Publications by authors named "Ilmo Leivo"

114 Publications

Clinical significance of tumor-stroma ratio in head and neck cancer: a systematic review and meta-analysis.

BMC Cancer 2021 Apr 30;21(1):480. Epub 2021 Apr 30.

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

Background: The clinical significance of tumor-stroma ratio (TSR) has been examined in many tumors. Here we systematically reviewed all studies that evaluated TSR in head and neck cancer.

Methods: Four databases (Scopus, Medline, PubMed and Web of Science) were searched using the term tumo(u)r-stroma ratio. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) were followed.

Results: TSR was studied in nine studies of different subsites (including cohorts of nasopharyngeal, oral, laryngeal and pharyngeal carcinomas). In all studies, TSR was evaluated using hematoxylin and eosin staining. Classifying tumors based on TSR seems to allow for identification of high-risk cases. In oral cancer, specifically, our meta-analysis showed that TSR is significantly associated with both cancer-related mortality (HR 2.10, 95%CI 1.56-2.84) and disease-free survival (HR 1.84, 95%CI 1.38-2.46).

Conclusions: The assessment of TSR has a promising prognostic value and can be implemented with minimum efforts in routine head and neck pathology.
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http://dx.doi.org/10.1186/s12885-021-08222-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086072PMC
April 2021

High-grade Transformation/Dedifferentiation in Salivary Gland Carcinomas: Occurrence Across Subtypes and Clinical Significance.

Adv Anat Pathol 2021 May;28(3):107-118

International Head and Neck Scientific Group, Padua, Italy.

High-grade transformation (HGT) or dedifferentiation has been described in a variety of salivary gland carcinomas, including acinic cell carcinoma, secretory carcinoma, adenoid cystic carcinoma, epithelial-myoepithelial carcinoma, polymorphous adenocarcinoma, low-grade mucoepidermoid carcinoma, and hyalinizing clear cell carcinoma. High-grade (HG) transformed tumors are composed of a conventional low-grade component characterized by specific microscopic and immunohistochemical features for the given entity, intermingled with or juxtaposed to areas of HG morphology. This is usually either poorly differentiated adenocarcinoma, carcinoma not otherwise specified, or undifferentiated carcinoma, in which the original line of differentiation is lost. The HG component is composed of solid nests of anaplastic cells with large vesicular pleomorphic nuclei, prominent nucleoli, and abundant cytoplasm. Frequent mitoses and extensive necrosis may be present. The Ki-67 labeling index is consistently higher in the HG component. The molecular genetic mechanisms responsible for HGT of salivary gland carcinomas are largely unknown, though p53 inactivation and human epidermal growth factor receptor 2 overexpression and/or gene amplification have been demonstrated in the HG component in a few examples, the frequency varies for each histologic type. Salivary gland carcinomas with HGT are more aggressive than conventional carcinomas, with a higher local recurrence rate and a poorer prognosis. They have a high propensity for cervical lymph node metastasis suggesting a need for a wider resection and neck dissection. HGT of salivary gland carcinoma can occur either at initial presentation or less commonly at the time of recurrence, sometimes following postoperative radiotherapy. The potential for HGT in almost any type of salivary gland carcinoma warrants a thorough sampling of all salivary gland malignancies to prevent oversight of a HG component.
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http://dx.doi.org/10.1097/PAP.0000000000000298DOI Listing
May 2021

Biomarkers for Immunotherapy of Oral Squamous Cell Carcinoma: Current Status and Challenges.

Front Oncol 2021 8;11:616629. Epub 2021 Mar 8.

Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Oral squamous cell carcinoma (OSCC) forms a major health problem in many countries. For several decades the management of OSCC consisted of surgery with or without radiotherapy or chemoradiotherapy. Aiming to increase survival rate, recent research has underlined the significance of harnessing the immune response in treatment of many cancers. The promising finding of checkpoint inhibitors as a weapon for targeting metastatic melanoma was a key event in the development of immunotherapy. Furthermore, clinical trials have recently proven inhibitor of PD-1 for treatment of recurrent/metastatic head and neck cancer. However, some challenges (including patient selection) are presented in the era of immunotherapy. In this mini-review we discuss the emergence of immunotherapy for OSCC and the recently introduced biomarkers of this therapeutic strategy. Immune biomarkers and their prognostic perspectives for selecting patients who may benefit from immunotherapy are addressed. In addition, possible use of such biomarkers to assess the response to this new treatment modality of OSCC will also be discussed.
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http://dx.doi.org/10.3389/fonc.2021.616629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982571PMC
March 2021

Back to basics: Hematoxylin and eosin staining is the principal tool for histopathological risk assessment of oral cancer.

Oral Oncol 2021 04 29;115:105134. Epub 2020 Dec 29.

Institute of Biomedicine, Pathology, University of Turku, Turku, Finland. Electronic address:

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http://dx.doi.org/10.1016/j.oraloncology.2020.105134DOI Listing
April 2021

Biopsy quality is essential for preoperative prognostication in oral tongue cancer.

APMIS 2021 Mar 28;129(3):118-127. Epub 2020 Dec 28.

Department of Pathology, University of Helsinki, Helsinki, Finland.

A role for incisional biopsy in preoperative prognostication is increasingly being advocated in oral tongue squamous cell carcinomas (OTSCC). Biopsies at two locations were compared, and prognostic factors in biopsies and their corresponding resections were evaluated. A total of 138 OTSCC biopsy slides from Finland and Saudi Arabia were compared for size (horizontal and vertical) and invasive front. The Finnish cases were assessed for tumor stroma ratio (TSR) and tumor-infiltrating lymphocytes (TILs) using light microscopy and digital image analysis assessment and compared. Furthermore, TSR, TILs, and previously analyzed budding and depth of invasion (BD) score in biopsies were compared with their evaluation in the corresponding resections. Fifty-nine percent of Finnish and 42% of Saudi Arabian biopsies were ≥ 5 mm deep, while 98% of Saudi Arabian and 76% of Finnish biopsies were ≥ 5 mm wide. Assessment of invasion front was possible in 72% of Finnish in comparison with 40% of Saudi Arabian biopsies. There was 86.8% agreement between TSR and 75% agreement between TIL evaluation using light microscopy and digital assessment. Significant agreement was obtained on comparing the TSR (p = 0.04) and BD (p < 0.001) values in biopsies and resections. Biopsies of ≥ 5 mm depth from representative OTSCC areas are essential for prognostic information. Clinical pathologists are advised to assess BD score and TSR for prognostic features in such biopsies.
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http://dx.doi.org/10.1111/apm.13104DOI Listing
March 2021

Matrix metalloproteinase-7, -8, -9, -15, and -25 in minor salivary gland adenoid cystic carcinoma.

Pathol Res Pract 2021 Jan 22;217:153293. Epub 2020 Nov 22.

Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Oral Pathology and Radiology, University of Turku, Turku University Hospital, Turku, Finland; Research Programs Unit, Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland.

Knowledge on the role of matrix metalloproteinases (MMPs) in adenoid cystic carcinoma (ACC) is limited. MMPs are capable of degrading almost all extracellular and pericellular components to promote invasion and metastasis. This study aimed to evaluate the immunohistochemical expression of MMP-7, -8, -9, -15, and -25 in ACC and to relate the results with clinicopathological factors and survival. The study included 68 patients with minor salivary gland ACC treated at the Helsinki University Hospital (Helsinki, Finland) in 1974-2012. Samples from 52 patients were available, consisting of 44 primary tumours and eight recurrent tumours. We scored immunostaining of MMP-7, -8, -9, -15, and -25 and analysed the immunoscore against clinical and pathological parameters using statistical correlation test. MMP-9 immunoexpression in pseudocysts of ACC and in peritumoural inflammatory cells associated with better survival and fewer treatment failures. High tumoural MMP-7 and -25 associated with better survival. High tumoural MMP-15 associated with poorer survival and high tumoural MMP-9 with advanced stage and regional recurrences. Tumour cells did not show MMP-8 immunopositivity. These results suggest that MMP-9 may contribute to ACC carcinogenesis in different roles. MMP-7, -8, and -9 can stimulate signalling pathways that may promote tissue modulation and metastatic potential. MMP-15 and -25 may reflect prognosis.
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http://dx.doi.org/10.1016/j.prp.2020.153293DOI Listing
January 2021

Comparison of nomogram with machine learning techniques for prediction of overall survival in patients with tongue cancer.

Int J Med Inform 2021 01 24;145:104313. Epub 2020 Oct 24.

Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; University of Turku, Institute of Biomedicine, Pathology, Turku, Finland; Department of Pathology, University of Helsinki, Helsinki, Finland; Faculty of Dentistry, University of Misurata, Misurata, Libya.

Background: The prediction of overall survival in tongue cancer is important for planning of personalized care and patient counselling.

Objectives: This study compares the performance of a nomogram with a machine learning model to predict overall survival in tongue cancer. The nomogram and machine learning model were built using a large data set from the Surveillance, Epidemiology, and End Results (SEER) program database. The comparison is necessary to provide the clinicians with a comprehensive, practical, and most accurate assistive system to predict overall survival of this patient population.

Methods: The data set used included the records of 7596 tongue cancer patients. The considered machine learning algorithms were logistic regression, support vector machine, Bayes point machine, boosted decision tree, decision forest, and decision jungle. These algorithms were mainly evaluated in terms of the areas under the receiver-operating characteristic (ROC) curve (AUC) and accuracy values. The performance of the algorithm that produced the best result was compared with a nomogram to predict overall survival in tongue cancer patients.

Results: The boosted decision-tree algorithm outperformed other algorithms. When compared with a nomogram using external validation data, the boosted decision tree produced an accuracy of 88.7% while the nomogram showed an accuracy of 60.4%. In addition, it was found that age of patient, T stage, radiotherapy, and the surgical resection were the most prominent features with significant influence on the machine learning model's performance to predict overall survival.

Conclusion: The machine learning model provides more personalized and reliable prognostic information of tongue cancer than the nomogram. However, the level of transparency offered by the nomogram in estimating patients' outcomes seems more confident and strengthened the principle of shared decision making between the patient and clinician. Therefore, a combination of a nomogram - machine learning (NomoML) predictive model may help to improve care, provides information to patients, and facilitates the clinicians in making tongue cancer management-related decisions.
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http://dx.doi.org/10.1016/j.ijmedinf.2020.104313DOI Listing
January 2021

Molecular Profiling of Clear Cell Myoepithelial Carcinoma of Salivary Glands With EWSR1 Rearrangement Identifies Frequent PLAG1 Gene Fusions But No EWSR1 Fusion Transcripts.

Am J Surg Pathol 2021 01;45(1):1-13

Institute of Biomedicine, University of Turku.

Myoepithelial carcinoma of salivary glands is an underrecognized and challenging entity with a broad morphologic spectrum, including an EWSR1-rearranged clear cell variant. Myoepithelial carcinoma is generally aggressive with largely unknown genetic features. A retrospective review of Salivary Gland Tumor Registry in Pilsen searching for the key words "clear cell myoepithelial carcinoma," "hyalinizing clear cell," and "clear cell malignant myoepithelioma" yielded 94 clear cell myoepithelial carcinomas (CCMCs) for molecular analysis of EWSR1 rearrangement using fluorescence in situ hybridization (FISH). Tumors positive for EWSR1 gene rearrangement were tested by next-generation sequencing (NGS) using fusion-detecting panels. NGS results were confirmed by reverse-transcription polymerase chain reaction or by FISH. Twenty-six tumors originally diagnosed as CCMC (26/94, 27.6%) revealed split signals for EWSR1 by FISH. Six of these tumors (6/26, 23%) displayed amplification of the EWSR1 locus. Fifteen cases were analyzable by NGS, whereas 9 were not, and tissue was not available in 2 cases. None of the CCMCs with EWSR1 rearrangements detected by FISH had an EWSR1 fusion transcript. Fusion transcripts were detected in 6 cases (6/15, 40%), including LIFR-PLAG1 and CTNNB1-PLAG1, in 2 cases each, and CHCHD7-PLAG1 and EWSR1-ATF1 fusions were identified in 1 case each. Seven cases, including those with PLAG1 fusion, were positive for PLAG1 rearrangement by FISH, with notable exception of CHCHD7-PLAG1, which is an inversion not detectable by FISH. One single case with EWSR1-ATF1 fusion in NGS showed ATF1 gene rearrangement by FISH and was reclassified as clear cell carcinoma (CCC). In addition, another 4 cases revealed ATF1 rearrangement by FISH and were reclassified as CCC as well. Moreover, 12/68 (17%) CCMCs with intact EWSR1 gene were selected randomly and analyzed by NGS. PLAG1 fusions were found in 5 cases (5/12, 41.6%) with LIFR (2 cases), FGFR1 (2 cases), and CTNNB1 (1 case) as partner genes. Overall, PLAG1 gene rearrangements were detected in 10/38 (26%) tested cases. None of the tumors had SMARCB1 loss by immunohistochemistry as a possible explanation for the EWSR1 abnormalities in FISH. Novel findings in our NGS study suggest that EWSR1-FISH positive CCMC is a gene fusion-driven disease with frequent oncogenic PLAG1 fusions, including LIFR-PLAG1 and CTNNB1-PLAG1 in most cases. Productive EWSR1 fusions are found only in a minority of EWSR1-ATF1-rearranged cases, which were in part reclassifiable as CCCs. Detectable EWSR1-FISH abnormality in CCMCs without gene fusion perhaps represents a passenger mutation with minor or no oncologic effect.
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http://dx.doi.org/10.1097/PAS.0000000000001591DOI Listing
January 2021

Molecular Profiling of Salivary Oncocytic Mucoepidermoid Carcinomas Helps to Resolve Differential Diagnostic Dilemma With Low-grade Oncocytic Lesions.

Am J Surg Pathol 2020 12;44(12):1612-1622

Institute of Biomedicine, University of Turku.

Oncocytic mucoepidermoid carcinoma (OMEC) is a rare but diagnostically challenging variant of mucoepidermoid carcinoma (MEC). OMEC is notable for differential diagnostic considerations that are raised as a result of overlap with other benign and low-grade oncocytic salivary gland tumors. Diffuse and strong immunoreactivity of p63 protein may be useful in distinguishing OMEC from its mimics. However, focal p63 staining can be present in benign oncytomas. Presence of mucin-containing cells, mucinous cystic formation, and foci of extravasated mucin are considered a hallmark of MEC. True mucocytes may be, however, very few and hardly discernable in OMECs. Recent evidence has shown that most MECs harbor gene fusions involving MAML2. A retrospective review of archived pathology files and the authors' own files was conducted to search for "low-grade/uncertain oncocytic tumor," "oncocytoma," and "oncocytic carcinoma" in the period from 1996 to 2019. The tumors with IHC positivity for p63 and/or p40, and S100 negativity, irrespective of mucicarmine staining, were tested by next-generation sequencing using fusion-detecting panels to detect MAML2 gene rearrangements. Two index cases from consultation practice (A.S. and A.A.) of purely oncocytic low-grade neoplasms without discernible mucinous cells showed a CRTC1-MAML2 fusion using next-generation sequencing, and were reclassified as OMEC. In total, 22 cases of oncocytic tumors, retrieved from the authors' files, and from the Salivary Gland Tumor Registry, harbored the MAML2 gene rearrangements. Presence of mucocytes, the patterns of p63 and SOX10 immunopositivity, and mucicarmine staining were inconsistent findings. Distinguishing OMEC devoid of true mucinous cells from oncocytoma can be very challenging, but it is critical for proper clinical management. Diffuse and strong positivity for p63 and visualization of hidden mucocytes by mucicarmine staining may be misleading and does not always suffice for correct diagnosis. Our experience suggests that ancillary studies for the detection of MAML2 rearrangement may provide useful evidence in difficult cases.
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http://dx.doi.org/10.1097/PAS.0000000000001590DOI Listing
December 2020

Stromal categorization in early oral tongue cancer.

Virchows Arch 2021 May 21;478(5):925-932. Epub 2020 Sep 21.

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

Stromal categorization has been used to classify many epithelial cancer types. We assessed the desmoplastic reaction and compared its significance with other stromal characteristics in early (cT1-2N0) oral tongue squamous cell carcinoma (OTSCC). In this multi-institutional study, we included 308 cases treated for early OTSCC at five Finnish university hospitals or at the A.C. Camargo Cancer Center in São Paulo, Brazil. The desmoplastic reaction was classified as immature, intermediate, or mature based on the amount of hyalinized keloid-like collagen and myxoid stroma. We compared the prognostic value of the desmoplastic reaction with a stromal grading system based on tumor-stroma ratio and stromal tumor-infiltrating lymphocytes. We found that a high amount of stroma with a weak infiltration of lymphocytes was associated statistically significantly with a worse disease-free survival with a hazard ratio (HR) of 2.68 (95% CI 1.26-5.69), worse overall survival (HR 2.95, 95% CI 1.69-5.15), and poor disease-specific survival (HR 2.66, 95% CI 1.11-6.33). Tumors having a high amount of stroma with a weak infiltration of lymphocytes were also significantly associated with a high rate of local recurrence (HR 4.13, 95% CI 1.67-10.24), but no significant association was found with lymph node metastasis (HR 1.27, 95% CI 0.37-4.35). Categorization of the stroma based on desmoplastic reaction (immature, intermediate, mature) showed a low prognostic value for early OTSCC in all survival analyses (P > 0.05). In conclusion, categorization of the stroma based on the amount of stroma and its infiltrating lymphocytes shows clinical relevance in early OTSCC superior to categorization based on the maturity of stroma.
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http://dx.doi.org/10.1007/s00428-020-02930-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099799PMC
May 2021

Cell-in-cell phenomenon associates with aggressive characteristics and cancer-related mortality in early oral tongue cancer.

BMC Cancer 2020 Sep 3;20(1):843. Epub 2020 Sep 3.

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

Background: Cell-in-cell structures (caused by cell cannibalistic activity) have been related to prognosis of many cancers. This is the first multi-institutional study to assess the prognostic impact of cell-in-cell structures in a large cohort of early oral tongue squamous cell carcinomas (OTSCC).

Methods: A total of 308 cases from five Finnish University Hospitals and from the A.C. Camargo Cancer Center, São Paulo, Brazil, were included in this study. Cell-in-cell structures were evaluated on surgical postoperative sections that stained with hematoxylin and eosin staining.

Results: We found that cell-in-cell structures associated with cancer-related mortality in univariable analysis with a hazard ratio (HR) of 2.99 (95%CI 1.52-5.88; P = 0.001). This association was confirmed in multivariable analysis (HR 2.22, 95%CI 1.12-4.44; P = 0.024). In addition, statistically significant associations were observed between the cell-in-cell structures and other adverse histopathologic characteristics including deep invasion (P <  0.001), high index of tumor budding (P = 0.007), worst pattern of invasion (P <  0.001), perineural invasion (P = 0.01), and stroma-rich pattern (P = 0.001).

Conclusions: Our findings demonstrate a significant relationship between cell-in-cell formation and aggressive characteristics of early OTSCC. Cell-in-cell structures have a distinct impact as a novel prognostic indicator in early OTSCC and they can be easily assessed during routine pathology practice.
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http://dx.doi.org/10.1186/s12885-020-07342-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469910PMC
September 2020

Expanding the Molecular Spectrum of Secretory Carcinoma of Salivary Glands With a Novel VIM-RET Fusion.

Am J Surg Pathol 2020 10;44(10):1295-1307

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

Background: Secretory carcinoma (SC), originally described as mammary analogue SC, is a predominantly low-grade salivary gland neoplasm characterized by a recurrent t(12;15)(p13;q25) translocation, resulting in ETV6-NTRK3 gene fusion. Recently, alternative ETV6-RET, ETV6-MAML3, and ETV6-MET fusions have been found in a subset of SCs lacking the classic ETV6-NTRK3 fusion transcript, but still harboring ETV6 gene rearrangements.

Design: Forty-nine cases of SC revealing typical histomorphology and immunoprofile were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). All 49 cases of SC were also tested for ETV6, RET, and NTRK3 break by fluorescence in situ hybridization and for the common ETV6-NTRK3 fusions using reverse transcription polymerase chain reaction.

Results: Of the 49 cases studied, 37 (76%) occurred in the parotid gland, 7 (14%) in the submandibular gland, 2 (4%) in the minor salivary glands, and 1 (2%) each in the nasal mucosa, facial skin, and thyroid gland. SCs were diagnosed more frequently in males (27/49 cases; 55%). Patients' age at diagnosis varied from 15 to 80 years, with a mean age of 49.9 years. By molecular analysis, 40 cases (82%) presented the classic ETV6-NTRK3 fusion, whereas 9 cases (18%) revealed an alternate fusion. Of the 9 cases negative for the ETV6-NTRK3 fusion, 8 cases presented with ETV6-RET fusion. In the 1 remaining case in the parotid gland, next-generation sequencing analysis identified a novel VIM-RET fusion transcript. In addition, the analysis indicated that 1 recurrent high-grade case in the submandibular gland was positive for both ETV6-NTRK3 and MYB-SMR3B fusion transcripts.

Conclusions: A novel finding in our study was the discovery of a VIM-RET fusion in 1 patient with SC of the parotid gland who could possibly benefit from RET-targeted therapy. In addition, 1 recurrent high-grade case was shown to harbor 2 different fusions, namely, ETV6-NTRK3 and MYB-SMR3B. The expanded molecular spectrum provides a novel insight into SC oncogenesis and carries important implications for molecular diagnostics, as this is the first SC-associated translocation with a non-ETV6 5' fusion partner. This finding further expands the definition of SC while carrying implications for selecting the appropriate targeted therapy.
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http://dx.doi.org/10.1097/PAS.0000000000001535DOI Listing
October 2020

What is hiding behind S100 protein and SOX10 positive oncocytomas? Oncocytic pleomorphic adenoma and myoepithelioma with novel gene fusions in a subset of cases.

Hum Pathol 2020 09 13;103:52-62. Epub 2020 Jul 13.

Department of Pathology, Charles University, Faculty of Medicine in Plzen, Plzen, 30605, Czech Republic; Bioptic Laboratory Ltd, Plzen, 32600, Czech Republic.

Oncocytomas (OCs) in salivary glands are rare benign tumors composed of mitochondria-rich epithelial cells (oncocytes), mostly localized in the parotid gland. The treatment of choice is simple excision. Extensive oncocytic metaplasia of pleomorphic adenoma (PA) and myoepithelioma (ME) can be diagnostically challenging and may camouflage the correct diagnosis. These tumors should be treated more carefully compared with OC, given the risk of frequent recurrences and the possibility of malignant transformation. We have investigated 89 oncocytic lesions from our files, including OC (n = 74) and metaplastic oncocytic variant of PA/ME (n = 15). All OCs were stained for S100 protein and SOX10. The tumors with immunohistochemical expression of one or both markers were tested by next-generation sequencing (NGS). The NGS results were confirmed by reverse transcription-polymerase chain reaction (RT-PCR) and/or fluorescence in situ hybridization (FISH). Ten cases originally diagnosed as OC, and 1 low-grade uncertain oncocytic tumor (11/74) revealed nuclear-cytoplasmic and/or nuclear positivity for S100 protein and/or SOX10, respectively. Fusion transcripts CHCHD7-PLAG1 and GEM-PLAG1 were found in 2 cases (1 fusion in each), and these were confirmed by RT-PCR and PLAG1 break-apart FISH probe, respectively. Another 5 cases were positive for PLAG1 rearrangement by FISH. In the control group of 15 oncocytic PA/ME, 4/15 tested tumors harbored gene fusions including NFT3-PLAG1, CHCHD7-PLAG1, FBXO32-PLAG1, and C1orf116-PLAG1 (1 fusion in each case) as detected by NGS. Two fusions were confirmed by RT-PCR, 1 case by FISH, and 1 case was not analyzable by FISH. We additionally tested 24 OCs negative for S100 protein and SOX10 by immunohistochemistry (IHC) and by FISH for rearrangement of PLAG1 gene, but none of them were positive. SOX10 and/or S100 protein immunopositivity in conjunction with rearrangement of the PLAG1 gene assisted in reclassification of a subset of oncocytomas as oncocytic variants of PA and ME. Therefore, we recommend to include S100 protein and SOX10 IHC when diagnosing tumors with predominantly oncocytoma-like differentiation. In addition, by NGS, 3 new gene fusions were detected in oncocytic ME, including NTF3-PLAG1, FBXO32-PLAG1, and GEM-PLAG1, and a new fusion C1orf116-PLAG1 was detected in oncocytic PA.
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http://dx.doi.org/10.1016/j.humpath.2020.07.009DOI Listing
September 2020

High tumor mutation burden predicts favorable outcome among patients with aggressive histological subtypes of lung adenocarcinoma: A population-based single-institution study.

Neoplasia 2020 09 22;22(9):333-342. Epub 2020 Jun 22.

Institute of Biomedicine, University of Turku and Department of Pathology, Turku University Hospital, Kiinamyllynkatu 10, 20520 Turku, Finland.

Objectives: Tumor mutation burden (TMB) is an emerging predictive cancer biomarker. Few studies have addressed the prognostic role of TMB in non-small cell lung carcinoma, with conflicting results. Moreover, the association of TMB with different histological subtypes of lung adenocarcinoma has hitherto not been systematically evaluated. Here we studied the prognostic value of TMB and its distribution in different histological subtypes of lung adenocarcinomas in a retrospective cohort using the most recent updated classification guidelines.

Materials And Methods: 176 surgically resected stage I-IV lung adenocarcinomas were histologically reclassified according to WHO 2015 guidelines. A modified classification subdividing the acinar subtype into classic acinar, complex glandular and cribriform subtypes was further applied and potentially prognostic histopathological characteristics such as tumor-infiltrating lymphocytes were evaluated. 148 patients with stage I-III tumors and complete follow-up data were included in the survival analyses. TMB was determined by a commercial next generation sequencing panel from 131 tumors, out of which 105 had survival data available.

Results: Predominant micropapillary, solid and complex glandular as well as nonpredominant cribriform histological subtypes were associated with significantly shorter survival. High TMB concentrated in micropapillary, solid and acinar predominant subtypes. Interestingly, TMB ≥ 14 mutations/MB conferred a stage- and histology-independent survival benefit compared to TMB < 14 in multivariable analysis for overall (HR 0.284, 95% CI 0.14-0.59, P=0.001) and disease-specific survival (HR 0.213, 95% CI 0.08-0.56, P=0.002).

Conclusion: TMB was an independent biomarker of favorable prognosis in our cohort of lung adenocarcinoma despite being associated with predominant histological subtypes considered aggressive.
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http://dx.doi.org/10.1016/j.neo.2020.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317687PMC
September 2020

Risk stratification in oral squamous cell carcinoma using staging of the eighth American Joint Committee on Cancer: Systematic review and meta-analysis.

Head Neck 2020 10 17;42(10):3002-3017. Epub 2020 Jun 17.

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

The eighth edition of the American Joint Committee on Cancer (AJCC8) staging manual has major changes in oral squamous cell carcinoma (OSCC). We searched PubMed, OvidMedline, Scopus, and Web of Science for studies that examined the performance of AJCC8 in OSCC. A total of 40 808 patients were included in the studies of our meta-analysis. A hazard ratio (HR) of 1.87 (95%CI 1.78-1.96) was seen for stage II, 2.65 (95%CI 2.51-2.80) for stage III, 3.46 (95%CI 3.31-3.61) for stage IVa, and 7.09 (95%CI 4.85-10.36) for stage IVb. A similar gradual increase in risk was noted for the N classification. For the T classification, however, there was a less clear variation in risk between T3 and T4. AJCC8 provides a good risk stratification for OSCC. Future research should examine the proposals introduced in the published studies to further improve the performance of AJCC8.
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http://dx.doi.org/10.1002/hed.26344DOI Listing
October 2020

Staging and grading of oral squamous cell carcinoma: An update.

Oral Oncol 2020 08 20;107:104799. Epub 2020 May 20.

Institute of Biomedicine, Pathology, University of Turku, Turku, Finland. Electronic address:

Oral squamous cell carcinoma (OSCC) is a common malignancy of the head and neck region. OSCC has a relatively low survival rate and the incidence of the disease is increasing in some geographic areas. Staging and grading of OSCC are established prerequisites for management, as they influence risk stratification and are the first step toward personalized treatment. The current AJCC/UICC TNM staging (8th edition, 2017) of OSCC has included significant modifications through the incorporation of depth of invasion in the T stage and extracapsular spread/extranodal extension in the N stage. Further modifications for AJCC 8 have been suggested. On the other hand, the World Health Organization (WHO) classification (4th edition, 2017) still endorses a simple, differentiation-based histopathologic grading system of OSCC (despite its low prognostic value) and ignores factors such as tumor growth pattern and dissociation, stromal reactions (desmoplasia, local immune response), and tumor-stroma ratio. The various controversies and possible developments of the current staging and grading criteria of OSCC are briefly discussed in this update together with possible applications of artificial intelligence in the context of screening and risk stratification.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104799DOI Listing
August 2020

A systematic review of predictive models for recurrence and mortality in patients with tongue cancer.

Eur J Cancer Care (Engl) 2020 03;29(2):e13211

Department of Pathology, University of Helsinki, Helsinki, Finland.

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http://dx.doi.org/10.1111/ecc.13211DOI Listing
March 2020

Overall assessment of tumor-infiltrating lymphocytes in head and neck squamous cell carcinoma: time to take notice.

Acta Otolaryngol 2020 Mar 5;140(3):246-248. Epub 2020 Feb 5.

Department of Otorhinolaryngology, Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

The immune response has an important role in cancer progression. At the same time, anti-tumor effect of the immune response has been speculated to cause destruction of cancer cells. Recent studies have highlighted the significance of tumor-infiltrating lymphocytes (TILs) in different cancers. The International Immuno-Oncology Biomarkers Working Group has in 2017 published a practical review proposing a standardized method to assess TILs in the routine hematoxylin and eosin (HE) stained sections. To discuss the association between TILs and survival in head and neck squamous cell carcinoma (HNSCC). We review recent studies having assessed TILs in HNSCC and showing that tumors having low TILs associate significantly with worse survival. These findings underline that HNSCC cases with low TILs might benefit from multimodality treatment and might be indicated to receive immunotherapy. The evaluation of TILs using routine HE-stained sections is practical and can be considered in assessment of antitumor activity. Here, we highlight the impact of overall assessment of TILs using the routine HE-stained specimens in HNSCC.
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http://dx.doi.org/10.1080/00016489.2020.1720284DOI Listing
March 2020

Histological characteristics of early-stage oral tongue cancer in young versus older patients: A multicenter matched-pair analysis.

Oral Dis 2020 Jul 14;26(5):1081-1085. Epub 2020 Feb 14.

Department of Pathology, University of Helsinki, Helsinki, Finland.

Little is known about the histopathological characteristics that may differentiate early oral tongue cancer (OTSCC) between young and older patients. From a total of 311 cases diagnosed with clinically early-stage OTSCC at 6 institutions, only 42 patients were young patients were aged ≤45 years. For comparison, 42 patients >60 years old were matched for center of management, clinical stage and gender. We compared epithelial and stromal histopathologic parameters between the two groups. Most of the parameters were similar between the two groups, although the young patients appeared to have marginally higher intensity of tumor budding, histologic risk score, infiltrative pattern of invasion and tumor-stroma ratio. However, none of the factors showed significant difference when comparing the two groups. The histological parameters reflect mechanisms of invasive growth and tissue response to invasive growth, but not the etiological difference in OTSCC between young and older patients. Further investigations are necessary to compare the genetic background of early OTSCC in the two groups.
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http://dx.doi.org/10.1111/odi.13288DOI Listing
July 2020

Comparison of supervised machine learning classification techniques in prediction of locoregional recurrences in early oral tongue cancer.

Int J Med Inform 2020 04 28;136:104068. Epub 2019 Dec 28.

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

Background: The proper estimate of the risk of recurrences in early-stage oral tongue squamous cell carcinoma (OTSCC) is mandatory for individual treatment-decision making. However, this remains a challenge even for experienced multidisciplinary centers.

Objectives: We compared the performance of four machine learning (ML) algorithms for predicting the risk of locoregional recurrences in patients with OTSCC. These algorithms were Support Vector Machine (SVM), Naive Bayes (NB), Boosted Decision Tree (BDT), and Decision Forest (DF).

Materials And Methods: The study cohort comprised 311 cases from the five University Hospitals in Finland and A.C. Camargo Cancer Center, São Paulo, Brazil. For comparison of the algorithms, we used the harmonic mean of precision and recall called F1 score, specificity, and accuracy values. These algorithms and their corresponding permutation feature importance (PFI) with the input parameters were externally tested on 59 new cases. Furthermore, we compared the performance of the algorithm that showed the highest prediction accuracy with the prognostic significance of depth of invasion (DOI).

Results: The results showed that the average specificity of all the algorithms was 71% . The SVM showed an accuracy of 68% and F1 score of 0.63, NB an accuracy of 70% and F1 score of 0.64, BDT an accuracy of 81% and F1 score of 0.78, and DF an accuracy of 78% and F1 score of 0.70. Additionally, these algorithms outperformed the DOI-based approach, which gave an accuracy of 63%. With PFI-analysis, there was no significant difference in the overall accuracies of three of the algorithms; PFI-BDT accuracy increased to 83.1%, PFI-DF increased to 80%, PFI-SVM decreased to 64.4%, while PFI-NB accuracy increased significantly to 81.4%.

Conclusions: Our findings show that the best classification accuracy was achieved with the boosted decision tree algorithm. Additionally, these algorithms outperformed the DOI-based approach. Furthermore, with few parameters identified in the PFI analysis, ML technique still showed the ability to predict locoregional recurrence. The application of boosted decision tree machine learning algorithm can stratify OTSCC patients and thus aid in their individual treatment planning.
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http://dx.doi.org/10.1016/j.ijmedinf.2019.104068DOI Listing
April 2020

Immunohistochemical and genetic analysis of respiratory epithelial adenomatoid hamartomas and seromucinous hamartomas: are they precursor lesions to sinonasal low-grade tubulopapillary adenocarcinomas?

Hum Pathol 2020 03 5;97:94-102. Epub 2019 Nov 5.

Department of Pathology, Charles University, Faculty of Medicine in Plzen, Plzen 30605, Czech Republic; Bioptic Laboratory, ltd, Plzen 32600, Czech Republic.

Respiratory epithelial adenomatoid hamartoma (REAH) and seromucinous hamartoma (SH) are rare tumor-like lesions of the nasal cavity, paranasal sinuses, and nasopharynx. The pathogenesis of REAH/SH is still unclear. Neoplastic proliferation, chronic mechanical irritation, inflammation, or possible embryological tissue misplacement are speculated as possible mechanisms of their development. Low-grade tubulopapillary adenocarcinoma (LGTA) is a rare variant of nonsalivary, nonintestinal type sinonasal adenocarcinoma. The aim of this study was to evaluate the immunohistochemical and genetic profiles of 10 cases of REAH/SH, with serous, mucinous, and respiratory components evaluated separately and to compare these findings with the features of 9 cases of LGTA. All cases of REAH/SH and LGTA were analyzed immunohistochemically with a cocktail of mucin antigens (MUC1, MUC2, MUC4, MUC5AC, MUC6) and with epithelial (CK7, CK20, CDX2, SATB2) and myoepithelial markers (S100 protein, p63, SOX10). The next-generation sequencing assay was performed using FusionPlex Solid Tumor Kit (ArcherDx) in 10 cases of REAH/SH, and the EGFR-ZNF267 gene fusion was detected in 1 of them. Two female REAH/SH cases were assessed for the presence of clonality. Using the human androgen receptor assay, 1 case was proved to be clonal. The serous component of REAH/SH was positive for CK7/MUC1 and SOX10 similarly to LGTA. Although REAH/SH and LGTA are histopathologically and clinically separate entities, the overlap in their morphological and immunohistochemical profiles suggests that REAH/SH might be a precursor lesion of LGTA.
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http://dx.doi.org/10.1016/j.humpath.2019.09.018DOI Listing
March 2020

Machine learning application for prediction of locoregional recurrences in early oral tongue cancer: a Web-based prognostic tool.

Virchows Arch 2019 Oct 17;475(4):489-497. Epub 2019 Aug 17.

Research Programme in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Estimation of risk of recurrence in early-stage oral tongue squamous cell carcinoma (OTSCC) remains a challenge in the field of head and neck oncology. We examined the use of artificial neural networks (ANNs) to predict recurrences in early-stage OTSCC. A Web-based tool available for public use was also developed. A feedforward neural network was trained for prediction of locoregional recurrences in early OTSCC. The trained network was used to evaluate several prognostic parameters (age, gender, T stage, WHO histologic grade, depth of invasion, tumor budding, worst pattern of invasion, perineural invasion, and lymphocytic host response). Our neural network model identified tumor budding and depth of invasion as the most important prognosticators to predict locoregional recurrence. The accuracy of the neural network was 92.7%, which was higher than that of the logistic regression model (86.5%). Our online tool provided 88.2% accuracy, 71.2% sensitivity, and 98.9% specificity. In conclusion, ANN seems to offer a unique decision-making support predicting recurrences and thus adding value for the management of early OTSCC. To the best of our knowledge, this is the first study that applied ANN for prediction of recurrence in early OTSCC and provided a Web-based tool.
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http://dx.doi.org/10.1007/s00428-019-02642-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828835PMC
October 2019

Hallmarks of cancer: Tumor budding as a sign of invasion and metastasis in head and neck cancer.

Head Neck 2019 10 22;41(10):3712-3718. Epub 2019 Jul 22.

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

Invasion and metastasis are hallmarks of cancer. The concept of tumor budding at tumor-host interface has been documented in many carcinomas. A growing body of evidence indicates that tumor budding is a sign of invasion and early step for metastasis of many epithelial cancers including head and neck squamous cell carcinoma (HNSCC). In addition, recent research has underlined the importance of tumor budding as a promising prognosticator in HNSCC. This review summarizes the findings regarding tumor budding in HNSCC and focuses on the role of tumor budding in invasion and metastasis. Also, we highlight the prognostic significance of tumor budding in HNSCC and its potential for improving clinical decision making in terms of recommending optimal individualized treatment for this patient population.
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http://dx.doi.org/10.1002/hed.25872DOI Listing
October 2019

Assessment of Tumor-infiltrating Lymphocytes Predicts the Behavior of Early-stage Oral Tongue Cancer.

Am J Surg Pathol 2019 10;43(10):1392-1396

Departments of Pathology.

Tumor-infiltrating lymphocytes (TILs) have shown a promising prognostic value in many epithelial cancers. We sought to assess the prognostic value of TILs in a multicenter cohort of early oral tongue squamous cell carcinoma (OTSCC). The percentage of TILs was assessed on the surgical resection slides stained with hematoxylin and eosin. The assessment of TILs was performed in the stromal compartment and in the intraepithelial compartment (at the invasive front and at the center of the tumor). We followed the method that was described recently by the International Immuno-Oncology Biomarker Working Group for the assessment of TILs. A total of 308 cases from the 5 Finnish university hospitals and from A.C. Camargo Cancer Center, São Paulo, Brazil, were included. We found a promising prognostic value for stromal TILs at the invasive front in the multivariable analysis with a hazard ratio of 2.61 (95% confidence interval [CI], 1.77-3.83; P<0.001) for overall survival, 1.99 (95% CI, 1.07-3.69; P=0.040) for disease-specific survival, and 1.94 (95% CI, 1.14-3.29; P=0.020) for disease-free survival. In conclusion, evaluation of TILs is simple and can aid in identifying the high-risk cases of early OTSCC. The method introduced by the International Immuno-Oncology Biomarker Working Group can be used for standardized determination of TILs in early OTSCC.
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http://dx.doi.org/10.1097/PAS.0000000000001323DOI Listing
October 2019

Expression of toll-like receptors in non-endemic nasopharyngeal carcinoma.

BMC Cancer 2019 Jun 25;19(1):624. Epub 2019 Jun 25.

Department of Otorhinolaryngology - Head and Neck Surgery, Turku University Hospital and University of Turku, Kiinamyllynkatu 4-8, 20521, Turku, Finland.

Background: Nasopharyngeal carcinoma (NPC) is a malignant disease with an enigmatic etiology. NPC associates with Epstein-Barr virus (EBV) and human papillomaviruses (HPVs), while immunological factors also play a role in carcinogenesis. Toll-like receptors (TLRs) are pattern recognition receptors that participate in the immunological defence against pathogens, but their functions are also linked to cancer.

Methods: In our whole population-based study, we retrieved 150 Finnish NPC cases and studied their tumour samples for TLR1, TLR2, TLR4, TLR5, TLR7, and TLR9 expressions by immunohistochemistry, and for the presence of EBV and high-risk HPVs with EBV RNA and HPV E6/E7 mRNA in situ hybridizations. In addition, we analyzed the TLR expression patterns according to age, tumour histology, EBV/HPV status, and outcome.

Results: We found that all TLRs studied were highly expressed in NPC. Viral status of the tumours varied, and 62% of them were EBV-positive, 14% HPV-positive, and 24% virus-negative. The tumours with strong TLR2 or TLR5 expression were mostly virus-negative or HPV-positive keratinizing squamous cell carcinomas, and the patients with these tumours were significantly older than those with mild or negative TLR2/TLR5 expression. In Kaplan-Meier analysis, the patients with strong TLR5 expression had worse survival compared to the patients with negative or mild TLR5 expression, but the results were linked to other patient and tumour characteristics. In multivariable-adjusted Cox regression analysis, the patients with positive TLR7 tumour expression had better overall survival than those with no TLR7 expression. The 5-year overall survival rates according to TLR7 expression were 66% (mild), 52% (moderate or strong), and 22% (negative).

Conclusions: TLRs are highly expressed in non-endemic NPC. Intensity of TLR2 and TLR5 expressions correlate with viral status, and TLR7 seems to be an independent prognostic factor of non-endemic NPC.
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http://dx.doi.org/10.1186/s12885-019-5816-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593602PMC
June 2019

MiR-455-3p, miR-150 and miR-375 are aberrantly expressed in salivary gland adenoid cystic carcinoma and polymorphous adenocarcinoma.

J Oral Pathol Med 2019 Oct 25;48(9):840-845. Epub 2019 Jun 25.

Department of Oral Pathology, Faculdade São Leopoldo Mandic, Instituto de Pesquisas São Leopoldo Mandic, Campinas, São Paulo, Brazil.

Background: Adenoid cystic carcinoma (AdCC) and polymorphous adenocarcinoma (PAC) are included among the most common salivary gland cancers. They share clinical and histological characteristics, making their diagnosis challenging in specific cases. MicroRNAs (miRNA) are short, non-coding RNA sequences of 19-25 nucleotides in length that are involved in post-transcriptional protein expression. They have been shown to play important roles in neoplastic and non-neoplastic processes and have been suggested as diagnostic and prognostic markers.

Methods: This study, using quantitative RT-PCR, investigated miR-150, miR-455-3p and miR-375 expression, in order to identify a possible molecular distinction between AdCC and PAC.

Results: miRNA-150 and miRNA-375 expression was significantly decreased in AdCC and PAC compared with salivary gland tissue controls, whilst miRNA-455-3p showed significantly increased expression in AdCC when compared to PAC, (P < 0.05). miR-150, miR-357 and miR-455-3p expression in AdCC, PAC and control was not associated with age, gender nor with anatomic site (major and minor salivary glands) (P > 0.05).

Conclusion: MiR-455-3p could be used as a complimentary tool in the diagnosis of challenging AdCC cases.
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http://dx.doi.org/10.1111/jop.12894DOI Listing
October 2019

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

A Proposal to Revise the Histopathologic Grading System of Early Oral Tongue Cancer Incorporating Tumor Budding.

Am J Surg Pathol 2019 05;43(5):703-709

Pathology.

The World Health Organization (WHO) grading system has a low prognostic value for early-stage oral tongue squamous cell carcinoma; greater prognostic power has been shown with tumor budding analysis. In this study, we combined tumor budding analysis with histopathologic grading according to WHO 2017. In our proposal, a revised grade I tumor is defined as a "well differentiated cohesive tumor"; revised grade II as a "moderately differentiated and/or slightly dissociated tumor"; and revised grade III as a "poorly differentiated and/or dissociated tumor." We evaluated the prognostic value of this proposed grading system in a multicenter cohort of 311 cases of early oral tongue squamous cell carcinoma. The proposed grading system showed significant prognostic value in multivariable analysis for disease-specific survival with a hazard ratio of 3.86 and a 95% confidence interval of 1.36-10.9 (P=0.001). For disease-free survival, the proposed grading system showed good predictive power in multivariable analysis (hazard ratio, 2.07; 95% confidence interval, 1.00-4.27; P=0.009). The conventional WHO grading system showed a low prognostic value for disease-specific survival and disease-free survival (P>0.05). In conclusion, the prognostic power of the WHO histopathologic grading improved significantly with incorporation of tumor budding. Our proposed grading system can be easily included in pathology reports.
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http://dx.doi.org/10.1097/PAS.0000000000001241DOI Listing
May 2019

Survival Impact of Adjuvant Therapy in Salivary Gland Cancers following Resection and Neck Dissection.

Otolaryngol Head Neck Surg 2019 06 5;160(6):1048-1057. Epub 2019 Feb 5.

2 Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Objective: To evaluate the impact of postoperative radiotherapy (PORT) and chemotherapy on survival in salivary gland cancer (SGC) treated with curative-intent local resection and neck dissection.

Study Design: Retrospective population-based cohort study.

Setting: National Cancer Database.

Subjects And Methods: Patients with SGC who were undergoing surgery were identified from the National Cancer Database between 2004 and 2013. Neck dissection removing a minimum of 10 lymph nodes was required. Because PORT violated the proportional hazards assumption, this variable was treated as a time-dependent covariate.

Results: Overall, 4145 cases met inclusion criteria (median follow-up, 54 months). PORT was associated with improved overall survival in multivariable analysis, both ≤9 months from diagnosis (hazard ratio [HR], 0.26; 95% CI, 0.20-0.34; P < .001) and >9 months (HR, 0.75; 95% CI, 0.66-0.86; P < .001). In propensity score-matched cohorts, 5-year overall survival was 67.1% and 60.6% with PORT and observation, respectively ( P < .001). Similar results were observed in landmark analysis of patients surviving at least 6 months following diagnosis. Adjuvant chemotherapy was not associated with improved survival (HR, 1.15; 95% CI, 0.99-1.34; P = .06).

Conclusion: PORT, but not chemotherapy, is associated with improved survival among patients with SGC for whom neck dissection was deemed necessary. These results are not applicable to low-risk SGCs not requiring neck dissection.
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http://dx.doi.org/10.1177/0194599819827851DOI Listing
June 2019

Epstein-Barr virus and human papillomaviruses as favorable prognostic factors in nasopharyngeal carcinoma: A nationwide study in Finland.

Head Neck 2019 02 14;41(2):349-357. Epub 2018 Dec 14.

Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland.

Background: Nasopharyngeal carcinoma (NPC) is related to Epstein-Barr virus (EBV) in endemic areas; however, the role of viruses in nonendemic countries is unclear. Our nationwide study investigated the prevalence and prognostic significance of EBV and human papillomaviruses (HPVs) in Finnish NPC tumors.

Methods: We analyzed samples from 150 patients diagnosed between 1990 and 2009. Viral status was determined using EBV and HPV RNA in situ hybridizations, and p16 immunohistochemistry. Patient and treatment characteristics were obtained from patient records.

Results: In our white patient cohort, 93 of 150 (62%) patients were EBV-positive and 21/150 (14%) patients were HPV-positive with no coinfections. Thirty-six (24%) tumors were negative for both viruses. The 5-year disease-specific survival for patients with EBV-positive, HPV-positive, and EBV/HPV-negative tumors was 69%, 63%, and 39%, respectively. In multivariable-adjusted analysis, overall survival was better among patients with EBV-positive (P = .005) and HPV-positive (P = .03) tumors compared to patients with EBV/HPV-negative tumors.

Conclusions: In our low-incidence population, EBV and HPV are important prognostic factors for NPC.
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http://dx.doi.org/10.1002/hed.25450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590344PMC
February 2019