[Diagnosis, prognosis and treatment of sinonasal carcinomas (excluding melanomas, sarcomas and lymphomas)]. / Diagnostic, pronostic et traitement des carcinomes nasosinusiens (hors mélanomes, sarcomes et lymphomes).

Sinonasal carcinomas account for 3% of ENT cancers. They are subdivided into squamous cell carcinomas (50%), adenocarcinomas [20%, mostly of intestinal type (ITAC)], and more rarely, adenoid cystic carcinomas, olfactory neuroblastomas (=esthesioneuroblastomas), neuroendocrine carcinomas or undifferentiated sinonasal carcinomas (SNUC). The 5-year survival rates are, in descending order, 72% for neuroblastomas, 63% for adenocarcinomas, 50-60% for large-cell neuroendocrine carcinomas, 53% for squamous cell carcinomas, 25-50% for adenoid cystic, 35% for small-cell neuroendocrine carcinomas and 35% for SNUC and newly discovered histologies. Surgery is the main treatment; endoscopic approaches reduce the morbidity with equivalent tumour control. Intensity-modulated radiation therapy (IMRT) is almost systematic. Nodal involvement is rare in ethmoidal adenocarcinomas and adenoid cystic carcinomas; it is intermediate and may justify prophylactic radiotherapy for N0 necks in SNUC, neuroblastoma, squamous cell carcinomas and sinonasal neuroendocrine carcinomas. IMRT or proton therapy is the mainstay of treatment of unresectable disease. Radiotherapy optimization by carbon ion therapy for adenoid cystic carcinomas, or by chemotherapy for all carcinomas with IMRT or proton therapy, is investigated within clinical trials in France. Neoadjuvant chemotherapy is reserved for rapidly progressive disease or histologies with a high metastatic potential such as neuroendocrine carcinomas or SNUC. Given their histologic and molecular specificities and different relapse patterns, an expertise of the REFCOR network, with REFCORpath review, is likely to correct diagnoses, rectify treatments, with an impact on survival.

Clinicopathologic and Molecular Features of a Series of 41 Biphenotypic Sinonasal Sarcomas Expanding Their Molecular Spectrum.

Biphenotypic sinonasal sarcoma (BSNS) is a locally aggressive tumor occurring in the sinonasal region. It harbors both myogenic and neural differentiation and is characterized by PAX3 rearrangement with MAML3 as the most frequent fusion partner, but the partner of PAX3 remains unidentified in a subset of cases. About 70 cases have been reported so far. In this study, we report a series of 41 cases with clinical, pathologic, and molecular description. Twenty-five (61%) patients were female individuals, and the median age was 49 years. Tumors arose predominantly in the nasal cavity and ethmoidal sinuses. Local recurrences occurred in 8 cases of the 25 (32%). Histologic features were characteristic of BSNS, with 5 cases showing focal rhabdomyoblastic differentiation. Immunohistochemistry showed a constant positivity of S100 protein and PAX3 and negativity of SOX10. MyoD1 was focally positive in 91% of cases, whereas only 20% were positive for myogenin. Molecular analysis showed a PAX3-MAML3 transcript in 37 cases (90%). RNA sequencing was performed in the 4 negative cases for PAX3-MAML3 fusion, and it showed that 1 case harbored a PAX3-FOXO1 fusion, as previously described in the literature, and 2 novel fusions: PAX3-WWTR1 fusion in 2 cases and PAX3-NCOA2 fusion in 1 case. RNA sequencing results were confirmed by fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and Sanger sequencing. The PAX3-NCOA2-positive case showed focal rhabdomyoblastic differentiation. In conclusion, we report 2 novel fusions (PAX3-WWTR1 and PAX3-NCOA2) in BSNS and show that MyoD1 is more sensitive than myogenin for demonstrating myogenic differentiation in this tumor.

[Diagnostic and treatment pitfalls and guidelines for variants of squamous cell carcinomas of the head and neck: on behalf of the REFCOR]. / Variants des carcinomes épidermoïdes dans les voies aérodigestives supérieures (VADS), implications pour le diagnostic et la prise en charge, selon les référentiels du REFCOR.

Among the 20,000 new cases of head and neck neoplasms in France each year, squamous cell carcinomas (HNSCC) represent about 90 % of the cases. Among these, variants of conventional squamous cell carcinomas represent between 5% and 10% of cases. Patient history and risk factors are often similar from those of conventional HSNCC. Variants may, however, be misdiagnosed, which can lead to therapeutic mismanagement due to confusion with sarcomas, glandular tumors or even benign tumors. Diagnostic workup needs to be more cautionary or to include additional exams not to omit their most aggressive component in the case of composite tumors or to under stage the tumor. Immunohistochemistry and specific molecular analyses may be required for proper diagnosis. Central pathological review may also be essential for some of these variants. In addition, some variants are radioresistant and, conversely, others are radiosensitive. An update of the REFCOR 2008 standards was carried out in the light of the international literature and the 2017 WHO/IARC classification for the seven main variants of HNSCC, verrucous, acantholytic (to be named adenoid carcinomas), basaloid, papillary, spindle cell (incorrectly named sarcomatoid), adenosquamous and lymphoepithelial carcinomas.

[Mucosal melanomas of the head and neck: State of the art and current controversies]. / Mélanomes muqueux de la tête et du cou : état actuel des pratiques et controverses.

Mucosal melanomas of the head and neck (sinonasal and oral cavity) account for 1% of neoplasms, 4% of all melanomas and over 50% of all mucosal melanomas. They have a high metastatic potential. Five-year overall survival does not exceed 30%. Diagnosis may be difficult and includes adequate immunohistochemical staining. Risk factors, presentation and molecular biology are different from those of cutaneous melanomas. The mainstay of treatment is surgery and postoperative radiotherapy. Endoscopic surgery should be evaluated prospectively. Neck dissection is recommended for N0 oral cavity melanomas, while it can generally be omitted for sinonasal melanomas. Inoperable tumors can be treated with exclusive radiotherapy. Molecular guidance for metastatic cases is a relevant option despite low level of evidence, based on the rarity of disease and low response rates to chemotherapy. c-KIT inhibitors and immunotherapy appear promising.

[Rare tumors of the head and neck; on behalf of the REFCOR, the French Network of rare head and neck tumors]. / Cancers ORL rares et REFCOR, Réseau d'expertise français sur les cancers ORL rares.

Malignant tumors of the upper aerodigestive tract may be rare by their histology (sarcoma, variants of conventional squamous cell carcinomas) and/or location (sinuses, salivary glands, ear, of various histologies themselves). They represent less than 10% of head and neck neoplasms. The confirmation of their diagnosis often requires a medical expertise and sometimes biomolecular techniques complementary to classical histology and immunohistochemistry. Due to their location, their treatment often requires a specific surgical technique. Radiation therapy is indicated based on histoclinical characteristics common to other head and neck neoplasms but also incorporate grade. Further, the technique must often be adapted to take into account the proximity of organs at risk. For most histologies, chemotherapy is relatively inefficient but current molecular advances may allow to consider pharmaceutical developments in the coming years. The REFCOR, the French Network of head and neck cancers aims to organize and promote the optimal management of these rare and heterogeneous diseases, to promote research and clinical trials.

[Pathologists and the French network of expertise on rare cancers ENT: The REFCORpath]. / Les pathologistes et le réseau d'expertise français sur les cancers ORL rares: le REFCORpath.

Aerodigestive tract tumors are very diverse, either in terms of location, or histologically. Also, this heterogeneity poses particular problems for the histological diagnosis but also for the establishment of the most appropriate treatment. Thus, the network REFCOR (réseau d'expertise français sur les cancers ORL rares/French expert network on rare ENT cancers) was created to better understand these issues, by proposing an epidemiological and diagnostic approach with research collaborations. This network is dedicated to all primary malignant tumors of the salivary glands, ear, nasal cavity and sinuses and all head and neck malignancies other than conventional squamous cell carcinoma. The REFCORpath network consists of expert pathologists and offers, through a network of scanned images, a second opinion or even a third.

A rationale for chemoradiation (vs radiotherapy) in salivary gland cancers? On behalf of the REFCOR (French rare head and neck cancer network).

BACKGROUND: Salivary gland carcinomas constitute a heterogeneous group of tumors, with over 20 histological subtypes of various prognoses. The mainstay of treatment is surgery, with radiotherapy advocated for unresectable disease or postoperatively in case of poor prognostic factors such as high grade, locally advanced and/or incompletely resected tumors. Concurrent chemotherapy is sometimes advocated in routine practice based on criteria extrapolated from squamous cell carcinomas of the head and neck, on radioresistance of salivary gland tumors and on results obtained in the metastatic setting. The aim of this review was to identify situations where chemotherapy is advocated. MATERIAL AND METHODS: A search of literature was performed with the following key words: parotid, salivary gland, neoplasm, cancer, malignant tumor, chemoradiation, chemotherapy, radiotherapy and treatment. Case report and studies published before 2000 were not included. RESULTS: Platinum-based regimens were the most frequent. Other regimens were reported and seemed dependent on histology. The level of evidence for the concurrent delivery of chemotherapy with radiation therapy is supported by a low level of evidence. Prescribing chemotherapy mostly relies on poor prognostic factors similar to those used to indicate high dose radiotherapy. Protocols vary with histology. CONCLUSION: The rationale for adding chemotherapy to radiotherapy remains to be demonstrated prospectively. Although the type of systemic treatments used may be adapted on histology, the strongest rationale remains in favor of cisplatin.

Newly visualized fibrillar collagen scaffolds dictate Entamoeba histolytica invasion route in the human colon.

The extracellular matrix (ECM) and its role in the outcome of infectious diseases have been poorly investigated. In this study, we determined the impact of the collagen fibres architecture on the invasive process of the enteric parasite Entamoeba histolytica. The behaviour of E. histolytica wild-type and silenced for the cysteine protease A5 (CP-A5) were compared on a three-dimensional collagen matrix and within human colon fragments for fibrillar collagen cleavage and migration. The interstitial collagen fibres within the connective tissue of the human colon, visualized by multiphoton and second harmonic generation signals imaging, presented a dense scaffold at the subepithelial level and a loose meshwork within the chorion. To penetrate the tissue, E. histolytica migrated on the dense scaffold that remained intact, reached the crypt of Lieberkhün, migrated along and then disorganized the loose scaffold to escape into the mucosa. Interestingly, in vitro, CP-A5 was not required for collagenase activity and migration through the matrix but was necessary within the tissue environment for collagen meshwork remodelling and subsequent invasion. The data point out that further step of invasion relay with ECM destruction that requires human components induced or activated in the presence of CP-A5.

[Myocardial involvement in invasive aspergillosis]. / Myocardite aspergillaire.

We report the case of a 48-year-old female patient who had a Crohn's disease treated by corticosteroids. The patient developed severe cardiac failure, which was refractory to treatment with inotropic agents. At necropsy, examination of the heart revealed myocardial abscesses. On microscopic study, we diagnosed an aspergillar myocarditis. Aspergillar myocarditis is a rare and fatal localisation in disseminated aspergillosis. Diagnosis is difficult and treatment, usually initiated late, is ineffective.

An ex-vivo human intestinal model to study Entamoeba histolytica pathogenesis.

Amoebiasis (a human intestinal infection affecting 50 million people every year) is caused by the protozoan parasite Entamoeba histolytica. To study the molecular mechanisms underlying human colon invasion by E. histolytica, we have set up an ex vivo human colon model to study the early steps in amoebiasis. Using scanning electron microscopy and histological analyses, we have established that E. histolytica caused the removal of the protective mucus coat during the first two hours of incubation, detached the enterocytes, and then penetrated into the lamina propria by following the crypts of Lieberkühn. Significant cell lysis (determined by the release of lactodehydrogenase) and inflammation (marked by the secretion of pro-inflammatory molecules such as interleukin 1 beta, interferon gamma, interleukin 6, interleukin 8 and tumour necrosis factor) were detected after four hours of incubation. Entamoeba dispar (a closely related non-pathogenic amoeba that also colonizes the human colon) was unable to invade colonic mucosa, lyse cells or induce an inflammatory response. We also examined the behaviour of trophozoites in which genes coding for known virulent factors (such as amoebapores, the Gal/GalNAc lectin and the cysteine protease 5 (CP-A5), which have major roles in cell death, adhesion (to target cells or mucus) and mucus degradation, respectively) were silenced, together with the corresponding tissue responses. Our data revealed that the signalling via the heavy chain Hgl2 or via the light chain Lgl1 of the Gal/GalNAc lectin is not essential to penetrate the human colonic mucosa. In addition, our study demonstrates that E. histolytica silenced for CP-A5 does not penetrate the colonic lamina propria and does not induce the host's pro-inflammatory cytokine secretion.

[Handling of neck dissection in head and neck tumours]. / Prise en charge des curages ganglionnaires cervicaux en pathologie tumorale ORL.

The presence of metastases in cervical lymph nodes (except distant metastasis) is the most significant independent prognostic factor in carcinoma of the head and neck. The purpose of this article is firstly to review the anatomy of the neck compartments, the types of neck dissection and secondly to describe recommendations for the technical procedures required and thus to provide a full informative report to optimise management by the clinician.

Expression of the granzyme B inhibitor PI9 predicts outcome in nasal NK/T-cell lymphoma: results of a Western series of 48 patients treated with first-line polychemotherapy within the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials.

Nasal NK/T-cell lymphoma is a rare disease entity with a poor outcome. Expression of antiapoptotic proteins has not been extensively investigated in this entity. Forty-eight patients with nasal T/NK-cell lymphoma who received first-line polychemotherapy (n = 44) or chemoradiotherapy (n = 4) were analyzed for expression of active caspase-3 (aC3), granzyme B protease inhibitor 9 (PI9), and Bcl-2 proteins. Lymphomas were CD3+/CD5-/granzyme B+ and EBV-associated. Median age was 46 years. Stage I/II disease was present in 75% of the cases and an International Prognostic Index (IPI) score less than 1 in 65%. With a median follow-up of 6.3 years, 5-year event-free survival (EFS) and overall survival (OS) rates were 39% and 49%, respectively. Apoptotic index was scored as high in 32% of cases and PI9 expression as positive in 68%, whereas 35% disclosed a high number of aC3+ tumor cells. Univariate analysis showed that absence of PI9 and low apoptotic index were associated with poor outcome, but not aC3 expression nor IPI score. By multivariate analysis, both parameters affected independently EFS (P = .02 and .08, respectively) and OS (P = .009 and .04). In view of its constitutive expression by normal NK cells, it is suggested that loss of PI9 expression in tumor cells may reflect some mechanism associated with progression.

Expression of CXCL13 by neoplastic cells in angioimmunoblastic T-cell lymphoma (AITL): a new diagnostic marker providing evidence that AITL derives from follicular helper T cells.

Angioimmunoblastic T-cell lymphoma (AITL) represents a distinct entity among peripheral T-cell lymphomas (PTCLs). The cellular origin of AITL remains unknown, although a possible derivation from follicular helper T cells (TFH) has been suggested based on the CD4/Bcl-6 phenotype. It has been recently shown that expression of CXCL13, a chemokine critically involved in B-cell migration into germinal centers, is characteristic of TFH cells, as compared with other T helper subsets. We compared CXCL13 expression in 29 AITLs, 20 PTCLs, unspecified, 10 anaplastic large cell lymphomas (ALCL), and 4 other PTCLs. We showed that CXCL13 is expressed by AITL (29 of 29, 100%) and a subset of PTCL, unspecified (6 of 20, 30%), which all showed borderline features with AITL, but in only 1 of 10 (10%) ALCLs, and 0 of 4 other PTCLs. Two-color immunostainings further showed that CXCL13 was found in the cytoplasm of atypical CD5-positive T cells that expressed CD10. We conclude that CXCL13 expression is a common characteristic of AITL, which can help to delineate the morphologic spectrum of the disease, and further supports its derivation from TFH cells. CXCL13 expression may also provide an additional useful tool for the diagnosis of AITL.

Radiofrequency in the treatment of craniofacial plexiform neurofibromatosis: a pilot study.

BACKGROUND: Neurofibromatosis type 1 manifests itself by the development of plexiform neurofibromas, with craniofacial deformities caused by bone alterations and soft-tissue infiltration. The medical treatment of this disease is disappointing, and the surgical management of these deformities calls for aggressive procedures. There is a strong risk of recurrence. METHODS: A pilot study was performed to test radiofrequency as a minimally invasive method with which to diminish the size of craniofacial neurofibromas either as an adjunct to craniofacial surgery (in cranio-orbital neurofibromas) or to avoid a visible scar in young patients (in infraorbital neurofibromas). Five patients ranging in age from 6 to 18 years were treated by three procedures 2 months apart using radiofrequency performed under local anesthesia or under sedation for the youngest patients. RESULTS: The tolerance of the treatment was excellent, with no major side effects and no pain in the postoperative course. A diminution of the size of the lesion was noted clinically in four patients and on computed tomography in two patients. A biopsy performed in one case illustrated the effect of the treatment. CONCLUSIONS: A partial diminution or stabilization of plexiform neurofibromas may be obtained using radiofrequency. This treatment is well tolerated. The best effect can be observed in the early stages of the disease. The optimal dose and frequency of the procedure require further study.

Brain damage after heat stroke.

Cerebellar syndromes and radiologic cerebellar atrophy after hyperpyrexia have occasionally been reported, mostly in neuroleptic malignant syndromes, but neuropathologic studies are extremely rare. We studied 3 patients (a 74-year-old woman, a 63-year-old man, and an 80-year-old man) who had heat stroke during heat waves in France. One patient had generalized seizures and died 28 hours after admission. The other patients survived one month and 2 months after admission; both had palatal myoclonus, and in one case, magnetic resonance imaging showed high signal intensity in the cerebral peduncles. The main neuropathology in the 3 cases was severe diffuse loss of Purkinje cells associated with heat shock protein 70 expression by Bergmann glia. In situ end labeling was negative in surviving Purkinje cells, suggesting that the mechanism of neuronal death was not apoptosis. Degeneration of Purkinje cells axons resulted in myelin pallor of the white matter of the folia and of the hilum of the dentate nuclei. DNA internucleosomal breakages were identified by in situ end labeling in the dentate nuclei and centromedian nuclei of the thalamus and were associated with degeneration of the cerebellar efferent pathways: superior cerebellar peduncles, decussation of the superior cerebellar peduncles (Wernekinck commissure), and dentatothalamic tract. These findings suggest that the mechanisms of neuronal death in the dentate nuclei and centromedian nuclei of the thalamus was different from that in Purkinje cells and more likely resulted from deafferentation. Ammon's horn and other areas susceptible to hypoxia were spared. These observations confirm the selective vulnerability of Purkinje cells to heat-induced injury and involvement of the cerebellar efferent pathways in palatal myoclonus.

[Value of the antibody cocktail anti p63 + anti p504s for the diagnosis of prostatic cancer]. / Apport d'un cocktail d'anticorps anti-(p63 + p504s) dans le diagnostic de cancer de prostate.

UNLABELLED: Numerous lesions of the prostate, such as atrophy, adenomatous atypical hyperplasia (adenosis) or PIN can be misdiagnosed with prostatic cancer, and confused with ASAP, leading to perform additional biopsies. In such lesions, the pathologist can perform an immunohistochemical study with the anti-high molecular weight cytokeratin antibody CK903 (34bE12), which confirms the absence of basal cells and supports the diagnosis of prostatic cancer. AIM OF THE STUDY: To compare markers of basal cells (cytokeratin 5/6, p63) and the marker of prostatic carcinomatous glands (p504s) or alpha methylacyl-CoA racemase (AMACR). MATERIAL AND METHODS: Retrospective study of 44 cases of paraffin-embedded prostatic specimens (36 biopsies, 4 PER, 1 adenomectomy and 3 radical prostatectomies), consisting in 20 cases of prostatic carcinomas (2 intraductal, 12 Gleason 6 (3+3), 4 Gleason 7 (4+3), 2 Gleason 8 (4+4)), 11 ASAP, 9 PIN (2 low grade, 7 high grade (2 isolated)), and 10 benign lesions (8 atrophy, 1 atypical adenomatous hyperplasia and 1 case of clear cell cribriform hyperplasia). All cases were tested with antibodies to CK 5/6, and with a cocktail to p63 and p504s, after heat antigenic retrieval on NEXES Ventana processor. RESULTS: Basal cells of normal prostatic glands stained with CK5/6 and p63 in 91,3% and 100% of cases, independently from the fixation procedure (Bouin or Formalin). Carcinomas had a p63-/p504s+ profile, PIN were p63+/p504s+, and benign lesions were p63+/p504s-. We observed an increase in sensitivity: p63/p504s (100%), CK5/6 (80%), p63 (90%), p504s (95%), and specificity: p53/p504s (90%), CK5/6 (87.5%), p63 (90.5%), p504s (90.9%). CONCLUSION: Our results show that the use of a cocktail to p63/p504s is more specific than the use of CK5/6 alone this technique supports a diagnosis of prostatic cancer in 40% of cases previously considered as ASAP.

Primary chronic interstitial nephritis in Crohn's disease.

BACKGROUND & AIMS: In Crohn's disease, cases of interstitial nephritis with renal failure have been reported in connection with the use of mesalamine. METHODS: We observed 4 patients with severe interstitial nephritis proven by examination of kidney biopsy specimens. Renal failure was discovered before or simultaneously with the diagnosis of Crohn's disease, and patients were not treated with mesalamine. Impairment of renal function progressed to end-stage renal failure in 3 of the 4 patients. RESULTS: Our results show that the kidney can be an extraintestinal target of Crohn's disease. CONCLUSIONS: Several unanswered questions remain concerning the frequency of interstitial nephritis in patients with Crohn's disease, as well as the exact role of mesalamine in the development of chronic interstitial nephritis.