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This morphological and immunohistochemical study demonstrates that tumors currently known as "middle ear adenomas" are truly well-differentiated epithelial neuroendocrine tumors (NETs) composed of cells comparable to normal intestinal L cells, and therefore, these tumors resemble hindgut NETs. These tumors show consistent expression of glucagon, pancreatic polypeptide, PYY, and the transcription factor SATB2, as well as generic neuroendocrine markers and keratins. The same L cell markers are expressed by cells within the normal middle ear epithelium. These markers define a valuable immunohistochemical profile that can be used for differential diagnosis of middle ear neoplasms, particularly in distinguishing epithelial NETs from paragangliomas. The discovery of neuroendocrine cells expressing the same markers in non-neoplastic middle ear mucosa opens new areas of investigation into the physiology of the normal middle ear and the pathophysiology of middle ear disorders., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Patients with non-supernumerary ring chromosome 7 syndrome have an increased incidence of hemangiomas, café-au-lait spots, and melanocytic nevi. The mechanism for the increased incidence of these benign neoplasms is unknown. We present the case of a 22-year-old man with ring chromosome 7 and multiple melanocytic nevi. Two nevi, one on the right ear and the other on the right knee, were biopsied and diagnosed as desmoplastic Spitz nevi. Upon targeted next-generation DNA sequencing, both harbored BRAF fusions. Copy number alterations and fluorescence in situ hybridization (FISH) for BRAF suggested that the fusions arose on the ring chromosome 7. Hence, one reason for increased numbers of nevi in patients with non-supernumerary ring chromosome 7 syndrome may be increased likelihood of BRAF fusions, due to the instability of the ring chromosome., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

After dedicated CT and MRI, Ga-DOTATATE PET/CT was performed in a patient with a temporal bone mass with primary diagnostic considerations of an endolymphatic sac tumor versus a glomus jugulotympanicum paraganglioma. The Ga-DOTATATE PET showed mild radiotracer uptake in the mass (SUVmax, 10.9). After surgical resection, pathology revealed an endolymphatic sac tumor. Immunohistochemical staining demonstrated somatostatin receptor type 2A expression in the vasculature of the mass, but not in the tumor cells.

Purpose: Synchrotron microbeam radiation therapy (MRT) is a method that spatially distributes the x-ray beam into several microbeams of very high dose (peak dose), regularly separated by low-dose intervals (valley dose). MRT selectively spares normal tissues, relative to conventional (uniform broad beam [BB]) radiation therapy., Methods and Materials: To evaluate the effect of MRT on radioresistant melanoma, B16-F10 murine melanomas were implanted into mice ears. Tumors were either treated with MRT (407.6 Gy peak; 6.2 Gy valley dose) or uniform BB irradiation (6.2 Gy)., Results: MRT induced significantly longer tumor regrowth delay than did BB irradiation. A significant 24% reduction in blood vessel perfusion was observed 5 days after MRT, and the cell proliferation index was significantly lower in melanomas treated by MRT compared with BB. MRT provoked a greater induction of senescence in melanoma cells. Bio-Plex analyses revealed enhanced concentration of monocyte-attracting chemokines in the MRT group: MCP-1 at D5, MIP-1α, MIP-1β, IL12p40, and RANTES at D9. This was associated with leukocytic infiltration at D9 after MRT, attributed mainly to CD8 T cells, natural killer cells, and macrophages., Conclusions: In light of its potential to disrupt blood vessels that promote infiltration of the tumor by immune cells and its induction of senescence, MRT could be a new therapeutic approach for radioresistant melanoma., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Primary cutaneous acral CD8+ T-cell lymphoma (TCL) is a rare, distinct type of cutaneous TCL. Despite its worrisome histological appearance it has a benign clinical course. It is therefore important to recognize this as a distinct entity from other more aggressive CD8+ lymphomas, for which the management is very different., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background/aim: The rabbit auricular VX2 carcinoma is an established animal model for human head and neck squamous cell carcinoma (HNSCC). Previously, we observed that intraperitoneal oxidative (O 3 /O 2 ) stress induced tumor remission. Our aim was to evaluate candidate genes associated with tumor regression., Materials and Methods: For identification of tumor remission-related genes, microarray analysis was performed with subsequent validation by polymerase chain reaction (PCR), in situ hybridization, immunohistochemistry and western blot analysis., Results: Microarray analysis indicated a prominent reduction of epidermal growth factor receptor (Egfr, Erbb1) expression levels in regressing tumors. Quantitative PCR confirmed a significant (p<0.005) down-regulation of Erbb1-3 mRNA in regressing VX2 tumors. Histological localization of Erbb1-3 mRNA transcript and protein indicated reduced Erbb gene expression occurring at the level of individual VX2 tumor cells rather than solely being an effect of tumor shrinkage. This study highlights changes in the Erbb gene signature of regressing VX2 carcinomas as a predictor for therapy response. The VX2 carcinoma animal model, therefore, appears suitable for the identification and evaluation of new diagnostic, prognostic and therapeutic biomarkers prior to their application in patients with HNSCC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Temporal bone squamous cell carcinoma (TBSCC) is an uncommon, aggressive malignancy with a poor prognosis in advanced cases. The dismal outcome is partially related to: the lack of reliable clinical or pathological prognostic factors and the largely unstandardized surgical and integrated treatments adopted. There is an undeniable need for novel diagnostic/therapeutic strategies to improve the prognosis. The purpose of this critical review was to explore the level of available knowledge concerning the molecular markers involved in the biology of TBSCC that have a prognostic potential. The Pub-Med and Scopus electronic databases were searched without publication date limits for studies investigating molecular markers in cohorts of patients with primary TBSCC. The search terms used were: "temporal bone cancer", "temporal bone carcinoma", "temporal bone malignancy", "ear cancer", "ear carcinoma", and "ear malignancy". We decided preliminarily not to consider series with less than five cases. Nine retrospective case series of TBSCC were found in which different analytical techniques had been used to study the role of several biomarkers (HPV, vimentin, transforming growth factor β, CD105, RECK, matrix metalloproteinase-9, MASPIN, EBV, p16, TP53 mutation, pSTAT3, relaxin-2). CD105 expression (in tumor vessel endothelial cells) and MASPIN cytoplasmic expression (in carcinoma cells) were, respectively, found directly and inversely related with the neoplasm's recurrence rate. CD105 expression was also inversely related with disease-free survival in TBSCC. A future goal of such analyses should be to ascertain the radio- and chemo-sensitivity profiles of individual TBSCCs, enabling truly personalized therapies. A further, more ambitious goal will be to find targets for therapeutic agents that might prove crucial in improving the disease-specific survival for patients with advanced TBSCC.

Objectives/hypothesis: The purpose of the present study is to explore, demonstrate, and describe the expression of genes related to the innate immune system in the human endolymphatic sac. It is hypothesized that the endolymphatic sac has a significant immunological function in the human inner ear., Study Design: DNA microarrays and immunohistochemistry were used for analyses of fresh human endolymphatic-sac tissue samples., Methods: Twelve tissue samples from the human endolymphatic sac were obtained during translabyrinthine surgery for vestibular schwannoma. Microarray technology was used to investigate tissue sample gene expression using adjacent dura mater as control. The expression of genes specific for the innate immune system was determined and results for selected key molecules verified by immunohistochemistry., Results: A comprehensive overview of expressed genes of the innate immune system was obtained. Multiple key elements of both the cellular and humoral innate immune system were expressed, including Toll-like receptors 4 and 7, as well as beta-defensin and lactoferrin., Conclusions: The present data provides the first direct evidence of an immunological capacity of the human endolymphatic sac. At the molecular level, the endolymphatic sac is capable of antigen recognition and processing for initiation of an immune response. In addition, potent molecules directly toxic to invading pathogens are expressed by the sac epithelium. This evidence strongly supports the endolymphatic sac as a significant immunological entity of the inner ear., Level of Evidence: N/A., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Adenomatous tumors in the middle ear and temporal bone are rare but highly morbid because they are difficult to detect prior to the development of audiovestibular dysfunction. Complete resection is often disfiguring and difficult because of location and the late stage at diagnosis, so identification of molecular targets and effective therapies is needed. Here, we describe a new mouse model of aggressive papillary ear tumor that was serendipitously discovered during the generation of a mouse model for mutant EGFR-driven lung cancer. Although these mice did not develop lung tumors, 43% developed head tilt and circling behavior. Magnetic resonance imaging (MRI) scans showed bilateral ear tumors located in the tympanic cavity. These tumors expressed mutant EGFR as well as active downstream targets such as Akt, mTOR and ERK1/2. EGFR-directed therapies were highly effective in eradicating the tumors and correcting the vestibular defects, suggesting these tumors are addicted to EGFR. EGFR activation was also observed in human ear neoplasms, which provides clinical relevance for this mouse model and rationale to test EGFR-targeted therapies in these rare neoplasms.

Objective: There is ongoing debate on the pathogenic mechanisms of cholesterol granuloma formation in the temporal bone. The purpose of this report is to provide evidence in support of the exposed marrow hypothesis in explaining the pathogenesis of petrous apex cholesterol granuloma., Study Design: Retrospective single case study., Main Outcome Measurement: The primary outcome evaluated was the diagnosis of a new cholesterol granuloma in a petrous apex that previously demonstrated radiologic evidence of bone marrow exposed to petrous apex air cells., Results: A patient with a unilateral petrous apex cholesterol granuloma develops a new, contralateral cholesterol granuloma in a hyperpneumatized temporal bone petrous apex shown previously to have medullary bone exposed to air cells., Conclusion: This report implicates the medullary-air cell interface in a hyperaerated temporal bone petrous apex in the development and growth of a petrous apex cholesterol granuloma.

Middle ear adenomas (MEAs) are benign neoplasms along a spectrum with neuroendocrine neoplasms (carcinoid tumors). Immunohistochemical (IHC) staining for myoepithelial markers has not been reported in these tumors. The archives of the Cleveland Clinic, University of Virginia and Armed Forces Institute of Pathology were retrospectively searched for tumors arising within the middle ear with material available for IHC staining. Twelve cases of MEAs, four cases of jugulotympanic paragangliomas (JPGs), 10 cases of ceruminous adenomas (CAs) and four cases of ceruminous adenocarcinomas (CACs) were obtained. IHC staining was performed for smooth muscle actin (SMA), p63, S-100 protein, cytokeratin 5/6 (CK5/6), and cytokeratin 7 (CK7). The MEAs were positive for: CK7 (92 %, luminal), CK5/6 (92 %, abluminal), p63 (83 %, abluminal), and negative for SMA and S-100 protein. The JPGs were negative for CK7, CK5/6, p63 and SMA; S-100 protein highlighted sustentacular cells. The CAs were positive for: CK7 (100 %, luminal), CK5/6 (100 %, abluminal), S-100 protein (80 %, abluminal), p63 (100 %, abluminal), and SMA (90 %, abluminal). CACs demonstrated two patterns, (1) adenoid cystic carcinoma-type: positive for CK7 (100 %, luminal), CK5/6, S-100 protein, p63, and SMA (all 100 %, abluminal); and (2) conventional-type: CK7 (50 % luminal), and no CK5/6, SMA, S-100 protein, or p63 expression. The IHC profile of MEAs suggests that these tumors harbor at least two cell populations, including luminal and basal cells. However, unlike ceruminous adenomas, MEAs lack true myoepithelial differentiation given the absence of S-100 protein and SMA staining in all cases.

The endolymphatic sac tumor (ELST) is a low-grade carcinoma originating in the ear. These extremely rare tumors are capable of invading the cerebellopontine angle and might be mistaken for choroid plexus tumors (CPTs) in this region. Currently, these tumors are distinguished by conventional morphologic and immunohistochemical studies for S-100, cytokeratin, and GFAP expression, but all markers are variably expressed by both tumors. Therefore, we examined new promising markers such as EAAT-1 and Kir7.1 in 4 ELSTs and 35 CPTs located in the fourth ventricle or at the cerebellopontine angle in adults. Immunohistochemical expression of Kir7.1 was found in 30 (100%) of 30 and EAAT-1 in 32 (91%) of 35 CPTs tested and was absent in all ELSTs. Expression of GFAP was found in 16 (55%) and S-100 in 29 (100%) of 29 CPTs tested, but both markers were also expressed in 2 of 4 ELSTs examined. Specificity and sensitivity of Kir7.1 (both 100%) and EAAT-1 (100% and 91%, respectively) were superior to the values for S-100 (50% and 100%, respectively) and GFAP (50% and 55%, respectively) for distinguishing CPT from ELST.

We present a case of a papillary tumour at the cerebellopontine angle in a 41-year-old man. He presented with left-sided facial and ear pain associated with dizziness, nystagmus and hearing loss. CT scan of the temporal bone showed a destructive tumour at the left cerebellopontine angle. Surgical excision was performed and the diagnosis of the endolymphatic sac tumour was made. Endolymphatic tumour is a low grade adenocarcinoma that originates from the endolymphatic sac. The definitive diagnosis requires a combination of clinical features, radiological finding and pathological correlation.

Objectives: Ceruminous adenoma of the external auditory canal (EAC) is a rare type of tumour that is diagnosed histologically. However, the clinical behaviour of these tumours remains controversial. Here, we report a case of ceruminous adenoma of the EAC and expression of a hypoxia marker., Case Report: A 78-year-old man presented with a 6-month history of recurrent otorrhoea in the right ear. Surgery was performed by the transmeatal approach with total removal of the mass. Histopathology revealed a ceruminous adenoma. Tumour cells were positive for CK, S-100 protein, Glut-1, HIF-1α, PI3K and p-Akt. There was no evidence of recurrence at last follow-up 27 months after the operation., Conclusions: Ceruminous adenoma of the EAC is a rare tumour. The treatment of choice is wide local excision with clear margins. To our knowledge, this is the first report of Glut-1 expression and the PI3K/Akt pathway in ceruminous adenoma of the EAC.

Endolymphatic sac tumor (ELST) is a rare neoplasm which can be encountered sporadically or in Von Hippel-Lindau (VHL) disease. Here we report a sporadic case of ELST in 31-year-old man. Neither the symptoms nor a family history of VHL disease were found in the patient. CT imaging demonstrated an expansile lytic lesion of the mastoid process of the left petrous bone. MR scanning revealed a 5.2 cm × 4.7 cm × 4.2 cm mass which showed hyperintensity on T1- and T2-weighted images. Histologic sections showed a papillary, cystic or glandular architecture. The papillary and glandular structures were lined by a single layer of flattened cuboidal-to-columnar cells. The stroma of the papillary fronds was richly vascularized and chronically inflamed. The tumor showed diffusely positive reactivity with cytokeratin (Pan), cytokeratin 19, cytokeratin 5/6, cytokeratin 7, EMA, vimentin, CD56, and NSE and also showed variable reactivity with glial fibrillary acidic protein (GFAP) and VEGF. The Ki-67 immunostain showed a proliferation index of < 1%. Because the mass was large, it was difficult to extirpate surgically. After surgery, the patient underwent gamma-knife radiosurgery for residual tumor. The findings indicate that ELST is a rare neoplasm with benign histopathological appearance and clinically destructive behavior. Because of the rarity of this tumor, it can easily be confused with other tumors such as paraganglioma, middle ear adenoma, adenocarcinoma, papillary carcinoma of thyroid or choroid plexus papilloma. Owing to its locally aggressive nature, it is difficult to extirpate surgically when it is large., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7973320646763012.

The negative feedback regulation of epidermal growth factor receptor (EGFR) and other tyrosine kinase receptors, including receptor dephosphorylation and endocytosis followed by degradation, is becoming recognized as a major determinant of receptor function. To evaluate the significance of the negative regulation of EGFR during carcinogenesis in vivo, we subjected the mutant mouse line Dsk5, in which the intrinsic activation of the receptor due to a point mutation is normally counterbalanced by increased posttranslational receptor down-regulation, to skin chemical carcinogenesis. Dsk5 mice showed reduced tumor numbers and tumor burden compared with control littermates, and Dsk5-derived tumors showed a reduction in the activation and total levels of EGFR. Furthermore, the transcript levels of several molecules known to act as negative regulators of EGFR were significantly increased in Dsk5-derived tumors. Another intriguing observation was the appearance of tumors with sebaceous differentiation in the ears of Dsk5 mice after chemical carcinogenesis. Further studies are necessary to reveal whether these tumors represent a cell type-specific evasion from EGFR negative feedback machinery. In conclusion, this study reveals that several negative feedback regulators contribute to suppression of the intrinsic activation of mutant EGFR during skin carcinogenesis, stressing the potential exploitation of negative regulators as either therapeutic targets or diagnostic tools in cancer and other diseases., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Adenomatous tumors of the middle ear and temporal bone are rare tumors. In this retrospective study, we examined nine patients who underwent surgery for an adenomatous tumor of the middle ear, mastoid cavity or eustachian tube. In seven patients, a middle ear adenoma (MEA) and in two patients an aggressive papillary tumor (APT) was diagnosed. We report the clinical, radiologic, morphologic, immunohistochemical and DNA image cytometrical characteristics that can help to correctly classify these tumors. Therapy consisted of surgical excision of the tumors in eight cases. In one elderly patient, only a large biopsy was taken, because this patient suffered from cardial and kidney disorders and was not suitable for an extended surgical approach. This patient received stereotactic radiotherapy. Seven patients underwent planned second look operation. Recurrences occurred in three patients (one with APT, two with MEA), whereas in two of these cases rather a residual tumor due to initial incomplete tumor resection occurred. By image analysis, DNA cytometry MEA were considered benign, whereas the appearance of aneuploid tumor cells in APT confirmed these tumors as low grade malignant lesions. The proliferation rates were equally low in both entities. APT and MEA are tumor entities which can only be correctly classified by a synopsis of histopathology, immunohistochemistry and DNA image cytometry. The recommended therapy is the complete tumor excision. In cases of APT, von Hippel-Lindau syndrome has to be excluded.

Objective: Reversion-inducing cysteine-rich protein with kazal motifs (RECK) may negatively regulate matrix metalloproteinase 9 (MMP9) activity and suppress tumor invasion and metastasis. The aim of this study was to investigate whether RECK and MMP were involved in regulating middle ear carcinoma invasion and metastasis., Methods: RECK and MMP9 were measured in 30 middle ear squamous cell carcinoma tissues and 20 adjacent normal external ear canal skin tissues using immunohistochemical analysis., Results: The positive rate of RECK expression in the middle ear squamous cell carcinoma was much lower than that in the normal external ear canal skin. In contrast, the positive rate of MMP9 expression was higher in middle ear squamous cell carcinoma tissue than that in normal external ear canal skin tissue. The expressions of RECK and MMP9 were correlated with the histological grade and tumor stage, but not with patient age or gender., Conclusions: RECK and MMP9 are involved in middle ear squamous cell carcinoma and may serve as markers to evaluate progression and metastasis., (Copyright © 2011 S. Karger AG, Basel.)

Objective: To investigate the expression and clinical significance of MMP9 and MVD in the carcinogenesis of squamous cell carcinoma of external auditory canal and middle ear., Method: Immunohistochemical SP method was used to detect the expression of MMP9 and MVD proteins in 26 squamous cell carcinoma tissues of external auditory canal and middle ear and 20 normal external ear canal skin tissues., Result: The positive rate of MMP9 in squamous cell carcinoma tissues of external auditory canal and middle ear was 73.1% (19/26) lower than that in the normal external ear canal skin tissues 25.0% (5/20). The positive rates of CD34 were 33.58 +/- 3.04 and 22.50 +/- 5.22, respectively. The positive rates of MMP9 and CD34 were correlated with the histological grade and tumor grade, but had no relationship with age and sex. The positive rates between MMP9 and CD34 were related (r=0.42, P<0.05)., Conclusion: MMP9 may be involved in the carcinogenesis of squamous cell carcinoma of external auditory canal and middle ear, and may play an important role in the invasion and metastasis of squamous cell carcinoma of external auditory canal and middle ear. MMP9 and CD34 play a cooperative role in the process of squamous cell carcinoma of external auditory canal and middle ear.

The vascular endothelial growth factor (VEGF) family are essential regulators of angiogenesis and vascular permeability. VEGF protein was found in the jugulotympanic paraganglioma, but it wasn't confirmed on mRNA level. Our aim of this study is the mRNA expression of VEGF in jugulotympanic paraganglioma. We chose six cases of primary jugulotympanic paraganglioma wax specimen by hybridisation in situ. It suggested that VEGF mRNA had significant expression in the tumour cytoplasm of jugulotympanic paraganglioma. The correlation is not yet clear. It could be suggested the higher degree of malignancy, the stronger expression of VEGF mRNA in cytoplasm, but not found in the cellular nucleus., (© 2009 Blackwell Publishing Ltd.)

We report two cases of a CD8-positive lymphoid proliferation presenting as solitary lesions on the ear and nose, respectively. Histopathologically, both cases were characterized by a diffuse non-epidermotropic dermal proliferation of clonal medium-sized CD8-positive T-lymphocytes with a lymphoblast-like appearance, having cells with large folded nuclei, prominent nucleoli and ample amphophilic or pale eosinophilic cytoplasm. Staging procedures excluded systemic involvement, and both lesions were successfully treated with localised radiotherapy without evidence of recurrence after 12 and 24 months' follow up, respectively. Previously reported cases on the ear had similar clinicopathological and immunophenotypical features, and together raise the possibility of a distinct entity, an indolent CD8-positive lymphoid proliferation.

First described in 1969, syringoid eccrine carcinoma (SEC) is a rare cutaneous tumor with some controversy regarding its correct definition. It consists of solid nests and small cords in a dense fibrocollagenous stroma. As it is rare, its clinical appearance is not well characterized and its biological behaviour is not defined. It usually affects skin of the scalp, extremities and more rarely, other sites. It behaves as locally aggressive tumor but metastases are rare. Although there have been some previous reports describing clinical presentation and management of SEC in the skin, there has been no previous reports describing clinical findings and management of this tumor in the external auditory canal. We report a case of a 57-year-old female with small solitary mass in left external auditory canal associated with discharge, severe itching and bleeding on manipulation. Complete local excision is the recommended method for diagnosis and treatment of this tumor in the external auditory canal. This extremely rare case serves as a springboard for the diagnosis as well as the management of SEC in external auditory canal., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

The clinicomorphological, immunohistochemical, and ultrastructural characteristics of 11 cases of extracranial meningioma versus 79 soft tissue perineuriomas were studied. There were significant similarities (cell morphology, immunoprofile, ultrastructural features of perineurial differentiation) of both entities. Considering the point of view that arachnoid and perineurial cells are anatomically, embryologically, and functionally related, it is most possible that extracranial meningiomas may be derived from perineurial cells (or their progenitor cell) rather than from displaced arachnoid cells.

The protein Merlin is involved in the regulation of cell proliferation and differentiation in the eyes and wings of Drosophila and is a homolog of the human protein encoded by the Neurofibromatosis 2 (NF2) gene whose mutations cause auricular nerve tumors. Recent studies show that Merlin and Expanded cooperatively regulate the recycling of membrane receptors, such as the epidermal growth factor receptor (EGFR). By performing a search for potential genetic interactions between Merlin (Mer) and the genes important for vesicular trafficking, we found that ectopic expression in the wing pouch of the clathrin adapter protein Lap involved in clathrin-mediated receptor endocytosis resulted in the formation of extra vein materials. On the one hand, coexpression of wild-type Merlin and lap in the wing pouch restored normal venation, while overexpression of a dominant-negative mutant Mer(DBB) together with lap enhanced ectopic vein formation. Using various constructs with Merlin truncated copies, we showed the C-terminal portion of the Merlin protein to be responsible for the Merlin-lap genetic interaction. Furthermore, we showed that the Merlin and Lap proteins colocalized at the cortex of the wing imaginal disc cells.

We report an unusual histopathological variant of a glomus tumor that arose in a peculiar topographic site, a sclerotic glomus tumor. Unlike conventional glomus tumors or glomangiomas that have a loose fibrous stroma with variable hyaline and myxoid changes, the case reported herein had a diffuse, hyalinized, sclerotic stroma. A further difference was that the majority of glomus tumors and glomangiomas occur in the subungual area, trunk, or extremities, whereas the present tumor occurred on the ear. Due to the peculiar histological features and location, other tumors were considered in the differential diagnosis to include Merkel cell carcinoma, primitive neuroectodermal tumor, and small cell melanoma. This article illustrates a unique variant of a glomus tumor, which to our knowledge has not been previously described.

The presence of two intermingled malignant components within the same cutaneous tumor is rare. Herein, we report a case of an exceedingly rare squamo-melanocytic tumor, favored to be a melanoma variant. Although the biologic behavior and prognostic significance of this tumor remain to be established, this unique case reaffirms the potential morphologic diversity of melanoma. We review the literature reporting similar neoplasms and discuss the potential histogenesis of this squamo-melanocytic tumor.

Background: Ceruminal gland carcinomas are rare neoplasms confined to the skin lining the cartilaginous part of the external auditory canal., Design: Retrospective., Results: The patients included 11 men and 6 women, aged 33-82 years (mean, 59.5 years). Patients presented clinically with a mass of the outer half of the external auditory canal (n = 14), hearing changes (n = 5), drainage (n = 4), or paralysis of the facial nerve (n = 3). The polypoid masses ranged in size from 0.5 to 3 cm in greatest dimension (mean, 1.8 cm). Histologically, the tumors demonstrated a solid to cystic pattern, composed of an infiltrating glandular to cribriform arrangement of epithelial cells. Histologic features included a dual cell population (although not the dominant histology), increased cellularity, moderate to severe nuclear pleomorphism, irregular nucleoli, increased mitotic figures (mean, 3/10 HPF), including atypical forms, and tumor necrosis (n = 2). Tumors were divided into three types of adenocarcinoma based on pattern of growth and cell type (ceruminous, NOS [n = 12], adenoid cystic [n = 4], mucoepidermoid [n = 1]). CK7 and CD117 highlighted the luminal cells, while S1-00 protein showed a predilection for the basal cells of ceruminous and adenoid cystic carcinomas. Metastatic adenocarcinoma or direct extension from salivary gland neoplasms are the principle differential considerations. Surgical resection was used in all patients with radiation used in four patients. Eleven patients were alive or had died of unrelated causes without evidence of disease (mean, 11.2 years); six patients had died with disease (mean, 4.9 years), all of whom had developed local recurrence., Conclusion: Ceruminous-type carcinomas, with the exception of ceruminous mucoepidermoid carcinoma, all demonstrated a dual cell population of basal myoepithelial-type cells and luminal apocrine cells. The specific histologic sub-type does not influence the long-term patient outcome.

Unlabelled: Myofibroma of the external auditory canal: report of an adult case., Objective: Myofibroma is a benign fibrous proliferative disease generally reported to occur in neonates and children. Similar lesions have been reported in adults, but solitary tumours affecting the external auditory canal are extremely rare. Only one such case has been reported in the literature., Case Report: The case of solitary myofibroma occurring in the external auditory canal of a 42-year-old woman is presented. The diagnosis of myofibromatosis was made on the basis of its histological appearance and corroborated by immunohistochemical staining., Conclusions: Clinicians and pathologists must be aware that myofibromatosis may occur in adults at extremely rare locations. Myofibroma should be included in the differential diagnosis of fibrous lesions in the external auditory canal.

Objective: To report the safe management and treatment of a catecholamine-secreting tympanicum glomus tumour., Case Report: A 73-year-old women presented with a catecholamine-producing glomus tympanicum tumour, complaining of hearing impairment and left ear pain. Physical examination revealed a red, pulsating swelling in the left tympanic membrane. Computed tomography demonstrated a soft tissue mass filling the entire middle-ear cavity and a partial osteolytic lesion in the internal carotid artery. Angiographic examination revealed a densely contrasting tumour with feeding vessels from the ascending pharyngeal artery. Concentrations of serum noradrenalin and urine vanillylmandelic acid (VMA) were high. The tumour was completely resected using a potassium titanyl phosphate laser, the feeding vessels having been embolised the previous day. Concentrations of serum noradrenalin and urine VMA normalised following the operation., Conclusion: Pre-operative embolisation is useful in the treatment of catecholamine-secreting tympanicum glomus tumours, not only for preventing a hypertensive crisis but also for reducing bleeding. The potassium titanyl phosphate laser is useful for complete resection of the tumour.

Objectives/hypothesis: Determine the role of estrogen receptor (ER) and progesterone receptor (PR) expression in sporadic and neurofibromatosis 2 (NF2)-related vestibular schwannomas (VS). Growth and proliferation signaling in human VS tumorigenesis may play a key role in molecular therapeutic targeting. VS carry mutations of the NF2 gene encoding the tumor suppressor, merlin, which interacts with ErbB2 in Schwann cells, implicating ErbB receptors in VS tumorigenesis. ErbB receptor family members are overexpressed or constitutively activated in many human tumors, and are effective therapeutic targets in some human cancers. VS occur more frequently in women and are larger, more vascular, and demonstrate increased growth rates during pregnancy. ER and PR may play a role in ErbB pathway activation and VS progression., Study Design: Quantitative real-time polymerase chain reaction (qRT-PCR) for ER and PR messenger RNA was performed using greater auricular and vestibular nerve controls (n = 8), sporadic VS (n = 23), and NF2-related VS (n = 16) tissues., Methods: The qRT-PCR data were normalized with standardization to a single constitutively expressed control gene, human cyclophylin., Results: Reverse transcription of messenger RNA from control and tumor specimens followed by RT Q-PCR demonstrated differences in ER and PR gene expression between sporadic and NF2-related VS., Conclusions: ER and PR expression in VS might have implications for development of a VS-specific drug delivery system using antihormone and ErbB pathway small molecule inhibitors, due to crosstalk between these receptors. These signals may be critical for re-establishing ErbB-mediated cell density dependent growth inhibition.

Objectives: Inflammatory cytokines are involved in the development of mucous cell metaplasia and hyperplasia (MCM) in otitis media (OM). However, which cytokines play an essential role in the MCM of OM is not clear at the moment., Methods: In this study, we hypothesized that interleukin-10 (IL-10) played an indispensable role in the MCM of bacterial OM, and we used IL-10 knockout mice to test this hypothesis., Results: In wild-type mice, both Streptococcus pneumoniae and Haemophilus influenzae triggered the development of MCM in the middle ear mucosa. In IL-10 knockout mice, the number of goblet cells and mucin-producing cells in the middle ear was significantly reduced after bacterial middle ear infection compared with that in wild-type mice., Conclusions: We conclude that IL-10 plays an essential role in the MCM of bacterial OM. Interleukin-10 is a potential target for the treatment of MCM in OM.

Background: Cutaneous, neutrophil-rich anaplastic large cell lymphoma (ALCL) is an uncommon variant of ALCL that may be confused with inflammatory dermatoses., Objective and Methods: We describe an eosinophil-rich variant of ALCL occurring on the left ear without systemic involvement. The lesion had inflammatory characteristics, which led initially to a histological diagnosis of an inflammatory process. Two months later, a second biopsy diagnosed eosinophil-rich variant of ALCL. The patient underwent radiation therapy, but due to the extensive deformation and mutilation of the ear, the patient elected to have the ear amputated. We discuss the clinicopathological findings and the differential diagnosis, Conclusions: To the best of our knowledge, the occurrence of a cutaneous, eosinophil-rich variant of ALCL has not been previously reported. It is important to alert pathologists to this variant of ALCL so that this possibility may be considered in the early differential diagnosis of inflammatory cutaneous conditions.

Hypothesis: Expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) may have an impact on the growth characteristics of sporadic vestibular schwannomas (VSs)., Background: Vestibular schwannoma is a benign, slow-growing neoplasm that accounts for 6% of all intracranial tumors. The biological backgrounds for neoplastic growth and especially for the various growth patterns of VS remain largely unknown. Because several angiogenic and cytotrophic factors have been described to be involved in the growth of malignant tumors, we initiated this study to examine 2 major representatives of such growth factors in VS and their possible correlation to the growth characteristics of sporadic VSs., Methods: Surgical specimens from 17 patients with sporadic VS were examined, and the expression of 2 major angiogenic and neurotrophic factors, bFGF and VEGF, was quantitatively analyzed at the mRNA and protein levels. The microvessel density (MVD) was defined by CD31 staining., Results: All tumors showed expression of bFGF and VEGF at both the mRNA and protein levels. The mRNA expression and the protein expression of both growth factors correlated positive to tumor volume, to tumor growth index, and to MVD., Conclusion: The bFGF and VEGF mRNA expression and the bFGF and VEGF protein expression in sporadic VS correlates to the tumour volume, to the tumor growth index, and to the MVD. This might indicate an angiogenic and neurotrophic influence of these factors and a possible involvement in the growth of sporadic VS.

Hypothesis: Hypoxia-inducible factor (HIF)-1alpha, erythropoietin (Epo), Epo receptor (EpoR), and bcl-2 are expressed in both sporadic unilateral vestibular schwannomas (VSs) and those associated with neurofibromatosis Type 2, and the expression data correlate with clinicopathological tumor features including microvessel density and Ki-67-labeling index., Background: Erythropoietin expression is regulated by the transcription factor, HIF-1alpha. Erythropoietin signaling via EpoR results in stimulation of cell proliferation and elevated expression of the antiapoptotic protein, bcl-2, and then inhibition of apoptosis. Erythropoietin has been shown to be associated with Schwann cell proliferation, and a recent report suggested a role in VS growth., Methods: Immunohistochemical analysis of HIF-1alpha, Epo, EpoR, and bcl-2 was performed on formalin-fixed paraffin-embedded archival surgical specimens. Microvessel density and Ki-67-labeling index of VS were analyzed and correlated with the immunoreactivity pattern of the examined factors., Results: Immunoreactivity data demonstrate robust protein expression for HIF-1alpha, Epo, EpoR, and bcl-2 in VS. Sixty-six percent of the cases showed Epo expression, and EpoR was found in 85% of tumor samples. A significantly positive correlation of the immunoreactivity scores of Epo/EpoR and bcl-2 expression could be noted. In case of tumor specimens with high levels of HIF-1alpha expression, a significantly higher Ki-67-labeling index was observed. There was no correlation between the expression of HIF-1alpha, Epo, EpoR, and bcl-2 and microvessel density, tumor size, sex, and age., Conclusion: Expression of Epo and EpoR might suggest a functional role in VS biology. The observed correlation of Epo/EpoR and bcl-2 expression levels may suggest a proliferative and antiapoptotic role of the Epo/EpoR system in VS.

Pleomorphic adenoma of the external auditory canal is a rare disease. It is considered to derive from the ceruminous glands. The objective of this study is to familiarize the clinician with the clinical presentation and treatment of this disease. We report the case of a 58-year-old woman. Complete resection should be applied for cases in which magnetic resonanace imaging (MRI) and computerize tomography (CT) examination indicate no erosion in the bone and cartilage tissue. The patient should be seen regularly for recurrence.

The von Hippel-Lindau (VHL) disease is caused by VHL germ line mutation. Inactivation of the wild-type copy of the VHL gene leads to up-regulation of hypoxic response and tumor formation within central nervous system (CNS), kidneys, pancreas, adrenal glands, epididymis, broad ligament, and the endolymphatic sac/petrous bone. Endolymphatic sac tumors (ELST) have been proposed to be derived from endolymphatic sac epithelium, but other possible structures of origin have been implicated. To clarify the anatomic and cellular origin of ELSTs, we did a morphologic and molecular pathologic analysis of 16 tumors. In addition, we investigated effects of VHL deficiency on "tumor-free" endolymphatic duct and sac of VHL patients. Several tumors included in this study were <1 cm in size, and their origin could be placed in the intraosseous portion of the endolymphatic duct/sac. Furthermore, by analysis of clinically uninvolved "tumor-free" endolymphatic duct and sac tissues of VHL patients, we discovered a variety of VHL-deficient microscopic abnormalities with morphologic similarities to ELSTs. We conclude that most, if not all, ELSTs arise within the intraosseous portion of the endolymphatic duct/sac, the vestibular aqueduct. In analogy to renal parenchyma and selected topographical sites within the CNS, endolymphatic duct/sac epithelia are preferentially and multifocally targeted in VHL disease. The primary effect of VHL deficiency on human endolymphatic duct/sac epithelium seems to be the generation of multifocal sites of VHL-deficient cell proliferations from which tumorigenesis may or may not occur. Therefore, inactivation of the VHL wild-type allele seems necessary but not sufficient for the formation of tumor.

A case of angiolymphoid hyperplasia with eosinophilia (ALH) is reported in a 33-year-old woman who developed an auricular nodule during the second trimester of her pregnancy. Angiolymphoid hyperplasia with eosinophilia usually occurs on the head and neck of young adults and is more common in women than in men. Characteristic histologic features of ALH present in this case included proliferation of thick-walled blood vessels lined by prominent endothelial cells, infiltration of the interstitium by chronic inflammatory cells (mainly eosinophils), and presence of lymphoid follicles with germinal centers. The auricular tumor was completely excised. Thirteen months after excision, the patient remains tumor free. Although there are not many case reports on ALH during pregnancy or involving use of oral contraceptive pills, sex hormones may play a role in the pathogenesis of ALH. This hypothesis, in the context of cases previously described in the literature, and the differential diagnosis of ALH are discussed.

ABCA2, which belongs to the A subclass of the ATP-binding cassette (ABC) transporter superfamily, is predominantly expressed in the cytoplasm of oligodendrocytes and Schwann cells, the myelin-forming cells in brain and peripheral nerve, respectively. Here, we demonstrate by immunoblot and immunohistochemistry that ABCA2 is expressed in benign vestibular schwannomas, which contain neither axons nor compact myelin. The expression patterns of ABCA2 in combination with other markers showed phenotypic heterogeneity in schwannomas. The majority of cells in fascicular Antoni type A areas coexpressed ABCA2, Ca2+-binding protein S100beta, and p75 nerve growth factor receptor. In contrast, considerably varied expression levels of ABCA2 and p75 were more prominent in hypocellular type B areas than in type A areas. These data suggest that ABCA2 may be useful as a marker for cellular characterization of schwannomas.

Melanoma is the aberrant proliferation of melanocytes, the cells in the skin responsible for pigment (melanin) production. In its early stages, melanoma can be surgically removed with great success, however, advanced stages of melanoma have a high mortality rate due to the lack of responsiveness to currently available therapies. We have previously characterized a mouse melanoma model, TG-3, which has implicated the ectopic expression of metabotropic glutamate receptor 1 (Grm1, formerly mGluR1), in melanomagenesis and metastasis [Pollock et al., 2003. Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia. Nat Genet. 34, 108-112.]. Here we report the characterization of several in vitro cell lines derived from independent mouse melanoma tumors. These cell lines show characteristic phenotypes of transformed melanocytes, and express Grm1, and Grm5 (another metabotropic glutamate receptor), as well as melanocyte-specific protein markers. To investigate the possible role of Grm5 in vivo during melanoma development in our mice, we have crossed Grm5 null mice with TG-3, generating a new line of transgenic mice, TGM. TGMs, which are homozygote knockouts for Grm5 and carry the TG transgene, develop tumors with onset, progression, and metastasis very similar to that described for TG-3. Taken together, these results indicate that Grm1 can act as an oncogene in melanocytes independently of Grm5 expression.

Multifocal to diffuse meningeal infiltration by neoplastic epithelial cells was observed in two aged cats with neurological signs and a history of surgical ablation of the auricular pinnae because of the presence of squamous cell carcinoma. In both cats, examination of the external ear canals revealed neoplastic lesions consistent with squamous cell carcinoma, but no changes of the tympanic bullae were noted. In one cat, post-mortem examination revealed marked thickening of the dura mater and infiltration of the arachnoid layer by cytokeratin-positive, neoplastic epithelial cells. In the other cat, no macroscopic brain lesions were noted, but multifocal dissemination of neoplastic epithelial cells to the leptomeninges was observed histologically. Several pathways by which neoplastic cells can reach the meninges have been suggested and haematogenous dissemination was considered most likely in these cats. Squamous cell carcinoma is the most common cutaneous malignant neoplasm in cats and meningeal carcinomatosis can be considered a rare complication.

Imaging follow-up of vestibular schwannomas (VS), such as CT or MR, does not allow assessing the response of the tumor tIssue to radiosurgery. Changes in contrast enhancement are frequently observed, with a loss of contrast enhancement within the treated VS. However, this typical aspect does not anticipate the long-term success of radiosurgery for VS. New functional and metabolic image modalities could be useful to assess in vivo radiosurgery-induced tIssue changes. Such data already exist, using techniques such as MR spectroscopy, positron emission tomography (PET) and SPECT, but they concern almost exclusively the evaluation of primary SNC tumors and metastases of systemic cancers. There are, however, very sparse metabolic and functional data concerning the in vivo evaluation of the response of the tumor tIssue to radiosurgery. Moreover, such information is only anecdotal in VS. In other disorders, PET and MR spectroscopy data suggest interesting new directions for the assessment of radiosurgery follow-up. Based on the predictive information provided by PET and MR spectroscopy in primary CNS tumors, it would be worthwhile to design a prospective study evaluating the role of these imaging modalities for in vivo assessment of radiosurgery-treated SV.

Background and Purpose: Radiosurgery has become a successful treatment modality in the management of vestibular schwannomas (VS) during the past four decades. Although the number of treated cases has been increasing continuously we know relatively little about the pathological effect of high dose irradiation on VS following radiosurgery. The purpose of this study was to analyze histopathological changes in VS after Leksell Gamma Knife (LGK) radiosurgery., Methods: Out of a series of 1350 VS cases treated with LGK surgery 22 patients underwent craniotomy for tumor removal in 6-92 Months interval after radiosurgery. Surgical pathology material was available in 17 cases. Routine histological and immunohistochemical investigations were performed on the tIssue samples. Histopathological findings were compared with clinical and radiological follow-up data., Results: Coagulation necrosis in the central part of the schwannomas surrounded with a transitional zone containing loosened tIssue structure of shrunken tumor cells covered with an outer capsule of vigorous neoplastic cells was the basic histopathological lesion. Granulation tIssue proliferation with inflammatory cell infiltration, different extent of hemorrhages and scar tIssue development was usually present. Endothelial destruction or wall damage of vascular channels was a common finding. Analyzing the follow-up data it turned out that 7 patients out of the 22 were operated on because of radiological progression only without clinical deterioration and 4 of them was removed during the latency period after radiosurgery., Conclusion: Results of the present histopathological study suggest that radiosurgery works with double effect on VS: it seems to destroy directly tumor cells (with necrosis or inducing apoptosis), and causes vascular damages as well. The loss of central contrast enhancement on CT and MR images following radiosurgery might be consequence of necrosis and vascular impairment. From clinical-pathological point of view we think that patients should not undergo craniotomy just because of radiological progression of the tumor without clinical deterioration, mainly in the latency period. This requires consultation and common decision-making between the radiosurgical and the microsurgical team.

Background: Ceruminous gland neoplasms are rare neoplasms. To date, a large clinicopathologic study of benign ceruminous gland neoplasms has not been reported., Design: Forty-one cases of ceruminous gland adenomas diagnosed between 1970 and 2000 were retrieved from the files of the Armed Forces Institute of Pathology. Histologic features were reviewed, immunohistochemical analysis was performed (n = 21), and patient follow-up was obtained (n = 40)., Results: The patients included 22 men and 19 women, 24 to 85 years of age (mean, 54.2 years). Patients presented clinically with a painless mass of the outer half of the external auditory canal (n = 33) or with hearing changes (n = 11). Symptoms were present for an average of 16.3 months. The polypoid masses affected the external auditory canal only and ranged in size from 0.4 to 2 cm in greatest dimension (mean, 1.1 cm). Histologically, the tumors demonstrated glands and small cysts lined by a tubuloglandular proliferation of inner ceruminous cells (cerumen-secreting epithelium with decapitation secretion) subtended by a spindled to cuboidal myoepithelial layer. A hyalinized stroma created an infiltrative pattern of growth; surface involvement (n = 8) was seen. Tumors were divided into ceruminous adenoma (n = 36), ceruminous pleomorphic adenoma (n = 4), and syringocystadenoma papilliferum (n = 1) types. The luminal cells were strongly and diffusely immunoreactive with CK7, while the basal cells were highlighted with CK5/6, S-100 protein, and p63. CD117 highlighted the luminal cells preferentially. The proliferation markers revealed a low index. Adenocarcinoma and middle ear adenoma are the principal differential consideration. Surgical excision was used in all patients. Four patients developed a recurrence due to incomplete excision. All patients were without evidence of disease at the last follow-up: alive (n = 28, mean 16.3 years) or dead (n = 12, mean 11.8 years)., Conclusion: Ceruminous gland adenomas are the most common external auditory canal tumors. They demonstrate a dual cell population of basal myoepithelial-type cells and luminal ceruminous (ceruminal) cells. Cerumen pigment, CK7, and p63 can help to distinguish this tumor from other neoplasms that occur in the region. Complete surgical excision results in an excellent long-term clinical outcome.