Role of Surgical Pathologist for Detection of Immunooncologic Predictive Factors in Head and Neck Cancer.

Immunotherapy has shown promising results in the treatment of recurrent and metastatic head and neck cancers. Antiprogrammed cell death (PD)-1 therapies have been recently approved in this setting and they are currently tested also in the treatment of locally advanced diseases and in the neoadjuvant setting. However, the clinical benefits of these treatments have been quite variable, hence the need to select those patients who may obtain the maximal efficacy through the identification of predictive biomarkers. Currently, PD-L1 immunohistochemical expression by tumor and immune cells is the most widely used predictive biomarker for immunotherapy in head and neck squamous cell carcinoma. Nevertheless, patients with PD-L1 - tumors may still respond to treatments, thereby emphasizing the need for the identification of other predictive biomarkers. In this review, we summarize the current data on histologic and molecular parameters that can be used to select patients with head and neck cancers for immunotherapy, with a focus on squamous cell carcinoma and salivary gland carcinomas.

MDM2 is a useful diagnostic marker for nasopharyngeal carcinoma.

BACKGROUND: The MDM2 gene appears to be involved in the development of nasopharyngeal carcinoma. The aim of this study was to examine MDM2 expression in a series of nasopharyngeal carcinoma biopsies to explore its potential diagnostic significance. METHODS: The study cohort consisted of 26 nasopharyngeal carcinomas, including 22 EBV positive non-keratinizing squamous cell carcinomas (NKSCC), 1 EBV negative NKSCC and 3 EBV negative keratinizing SCC. For comparison, we selected 48 oropharyngeal carcinomas, including 17 HPV positive SCC (14 non-keratinizing and 3 keratinizing) and 31 HPV negative SCCs (28 keratinizing and 3 non-keratinizing). In addition, we examined MDM2 expression in a group of 26 cervical lymph node metastases, including 5 with EBV positive nasopharyngeal NKSCC and 21 from oropharyngeal carcinoma (18 non keratinizing HPV positive, 1 keratinizing HPV positive, 1 keratinizing HPV negative and 1 non-keratinizing HPV negative). Finally, 2 bone metastases from EBV positive nasopharyngeal NKSCC were also included. A tissue microarray was constructed from formalin-fixed paraffin embedded tumor tissue specimens. Sections were immunostained for MDM2 and in situ hybridization for EBER and CISH analysis for the MDM2 gene were also conducted in all cases. RESULTS: Overall, MDM2 positivity was detected in 28 of 102 SCCs (27.2 %). MDM2 positivity was significantly more frequent in EBV positive NKSCC (80 %) than in oropharyngeal HPV positive NKSCC (6.1 %) and keratinizing SCCs (9.4 %) (p < 0.001, Pearson chi square). Considering only the primary tumors, 86.4 % of the nasopharyngeal carcinomas were positive, versus 13.5 % of the oropharyngeal carcinomas (p < 0.001, Pearson chi square). Considering the lymph node metastases, 3 of 5 EBV positive carcinomas with nasopharyngeal primary were positive, whereas only one of the HPV positive carcinomas was positive. Finally, both the bone metastases from EBV positive nasopharyngeal carcinoma were positive for MDM2. No amplification of the MDM2 gene was identified by in situ hybridization analysis. CONCLUSIONS: Our data indicate that MDM2 could be a valuable diagnostic marker to support the diagnosis of nasopharyngeal EBV positive NKSCC.

Towards a Molecular Classification of Sinonasal Carcinomas: Clinical Implications and Opportunities.

Sinonasal carcinomas are a heterogeneous group of rare tumors, often with high-grade and/or undifferentiated morphology and aggressive clinical course. In recent years, with increasing molecular testing, unique sinonasal tumor subsets have been identified based on specific genetic alterations, including protein expression, chromosomal translocations, specific gene mutations, or infection by oncogenic viruses. These include, among others, the identification of a subset of sinonasal carcinomas associated with HPV infection, the identification of a subset of squamous cell carcinomas with EGFR alterations, and of rare variants with chromosomal translocations (DEK::AFF2, ETV6::NTRK and others). The group of sinonasal adenocarcinomas remains very heterogeneous at the molecular level, but some recurrent and potentially targetable genetic alterations have been identified. Finally, poorly differentiated and undifferentiated sinonasal carcinomas have undergone a significant refinement of their subtyping, with the identification of several new novel molecular subgroups, such as NUT carcinoma, IDH mutated sinonasal undifferentiated carcinoma and SWI/SNF deficient sinonasal malignancies. Thus, molecular profiling is progressively integrated in the histopathologic classification of sinonasal carcinomas, and it is likely to influence the management of these tumors in the near future. In this review, we summarize the recent developments in the molecular characterization of sinonasal carcinomas and we discuss how these findings are likely to contribute to the classification of this group of rare tumors, with a focus on the potential new opportunities for treatment.

MUC4 is a valuable marker for distinguishing secretory carcinoma of the salivary glands from its mimics.

AIMS: Secretory carcinoma (SC) (synonym: mammary analogue secretory carcinoma) is a low-grade salivary gland tumour that occurs in both major and minor salivary glands. SC is known for its wide morphological, architectural and immunohistochemical spectrum, which overlaps with those of several salivary gland neoplasms, including acinic cell carcinoma (AciCC) and intercalated duct-type intraductal carcinoma (IDC) in major salivary glands, and polymorphous adenocarcinoma (PAC) in minor salivary glands. These tumours share with SC some morphological features and SOX10 immunoreactivity; also, with the exception of AciCC, they all coexpress S100 and mammaglobin. METHODS AND RESULTS: We compared MUC4 and mammaglobin expression in 125 salivary gland carcinomas (54 genetically confirmed SCs, 20 AciCCs, 21 PACs, and 30 IDCs) to evaluate the potential of these two markers to differentiate these entities. Moderate to strong diffuse MUC4 positivity was detected in 49 SCs (90.7%), as compared with none of the IDCs and PACs. In contrast, mammaglobin was frequently expressed in SCs (30 of 36 cases; 83.3%), IDCs (24/28; 85.7%), and PACs (7/19; 36.8%). Two of three high-grade SCs lost MUC4 expression in the high-grade tumour component. No significant correlation was found between MUC4 expression and the fusion variant in SC (ETV6-NTRK versus non-ETV6-NTRK). CONCLUSION: The results of our study identify MUC4 as a sensitive (90.7%) and specific (100%) marker for SC, with high positive (100%) and negative (93.4%) predictive values. Thus, MUC4 may be used as a surrogate for SC in limited biopsy material and in cases with equivocal morphology.

Papillary-cystic neoplasms of the middle ear are distinct from endolymphatic sac tumours.

AIMS: Papillary neoplasms of the middle and inner ear are rare and poorly characterised. The current World Health Organization classification divides them into two major subtypes: aggressive papillary tumours (APTs) and endolymphatic sac tumours (ELSTs). The aim of this article is to present two papillary neoplasms of the middle ear that do not fit into either the classic APT category or the classic ELST category, and compare them with three ELSTs. METHODS AND RESULTS: The patients were a 48-year-old female and a 59-year-old male without a history of other neoplasms. Histology showed papillary-cystic growth of predominantly oncocytic (Case 1) or mucinous (Case 2) cells surrounded by a p63-positive basal layer. The overall histology was reminiscent of oncocytic sinonasal papilloma (Case 1) and pancreatobiliary or salivary intraductal papillary mucinous neoplasms (Case 2). Ovarian-type stroma, invasion and malignant features were absent. Immunohistochemistry revealed expression of cytokeratin (CK) 7, but not carbonic anhydrase IX (CAIX) or paired box gene 8 (PAX8) (except for very focal PAX8 expression in Case 1). The TST15 gene panel and HRAS sequencing revealed no pathogenic mutations in BRAF, KRAS, EGFR, AKT1, or HRAS. The TruSight RNA fusion panel revealed an MKRN1-BRAF fusion in Case 1. No fusion was detected in Case 2. The three ELSTs showed classic features of the entity, expressed CK7, epithelial membrane antigen, PAX8, and CAIX, and lacked a basal cell layer. CONCLUSION: These novel cases suggest that papillary tumours of the ear represent a heterogeneous spectrum of distinct neoplasms unified by a prominent papillary-cystic pattern rather than a single entity. Future studies should clarify whether the MKRN1-BRAF fusion is a defining recurrent driver event, especially in those cases reported as sinonasal-type middle ear papillomas.

Current role of computed tomography imaging in the evaluation of cartilage invasion by laryngeal carcinoma.

OBJECTIVES: To evaluate thyroid, arytenoid, and cricoid cartilage invasion on computed tomography (CT) imaging in patients undergoing total laryngectomy for both primary and recurrent laryngeal carcinoma. Secondary endpoint was to compare laryngeal cartilage invasion between primary and recurrent tumours. METHODS: Pre-treatment CT of 40 patients who had undergone total laryngectomy was retrospectively evaluated and compared with histology. Focal erosions of thyroid cartilage were accounted for neoplastic invasion of the inner cortex. Full-thickness thyroid cartilage invasion was defined as a tumour-like tissue replacing thyroid cartilage or extended in extra-laryngeal soft tissues. Sclerosis and erosion of arytenoid and cricoid cartilages were assessed as signs of neoplastic invasion. RESULTS: CT erosion showed perfect agreement for thyroid inner cortex and cricoid cartilage invasion and almost perfect agreement (87%) for arytenoid cartilage invasion. For tumours in contact with thyroid cartilages, the absence of CT erosion underestimated inner cortex infiltration. CT showed perfect agreement in predicting full-thickness thyroid cartilage invasion only in the case of extra-laryngeal neoplastic extension. Arytenoid sclerosis showed poor correlation with neoplastic invasion. For primary tumours, CT demonstrated good (inner cortex 75%; full-thickness 85%), substantial (67.5%), and perfect (100%) accuracy in thyroid, arytenoid, and cricoid cartilage invasion, respectively. No CT differences were observed between primary and recurrent laryngeal tumours. CONCLUSION: Tumour-like tissue extension in the extra-laryngeal soft tissues was accurate in predicting thyroid cartilage full-thickness invasion. Erosions of arytenoid, cricoid, and thyroid cartilages' inner cortex on CT were highly indicative of neoplastic infiltration. No CT difference in cartilage infiltration between primary and recurrent tumours was observed.

A critical evaluation of computed tomography-derived depth of invasion in the preoperative assessment of oral cancer staging.

BACKGROUND: Depth of invasion (DOI) has been introduced into the latest TNM classification of oral squamous cell carcinoma (OSCC). Despite its primarily pathological definition (pDOI), a preoperative evaluation of a radiological DOI (rDOI) would be useful but a standard and practical definition is lacking. The primary aim of this study is to measure the rDOI by computed tomography (CT) and compare it to the pDOI in a cohort of OSCC patients. Then, we analyze the utility and reliability of rDOI in the preoperative setting. METHODS: 58 cases of OSCC operated at our Institution from 2016 to 2019 were included. After accounting for plane-specific shrinkage factors and for different oral subsites, we have compared pDOI and rDOI for each spatial plane by paired difference test and correlation coefficient. Radiological accuracy and survival analysis were also determined to identify rDOI's clinical value. RESULTS: For lateral tongue, pDOI was more strongly related with axial rDOI (P < 0.01); for hard palate, the best plane was the sagittal one (P < 0.01); in floor of mouth (FOM) lesions, the strongest correlation was with coronal rDOI (P < 0.01), as well as for cheek buccal mucosa; sagittal scans seem to be the best to evaluate dorsum of the tongue and retromolar trigone; gingiva (P < 0.01) was most correctly evaluated in the coronal plane. Overall accuracy of rDOI restaging was 75.41%. Disease-free survival seems to be worse as rDOI increases. CONCLUSIONS: We suggest that with a standardized imaging protocol patients could be better classified according to CT-derived DOI.

The role of diffusion-weighted and dynamic contrast enhancement perfusion-weighted imaging in the evaluation of salivary glands neoplasms.

OBJECTIVES: To evaluate the association of magnetic resonance diffusion-weighted imaging (DwI) and dynamic contrast-enhanced perfusion-weighted imaging (DCE-PwI) with a temporal resolution of 5 s, wash-in < 120 s, and wash-out ratio > 30% in the evaluation of salivary glands neoplasms. METHODS: DwI and DCE-PwI of 92 salivary glands neoplasms were assessed. The apparent diffusion coefficient (ADC) was calculated by drawing three regions of interest with an average area of 0.30-0.40 cm2 on three contiguous axial sections. The time/intensity curve was generated from DCE-PwI images by drawing a region of interest that included at least 50% of the largest lesion section. Vessels, calcifications, and necrotic/haemorrhagic or cystic areas within solid components were excluded. The association of ADC ≥ 1.4 × 10-3 mm2/s with type A curves (progressive wash-in) and ADC 0.9-1.4 × 10-3 mm2/s with type C curves (rapid wash-in/slow wash-out) were tested as parameters of benignity and malignancy, respectively. Type B curve (rapid wash-in/rapid wash-out) was not used as a reference parameter. RESULTS: ADC ≥ 1.4 × 10-3 mm2/s and type A curves were observed only in benign neoplasms. ADC of 0.9-1.4 × 10-3 mm2/s and type C curves association showed specificity of 94.9% and positive predictive value of 81.8% for epithelial malignancies. The association of ADC < 0.9 × 10-3 mm2/s with type B and C curves showed diagnostic accuracy of 94.6% and 100% for Warthin tumour and lymphoma, respectively. CONCLUSIONS: ADC ≥ 1.4 × 10-3 mm2/s and type A curves association was indicative of benignity. Lymphomas exhibited ADC < 0.7 × 10-3 mm2/s and type C curves. The association of ADC < 0.9 × 10-3 mm2/s and type B and C curves had accuracy 94.6% and 88.5% for Warthin tumour and epithelial malignancies, respectively.

[Ventricular storm in a young man with primary hypokinetic dilated cardiomyopathy: why thinking of sarcoidosis?] / Storm ventricolare in un giovane con cardiomiopatia ipocinetico-dilatativa primitiva: perché pensare alla sarcoidosi.

The diagnostic approach to patients with cardiac sarcoidosis is challenging, as the disease may occur as a subclinical entity or have heterogeneous clinical manifestations ranging from ventricular arrhythmias to advanced cardiac failure. Therefore, while clinical suspicion remains key, imaging techniques such as nuclear magnetic resonance imaging and myocardial scintigraphy play an important confirmatory role. Final diagnosis requires histological proof on cardiac or extracardiac biopsy. A multidisciplinary context is essential for appropriate diagnosis, staging and management. We present the case of a young man with dilated cardiomyopathy in whom, following the onset of malignant and recurrent ventricular arrhythmias, a final diagnosis of cardiac sarcoidosis was reached based on a host of invasive and non-invasive diagnostic techniques, allowing tailored treatment.

Immunohistochemical profiling of mucins in sinonasal adenocarcinomas.

In this study we investigated the expression of mucins (MUC1, MUC2, MUC4, MUC5AC and MUC6) in a series of 66 sinonasal adenocarcinomas, in order to establish their distribution and the possible correlation with clinicopathological and prognostic parameters. The series included 51 intestinal type adenocarcinomas, 4 non-intestinal type adenocarcinomas, and 11 salivary gland type carcinomas. The immunohistochemical analysis was conducted on a tissue microarray obtained from formalin fixed-paraffin embedded tumor tissue samples. Thirty-nine adenocarcinomas (59.1%) resulted positive for MUC1, 21 (41.2%) for MUC2, 47 (71.2%) for MUC4, and 16 (24.2%) for MUC5AC, while MUC6 was negative in all cases tested. MUC1 was significantly more expressed in ITACs than in non-ITACs (70% vs 20%, p = 0.0007) while MUC2 was expressed only in ITACs (p = 0.0015) with a clear prevalence in the mucinous subtype (p < 0.0001). Conversely, MUC4 and MUC5AC were similarly expressed in the sinonasal adenocarcinoma subtypes tested. High expression of MUC 1 was related to a significantly shorter overall survival, both in the whole series (p = 0.04), while adenocarcinomas positive for MUC 2 tended to have a worse overall survival (p = 0.07). In addition, MUC2 expression was higher in ITACs with distant metastasis, being expressed in 4 out of 5 cases (p = 0.015). We conclude that sinonasal adenocarcinomas have a characteristic expression of different mucin types, with significant clinicopathologic correlations. In view of the extensive involvement of mucins in different aspects of tumor growth and their emerging role as possible therapeutic targets, our study suggests that these factors could be considered clinically relevant biomarkers and attractive targets for new treatments in sinonasal adenocarcinomas.

Telocytes constitute a widespread interstitial meshwork in the lamina propria and underlying striated muscle of human tongue.

Telocytes have recently emerged as unique interstitial cells defined by their extremely long, thin and moniliform prolongations termed telopodes. Despite growing evidence that these cells consistently reside in the stromal compartment of various organs from human beings, studies dealing with telocytes in structures of the oral cavity are scarce. Hence, the present morphologic study was undertaken to explore for the first time the presence and specific localization of telocytes within tissues of the normal human tongue, a complex muscular organ whose main functions include taste, speech, and food manipulation in the oral cavity. Telocytes were initially identified by CD34 immunostaining and confirmed by CD34/PDGFRα double immunofluorescence and transmission electron microscopy. CD34+/PDGFRα+ telocytes were organized in interstitial meshworks either in the tongue lamina propria or in the underlying striated muscle. Lingual telocytes were immunonegative for CD31, c-kit and α-SMA. Telopodes were finely distributed throughout the stromal space and concentrated beneath the lingual epithelium and around CD31+ vessels, skeletal muscle bundles/fibers, and intramuscular nerves and ganglia. They also enveloped salivary gland units outside the α-SMA+ myoepithelial cells and delimited lymphoid aggregates. These findings establish telocytes as a previously overlooked interstitial cell population worth investigating further in the setting of human tongue pathophysiology.

Phonosurgical Resection Using Submucosal Infusion Technique for Early Glottic Lesions: Diagnostic and Therapeutic Procedure?

OBJECTIVES:: The aim of this study was to assess the feasibility of the submucosal infusion combined with microflap dissection via laser CO2 as both a diagnostic and therapeutic procedure for superficial glottic lesions. To define a safe surgical procedure in terms of local control, a morphometric study of surgical margins was performed. METHODS:: From January 2011 to January 2016, we treated 122 patients with early glottic lesions with phonomicrosurgery. Patients with effective hydrodissection underwent a microflap and type I-II diagnostic cordectomy. In the others, a biopsy was carried out, and in the case of a malignant lesion, a type III to VI cordectomy was performed. Disease-free survival (DFS) for all the lesions was also determined according to comparative assessments of surgical margins. The Voice Handicap Index was used to evaluate functional outcomes. RESULTS:: In 27 cases (32%), hydrodissection was effective; specifically, 24 (88.8%) were premalignant lesions, and 3 (11.2%) had a carcinoma. In 56 patients (68%), hydrodissection was not adequate, and a biopsy was performed: 9 (16%) were premalignant and 47 (84%) malignant lesions. The DFS analysis suggests that margins >0.7 mm resulted in a cutoff that can guarantee a safe procedure in the case of effective hydrodissection ( P < .05). CONCLUSION:: Phonomicrosurgery may be both a diagnostic and therapeutic option with oncological efficacy for superficial glottic lesions of undetermined nature when surgical margins exceed 0.7 mm. In case of inadequate hydrodissection, the hypothesis of an infiltrative carcinoma warrants a wider cordectomy.

A Critical Reappraisal of Primary and Recurrent Advanced Laryngeal Cancer Staging.

OBJECTIVES:: Laryngeal squamous cell carcinoma (LSCC) can involve different anatomic subunits with peculiar surgical and prognostic implications. Despite conflicting outcomes for the same stage of disease, the current staging system considers different lesions in a single cluster. The aim of this study was to critically discuss clinical and pathologic staging of primary and recurrent advanced LSCC in order to define current staging pitfalls that impede a precise and tailored treatment strategy. METHODS:: Thirty patients who underwent total laryngectomy in the past 3 years for primary and recurrent advanced squamous cell LSCC were analyzed, comparing endoscopic, imaging, and pathologic findings. Involvement of the different laryngeal subunits, vocal-fold motility, and spreading pattern of the tumor were blindly analyzed. The diagnostic accuracy and differences between clinicoradiologic and pathologic findings were studied with standard statistical analysis. RESULTS:: Discordant staging was performed in 10% of patients, and thyroid and arytenoid cartilage were the major diagnostic pitfalls. Microscopic arytenoid involvement was significantly more present in case of vocal-fold fixation ( P = .028). Upstaging was influenced by paraglottic and pre-epiglottic space cancer involvement, posterior commissure, subglottic region, arytenoid cartilage, and penetration of thyroid cartilage; on the contrary, involvement of the inner cortex or extralaryngeal spread tended to be down-staged. Radiation-failed tumors less frequently involved the posterior third of the paraglottic space ( P = .022) and showed a significantly worse pattern of invasion ( P < .001). CONCLUSIONS:: Even with the most recent technologies, 1 in 10 patients with advanced LSCC in this case series was differently staged on clinical examination, with cartilage involvement representing the main diagnostic pitfall.

Primary parapharyngeal leiomyosarcoma: A case report.

Leiomyosarcoma is a rare malignant soft-tissue tumor whose cells resemble smooth-muscle tissue. It has been reported to arise in different areas of the head and neck region. Primary leiomyosarcoma of the parapharyngeal space, however, is extremely rare, as only 4 cases have been previously reported to date. We describe the somewhat urgent case of a primary leiomyosarcoma of the right parapharyngeal space in a 30-year-old man. We also review the diagnostic and therapeutic challenges that clinicians face in managing this rare tumor.

Frequent expression of somatostatin receptor 2a in olfactory neuroblastomas: a new and distinctive feature.

Olfactory neuroblastoma (ONB) is a malignant neuroendocrine neoplasm with a usually slow course, but with considerable recurrence rate. Many neuroendocrine tumors have shown good response to the treatment with somatostatin analogs and somatostatin radioreceptor therapy. In ONBs, there are scarce data on somatostatin-based treatment and the cellular expression of somatostatin receptors (SSTR), the prerequisite for binding and effect of somatostatin on normal and tumor cells. The aim of our study was to investigate the immunohistochemical expression of SSTR2A and SSTR5 in a cohort of 40 ONBs. In addition, tissue microarrays containing 40 high-grade sinonasal carcinomas as well as 6 sinonasal lymphomas, 3 rhabdomyosarcomas, and 3 Ewing sarcomas were evaluated. Volante system was applied for staining evaluation. Thirty cases (75%) were immunopositive for SSTR2A and 3 (7.5%) for SSTR5. Among the 30 SSTR2A-positive ONBs, 19 tumors (63.3%) scored 2+ and 11 (36.7%) scored 3+. All SSTR5-positive ONBs scored 2+. Neither sinonasal carcinomas nor sinonasal small round blue cell neoplasms expressed SSTR2A or SSTR5. The frequent expression of SSTR2A provides a rationale for radioreceptor diagnosis and therapy with SST analogs in ONBs. SSTR2A expression in ONBs is a helpful adjunct in the differential diagnosis of ONBs.

RANK and RANK Ligand Expression in Parotid Gland Carcinomas.

Recently, it has been reported that deregulation of the receptor activator of NFkB ligand (RANKL)/RANK signaling axis results in salivary gland tumor development in a mouse transgenic model. The aim of this study was to ascertain RANKL and RANK protein expression in a series of primary parotid gland carcinomas and to correlate it with clinicopathologic parameters. Formalin-fixed paraffin-embedded tumor samples from 46 consecutive cases of parotid gland carcinoma were selected for this study. For comparison, we examined a group of 40 randomly chosen parotid gland adenomas, including 20 pleomorphic adenomas, 10 myoepitheliomas, and 10 Warthin tumors. Immunohistochemical analysis for RANK and RANKL was conducted on tissue microarrays. Overall, 33 carcinomas (71.7%) were scored as positive for RANK and 25 (54.3%) for RANKL. The expression of both RANK and RANKL was significantly higher in carcinomas than in adenomas as only 6 (15%) adenomas were positive for RANK, and RANKL was negative in all benign tumors (P<0.001 for both, Fisher exact test). Some histologic types, including salivary duct carcinoma, mucoepidermoid carcinoma, and carcinoma ex-pleomorphic adenoma presented a high frequency of RANK and RANKL expression. No significant correlation was observed between RANK/RANKL expression and clinical parameters. Our study indicates that the expression of RANK and RANKL in parotid gland neoplasms is associated with the acquisition of a malignant phenotype and this pathway may represent an attractive therapeutic target in patients with parotid gland carcinomas.

Claw foot A case report.

A cutaneous horn could be defined as a conical projection on the surface of skin made of cornified material and resembling an animal horn. These lesions most commonly affect light-skinned men aged between 50 to 89 years and usually appear in sun exposed areas. Radiation, chronic irritation and even human papilloma virus-2 infection may be precipitating factors. More than half of the cases originate from either malignant or premalignant lesions, therefore the base of the lesion must be carefully examined histologically. Long standing presence of the lesion, conspicuous protrusion of the horn and pain are positive predictive factors for malignancy and invasivity. In these cases an invasive surgical approach is needed. KEY WORDS: Basal cell carcinoma, Cancer, Clow foot, Non melanoma skin cancer, Skin cancer.

Miescher's cheilitis: Surgical management and long term outcome of an extremely severe case.

INTRODUCTION: Miescher's cheilitis is clinically characterized by persistent swelling of the lip(s). Its pathogenesis is still unknown. Histopathologically is characterized by sub-epithelial edema, increased number of dilated lymphatic vessels and an inflammatory infiltrate and/or non-caseating/non- necrotic granulomas. Even if the disorder must be controlled by medical therapy, surgery may be required to treat most severe cases. PRESENTATION OF THE CASE: We report a 30-year-old man who presented a persistent swelling of both lips since 8 years, previously treated with intralesional steroid and immunosuppressive therapy. Clinical examination did not show facial nerve palsy or other associated conditions. On the base of clinical and histopathological findings, a diagnosis of Miescher's syndrome was made. Patient underwent Conway's reduction cheilopasty repaired with local flaps. At one-year follow-up, the patient does not show local recurrence of the deformity; both oral continence and lip sensation are preserved. DISCUSSION: Because of its extreme rarity and unknown etiopathogenesis, Miescher's cheilitis receives poor attention and may often remain misdiagnosed. Several medical therapies are proposed, in particular steroids and immunosuppression. Even if medical therapy remains the main treatment, surgery may be required. CONCLUSION: Satisfactory results have been obtained combining medical therapy and surgical approach.