Publications by authors named "Stephan Ihrler"

51 Publications

Why is the histomorphological diagnosis of tumours of minor salivary glands much more difficult?

Histopathology 2021 May 27. Epub 2021 May 27.

Dental School, Ludwig-Maximilians-University, Munich, Germany.

Aims: There is widespread perception in clinic and pathology, that the histomorphological assessment of minor salivary gland tumours (MinSG) is more difficult and hampared by more misdiagnoses than that of major salivary glands. This is based on a vague, subjective clinical impression, while scientific proof of the difference and of potentional reasons that would explain this are lacking.

Methods And Results: We identified fourteen putative clinical, pathological, and combined clinico-pathological reasons, which altogether could explain the phenomenon of perceived greater diagnostic difficulty of tumours of MinSG. We performed a comprehensive literature search and a statistical comparison of data from a large personal consultation series (biased for difficult cases) with cumulative data from straightforward, unselected (non-consultation) series from the literature. By that comparison we could prove with statistical significance a comprehensive series of reasons, as well as of consequences of greater diagnostic difficulty in MinSG.

Conclusions: Within the 14 criteria a high frequency of initial incisional biopsies and of low-grade category in malignant tumours emerged as the two most important reasons for enhanced diagnostic difficulty. Very rare entities, unusual locations, shortcomings in clinico-pathological communication, as well as pecularities of the special anatomic location of the hard palate, such as tumour necrosis, mucosal ulceration, pseudoinvasion, and the peculiar phenomenon of "tumoural-mucosal fusion", contribute to further diagnostic difficulties. The awareness of these shortcomings and pitfalls enables a series of recommendations for clinic and pathology, which might help aid assessment and reduce the rate of misdiagnosis in tumours of MinSG.
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http://dx.doi.org/10.1111/his.14421DOI Listing
May 2021

Microsecretory Adenocarcinoma of Salivary Glands: An Expanded Series of 24 Cases.

Head Neck Pathol 2021 May 12. Epub 2021 May 12.

Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.

Microsecretory adenocarcinoma (MSA) is a recently described salivary gland tumor with a characteristic histologic and immunophenotypic profile and recurrent MEF2C-SS18 fusions. Because only six cases of MSA have been published, its complete clinicopathologic spectrum is unclear, and its biologic behavior has not been documented. Here, we present an updated and expanded experience of 24 MSA cases. All cases of MSA were obtained from the authors' files. Immunohistochemistry for S100, SOX10, p63, p40, SMA, calponin, and mammaglobin was performed. Molecular analysis was performed by targeted RNA sequencing, SS18 break apart fluorescence in situ hybridization, and/or reverse transcriptase polymerase chain reaction for MEF2C-SS18 fusion. Clinical follow-up was obtained from medical records. A total of 24 MSA cases were collected, from 13 women and 11 men, ranging from 17 to 83 years (mean 49.5 years). The vast majority (23 of 24) arose in the oral cavity, with the palate (n = 14) and buccal mucosa (n = 6) as the most frequent subsites. Tumors showed consistent histologic features including: (1) microcystic tubules, (2) flattened intercalated duct-like cells, (3) monotonous oval hyperchromatic nuclei, (4) abundant basophilic luminal secretions, (5) fibromyxoid stroma, and (6) circumscribed borders with subtle infiltration. The tumors were very consistently positive for S100 (24 of 24), p63 (24 of 24), and SOX10 (14 of 14) and negative for p40 (0 of 21), calponin (0 of 12) and mammaglobin (0 of 16), while SMA (4 of 20) was variable. MEF2C-SS18 fusion was demonstrated in 21 of 24 cases; in the remaining 3 cases with insufficient RNA, SS18 break apart FISH was positive. Treatment information was available in 17 cases, all of which were managed with surgery only. In 14 cases with follow-up (1-216 months, mean 30), no cases recurred or metastasized. MSA is a distinct salivary gland neoplasm with remarkably consistent clinical, histologic, immunophenotypic, and genetic features that generally behaves in an indolent manner following surgery alone. These observations solidify MSA as a unique, low-grade salivary gland carcinoma that warrants inclusion in the next version of the WHO classification of head and neck tumors.
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http://dx.doi.org/10.1007/s12105-021-01331-7DOI Listing
May 2021

ALK Rearrangements Characterize 2 Distinct Types of Salivary Gland Carcinomas: Clinicopathologic and Molecular Analysis of 4 Cases and Literature Review.

Am J Surg Pathol 2021 Mar 22. Epub 2021 Mar 22.

*Institute of Pathology ¶Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Comprehensive Cancer Center (CCC) Erlangen-EMN, Erlangen §DERMPATH Muenchen ∥Institute of Pathology, Ludwig Maximilians University, Munich, Germany †Department of Pathology, Charles University, Faculty of Medicine in Plzen ‡Bioptic Laboratory Ltd, Plzen, Czech Republic #Department of Translational Research, University of Pisa, School of Medicine, Pisa, Italy.

The majority of salivary gland carcinomas are characterized by recurrent gene fusions that proved highly valuable diagnostically, but only rarely of therapeutic impact. Most of these fusion-positive carcinomas belong to the low-grade or intermediate-grade biological category. To date, only 5 cases of salivary gland carcinomas carrying an oncogenic ALK fusion have been reported in 4 recent studies, but their phenotypic spectrum and their nosological classification remain uncharacterized. We herein describe in detail the clinicopathologic and molecular features of 4 ALK-fusion-positive salivary carcinomas and review previously reported cases to assess if they could be classified into a defined World Health Organization (WHO) category. Patients were 3 men and 1 woman aged from 67 to 79 years (median: 70 y). All tumors originated in the parotid gland. Their size ranged from 1.1 to 3 cm (mean, 2 cm). Three tumors were de novo high-grade salivary duct carcinomas (SDCs) and 1 was a low-grade intercalated-type intraductal carcinoma. Histologically, high-grade tumors were predominantly solid, composed of intimately admixed basal (CK5, androgen) and luminal (CK5, androgen) components. The remarkable basal component showed squamoid basophilic pattern imparting an adenosquamous-like appearance in all cases. Conventional apocrine intraductal high-grade carcinoma was noted in 1 case. Prominent intraductal growth of the solid basal component (highlighted by p63 staining) was seen in all cases. The tumor cells expressed CK7 (3/3), mammaglobin (3/3, 1 focal), GATA3 (3/3, 1 focal), variably CK5 (3/3), and focally the androgen receptor (1/3), but lacked expression of HER2/neu, SOX10, MUC4, TTF1, S100, and Napsin A. The low-grade tumor showed classic histologic and immunophenotypic features of intercalated-type noninvasive intraductal carcinoma. Molecular profiling showed rearrangements involving exon 20 of ALK in all cases, confirmed by ALK immunohistochemistry (IHC and FISH). The fusion partner was EML4 (n=2) and STRN (n=1) in high-grade tumors and EML4 in the intraductal carcinoma. Two patients with high-grade tumors developed progressive disease (1 died at 9 mo; 1 alive under palliative therapy at 5 mo). This series and a review of 5 published cases indicate that ALK rearrangements characterize 2 distinct subsets of salivary gland carcinomas in the spectrum of high-grade androgen-poor, basal-like SDC (total reported: 5 cases) and low-grade intercalated-type intraductal carcinomas (4 cases). Given the therapeutic relevance of ALK fusions, inclusion of ALK IHC in any atypical-looking or androgen-poor SDC and in high-grade adenocarcinoma-not otherwise specified is recommended. Absence of aberrant ALK expression in genetically characterized secretory (n=15) and intraductal (n=9) carcinomas lacking ALK fusions underlines the value of ALK IHC as a diagnostic screening method for identifying potential cases.
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http://dx.doi.org/10.1097/PAS.0000000000001698DOI Listing
March 2021

[Is there a new salivary gland? - Rather not!]

Laryngorhinootologie 2021 01 16;100(1):12-14. Epub 2020 Nov 16.

Institut für Anatomie, Universität Leipzig.

In October 2020, the lay press, but also some medical journals and websites reported the putative discovery of a new salivary gland in the nasopharynx based on prostate-specific membrane antigen positron emission tomography computed tomography (PSMA-PET/CT) examinations. As an interdisciplinary group from the fields of anatomy, pathology, nuclear medicine and otorhinolaryngology, we come to the view that an accumulation of minor salivary glands has been described here. Minor salivary glands in the nasopharynx and in the peritubar region have been described at least since 1866. The current description in PSMA-PET/CT does not justify the definition of a new, independent salivary gland. The PSMA-PET/CT could, however, be suitable to better protect salivary glands in the nasopharynx when planning radiation therapy. This should be evaluated in clinical trials.
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http://dx.doi.org/10.1055/a-1307-3872DOI Listing
January 2021

S3 guideline for actinic keratosis and cutaneous squamous cell carcinoma (cSCC) - short version, part 2: epidemiology, surgical and systemic treatment of cSCC, follow-up, prevention and occupational disease.

J Dtsch Dermatol Ges 2020 Apr 4;18(4):400-413. Epub 2020 Apr 4.

Department of Dermatology, Knappschaftskrankenhaus Recklinghausen, Recklinghausen, Germany.

Actinic keratoses (AKs) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guidelines for actinic keratosis and cutaneous squamous cell carcinoma were developed using the highest level of methodology (S3) according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF). The guidelines are aimed at dermatologists, general practitioners, ENT specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings as well as other medical specialties involved in the diagnosis and treatment of patients with AKs and cSCC. The guidelines are also aimed at affected patients, their relatives, policy makers and insurance funds. In the second part, we will address aspects relating to epidemiology, etiology, surgical and systemic treatment of cSCC, follow-up and disease prevention, and discuss AKs and cSCC in the context of occupational disease regulations.
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http://dx.doi.org/10.1111/ddg.14072DOI Listing
April 2020

S3 guideline for actinic keratosis and cutaneous squamous cell carcinoma - short version, part 1: diagnosis, interventions for actinic keratoses, care structures and quality-of-care indicators.

J Dtsch Dermatol Ges 2020 Mar;18(3):275-294

Department of Dermatology, Knappschaftskrankenhaus Recklinghausen, Recklinghausen, Germany.

Actinic keratoses (AK) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guideline "actinic keratosis and cutaneous squamous cell carcinoma" was developed using the highest level of methodology (S3) according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF). The guideline is aimed at dermatologists, general practitioners, ENT specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings as well as other medical specialties involved in the diagnosis and treatment of patients with AK and cSCC. The guideline is also aimed at affected patients, their relatives, policy makers and insurance funds. In the first part, we will address aspects relating to diagnosis, interventions for AK, care structures and quality-of-care indicators.
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http://dx.doi.org/10.1111/ddg.14048DOI Listing
March 2020

Salivary ghost cell carcinoma: case report and proposal of a new entity.

Virchows Arch 2020 Mar 15;476(3):465-468. Epub 2019 Oct 15.

DERMPATH MÜNCHEN, Munich, Germany.

Various topographically heterogeneous, histologically related groups of basaloid tumours are characterized by ghost cell differentiation with associated CTNNB1 mutations and nuclear β-catenin expression. We describe the unique case of a malignant tumour with ghost cell differentiation in the floor of the mouth, in which clinical, radiological, histological, immunohistological and molecular data altogether strongly indicate classification as a new type of salivary gland carcinoma.
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http://dx.doi.org/10.1007/s00428-019-02657-yDOI Listing
March 2020

NCOA4-RET and TRIM27-RET Are Characteristic Gene Fusions in Salivary Intraductal Carcinoma, Including Invasive and Metastatic Tumors: Is "Intraductal" Correct?

Am J Surg Pathol 2019 10;43(10):1303-1313

Institute of Biomedicine, Pathology, University of Turku, and Turku University Hospital, Turku, Finland.

Intraductal carcinoma (IC) is the new WHO designation for tumors previously encompassed by "low-grade cribriform cystadenocarcinoma" and "low-grade salivary duct carcinoma." The relationship of IC to salivary duct carcinoma (SDC) is controversial, even though they are considered to be distinct entities. IC is a rare low-grade malignant salivary gland neoplasm with histopathological features reminiscent of atypical ductal hyperplasia or ductal carcinoma in situ of the breast, showing diffuse S100 protein and mammaglobin positivity, while it is partially defined genetically. Recently, RET rearrangements including NCOA4-RET and TRIM27-RET have been described in IC. Here, we genetically characterize the largest cohort of IC to date (33 cases) including 8 cases with focal or widespread invasive growth and 1 case with lymph node metastasis. Thirty-three cases of IC were analyzed by next-generation sequencing (NGS) using the FusionPlex Solid Tumor kit (ArcherDX). Identified gene fusions were confirmed using fluorescence in situ hybridization break-apart and fusion probes and an reverse transcription polymerase chain reaction designed specifically for the detected breakpoints. Ten cases of SDC were analyzed for comparison using NGS panels that detect mutations and fusion transcripts. NGS analysis detected an NCOA4-RET fusion transcript in 11 cases of intercalated duct-type IC joining exon 7 or 8 of NCOA4 gene and exon 12 of the RET gene. Eight cases of IC had an invasive growth pattern, including one with widespread invasion and lymph node metastasis. Three invasive ICs harbored an NCOA4-RET fusion transcript, while 1 case was negative, and 2 cases were not analyzable. In addition, a novel TRIM27-RET fusion transcript between exon 3 of TRIM27 and exon 12 of RET was identified in 2 cases of IC with apocrine features, and one of them displayed invasive growth. Two IC cases with invasive growth harbored novel fusions TUT1-ETV5 and KIAA1217-RET, respectively. A total of 42.4% of the cases in this series of IC harbored fusions involving RET. Such fusion transcripts were not detected in any of the 10 SDC cases. We have confirmed NCOA4-RET as a predominant fusion in intercalated duct-type IC, including 3 cases with invasive growth pattern. A novel finding in our series was a case of widely invasive intercalated duct-type IC, with a single lymph node metastasis that revealed an NCOA4-RET fusion transcript. We also demonstrated that a subset of apocrine ICs harbored a TRIM27-RET gene fusion, including one case with invasive growth. In contrast, neither NCOA4-RET nor TRIM27-RET fusions were detected in any tested SDCs. Thus, the distinct molecular findings in IC and SDC support that the tumors are separate malignant salivary tumor entities. The presence of tumor-type-specific NCOA4-RET or TRIM27-RET translocations in a subset of widely invasive carcinomas with intercalated duct-like immunoprofiles suggests that a recharacterization of IC including its redesignation as "intercalated duct carcinoma, invasive or noninvasive" may be appropriate.
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http://dx.doi.org/10.1097/PAS.0000000000001301DOI Listing
October 2019

Nuclear NR4A3 Immunostaining Is a Specific and Sensitive Novel Marker for Acinic Cell Carcinoma of the Salivary Glands.

Am J Surg Pathol 2019 09;43(9):1264-1272

Institute of Pathology.

Recently, we discovered the recurrent genomic rearrangement [t(4;9)(q13;q31)] enabling upregulation of the transcription factor Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3) through enhancer hijacking as the oncogenic driver event in acinic cell carcinoma (AciCC) of the salivary glands. In the current study, we evaluated the usefulness of NR4A3 immunostaining and NR4A3 fluorescence in situ hybridization (FISH) in the differential diagnosis of AciCC, comparing a total of 64 AciCCs including 17% cases with high-grade transformation, 29 secretory (mammary analog) carcinomas (MASC), and 70 other salivary gland carcinomas. Nuclear NR4A3 immunostaining was a highly specific (100%) and sensitive (98%) marker for AciCC with only 1 negative case, whereas NR4A3 FISH was less sensitive (84%). None of the MASCs or other salivary gland carcinomas displayed any nuclear NR4A3 immunostaining. The recently described HTN3-MSANTD3 gene fusion was observed in 4 of 49 (8%) evaluable AciCCs, all with nuclear NR4A3 immunostaining. In summary, NR4A3 immunostaining is a highly specific and sensitive marker for AciCC, which may be especially valuable in cases with high-grade transformation and in "zymogen granule"-poor examples within the differential diagnostic spectrum of AciCC and MASC.
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http://dx.doi.org/10.1097/PAS.0000000000001279DOI Listing
September 2019

Fibroblast growth factor receptor 4 single nucleotide polymorphism Gly388Arg in head and neck carcinomas.

World J Clin Oncol 2019 Mar;10(3):136-148

Department of Otorhinolaryngology, Ludwig-Maximilians-University, Munich 81377, Germany.

Background: Head and neck squamous cell carcinoma (HNSCC) is considered to be a progressive disease resulting from alterations in multiple genes regulating cell proliferation and differentiation like receptor tyrosine kinases (RTKs) and members of the fibroblast growth factor receptors (FGFR)-family. Single-nucleotide polymorphism (SNP) Arg388 of the FGFR4 is associated with a reduced overall survival in patients with cancers of various types. We speculate that FGFR4 expression and SNP is associated with worse survival in patients with HSNCC.

Aim: To investigate the potential clinical significance of FGFR4 Arg388 in the context of tumors arising in HNSCC, a comprehensive analysis of FGFR4 receptor expression and genotype in tumor tissues and correlated results with patients' clinical data in a large cohort of patients with HNSCC was conducted.

Methods: Surgical specimens from 284 patients with HNSCC were retrieved from the Institute of Pathology at the Ludwig-Maximilian-University in Germany. Specimens were analyzed using immunohistochemistry and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The expression of FGFR4 was analyzed in 284 surgical specimens of HNSCC using immunohistochemstry. FGFR4 polymorphism was detected by PCR-RFLP. Patients' clinical data with a minimum follow-up of 5 years were statistically evaluated with a special emphasis on survival analysis employing Kaplan-Meier estimator and Cox regression analysis.

Results: Concerning the invasive tumor areas the intensity of the FGFR4 expression was evaluated in a four-grade system: no expression, low expression, intermediate and high expression. FGFR4 expression was scored as "high" (+++) in 74 (26%), "intermediate" (++) in 103 (36.3%), and "low" (+) in 107 (36.7%) cases. Analyzing the FGFR4 mutation it was found in 96 tumors (33.8%), 84 of them (29.6%) having a heterozygous and 12 (4.2%) homozygous mutated Arg388 allele. The overall frequency concerning the mutant alleles demonstrated 65% 34% mutated alleles in general. FGFR4 Arg388 was significantly associated with advanced tumor stage ( < 0.004), local metastasis ( < 0.0001) and reduced disease-free survival ( < 0.01). Furthermore, increased expression of FGFR4 correlated significantly with worse overall survival ( < 0.003).

Conclusion: In conclusion, the FGFR4 Arg388 genotype and protein expression of FGFR4 impacts tumor progression in patients with HNSCC and may present a useful target within a multimodal therapeutic intervention.
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http://dx.doi.org/10.5306/wjco.v10.i3.136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441662PMC
March 2019

S2k Guidelines for Cutaneous Basal Cell Carcinoma - Part 2: Treatment, Prevention and Follow-up.

J Dtsch Dermatol Ges 2019 Feb;17(2):214-230

Department of Dermatology, Mainz University Medical Center, Mainz, Germany.

Basal cell carcinoma (BCC) is the most common malignant tumor among fair-skinned individuals, and its incidence had been steadily rising in the past decades. In order to maintain the highest quality of patient care possible, the German S2k guidelines were updated following a systematic literature search and with the participation of all professional societies and associations involved in the management of the disease. Part 2 addresses issues such as proper risk stratification, the various therapeutic approaches, and prevention as well as follow-up of patients with basal cell carcinoma.
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http://dx.doi.org/10.1111/ddg.13755DOI Listing
February 2019

S2k Guidelines for Cutaneous Basal Cell Carcinoma - Part 1: Epidemiology, Genetics and Diagnosis.

J Dtsch Dermatol Ges 2019 Jan 28;17(1):94-103. Epub 2018 Dec 28.

Department of Dermatology, Mainz University Medical Center, Mainz, Germany.

Basal cell carcinoma is the most common malignant tumor among fair-skinned individuals, and its incidence has been rising steadily in the past decades. In order to maintain the highest quality of patient care possible, the German S2k guidelines were updated following a systematic literature search and with the participation of all professional societies and associations involved in the management of the disease. Part 1 highlights new developments in genetics in particular as well as aspects regarding epidemiology, diagnosis, and histology.
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http://dx.doi.org/10.1111/ddg.13733DOI Listing
January 2019

Contemporary Management of Benign and Malignant Parotid Tumors.

Front Surg 2018 11;5:39. Epub 2018 May 11.

Department of Otorhinolaryngology, Universitätsklinikum Jena, Jena, Germany.

To report the standard of care, interesting new findings and controversies about the treatment of parotid tumors. Relevant and actual studies were searched in PubMed and reviewed for diagnostics, treatment and outcome of both benign and malignant tumors. Prospective trials are lacking due to rarity of the disease and high variety of tumor subtypes. The establishment of reliable non-invasive diagnostics tools for the differentiation between benign and malignant tumors is desirable. Prospective studies clarifying the association between different surgical techniques for benign parotid tumors and morbidity are needed. The role of adjuvant or definitive radiotherapy in securing loco-regional control and improving survival in malignant disease is established. Prospective clinical trials addressing the role of chemotherapy/molecular targeted therapy for parotid cancer are needed. An international consensus on the classification of parotid surgery techniques would facilitate the comparison of different trials. Such efforts should lead into a clinical guideline.
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http://dx.doi.org/10.3389/fsurg.2018.00039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958460PMC
May 2018

HPV-related Multiphenotypic Sinonasal Carcinoma: An Expanded Series of 49 Cases of the Tumor Formerly Known as HPV-related Carcinoma With Adenoid Cystic Carcinoma-like Features.

Am J Surg Pathol 2017 Dec;41(12):1690-1701

*Departments of Pathology, Oncology, and Otolaryngology-Head and Neck Surgery, The Johns Hopkins University, Baltimore, MD †Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX Departments of ‡Otorhinolaryngology Head & Neck Surgery and Audiology ¶¶¶Pathology, Copenhagen University Hospital, Copenhagen §Department of Otorhinolaryngology and Maxillofacial Surgery, Zealand University Hospital, Køge, Denmark ∥Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital ¶School of Medicine, National Yang-Ming University, Taipei, Taiwan #Department of Pathology, Dalhousie University, Halifax, NS, Canada **Mayo Clinic School of Medicine, Mayo Clinic ‡‡Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, MN ††Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy §§Department of Pathology, Warren Alpert School of Medicine at Brown University (retired), Providence, RI ∥∥Department of Pathology, University of Miami, Miami, FL ¶¶Laboratory for Dermatohistology and Oral Pathology, Munich, Germany ##Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN ***Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA †††Department of Pathology, Loyola University Medical Center, Chicago, IL ‡‡‡Department of Pathology, Imperial College, London, United Kingdom §§§Department of Pathology, University of Toulouse, Toulouse, France ∥∥∥Department of Pathology, University of Virginia, Charlottesville, VA.

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC), originally known as HPV-related carcinoma with adenoid cystic carcinoma-like features, is a peculiar neoplasm that is restricted to the sinonasal tract, exhibits features of both a surface-derived and salivary gland carcinoma (particularly adenoid cystic carcinoma), and is associated with high-risk HPV. Given the limited number of published cases, the full clinicopathologic spectrum of this neoplasm is unclear. Here, we present an updated experience of 49 cases. All cases of HMSC were obtained from the authors' files. Immunohistochemistry for p16, c-kit, and myoepithelial cell markers (S100, actin, calponin, p63, and/or p40) was performed along with RNA in situ hybridization for HPV (type 33-specific as well as a high-risk cocktail). Fluorescence in situ hybridization studies for fusions of MYB, NFIB, and MYBL1 was performed on a subset of cases. Clinical follow-up was obtained from medical records. A total of 49 cases of HMSC were collected. Twenty-eight (57%) were from women and 18 (43%) from men, ranging in age from 28 to 90 years (mean, 54 y). Of 40 cases with detailed staging information, 43% of HMSCs presented with a high T-stage (T3 or T4). Histologically, most grew predominantly as solid nests of basaloid cells exhibiting high mitotic rates and frequent necrosis, with histologic and immunohistochemical evidence of myoepithelial differentiation. Most cases also demonstrated foci of cribriform and/or tubular growth, along with an inconspicuous population of ducts. Thirty-four (69%) cases demonstrated an unusual pattern of surface involvement where markedly atypical squamous cells colonized tracts of the sinonasal mucosa. Less consistent histologic features included squamous differentiation within the invasive tumor (n=6), sarcomatoid transformation (n=5) including overt chondroid differentiation (n=3), and prominent epithelial-myoepithelial carcinoma-like growth (n=3). All cases were positive for p16 by immunostaining and HPV by RNA in situ hybridization. Thirty-three (67%) were positive for HPV 33. No cases tested for MYB, MYBL1, or NFIB gene fusions were positive. In the 38 cases with follow-up data, (mean follow-up, 42 mo) 14 recurred locally and 2 metastasized (lung, finger). There were no regional lymph node metastases, and no tumor-related deaths. HMSC is a distinct sinonasal neoplasm characterized by myoepithelial differentiation, frequent surface epithelial involvement, and the presence of high-risk HPV (especially type 33). Although it classically exhibits a cribriforming pattern that closely resembles adenoid cystic carcinoma, our expanded series highlights a histologic spectrum that is much broader than previously recognized, warranting a change in terminology. HMSC usually presents as a large and destructive sinonasal mass with high-grade histologic features, but it paradoxically behaves in a relatively indolent manner, underscoring the importance of distinguishing HMSC from true adenoid cystic carcinoma, squamous cell carcinoma, and other histologic mimickers.
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http://dx.doi.org/10.1097/PAS.0000000000000944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680105PMC
December 2017

Histological, immunohistological and molecular characteristics of intraductal precursor of carcinoma ex pleomorphic adenoma support a multistep carcinogenic process.

Virchows Arch 2017 Jun 28;470(6):601-609. Epub 2017 Mar 28.

Institute of Pathology, Technical University of Munich, Munich, Germany.

In recent years, multistep carcinogenesis of carcinoma ex pleomorphic adenoma (CEPA) has been identified, starting with intraductal neoplasia within pre-existent pleomorphic adenoma (PA). However, as yet there is no consensus regarding clinical relevance and appropriate terminology of precursor lesions in CEPA. We therefore decided to investigate precursor lesions, especially intraductal carcinoma, in a series of 85 cases of CEPA. Intraductal carcinoma confined by benign myoepithelial cells was found in 60 cases and mostly exhibited high-grade cellular atypia, increased cellular proliferation and frequent genetic alterations (TP53, Her2-neu, androgen receptor). Intraductal carcinoma was absent only in the myoepithelial type of CEPA. In 26 cases, purely intraductal CEPA with extensive intraductal expansion was found. This suggests that there is a long period of intraductal growth before extraductal intracapsular infiltration of the PA. We identified two different histomorphological types of intraductal carcinoma, which we call 'clinging' and 'solid' types. In summary, combined histological, immunohistological and molecular data strongly support multistep carcinogenesis starting with intraductal carcinoma for all non-myoepithelial types of CEPA. The clinical significance of our finding of two histomorphological types of intraductal carcinoma (clinging and solid) is not yet clear. Intraductal carcinoma, intracapsular invasive CEPA and minor extracapsular invasive CEPA (up to about 6 mm) all show favourable prognosis and together comprise half of the cases in our study.
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http://dx.doi.org/10.1007/s00428-017-2106-2DOI Listing
June 2017

Cyclin D1 Expression in Ectomesenchymal Chondromyxoid Tumor of the Anterior Tongue.

Int J Surg Pathol 2016 Oct 29;24(7):586-94. Epub 2016 May 29.

The Fingerland Department of Pathology, Charles University in Prague, Faculty of Medicine and University Hospital in Hradec Kralove, Czech Republic.

Ectomesenchymal chondromyxoid tumor (ECT) is a rare benign tumor of uncertain lineage, which almost exclusively affects the anterior tongue. Herein, we report 2 cases of ECT occurring in 58- and 56-year-old males on the right and on the left side of the dorsum of the anterior tongue, measuring 18 mm and 10 mm, respectively. Despite positive resection margin in one case, none of the tumors recurred during follow-up of 6 and 5 years. Microscopically, both tumors had lobular architecture with a mixture of solid, microcystic, and chondromyxoid areas. The tumor cells were polygonal or elongated and showed mild atypia in one case. Immunohistochemically, both tumors showed diffuse expression of vimentin and focal positivity of CD10 and of smooth muscle actin. Regarding neural tissue-related markers, there was nearly diffuse expression of CD56 and neuron-specific enolase and focal positivity of PGP 9.5 in both cases and variable expression of CD57, synaptophysin, glial fibrillary acidic protein, and S-100 protein. Interestingly, we observed diffuse expression of SOX10 in one case. In both tumors, diffuse strong nuclear expression of cyclin D1 was present, without CCND1/IGH translocation or CCND1 amplification. The EWSR1 gene rearrangement was not detected. To the best of our knowledge, expression of SOX10, which may support neural crest origin of this peculiar lesion, has not been reported in ECT. The significance of strong cyclin D1 expression remains to be further investigated.
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http://dx.doi.org/10.1177/1066896916652221DOI Listing
October 2016

Towards personalised treatment in primary Sjögren's syndrome: baseline parotid histopathology predicts responsiveness to rituximab treatment.

Ann Rheum Dis 2016 Nov 12;75(11):1933-1938. Epub 2016 Jan 12.

Department of Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Objectives: The aims of this study were (1) to assess the effect of rituximab (RTX; anti-CD20) treatment in patients with primary Sjögren's syndrome (pSS) based on sequential parotid biopsies obtained in a placebo-controlled, randomised clinical trial, and (2) to assess the prognostic value of the histological characteristics of parotid gland tissue with regard to responsiveness to RTX treatment.

Methods: In a double-blinded, placebo-controlled trial, sequential parotid gland biopsies were taken from 20 RTX-treated and 10 placebo-treated patients with pSS, at baseline and 12 weeks after treatment. The relative amount of lymphocytic infiltrate (stained for CD45), absolute number of T cells and B cells per mm parenchyma (stained for CD3 and CD20, respectively), focus score, number of germinal centres and of lymphoepithelial lesions per mm in parotid gland parenchyma were assessed. Histopathological data were compared between clinical responders (decrease in European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) score of ≥3 at 12 weeks compared with baseline) and non-responders (change in ESSDAI<3) to RTX treatment.

Results: In RTX-treated patients, a significant reduction in the number of CD20+ B cells/mm parenchyma was observed, while no such reduction was observed in placebo-treated patients. The number of CD3+ T cells/mm in parenchyma did not change in either group. Furthermore, the number and the severity of lymphoepithelial lesions/mm and number of germinal centres/mm was significantly reduced in RTX-treated patients, but did not change in placebo-treated patients. When comparing the pretreatment characteristics of clinical responders with non-responders, the median number of CD20+ B cells/mm parenchyma at baseline was significantly higher in responders (1871 vs 353 cells/mm, p<0.05). Other histopathological baseline characteristics were not predictive for response to RTX treatment.

Conclusions: RTX treatment in pSS leads to a major reduction of lymphocytic infiltration and to fewer B cells, germinal centres and lymphoepithelial lesions in parotid gland parenchyma. A high pretreatment number of CD20+ B cells/mm parotid gland parenchyma predicts better responsiveness of patients with pSS to RTX treatment. Pretreatment parotid gland histopathological characteristics could therefore contribute to a more personalised treatment approach to pSS.
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http://dx.doi.org/10.1136/annrheumdis-2015-208304DOI Listing
November 2016

Evaluation of confocal laser endomicroscopy as an aid to differentiate primary flat lesions of the larynx: A prospective clinical study.

Head Neck 2016 04 28;38 Suppl 1:E1695-704. Epub 2015 Nov 28.

Department of Otorhinolaryngology, Head and Neck Surgery, Klinikum der Universität München, Munich, Germany.

Background: In this trial, the ability of confocal laser endomicroscopy (CLE), a new imaging modality with a cellular resolution, to further differentiate primary flat lesions of the larynx was evaluated.

Methods: First, an optical coherence tomography was used to filter out normal tissue and carcinoma. All other lesions (30 lesions in 19 patients) were investigated with CLE. The suspected diagnosis was compared to histopathology.

Results: Optical coherence tomography identified all noninvasive lesions. CLE provided further information with cellular resolution. In 2 of 30 cases, low image quality prevented classification. In laryngeal lesions (27 of 30), moderate to high-grade dysplasia was correctly suspected in 10 of 10 cases (100%). Hyperplasia was overrated as dysplasia in 7 of 15 cases (46.7%). Sensitivity was 100% and specificity was 40%.

Conclusion: When used in conjunction with optical coherence tomography, CLE seems helpful for discrimination of noninvasive lesions, although it tends to overrate the severity of the changes. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1695-E1704, 2016.
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http://dx.doi.org/10.1002/hed.24303DOI Listing
April 2016

Intraparotid classical and nodular lymphocyte-predominant Hodgkin lymphoma: pattern analysis with emphasis on associated lymphadenoma-like proliferations.

Am J Surg Pathol 2015 Sep;39(9):1206-12

*Institute of Pathology, University Hospital, Erlangen †Comprehensive Cancer Center Mainfranken, Institute of Pathology, University of Würzburg, Würzburg ‡Institute of Pathology, Klinikum Augsburg, Augsburg §Laboratory for Dermatohistology & Oral Pathology ∥Institute of Pathology, Ludwig Maximilian University, München, Germany.

Most of the lymphoproliferative diseases involving the salivary glands represent indolent non-Hodgkin B-cell lymphoma (marginal zone lymphoma) related to chronic autoimmune sialadenitis (Sjögren disease). Other types of non-Hodgkin lymphomas involve the salivary glands less frequently. On rare occasions, classical Hodgkin lymphoma (CHL) and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) present initially as a primary salivary gland mass. We analyzed a series of CHL (n=3) and NLPHL (n=6) presenting initially as parotid gland tumors concerning their pattern (parenchymal vs. intraparotid lymph node) and the presence of salivary inclusions and epithelial proliferations within the lymphoma infiltrate. The pattern of infiltration was determined on hematoxylin and eosin-stained slides assisted by immunostaining for pancytokeratin to highlight lobular salivary gland parenchyma. Patients included 6 male and 3 female individuals with a mean age of 62 years (range, 36 to 88 y). Lymphoma was localized within intraparotid lymph nodes in 8 cases and was limited to salivary parenchyma in 1 case. Parenchymal involvement in nodal-based cases was scored as absent (3) or minimal (5). Salivary inclusions (acini and ductules) within affected lymph nodes were noted in 6 cases (4/5 NLPHLs and 2/3 CHLs). In 3/6 NLPHL cases, salivary inclusions showed variable proliferative changes ranging from prominent lymphoepithelial lesions to cystic and oncocytic (Warthin-like) epithelial changes. Scanty small lymphoepithelial lesions were seen in 1 of the 3 CHL cases. One NLPHL in the intraparotid lymph node was accompanied by prominent lymphoepithelial sialadenitis in the absence of clinical signs of Sjögren disease. This study highlights that a majority of parotid gland Hodgkin lymphomas arise within intraparotid lymph nodes. Frequent entrapment and proliferation of salivary ducts and acini within the lymphoma infiltrate might mimic a variety of benign lymphoepithelial mass-forming lesions (nonsebaceous lymphadenoma, Warthin tumor, and autoimmune sialadenitis). Pancytokeratin stain is helpful for reliable assessment of the background architecture.
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http://dx.doi.org/10.1097/PAS.0000000000000440DOI Listing
September 2015

Fibroblast growth factor receptor-1 as a potential therapeutic target in sinonasal cancer.

Head Neck 2014 Sep 1;36(9):1253-7. Epub 2014 Feb 1.

Department of Otorhinolaryngology / Head and Neck Surgery, University of Bonn, Germany; Department of Prostate Cancer Research, University of Bonn, Bonn, Germany.

Background: Despite multimodal treatment, sinonasal malignancies have an unfavorable prognosis. The purpose of this study was to elucidate if these tumors harbor amplifications of the fibroblast growth factor receptor 1 (FGFR1) gene, which has recently been identified as a potential therapeutic target in squamous cell lung cancer.

Methods: One hundred twelve primary tumors (including squamous cell carcinoma [SCC], carcinoma associated with an inverted papilloma, sinonasal undifferentiated carcinoma [SNUC], adenocarcinoma, adenoid cystic carcinoma [ACC], esthesioneuroblastoma, and 9 corresponding lymph node metastases) were assessed by fluorescence in situ hybridization (FISH) for FGFR1 copy number status. Human papillomavirus (HPV) status was assessed by p16 immunohistochemical as a surrogate marker.

Results: FGFR1 amplification was found in subsets of sinonasal SCCs (20%), carcinomas associated with an inverted papilloma (33%), and SNUCs (5%). In all cases, metastatic tumor samples shared the same FGFR1 amplification status as the corresponding primary tumor tissue. None of the FGFR1-amplified tumors expressed p16.

Conclusion: FGFR1 amplification represents a potential molecular target in a subset of patients with sinonasal cancer. © 2014 Wiley Periodicals, Inc. Head Neck 36: 1253-1257, 2014.
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http://dx.doi.org/10.1002/hed.23443DOI Listing
September 2014

Sex determining region Y-box 2 (SOX2) amplification is an independent indicator of disease recurrence in sinonasal cancer.

PLoS One 2013 27;8(3):e59201. Epub 2013 Mar 27.

Department of Otorhinolaryngology/Head and Neck Surgery, University of Bonn, Bonn, Germany.

Objectives: The transcription factor SOX2 (3q26.3-q27) is an embryonic stem cell factor contributing to the induction of pluripotency in terminally differentiated somatic cells. Recently, amplification of the SOX2 gene locus has been described in squamous cell carcinoma (SCC) of different organ sites. Aim of this study was to investigate amplification and expression status of SOX2 in sinonasal carcinomas and to correlate the results with clinico-pathological data.

Materials And Methods: A total of 119 primary tumor samples from the sinonasal region were assessed by fluorescence in-situ hybridization and immunohistochemistry for SOX2 gene amplification and protein expression, respectively. Of these, 59 were SSCs, 18 sinonasal undifferentiated carcinomas (SNUC), 10 carcinomas associated with an inverted papilloma (INVC), 19 adenocarcinomas (AD) and 13 adenoid cystic carcinomas (ACC).

Results: SOX2 amplifications were found in subsets of SCCs (37.5%), SNUCs (35.3%), INVCs (37.5%) and ADs (8.3%) but not in ACCs. SOX2 amplification resulted in increased protein expression. Patients with SOX2-amplified sinonasal carcinomas showed a significantly higher rate of tumor recurrences than SOX2 non-amplified tumors.

Conclusion: This is the first study assessing SOX2 amplification and expression in a large cohort of sinonasal carcinomas. As opposed to AD and ACC, SOX2 amplifications were detected in more than 1/3 of all SCCs, SNUCs and INVCs. We therefore suggest that SNUCs are molecularly closely related to SCCs and INVCs and that these entities represent a subgroup of sinonasal carcinomas relying on SOX2 acquisition during oncogenesis. SOX2 amplification appears to identify sinonasal carcinomas that are more likely to relapse after primary therapy, suggesting that these patients might benefit from a more aggressive therapy regime.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0059201PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609820PMC
September 2013