients (16 tumeurs) et revue de la littérature.

INTRODUCTION: Marjolin's ulcer (MU) is a large entity representing skin cancers resulting from the transformation of chronic wounds of a heterogeneous nature. Burn scars are the most at risk of degeneration, in particular because there are the sites of important skin tension. Atypical forms are not uncommon. The objective of this study is to present these exceptions which are underestimated. MATERIALS AND METHODS: All patients with UM in our centre between January 2011 and February 2019 have been included permitting to report the initial pathology, the location, the latency time, the histology and the management carried out. RESULTS: Eight patients were treated in our center for MU, they developed 16 skin cancers. Fourteen were squamous cell carcinomas (SCC). The shortest latency period was 2 months. The youngest patient was 22 years old when she was diagnosed with MU. Three patients had at least 2 synchronous SCC. One patient had a recurrence after a split-thickness skin grafting on artificial dermis and 2 patients had second locations. CONCLUSION: Atypic forms are not rare. MU is commonly recurrent, multiple, early arising and may appear in young people. The treatment of chronic wounds cannot be dissociated from the treatment of contractures, otherwise the wound will inevitably reappear.

MicroRNA-378-3p/5p suppresses the migration and invasiveness of oral squamous carcinoma cells by inhibiting KLK4 expression.

Distant metastasis frequently occurs in oral squamous cell carcinoma (OSCC) and contributes to the adverse prognosis for patients with OSCC. However, the potential mechanisms behind the metastasis have not yet been clarified. This study investigated the role of miR-378 in the migration and invasiveness of OSCC in vitro and in vivo. According to our results, the migration and invasiveness of OSCC cells were increased in cells overexpressing miR-378, and reduced in cells where miR-378-3p/5p was silenced. In addition, overexpression of miR-378 suppressed the expressions and activities of matrix metalloproteinase 9 (MMP-9) and MMP-2. Epithelial-mesenchymal transition (EMT) was restrained by overexpression of miR-378, as evidenced by an increase in E-cadherin expression and decrease in N-cadherin and uPA expression. However, knockdown of miR-378-3p/5p produced the opposite results. Moreover, kallikrein-related peptidase 4 (KLK4) was confirmed to be a target gene of miR-378. Overexpression of KLK4 reversed the induced decrease in migration and invasiveness of cells overexpressing miR-378 by upregulating the levels of MMP-9, MMP-2, and N-cadherin, and downregulating the level of E-cadhrin. Finally, the number of metastasis nodules in the lung tissues of nude mice was reduced by overexpression of miR-378, whereas the number of metastases increased with knockdown of miR-378. Taken together, our results suggest that the miR-378-KLK4 axis is involved in the mechanisms behind the migration and invasiveness of OSCC cells. Targeting the miR-378-KLK4 axis may be an effective measure for treating OSCC.

[Study of the Human Papillomavirus (HPV) prevalence in head and neck carcinomas in a French monocentric cohort of 372 patients]. / Étude de la prévalence du papillomavirus (HPV) dans les cancers des voies aéro-digestives sur une cohorte unicentrique française de 372 patients.

INTRODUCTION: French data about HPV role in head and neck carcinomas are sparse, although French patients are mostly heavy smokers. In this series of oropharyngeal et non-oropharyngeal tumors, we aimed to determine what were the clinicopathological features associated with HPV and evaluate survival of patients according to HPV status. METHODS: Three hundred and seventy-two cases of head and neck squamous cell carcinomas were reviewed and clinicopathological data were detailed. For each case, we performed a HPV PCR and an immunostaining against p16 protein (paraffin embedded tissues). RESULTS: The series contained 90% of heavy smokers and 36% of tumors were located in oropharynx. HPV DNA was detected in 46% of oropharyngeal carcinomas and 16% of non-oropharyngeal carcinomas. Genotype 16 was the most frequently detected (84%). Clinicopathological features significantly associated with HPV DNA were: oropharyngeal location; absence of tobacco smoking; nodal involvement; poorly-differentiated non-keratinizing histology; positive p16 immunostaining. HPV infection was significantly associated with a longer survival for oropharyngeal carcinomas. It was not the case for non-oropharyngeal carcinomas. CONCLUSION: In this French series with lot of heavy smokers, under half of carcinomas are HPV induced. Clinicopathological features and survival data associated with HPV infection are the same as those classically described in literature.

[Regression of cutaneous basal cell and squamous cell carcinoma under pembrolizumab]. / Régression de carcinomes basocellulaire et épidermoïde cutanés sous pembrolizumab.

BACKGROUND: The recommended treatments for advanced squamous cell carcinoma (SCC) (chemotherapy, radiotherapy, anti-EGFR) and advanced basal cell carcinoma (BCC) (vismodegib and sonidegib) have many side effects. Nivolumab (anti-PD1 antibody) may be used as second-line therapy in SCC of the head and neck. We report the case of a patient with advanced SCC and BCC which regressed under pembrolizumab. PATIENTS AND METHODS: A 69-year-old man consulted for a large vertex SCC measuring 15cm in diameter. He also had BCC on the left nostril and sternal Bowen disease. Radiological assessment revealed cervical and parotid lymph node involvement. Treatment with pembrolizumab 2mg/kg every 3 weeks was decided at a Multidisciplinary Concertation Meeting. Tumor regression of the vertex SCC was noted at the third course of treatment, as well as regression of the nasal BCC and the sternal Bowen disease. A complete response was observed after 11 courses of treatment for SCC, 7 courses for BCC, and 10 courses for Bowen disease. CONCLUSION: We report an original case of cure of BCC with anti-PD1 (pembrolizumab) prescribed for locally advanced inoperable SCC. The place of this treatment in the therapeutic arsenal remains to be defined. Clinical trials are in progress concerning use of this treatment in advanced cutaneous SCC and inoperable BCC.

Knockdown of RNF2 enhances the radiosensitivity of squamous cell carcinoma in lung.

A previous study has reported that knockdown of RING finger protein 2 (RNF2) increases the radiosensitivity of esophageal cancer cells both in vitro and in vivo. However, the effect of RNF2 knockdown on radiosensitivity in squamous cell carcinoma (SqCC) remains unknown. For this, NCI-H226 and SK-MES-1 cells were exposed to X-ray irradiation and then RNF2 levels were determined. RNF2 was knocked-down and stable transfectants were selected. Radiosensitivity, cell proliferation, apoptosis, cell cycle, and γ-H2AX foci formation were evaluated. Interaction among ataxia telangiectasia mutated protein (ATM), mediator of DNA damage checkpoint 1 (MDC1), and H2AX were examined. Xenograft models were used to explore the effect of RNF2 knockdown on radiosensitivity in vivo. The results showed that RNF2 expression was significantly increased by X-ray irradiation. RNF2 knockdown combined with X-ray irradiation markedly inhibited cell proliferation, caused cell cycle arrest at the G1 phase, and induced cell apoptosis. In addition, RNF2 knockdown enhanced the radiosensitivity of SqCC cells, inhibited irradiation-induced γ-H2AX foci formation, and impaired the interactions among ATM, MDC1, and H2AX. Furthermore, combination of RNF2 knockdown and X-ray irradiation suppressed tumor growth and promoted tumor cell apoptosis in vivo. RNF2 may be a new therapeutic target to enhance the radiosensitivity of SqCC cells in lung.

[Carcinoma cuniculatum: An unusual oral tumor]. / Carcinome cuniculatum : une tumeur orale inhabituelle.

We report on a case of carcinoma cuniculatum (CC) of the maxillary gingival mucosa. A 60-year-old woman presented with an exophytic gingivo-palatal mass with slow growth and osteolytic evolution. A first performed biopsy was negative for malignancy. The diagnosis of CC was established on the surgical representative biopsy. CC is a rare low-grade variant of squamous cell carcinoma that is usually found in the foot or in oral cavity. The pathognomonic microscopic feature of CC is an endo- and/or exophytic lesion composed by a well differentiated squamous epithelium infiltrating into underlying stroma forming a complex pattern of keratin cores and keratin filled "rabbit warren" crypts. CC is a locally evolutive carcinoma with a usually good prognosis usually without lymph node or distant metastatic evolution.

Kératoses actiniques : diagnostic anatomoclinique: Clinicopathologic diagnosis of actinic keratosis.

Actinic keratoses are epidermal preneoplastic lesions localised in photo-exposed areas. They are made of a keratosis of variable thickness overlying an erythematous area, that may be indurated. A field of cancerization is characterized by multiple actinic keratoses in a chronically sun exposed area, especially on the bald area of the scalp in aged males. In general, the diagnosis is made on clinical basis, but a biopsy is necessary in case of ulceration, induration, post-treatment recurrence or bleeding. Biopsy is also mandatory for atypical keratosis, especially the pigmented variants. Histopathology shows dysplasia of the epidermal basal layer, with irregular and hyperchromatic nuclei, parakeratosis and generally a dermal lymphocytic infiltrate. There are hypertrophic, atrophic, pigmented and lichenoid variants among the most common subtypes. The main clinicopathological issue is transformation of actinic keratosis into squamous cell carcinoma, defined by epidermal sheaths of atypical cells penetrating into the dermis. These cells are eosinophilic and show images of dyskeratosis or squamous whorls. Dermatoscopy (and other non invasive imaging techniques) might be useful to help decision making - when to perform a biopsy - and for differential diagnosis. © 2019 Elsevier Masson SAS. All rights reserved. Cet article fait partie du numéro supplément Kératoses actiniques : comprendre et traiter réalisé avec le soutien institutionnel de Galderma International.

MiR-154 inhibits the growth of laryngeal squamous cell carcinoma by targeting GALNT7.

MicroRNAs are critical regulators of the development and progression of laryngeal squamous cell carcinoma (LSCC). However, the role of microRNA-154 (miR-154) in the development and progression of LSCC has not been clarified. We found that down-regulated miR-154 expression in LSCC tissues was associated with poorer prognosis in LSCC patients. MiR-154 over-expression inhibited the proliferation, clonogenicity, and migration of LSCC cells and induced cell cycle arrest, which were reversed by miR-154 inhibition. MiR-154 targeted GALNT7 expression by reducing GALNT7-regulated luciferase activity in LSCC cells while up-regulating GALNT7 mRNA transcription in LSCC tissues and cells. GALNT7 silencing significantly attenuated the proliferation, clonogenicity, and migration of LSCC cells and induced cell cycle arrest. Finally, intravenous treatment with lentivirus for miR-154, but not scrambled control miRNA, significantly restrained the growth of implanted LSCC Hep-2 tumors and decreased the tumor mass by reducing GALNT7 expression in mice. Therefore, miR-154 may serve as a novel prognostic marker and therapeutic target for LSCC.

Defining the regulatory role of programmed cell death 4 in laryngeal squamous cell carcinoma.

Programmed cell death 4 (PDCD4) is decreased in many different kinds of malignant tumors. EMT endows tumor cells invasive and metastatic properties. However, few studies have determined the role of PDCD4 in the regulation of EMT in the context of laryngeal carcinoma. We examined the relationship between PDCD4 and EMT-associated proteins E-cadherin and N-cadherin using laryngeal carcinoma tissues. Gene manipulation was used to define the regulatory capacity of PDCD4. We report that PDCD4 and E-cadherin/N-cadherin expression were significantly changed in the carcinoma tissues, and their expression was associated with pathological grade, metastatic state, and clinical stage. The suppression of PDCD4 (and consequently, E-cadherin) was concomitant with increased proliferation and G2-phase arrest, decreased apoptosis, and increased cell invasion. PDCD4 upregulation reversed the above-mentioned results. In nude mice, PDCD4 knockdown increased tumor growth and pathological features, confirming the tumorigenic role of PDCD4. Finally, PDCD4 silencing was associated with dysregulation of the carcinogenic Wnt-ß-catenin and the STAT3-miR-21 signaling pathways. This study revealed a dynamic regulatory relationship between PDCD4 and critical factors for EMT, establishing a broad, functional role for PDCD4 in laryngeal carcinoma, which may be propagated by the STAT3-miR-21 pathway. These findings provide new information on an EMT-associated target that may lead to a novel therapy.

[Rapidly growing squamous cell carcinoma after ingenol mebutate treatment]. / Carcinome épidermoïde de croissance rapide après traitement par mébutate d'ingénol.

INTRODUCTION: Ingenol mebutate is an actinic keratosis treatment, which has a dual action mechanism. It allows a rapid cellular death and a severe inflammation. OBSERVATION: We report the case of a 75 years old patient with a rapidly growing tumor 5 weeks after application of ingenol mebutate on typical actinic keratosis. Histological analysis after surgical excision showed an invasive squamous cell carcinoma (SCC); with aggressiveness signs: perineural infiltration and vascular permeation. DISCUSSION: Ingenol mebutate's common side effects are benign and regressive within 2 to 4 weeks. There are erythema, edema, crusts, and ulcerations/erosions. Squamous cell carcinoma development was rarely reported. We have tried to collect other cases in the literature and in pharmacovigilance centres: three similar cases were recently published in the literature, 21 cases were notified to the European Medicines Agency and we asked French pharmacovigilance centres and found 5 cases of SCC after ingenol mebutate application. The role of the molecule in SCC development is currently unknown. Induced inflammation could take part in the development of these tumors. We compare this case with other situations of inflammation, such skin graft donor site or surgical incision, complicated of rapidly growing SCC. Our case, literature's and pharmacovigilance's cases encourage us to follow ingenol mebutate's side effects. Careful follow-up and registration of such cases are important to gain further insight on this topic.

[Squamous cell carcinoma associated with use of skin-lightening cream]. / Carcinome épidermoïde associé à une dépigmentation volontaire.

BACKGROUND: Women widely use skin-lightening products for cosmetic purposes in sub-Saharan Africa despite numerous reported cutaneous and systemic complications. The occurrence of epidermoid carcinoma has long been reported, but only three cases have been published so far. We report the first case in Mali. PATIENTS AND METHODS: A 30-year old woman with no noteworthy medical history was seen at our outpatient center for cervical ulceration that had been present for the last 5 years. She had used cosmetic bleaching cream over a period of around ten years. Physical examination revealed extensive ulceration on the left side of her neck. Blood tests for viral hepatitis and human immunodeficiency virus were negative. The pathological examination of the skin biopsy confirmed the diagnosis of squamous cell carcinoma. After failure of the initial excision with early relapse, multiple surgical ablations were performed 3 months later. DISCUSSION: The high prevalence of skin-lightening cosmetic use contrasts with the rarity of epidermoid carcinoma in depigmented skin. However, a large chronic ulcer on uncovered parts of the upper body, particularly the neck, should prompt physicians to consider skin cancer. Appropriate preventive measures include the promotion of educational messages for the general population, the use of sun-protection devices, and routine skin biopsy for all women presenting chronic cervical ulceration after long-term use of skin-lightening products.

Cutaneous squamous cell carcinomas (SCC) associated with cosmetic skin whitening: 8 cases reported in Senegal.

BACKGROUND: The cosmetic use of bleaching products is common among women from sub-Saharan Africa. The most frequently used products are highly potent corticosteroids (clobetasol propionate) and hydroquinone. Herein, we report 8 cases of SCC in women using skin bleaching products for cosmetic purposes. Our aim is to describe the epidemiological, clinical and pathological aspects of the carcinomas observed during the course of skin lightening. METHODS: We conducted a descriptive multicentre study from August 2005 to January 2016 in three dermatology units in Senegal. We included all patients consulting for cutaneous squamous cell carcinoma associated with skin bleaching. Sociodemographic, clinical, paraclinical and therapeutic data were recorded. RESULTS: A total of 8 female patients were included. The mean age was 48.1 years (37-63 years). Topical hydroquinone and highly potent corticosteroids were the main products used over the whole body, for an average duration of 20.3 years. No pre-neoplastic skin disease was found in our patients. The clinical aspects of tumours were as follows: cauliflower-like (n=4), ulcerated (n=3) and nodular (n=1). The average development time before consultation was 6.75 months. All the cutaneous squamous cell carcinomas were localized to lichenoid lesions or exogenous ochronotic lesions on photo-exposed areas: face (n=1), neck (n=3) or upper back (n=4). The most common histopathological type was the infiltrating form and there was one case of in situ carcinoma. The outcome was favourable in six of eight patients after surgical resection. Two deaths occurred: one through tumour recurrence and the other through haemorrhagic shock. CONCLUSIONS: From 2005 to 2016, eight cases of cutaneous squamous cell carcinomas associated with cosmetic use of bleaching products were reported in Senegal. The mechanism was not fully elucidated and further studies are necessary. These observations provide an additional argument for combating this practice and including skin bleaching among known risk factors for squamous cell carcinoma.

[Beyond actinic keratoses: Field cancerization of the skin]. / Au-delà des kératoses actiniques, le champ de cancérisation cutané.

Lesions occurring in actinic keratoses (AK) form erythematous, squamous, crusty and keratotic papules that appear on skin chronically exposed to the sun due to ultraviolet radiation. They are formed by the proliferation of atypical keratinocytes limited to the epidermis and may progress to squamous cell carcinoma in situ and to cutaneous squamous cell carcinoma (CEC). Although low, the metastatic risk associated with the CEC is not negligible. The concept of field cancerization was introduced in 1953 following studies of neoplastic lesions of the oral mucosa. A cancer field is a normal-looking pre-tumoral zone with subclinical, multifocal anomalies, which may constitute a base for new neoplastic lesions. Such fields are frequently seen in areas of photo-exposed skin and around the edges of AK and CEC. In this event, treatment should not be limited to visible or palpable AK lesions, and if a cancer field is suspected, treatment involving the physical destruction or elimination of atypical keratinocytes from the entire area should be considered. Such an approach may improve the long-term prognosis, reduce treatment costs and ensure optimal cosmetic outcome.