Lobular capillary hemangioma (pyogenic granuloma) of the oral cavity.

Head & Neck, Oral Cavity/Gnathic (Jaw)
Thompson LD.
Ear Nose Throat J. 2017 Jul;96(7):240.
FIRST PARAGRAPH: Lobular capillary hemangioma (LCH), sometimes also called pyogenic granuloma or epulis gravidarum, is a benign overgrowth of capillaries showing a vascular phenotype. There are several etiologic factors, including hormones (increased in pregnancy and in patients using oral contraceptives), localized trauma (biting, fractured tooth, poor restorations), and when there is poor oral hygiene.
PubMed ID: 28719705
Article Size: <1 MB

Localized Nasopharyngeal Amyloidosis: A Clinicopathologic Series of 7 Cases with a Literature Review

Head & Neck, Sinonasal Tract
Sakagiannis G, Giotakis E, Thompson LDR.
Head Neck Pathol. 2018 Dec;12(4):542-547.
Localized nasopharyngeal amyloidosis is an extremely rare entity with only 25 cases described in the English and German literature. We present a case series of seven patients with localized nasopharyngeal amyloidosis and combine the findings with a thorough review the literature.
PubMed ID: 29282670
Article Size: 1.2 MB
 

Long-term follow-up of a patient with malignant transformation of inverted papilloma into sinonasal undifferentiated carcinoma.

Head & Neck, Sinonasal Tract
Orgain CA, Shibuya TY, Thompson LD, Keschner DB, Garg R, Lee JT.
Allergy Rhinol (Providence). 2017 Oct 1;8(3):173-177.
INTRODUCTION: Inverted papillomas (IP) are benign sinonasal neoplasms, which account for 0.5-4% of all nasal tumors. IPs have been known to transform into squamous cell carcinoma in 5-15% of cases. Rarely, transformations to other malignancies have been reported. Here we report a unique case of malignant transformation of an IP into sinonasal undifferentiated carcinoma (SNUC).
METHODS: A case report with a literature review; institutional review board exempted. The clinical presentation, radiographic features, surgical intervention, histopathologic analysis, treatment, and outcome of the case were examined.
RESULTS: A 62-year-old man presented with a 3-month history of nasal airway obstruction, rhinorrhea, and postnasal drip refractory to medical therapy. He had a long history of exposure to fumes, chemicals, dusts, and solvents as a professional painter as well as a 45 pack-year history of smoking and alcohol abuse. The patient was ultimately found to have a left ethmoidal IP with a focus of malignant transformation into SNUC. Endoscopic resection was performed, followed by concurrent chemoradiation and adjuvant chemotherapy. After surgery, he had no evidence of recurrent disease after 9 years of follow-up.
CONCLUSIONS: IP is known to transform into squamous cell carcinoma. Here we report a rare case of malignant transformation into SNUC, a much more uncommon and aggressive lesion. Although traditionally associated with a poorer prognosis, the positive outcome for SNUC observed in this patient may potentially be attributed to early detection and timely therapeutic intervention.
PubMed ID: 29070275
Article Size: 1 MB
 

Nasopharyngeal papillary adenocarcinoma.

Head & Neck, Sinonasal Tract
Thompson LD.
Ear Nose Throat J. 2017 Dec;96(12):456-457.
FIRST PARAGRAPH: The most common malignancy of the nasopharynx is nasopharyngeal carcinoma. However, nasopharyngeal papillary adenocarcinoma is a rare primary tumor of this location. This tumor shows a remarkable papillary architecture, arising from the surface epithelium and in general showing indolent biologic behavior. There are no known etiologic agents, lacking any Epstein Barr virus or human papillomavirus association.
PubMed ID: 29236265
Article Size: <1 MB

New tumor entities in the 4th edition of the World Health Organization classification of head and neck tumors: Nasal cavity, paranasal sinuses and skull base

Head & Neck, Sinonasal Tract
Thompson LDR, Franchi A.
Virchows Arch. 2018 Mar;472(3):315-330.
TheWorld Health Organization recently published the 4th edition of the Classification of Head and Neck Tumors, including several new entities, emerging entities, and significant updates to the classification and characterization of tumor and tumor-like lesions, specifically as it relates to nasal cavity, paranasal sinuses, and skull base in this overview. Of note, three new entities (NUT carcinoma, seromucinous hamartoma, biphenotypic sinonasal sarcoma,) were added to this section, while emerging entities (SMARCB1-deficient carcinoma and HPV-related carcinoma with adenoid cystic-like features) and several tumor-like entities (respiratory epithelial adenomatoid hamartoma, chondromesenchymal hamartoma) were included as provisional diagnoses or discussed in the setting of the differential diagnosis. The sinonasal tract houses a significant diversity of entities, but interestingly, the total number of entities has been significantly reduced by excluding tumor types if they did not occur exclusively or predominantly at this site or if they are discussed in detail elsewhere in the book. Refinements to nomenclature and criteria were provided to sinonasal papilloma, borderline soft tissue tumors, and neuroendocrine neoplasms. Overall, the new WHO classification reflects the state of current understanding for many relatively rare neoplasms, with this article highlighting the most significant changes.
PubMed ID: 28444451
Article Size: 6 MB

Ossifying fibroma of the maxilla and sinonasal tract: Case series

Head & Neck, Sinonasal Tract
Liu JJ, Thompson LD, Janisiewicz AM, Shibuya TY, Keschner DB, Garg R, Lee JT.
Allergy Rhinol (Providence). 2017 Mar 1;8(1):32-36. doi: 10.2500/ar.2017.8.0190
BACKGROUND: Head and neck ossifying fibroma (OF) is a rare, benign, locally aggressive, fibro-osseous tumor. The mandible is the most common site of involvement, followed by the maxilla, and, less frequently, the sinonasal cavities, orbit, skull base, and calvarium. In this study, we aimed to expand our understanding of this entity by presenting a case series of OF that involved the maxilla and sinonasal tract.
METHODS: A multicenter retrospective review was performed on all the patients with a diagnosis of OF from 2004 to 2013. Data were collected with respect to age, sex, clinical presentation, treatment, and outcome.
RESULTS: A total of 13 patients were identified. The mean age was 37 years, with a female predominance (69%). The maxillary sinus was most frequently involved site (46%). Eighty-five percent underwent open surgical resection. After a mean follow-up time of 47.3 months, three patients (23%) developed recurrent disease; all of whom were treated with an open approach.
CONCLUSION: Of the maxilla and sinonasal tract is an uncommon clinicopathologic entity. Although a timely diagnosis may obviate the need for external approaches, open surgical resection is often still necessary for management of extensive lesions. Close follow-up and additional surgery may also be required to treat recurrent disease.
PubMed ID: 28381325
Article Size: <1 MB
 

The HTN3-MSANTD3 Fusion Gene Defines a Subset of Acinic Cell Carcinoma of the Salivary Gland.

Head & Neck, Salivary Gland
Andreasen S, Varma S, Barasch N, Thompson LDR, Miettinen M, Rooper L, Stelow EB, Agander TK, Seethala RR, Chiosea SI, Homøe P, Wessel I, Larsen SR, Erentaite D, Bishop JA, Ulhøi BP, Kiss K, Melchior LC, Pollack JR, West RB.
Am J Surg Pathol. 2019 Apr;43(4):489-496
The spectrum of tumors arising in the salivary glands is wide and has recently been shown to harbor a network of tumor-specific fusion genes. Acinic cell carcinoma (AciCC) is one of the more frequently encountered types of salivary gland carcinoma, but it has remained a genetic orphan until recently when a fusion between the HTN3 and MSANTD3 genes was described in one case. Neither of these 2 genes is known to be implicated in any other malignancy. This study was undertaken to investigate whether the HTN3-MSANTD3 fusion is a recurrent genetic event in AciCC and whether it is a characteristic of one of its histological variants. Of the 273 AciCCs screened, 9 cases showed rearrangement of MSANTD3 by break-apart fluorescence in situ hybridization, 2 had 1 to 2 extra signals, and 1 had gain, giving a total of 4.4% with MSANTD3 aberrations. In 6 of 7 available cases with MSANTD3 rearrangement, the HTN3-MSANTD3 fusion transcript was demonstrated with real-time polymerase chain reaction . Histologically, all fusion-positive cases were predominantly composed of serous tumor cells growing in solid sheets, with serous tumor cells expressing DOG-1 and the intercalated duct-like cell component being CK7 positive and S-100 positive in 6/9 cases. All but one case arose in the parotid gland, and none of the patients experienced a recurrence during follow-up. In contrast, the case with MSANTD3 gain metastasized to the cervical lymph nodes and lungs. In conclusion, we find the HTN3-MSANTD3 gene fusion to be a recurrent event in AciCC with prominent serous differentiation and an indolent clinical course.
PubMed ID: 30520817
Article Size: <1 MB
 

Radiographic nodal prognostic factors in stage I HPV-related oropharyngeal squamous cell carcinoma.

Head & Neck, Oropharynx
Bhattasali O, Thompson LDR, Schumacher AJ, Iganej S.
Head Neck. 2019 Feb;41(2):398-402. doi: 10.1002/hed.25504.
BACKGROUND: The updated AJCC Cancer Staging Manual groups all p16-positive oropharyngeal squamous cell carcinoma (OPSCC) with unilateral nodal involvement within 6 cm into the new clinical N1 classification, consolidating a heterogeneous group of disease with varying radiographic findings.
METHODS: A central radiological review was conducted identifying 233 patients with stage I node-positive (cT1-2N1) disease who underwent definitive concurrent chemoradiation. Factors evaluated included lymph node size, low-neck lymphadenopathy, retropharyngeal lymphadenopathy, overt radiographic extracapsular extension, and matted lymphadenopathy.
RESULTS: On multivariate analysis adjusted for age, smoking history, and chemotherapy regimen, low-neck lymphadenopathy (hazard ratio (HR) = 6.55; P < .001) and retropharyngeal lymphadenopathy (HR = 3.36; P = .009) predicted for inferior progression-free survival (PFS). low-neck lymphadenopathy (HR = 6.38; P = .001) and retropharyngeal lymphadenopathy (HR = 3.32; P = .02) also predicted for inferior overall survival (OS). All other radiographic characteristics showed no prognostic impact for PFS or OS.
CONCLUSIONS: This analysis suggests that caution should be advised against de-intensification efforts among patients with stage I node-positive p16-positive OPSCC with low-neck lymphadenopathy or retropharyngeal lymphadenopathy.
PubMed ID: 30552839
Article Size: <1 MB
 

A Rainbow of Colors and Spectrum of Textures: An Approach to Oral Mucosal Entities.

Head & Neck, Oral Cavity/Gnathic (Jaw)
Nelson BL, Thompson LDR.
Head Neck Pathol. 2019 Mar;13(1):1-3. doi: 10.1007/s12105-019-01007-3. Epub 2019 Jan 29.
FIRST PARAGRAPH: Nearly all surgical pathologists will encounter oral mucosal biopsies in their day to day practice. Many of these biopsies are fraught with diagnostic difficulty and may be challenging, usually due to inadequate clinical information, an unfamiliarity with anatomic landmarks and/or terminology used by the submitting physician or dentist, and the often limited size of the sample. A clinical description and history to accompany the submitted biopsy is often essential to the proper diagnosis and subsequent treatment of many oral conditions. A clinical history is a requirement recognized by the College of American Pathologist (CAP). The value and utility of a clinical history in the practice of pathology is undisputed. However, between 5.9 and 8.4% of cases submitted for pathologic review have no clinical history, or include vague information like “lesion,” “bump” or “ulcer.” Often the exact anatomic site is not included, stating only “oral cavity,” or “soft tissue” without any further designation as to exact anatomic site. This lack of important information may result in less than ideal interpretations. Additionally, concise clinical histories have been associated with shorter sign-out turnaround times. Pathologists find it too difficult to communicate with providers to obtain additional clinical information, claiming they are not in the office, they don’t return messages, or clinicians are too busy to be bothered. With nearly ubiquitous access to photography, the old adage, “A picture is worth a thousand words,” would seem to go a long way towards providing further clinical information. The clinical appearance, with the various nuances of color, texture and location are well suited to clinical photography. Cerroni et al., studied the utility of submitting clinical photographs with biopsy requests to dermatopathologists. The study showed that clinical photographs facilitated better pathology interpretation. Further, Ferrara et al., highlighted that clinical photographs do not introduce bias into the diagnosis of melanocytic lesion of the skin. There is a long held misconception by many physicians and dentists that clinically describing the sampled lesion unduly biases the pathologist: how patently false. Clear and concise clinical descriptions of mucosal lesions are essential to developing an appropriate differential diagnosis and a subsequent accurate interpretation. In an effort to highlight the importance of these characteristics, the topics covered by the contributing authors to this special issue have been divided by color, texture and location.
PubMed ID: 30693461
Article Size: <1 MB

Inter-observer Variability in the Diagnosis of Proliferative Verrucous Leukoplakia: Clinical Implications for Oral and Maxillofacial Surgeon Understanding: A Collaborative Pilot Study.

Head & Neck, Oral Cavity/Gnathic (Jaw)
Upadhyaya JD, Fitzpatrick SG, Cohen DM, Bilodeau EA, Bhattacharyya I, Lewis JS Jr, Lai J, Wright JM, Bishop JA, Leon ME, Islam MN, Seethala R, Padilla RJ, Carlos R, Müller S, Thompson LDR.
Head Neck Pathol. 2020 Mar;14(1):156-165. doi: 10.1007/s12105-019-01035-z. Epub 2019 Apr 10.
The use of diverse terminology may lead to inconsistent diagnosis and subsequent mistreatment of lesions within the proliferative verrucous leukoplakia (PVL) spectrum. The objectives of this study were: (a) to measure inter-observer variability between a variety of pathologists diagnosing PVL lesions; and (b) to evaluate the impact of diverse terminologies on understanding, interpretation, and subsequent treatment planning by oral and maxillofacial surgeons (OMFS). Six oral pathologists (OP) and six head and neck pathologists (HNP) reviewed 40 digitally scanned slides of PVL-type lesions. Inter-observer agreement on diagnoses was evaluated by Fleiss’ kappa analysis. The most commonly used diagnostic terminologies were sent to ten OMFS to evaluate their resulting interpretations and potential follow-up treatment approaches. The overall means of the surgeons’ responses were compared by Student t test. There was poor inter-observer agreement between pathologists on the diagnosis of PVL lesions (κ = 0.270), although there was good agreement (κ = 0.650) when diagnosing frankly malignant lesions. The lowest agreement was in diagnosing verrucous hyperplasia (VH) with/without dysplasia, atypical epithelial proliferation (AEP), and verrucous carcinoma (VC). The OMFS showed the lowest agreement on identical categories of non-malignant diagnoses, specifically VH and AEP. This study demonstrates a lack of standardized terminology and diagnostic criteria for the spectrum of PVL lesions. We recommend adopting standardized criteria and terminology, proposed and established by an expert panel white paper, to assist pathologists and clinicians in uniformly diagnosing and managing PVL spectrum lesions.
PubMed ID: 30972634
Article Size: 2.2 MB

Early squamous cell carcinoma of the oral tongue with histologically benign lymph nodes: A model predicting local control and vetting of the eighth edition of the American Joint Committee on Cancer pathologic T stage.

Head & Neck, Oral Cavity/Gnathic (Jaw)
Sridharan S, Thompson LDR, Purgina B, Sturgis CD, Shah AA, Burkey B, Tuluc M, Cognetti D, Xu B, Higgins K, Hernandez-Prera JC, Guerrero D, Bundele MM, Kim S, Duvvuri U, Ferris RL, Gooding WE, Chiosea SI.
Cancer. 2019 Sep 15;125(18):3198-3207. doi: 10.1002/cncr.32199. Epub 2019 Jun 7.
BACKGROUND: The eighth edition of the American Joint Committee on Cancer staging manual (AJCC8) added depth of invasion to the definition of pathologic T stage (pT). In the current study, the authors assess pT stage migration and the prognostic performance of the updated pT stage and compare it with other clinicopathologic variables in patients with early squamous cell carcinoma of the oral tongue (OTSCC; tumors measuring ≤4 cm) with histologically benign lymph nodes (pN0).
METHODS: A multi-institutional cohort of patients with early OTSCC was restaged as per AJCC8. Primary endpoints were local recurrence (LR) and locoregional recurrence (LRR). Influential variables were identified and an LR/LRR prediction model was developed.
RESULTS: There were a total of 494 patients, with 49 LR and 73 LRR. AJCC8 pT criteria resulted in upstaging of 37.9% of patients (187 of 494 patients), including 34.5% (64 of 185 patients) from pT2 to pT3, without improving the prognostication for LR or LRR. Both LR and LRR were found to be similar for patients with AJCC8 pT2 and pT3 disease. On multivariate analysis, LR was only found to be associated with distance to the closest margin (hazard ratio, 0.36; 95% CI, 0.20-0.64 [P = .0007]) and perineural invasion (hazard ratio, 1.92; 95% CI, 1.10-0.64 [P = .046]). Based on these 2 predictors, a final proportional hazards regression model (which may be used similar to a nomogram) was developed. The proposed model appeared to be superior to AJCC pT stage for estimating the probability of LR and LRR for individual patients with early OTSCC.
CONCLUSIONS: AJCC8 pT criteria resulted in pT upstaging of patients with pN0 disease without improved LR or LRR prognostication. The proposed model based on distance to the closest margin and perineural invasion status outperformed pT as a predictor of LR and LRR in patients with early OTSCC.
PubMed ID: 31174238
Article Size: <1 MB

Elastofibroma.

Head & Neck, Neck
Thompson LD.
Ear Nose Throat J. 2017 Apr-May;96(4-5):160.
FIRST PARAGRAPH: Elastofibroma is an ill-defined fibroelastic tumor-like condition that affects the neck and upper shoulders. There is a genetic predisposition, with multifocality suggesting an enzymatic defect that results from abnormal elastogenesis. Patients usually present in the 60- to 70-year range, with females affected much more often than males (5:1). Although perhaps due to reporting bias, there is an increased incidence in Japanese patients.
PubMed ID: 28489232
Article Size: <1 MB

Neuroendocrine tumors of the larynx.

Head & Neck, Larynx
Thompson LD.
Ear Nose Throat J. 2016 Jul;95(7):262-6.
FIRST PARAGRAPH: Neuroendocrine neoplasms of the larynx encompass five separate tumors: paraganglioma, typical carcinoid, atypical carcinoid, small cell carcinoma, and large cell neuroendocrine carcinoma. Many synonyms are employed, with well-, moderately, and poorly differentiated neuroendocrine carcinoma commonly applied to the middle three tumors (World Health Organization preferred terminology). Paraganglioma is an exceedingly uncommon neuroendocrine tumor in the larynx, as is large cell neuroendocrine carcinoma, and therefore these will not be further discussed.
PubMed ID: 27434472
Article Size: <1 MB

Secretory carcinoma.

Head & Neck, Salivary Gland
Thompson LD.
Ear Nose Throat J. 2016 Dec;95(12):474-476.
FIRST PARAGRAPH: Secretory carcinoma, first described as mammary analogue secretory carcinoma (MASC), is a recently described, distinctive malignant salivary gland tumor that is quite similar to secretory breast carcinoma, defined by the t(12;15)(p13;q25) translocation resulting in an ETV6-NTRK3 fusion product. The vast majority of these tumors used to be included in the acinic cell carcinoma category.
PubMed ID: 27929593
Article Size: <1 MB

HPV-Related Multiphenotypic Sinonasal Carcinoma.

Head & Neck, Sinonasal Tract
Thompson LDR.
Ear Nose Throat J. 2020 Feb;99(2):94-95. doi: 10.1177/0145561319871711.
FIRST PARAGRAPH: Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (originally called HPV-related carcinoma with adenoid cystic-like features) is a recently recognized variant of sinonasal carcinoma showing histologic features of surface dysplasia and salivary gland carcinoma (adenoid cystic carcinoma specifically) and showing a strong association with HPV, especially HPV 33. Women are affected slightly more often than men, with a mean age at presentation in the sixth decade, frequently with high T-stage disease. Tumors involve the nasal cavity and paranasal sinuses, often with extension into adjacent structures. Even though the tumors are often large and destructive sinonasal tract tumors, they tend to exhibit a relatively indolent behavior, although local recurrence is frequent, but distant metastasis and death from disease are very uncommon. As such, this tumor should be distinguished from histologic mimics as there is a better prognosis.
PubMed ID: 31476886
Article Size: <1 MB

Impact of chemotherapy regimen on treatment outcomes in patients with HPV-associated oropharyngeal cancer with T4 disease treated with definitive concurrent chemoradiation.

Head & Neck, Oropharynx
Bhattasali O, Ryoo JJ, Thompson LDR, Abdalla IA, Chen J, Iganej S.
Oral Oncol. 2019 Aug;95:74-78. doi: 10.1016/j.oraloncology.2019.06.007. Epub 2019 Jun 11.
OBJECTIVES: Although human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is typically associated with a good prognosis, patients with T4 disease experience relatively high rates of treatment failure. Our aim was to identify predictors of relapse among patients with clinical T4 disease.
MATERIAL & METHODS: A retrospective review was conducted of 93 consecutive patients who underwent definitive concurrent chemoradiation for HPV-associated OPSCC with clinical T4 disease from July 2006 to December 2015. Three-year outcomes, including locoregional recurrence (LRR), distant metastasis (DM), overall survival (OS), and cancer-specific survival (CSS), were examined and reported from the date of treatment completion. Multivariable analysis using a Cox proportional hazards model was performed to test associations between outcome and patient and disease characteristics as well as chemotherapy regimen (high-dose cisplatin (HDC) vs. other).
RESULTS: Median follow-up for surviving patients was 50 months (range 18-133). For all-comers, 3-year rates of LRR, DM, OS, and CSS were 15%, 19%, 79%, and 86%, respectively. On multivariable analysis, the only factor prognostic for patient outcomes was the chemotherapy regimen. For patients who received HDC vs. an alternative regimen, 3-year LRR, DM, OS, and CSS, were 9% vs. 20% (p = 0.09), 10% vs. 28% (p = 0.04), 89% vs. 67% (p = 0.04), and 96% vs. 77% (p = 0.02), respectively.
CONCLUSION: In patients with HPV-associated OPSCC bearing clinical T4 disease, receipt of a concurrent systemic agent other than HDC resulted in increased treatment failure and inferior survival. This analysis suggests that HDC should remain the preferred concurrent regimen for these patients.
PubMed ID: 31345397
Article Size: <1 MB

Triweekly carboplatin as a potential de-intensification agent in concurrent chemoradiation for early-stage HPV-associated oropharyngeal cancer.

Head & Neck, Oropharynx
Iganej S, Beard BW, Chen J, Buchschacher GL Jr, Abdalla IA, Thompson LDR, Bhattasali O.
Oral Oncol. 2019 Aug 2;97:18-22. doi: 10.1016/j.oraloncology.2019.07.016. [Epub ahead of print]
OBJECTIVE: We compared high-dose cisplatin (HDC) vs. triweekly carboplatin (TC)-based chemoradiation in patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC).
MATERIALS AND METHODS: A retrospective review was conducted from 2006 to 2015 of 421 patients with locally advanced p16-positive OPSCC receiving definitive radiotherapy concurrent with 3 cycles of HDC (100 mg/m2, n = 230) or TC (AUC = 5, n = 191). Three-year locoregional recurrence (LRR), distant metastasis (DM), overall recurrence rate (ORR), overall survival (OS), and cause-specific survival (CSS) are reported. HDC and TC were compared accounting for age, sex, comorbidity index score, smoking history, T stage, and N stage.
RESULTS: For all-comers, no difference was observed between HDC and TC for any outcome except for ORR which was lower in patients receiving HDC (12% vs. 17%, p = 0.03). On stage-based analysis, no difference was observed between agents for any outcome for stage I or II disease. However, patients with stage III disease receiving HDC had lower rates of LRR (9% vs. 21%, p = 0.03), DM (7% vs. 28%, p = 0.006), and ORR (14% vs. 40%, p = 0.002), and superior OS (89% vs. 78%, p = 0.04) and CSS (95% vs. 80%, p = 0.02). Patients receiving HDC experienced higher rates of grade 3 leukopenia (25% vs. 11%, p < 0.001), weight loss ≥20% from baseline (21% vs. 8%, p < 0.001), and gastrostomy-tube placements (66% vs. 27%, p < 0.001).
CONCLUSION: TC demonstrated comparable outcomes to HDC for stage I or II HPV-associated OPSCC but was inferior to HDC for stage III disease. TC was associated with less toxicity and may be a potential de-intensification agent for early-stage disease.
PubMed ID: 31421466
Article Size: <1 MB

Sclerosing Polycystic “Adenosis” of Salivary Glands: A Neoplasm Characterized by PI3K Pathway Alterations More Correctly Named Sclerosing Polycystic Adenoma.

Head & Neck, Salivary Gland
Bishop JA, Gagan J, Baumhoer D, McLean-Holden AL, Oliai BR, Couce M, Thompson LDR.
Head Neck Pathol. 2020 Sep;14(3):630-636. doi: 10.1007/s12105-019-01088-0. Epub 2019 Oct 11.
Sclerosing polycystic adenosis (SPA) is a rare benign salivary gland lesion that usually arises from the parotid gland. SPA was originally interpreted to be a non-neoplastic alteration analogous to fibrocystic changes of the breast, but now there is uncertainty about whether it may represent a neoplasm. SPA often contains intraductal proliferations with an appearance similar to ductal neoplasia of the breast, and one study reported X-chromosome inactivation using polymorphisms of the human androgen receptor (Skalova et al., in AJSP 30:939-944, 2006). We investigated the genetics of SPA through targeted next generation sequencing (NGS). Four cases of SPA were retrieved from the authors’ consultation files. A custom, targeted NGS panel including 1425 cancer-related genes was performed on all cases, followed by immunohistochemistry for PTEN. All four cases developed in females, ranging from 40 to 69 years (mean 52.5 years), affecting the parotid (n = 3) and submandibular glands (n = 1). All cases exhibited characteristic histologic features of SPA: well-circumscribed lesions with fibrosis and an admixture of ducts, myoepithelial cells and acinar cells, the latter containing brightly eosinophilic intracytoplasmic granules. Two cases had intraductal apocrine epithelial proliferations. By targeted NGS, loss-of-function mutations in PTEN were revealed in all 4 cases. In addition, 2 of 4 cases harbored PIK3CA mutations and 2 of 4 possessed PIK3R1 alterations; one case lacked both PIK3CA and PIK3R1 mutations. PTEN expression by immunohistochemistry was lost in the ductal and acinar elements but not the myoepithelial cells in all cases. SPA is characterized by genetic alterations in the PI3K pathway, with PTEN mutations seen most frequently. This molecular profile is similar to salivary duct carcinoma and the apocrine variant of intraductal carcinoma (i.e., salivary duct carcinoma-in situ). PI3K pathway alterations were found in cases both with and without intraductal apocrine proliferations, and PTEN immunohistochemistry suggested that the ductal and acinar cells, but not myoepithelial cells, were affected. Taken together, these findings strongly support that SPA is a neoplasm, more correctly named “sclerosing polycystic adenoma.” The salivary duct carcinoma-like genetic alterations, coupled with the fact that the surrounding myoepithelial cells appear to be non-neoplastic, suggest a close relationship between SPA and apocrine intraductal carcinoma.
PubMed ID: 31605313
Article Size: 1.9 MB

Oropharyngeal Squamous Cell Carcinoma in 390 Patients: Analysis of Clinical and Histological Criteria Which Significantly Impact Outcome

Head & Neck, Oropharynx
Thompson LDR, Burchette R, Iganej S, Bhattasali O.
Head Neck Pathol. 2020 Sep;14(3):666-688. doi: 10.1007/s12105-019-01096-0. Epub 2019 Nov 18.
This study evaluates the prognostic impact of several factors in oropharyngeal squamous cell carcinoma (OPSCC), controlling for human papillomavirus (HPV)-associated tumors and stage (American Joint Committee on Cancer 8th edition). All patients in Southern California Permanente Medical Group diagnosed with OPSCC between 2006 and 2012 tested for p16 immunohistochemistry were included. Review of all pathology materials was combined with central p16 testing. Multivariable analyses were performed. The cohort of 390 patients included 342 p16-positive and 48 p16-negative tumors. For all-comers, on univariate analysis, the following factors, when present, were associated with improved patient survival: p16-positive tumor (n = 324, p < 0.001); crypt versus surface tumor location (n = 312, p = 0.004); nonkeratinizing type (n = 309, p < 0.0001); nonkeratinizing with maturation type (n = 37, p < 0.0001); basaloid pattern (n = 284, p = 0.005); and a broad, pushing border of infiltration (n = 282, p = 0.004). Inferior survival outcomes were observed with: age ≥ 55 years (p < 0.0001); ≥ 10 pack-year smoking history (n = 183, p = 0.003); increasing tumor stage (p < 0.0001); overt radiographic extranodal extension (ORENE) (n = 58, p < 0.0001); low level IV/Vb lymph node involvement (n = 45, p = 0.0002); a jagged pattern of infiltration (n = 76, p = 0.0004); tumor ulceration (n = 76, p = 0.0004); absent lymphocytic infiltrate (p < 0.0001); and concurrent dysplasia (n = 125, p = 0.009). On multivariable analysis, accounting for patient age, smoking history ≥ 10 pack-years, and TNM stage, for patients with p16-positive disease, advanced TNM stage (p = 0.007), the presence of ORENE (p = 0.0002), and low-neck lymphadenopathy (p = 0.0001) were independent negative prognostic factors for disease free survival (DFS). Older age (p < 0.0001), smoking history ≥ 10 pack-years (p = 0.02), advanced TNM stage (p = 0.0002), ORENE (p = 0.004), and low-neck lymphadenopathy (p = 0.002) were independent negative prognostic factors for OS. Among patients with p16-positive OPSCC, older age, smoking history, advanced stage, ORENE, and low-neck lymphadenopathy were significant negative prognostic factors for DFS and/or OS. Further refinement of staging to incorporate additional lymph node findings may be warranted.
PubMed ID: 31741151
Article Size: 11 MB

Tongue Schwannoma: A Clinicopathologic Study of 19 Cases.

Head & Neck, Oral Cavity/Gnathic (Jaw)
Thompson LDR, Koh SS, Lau SK.
Head Neck Pathol. 2020 Sep;14(3):571-576. doi: 10.1007/s12105-019-01071-9. Epub 2019 Sep 4.
Schwannomas commonly occur in the head and neck but infrequently involve the oral cavity and rarely affect the tongue. The clinical and pathologic features of 19 cases of schwannoma arising in the tongue were analyzed. There were 13 males and 6 females ranging in age from 12 to 82 years (mean 34 years; median 29 years). The majority of tumors presented as an asymptomatic mass localized to the anterior two-thirds of the tongue. Histologically, 18 schwannomas exhibited characteristic Antoni A and B areas with the former pattern predominating. One tumor was composed exclusively of cellular Antoni A tissue and was classified as a cellular schwannoma. Tumor encapsulation was variable with nearly half of the lesions lacking a well-defined fibrous capsule. All were strongly and diffusely positive for S-100 protein. No recurrences were observed on clinical follow-up. Schwannoma of the tongue, although rare, should be separated from other types of lingual nerve sheath proliferations and tumors.
PubMed ID: 31485983
Article Size: 2.2 MB

Don’t stop the champions of research now: a brief history of head and neck pathology developments.

Head & Neck, Salivary Gland
Thompson LDR, Lewis JS Jr, Skálová A, Bishop JA.
Hum Pathol. 2020 Jan;95:1-23. doi: 10.1016/j.humpath.2019.08.017. Epub 2019 Aug 23.
The field of Head and Neck Pathology was just developing 50years ago, but has certainly come a long way in a relatively short time. Thousands of developments in diagnostic criteria, tumor classification, malignancy staging, immunohistochemistry application and molecular testing have been made during this time, with an exponential increase in literature on the topics over the past few decades: There were 3506 articles published on head and neck topics in the decade between 1969 and 1978 (PubMed source), with a staggering 89266 manuscripts published in the most recent decade. It is daunting and impossible to narrow the more than 162000 publications in this field and suggest only a few topics of significance. However, the breakthru in this anatomic discipline has been achieved in three major sites: oropharyngeal carcinoma, salivary gland neoplasms, and sinonasal tract tumors. This review will highlight selected topics in these anatomic sites in which the most profound changes in diagnosis have occurred, focusing on the information that helps to guide daily routine practice of surgical pathology.
PubMed ID: 31449826
Article Size: 9.5 MB

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

Head & Neck, Salivary Gland
Skálová A, Ptáková N, Santana T, Agaimy A, Ihrler S, Uro-Coste E, Thompson LDR, Bishop JA, Baněčkova M, Rupp NJ, Morbini P, de Sanctis S, Schiavo-Lena M, Vanecek T, Michal M, Leivo I.
Am J Surg Pathol. 2019 Oct;43(10):1303-1313. doi: 10.1097/PAS.0000000000001301.
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.
PubMed ID: 31162284
Article Size: <1 MB

Desmoid-Type Fibromatosis.

Head & Neck, Neck
Thompson LDR.
Ear Nose Throat J. 2021 Sep;100(5_suppl):518S-519S. Doi: 10.1177/0145561319890151.
FIRST PARAGRAPH: Desmoid-type fibromatosis is a locally aggressive, nonmetastasizing, well-differentiated, unencapsulated monoclonal myofibroblastic proliferation with a tendency for local invasion and recurrence. The tumor is intermediate between a fibroma and fibrosarcoma. Without a well documented etiology, trauma, surgery, and mutations in the CTNNB1 gene have all been implicated.
PubMed ID: 31760797
Article Size: <1 MB

IgG4-Related Sialadenitis.

Head & Neck, Salivary Gland
Thompson LDR.
Ear Nose Throat J. 2021 Sep;100(5_suppl):531S-532S. doi: 10.1177/0145561319890153.
FIRST PARAGRAPH: IgG4-related sialadenitis, formally Ku¨ttner tumor, is a chronic fibroinflammatory tumefactive salivary gland disorder characteristically showing dense lymphoplasmacytic infiltrate, storiform fibrosis, phlebitis, and increased IgG4-positive plasma cells, often with elevated serum IgG4 concentrations. This immune-mediated disorder often has systemic findings, including autoimmune pancreatitis, retroperitoneal fibrosis, cholangitis, lacrimal gland dacryoadenitis, Riedel thyroiditis, and other glands affected by a similar inflammatory fibroblastic disorder. The disorder is characterized by a prominent lymphoplasmacytic infiltrate and cytotoxic T-cell populations. In some submandibular cases, sialolithiasis may be a confounding factor.
PubMed ID: 31760789
Article Size: <1 MB

Inflammatory Myofibroblastic Tumor.

Head & Neck, Larynx
Thompson LDR.
Ear Nose Throat J. 2021 Sep;100(5_suppl):520S-521S. doi: 10.1177/0145561319890165.
FIRST PARAGRAPH: Inflammatory myofibroblastic tumor (IMT) is a distinctive, rarely metastasizing, (myo)fibroblastic neoplasm composed of spindle cells accompanied by an inflammatory infiltrate of plasma cells, lymphocytes, and/or eosinophils. Genetically, most IMTs harbor tyrosine kinase fusions, usually the ALK gene with an ever-expanding list of partner genes (TIMP3-ALK is most common), although these rearrangements are rare in adults. More common in abdominal soft tissue and lung sites, head and neck tumors comprise about 20% of all IMTs. Children and young adults are usually affected, with a slight female predominance. Symptoms are nonspecific and generally related to obstructive symptoms due to mass effect. Patients are generally managed surgically, although molecular-targeted therapy (eg, crizotinib) shows good response. While metastatic disease is exceptional, local recurrences are seen in about 25% of patients.
PubMed ID: 31760795
Article Size: <1 MB

Odontoma.

Head & Neck, Oral Cavity/Gnathic (Jaw)
Thompson LDR.
Ear Nose Throat J. 2021 Sep;100(5_suppl):536S-537S. doi: 10.1177/0145561319890175.
FIRST PARAGRAPH: Odontomas are hamartomas of odontogenic epithelium and ectomesenchyme, separated into compound and complex types. Both considered as a developmental anomaly, compound odontomas show diminutive tooth-like structures (Figures 1A and 2A), while complex odontomas show a haphazard aggregate of enamel and dentin (Figures 1B and 2B). Odontomas are considered to be one of the most common odontogenic tumors, with most presenting in the first 2 decades of life without sex predilection. Compound odontomas are more common in the anterior maxilla, while complex odontomas are more common in the posterior mandible (Figure 1B). The lesions are usually asymptomatic, detected on routine dental imaging studies, with a few cases reported in Rubinstein-Taybi syndrome. Radiographic features are considered diagnostic, with tooth-shaped structures surrounded by a radiolucent zone in compound odontomas versus a radiodense mass with a radiolucent zone seen in complex odontoma. Simple excision is curative without risk of recurrence.
PubMed ID: 31760790
Article Size: <1 MB

Oral Syphilis.

Head & Neck, Oral Cavity/Gnathic (Jaw)
Thompson LDR.
Ear Nose Throat J. 2021 Sep;100(5_suppl):538S-539S. doi: 10.1177/0145561319890154.
FIRST PARAGRAPH: There has been a recent reemergence in the development of oral syphilis, a sexually transmitted infection caused by the Treponema pallidum subspecies pallidum spirochaeta bacterium, with oral manifestations dependent on stage at presentation (early: primary, secondary, early latent; late: late latent, tertiary). Oral sex has contributed to the overall increase in disease spread, with the highest incidence in 25- to 29-yearold males (88% of oral cases documented in males, especially in males who have sex with males). Concurrent infections with HIV or other sexually transmitted infections are common. The lips, tongue, and palate are most commonly infected, while tonsils and gingiva may also be affected. Early primary presentation is of a painless, usually solitary ulcer (chancre) which forms about 3 weeks after inoculation (Figure 1). Early secondary presentation is about 3 to 12 weeks after chancre resolution and is the stage most oral syphilis is diagnosed. There are mucous white patches, sometimes multifocal. Condyloma lata is a papillary lesion. Latent syphilis is considered inactive disease, with serologic proof of infection, but without disease symptoms, usually >1 year after secondary syphilis. Tertiary syphilis may develop anywhere up to 15 years after initial infection, showing gumma (granulomatous inflammation) of the palate and/or tongue with atrophic luetic glossitis. Congenital manifestations are rare (screwdriver-shaped incisors and mulberry molars). Treatment involves intramuscular penicillin injections with appropriate counseling and screening for other sexually transmitted diseases.
PubMed ID: 31760793
Article Size: <1 MB

Verrucous Squamous Cell Carcinoma.

Ear & Temporal Bone, Head & Neck
Thompson LDR.
Ear Nose Throat J. 2021 Sep;100(5_suppl):540S-541S. Doi: 10.1177/0145561319871712.
FIRST PARAGRAPH: Verrucous squamous cell carcinoma (VSCC), sometimes called Ackerman tumor, is a highlight differentiated, lowgrade squamous cell carcinoma (SCC) variant that is characterized by an exophytic, warty growth, and a broad, pushing border of infiltration below the level of the adjacent uninvolved epithelium basement membrane, comprised of cytologically bland, amitotic squamous epithelium. As a SCC variant, it is strongly associated with tobacco and alcohol abuse. The vast majority of tumors are identified in the oral cavity (Figure 1), with the remaining tumors identified in the larynx, sinonasal tract, and pharynx. Women are affected more often than men by oral cavity tumors, with the reverse in the larynx. Patients present in the sixth and seventh decades of life with large tumors are seen as broad-based, fungating, exophytic, firm masses, generally lacking ulceration. Conservative surgery is usually employed without neck dissection or radiation to achieve an excellent >90% 5-year survival.
PubMed ID: 31760791
Article Size: <1 MB

Sinonasal Undifferentiated Carcinoma (SNUC): From an Entity to Morphologic Pattern and Back Again-A Historical Perspective.

Head & Neck, Sinonasal Tract
Agaimy A, Franchi A, Lund VJ, Skálová A, Bishop JA, Triantafyllou A, Andreasen S, Gnepp DR, Hellquist H, Thompson LDR, Rinaldo A, Ferlito A.
Adv Anat Pathol. 2020 Mar;27(2):51-60. doi: 10.1097/PAP.0000000000000258.
Since the first description of sinonasal undifferentiated carcinoma (SNUC) as a distinctive highly aggressive sinonasal neoplasm with probable origin from the sinonasal mucosa (Schneiderian epithelium), SNUC has been the subject of ongoing study and controversy. In particular, the SNUC category gradually became a “wastebasket” for any undifferentiated or unclassifiable sinonasal malignancy of definite or probable epithelial origin. However, with the availability of more specific and sensitive immunohistochemical antibodies and increasing implementation of novel genetic tools, the historical SNUC category became the subject of progressive subdivision leading to recognition of specific genetically defined, reproducible subtypes. These recently recognized entities are characterized by distinctive genetic aberrations including NUTM1-rearranged carcinoma (NUT carcinoma) and carcinomas associated with inactivation of different members of the SWI/SNF chromatin-remodeling gene complex such as SMARCB1-deficient and less frequently SMARCA4-deficient carcinoma. The ring became almost closed, with recent studies highlighting frequent oncogenic IDH2 mutations in the vast majority of histologically defined SNUCs, with a frequency of 82%. A review of these cases suggests the possibility that “true SNUC” probably represents a distinctive neoplastic disease entity, morphologically, phenotypically, and genetically. This review addresses this topic from a historical perspective, with a focus on recently recognized genetically defined subsets within the SNUC spectrum.
PubMed ID: 31876536
Article Size: <1 MB

Histologic Classification and Molecular Signature of Polymorphous Adenocarcinoma (PAC) and Cribriform Adenocarcinoma of Salivary Gland (CASG): An International Interobserver Study.

Head & Neck, Salivary Gland
Xu B, Barbieri AL, Bishop JA, Chiosea SI, Dogan S, Di Palma S, Faquin WC, Ghossein R, Hyrcza M, Jo VY, Lewis JS Jr, Lozada JR, Michal M, Pareja FG, Perez-Ordonez B, Prasad ML, Purgina B, Reis-Filho JS, Scognamiglio T, Sebastiao APM, Seethala RR, Skálová A, Smith SM, Tekkeşin MS, Thompson LDR, Wasseman JK, Wenig BM, Weinreb I, Katabi N.
Am J Surg Pathol. 2020 Apr;44(4):545-552. doi: 10.1097/PAS.0000000000001431.
Polymorphous adenocarcinoma (PAC) shows histologic diversity with streaming and targetoid features whereas cribriform adenocarcinoma of salivary gland (CASG) demonstrates predominantly cribriform and solid patterns with glomeruloid structures and optically clear nuclei. Opinions diverge on whether CASG represents a separate entity or a variant of PAC. We aimed to assess the level of agreement among 25 expert Head and Neck pathologists in classifying these tumors. Digital slides of 48 cases were reviewed and classified as: PAC, CASG, tumors with ≥50% of papillary architecture (PAP), and tumors with indeterminate features (IND). The consensus diagnoses were correlated with a previously reported molecular alteration. The consensus diagnoses were PAC in 18/48, CASG in16/48, PAP in 3/48, and IND in 11/48. There was a fair interobserver agreement in classifying the tumors (κ=0.370). The full consensus was achieved in 3 (6%) cases, all of which were classified as PAC. A moderate agreement was reached for PAC (κ=0.504) and PAP (κ=0.561), and a fair agreement was reached for CASG (κ=0.390). IND had only slight diagnostic concordance (κ=0.091). PAC predominantly harbored PRKD1 hotspot mutation, whereas CASG was associated with fusion involving PRKD1, PRKD2, or PRKD3. However, such molecular events were not exclusive as 7% of PAC had fusion and 13% of CASG had mutation. In conclusion, a fair to moderate interobserver agreement can be achieved in classifying PAC and CASG. However, a subset (23%) showed indeterminate features and was difficult to place along the morphologic spectrum of PAC/CASG among expert pathologists. This may explain the controversy in classifying these tumors.
PubMed ID: 31917707
Article Size: <1 MB

Biphenotypic Branchioma: A Better Name Than Ectopic Hamartomatous Thymoma for a Neoplasm with HRAS Mutation

Head & Neck, Neck
Thompson LDR, Gagan J, Washington A, Miller RT, Bishop JA.
Head Neck Pathol. 2020 Dec;14(4):884-888. doi: 10.1007/s12105-020-01132-4. Epub 2020 Feb 5.
Ectopic hamartomatous thymoma is a rare neck lesion originally thought to represent a non-neoplastic hamartoma, even though thymic origin has been questioned, and there is uncertainty about whether the lesion is a neoplasm. We investigated the genetics by performing targeted next generation sequencing (NGS). Three cases were identified from the authors’ consultation files. A custom, targeted NGS panel including 1385 pan-cancer‐related genes was performed on all cases. Three patients included 2 males and 1 female, aged 50, 58 and 70 years, respectively (mean 59.3 years), with tumors arising in the low anterior neck. All cases showed classical histologic features of EHT, with one case showing intraductal carcinoma in association with the EHT. By targeted NGS, one case harbored a hotspot HRAS mutation (p.Gln61Lys), while the other two cases only showed non oncogenic variants. Dual mesoderm and endoderm derivation/differentiation (biphenotypic) has been previously recognized, with epithelial and myoepithelial components, and arising from the apparatus contributing to neck development (branchial apparatus). Thus, EHT has been shown to have genetic alterations in HRAS. These findings, without evidence of thymic derivation or an ectopic tissue location, strongly support that EHT is a true neoplasm. The name biphenotyic branchioma more correctly reflects the true nature of this dual mesoderm and endoderm derived tumor occurring in the lower neck.
PubMed ID: 32026292
Article Size: 2 MB

Developing Classifications of Laryngeal Dysplasia: The Historical Basis.

Head & Neck, Larynx
Hellquist H, Ferlito A, Mäkitie AA, Thompson LDR, Bishop JA, Agaimy A, Hernandez-Prera JC, Gnepp DR, Willems SM, Slootweg PJ, Rinaldo A.
Adv Ther. 2020 Jun;37(6):2667-2677. doi: 10.1007/s12325-020-01348-4. Epub 2020 Apr 23.
During the last 60 years numerous significant attempts have been made to achieve a widely acceptable terminology and histological grading for laryngeal squamous intraepithelial lesions. While dysplasia was included in the pathology of the uterine cervix already in 1953, the term dysplasia was accepted in laryngeal pathology first after the Toronto Centennial Conference on Laryngeal Cancer in 1974. In 1963 Kleinsasser proposed a three-tier classification, and in 1971 Kambic and Lenart proposed a four-tier classification. Since then, four editions of the World Health Organisation (WHO) classification have been proposed (1978, 1991, 2005 and 2017). Several terms such as squamous intraepithelial neoplasia (SIN) and laryngeal intraepithelial neoplasia (LIN) are now being abandoned and replaced by squamous intraepithelial lesions (SIL). The essential change between the 2005 and 2017 WHO classifications is the attempt to induce a simplification from a four- to a two-tier system. The current WHO classification (2017) thus recommends the use of a two-tier system with reasonably clear histopathological criteria for the two groups: low-grade and high-grade dysplasia. Problems with interobserver variability apart, subjectivities and uncertainties remain, but to a lesser degree. Ongoing and additional molecular studies may help to clarify underlying events that will increase our understanding and possibly can facilitate our attempts to obtain an even better classification. The classification needs to be easier for the general pathologist to perform and easier for the clinician to interpret. These two objectives are equally important to provide each patient the best personalised treatment available for squamous intraepithelial lesions.
PubMed ID: 32329013
Article Size: <1 MB

Lymphoepithelial Carcinoma of Salivary Gland EBV‑association in Endemic versus Non‑Endemic Patients: A Report of 16 Cases

Head & Neck, Salivary Gland
Whaley RD, Carlos R, Bishop JA, Rooper L, Thompson LDR.
Head Neck Pathol. 2020 Dec;14(4):1001-1012. doi: 10.1007/s12105-020-01172-w. Epub 2020 May 27.
Lymphoepithelial carcinoma of salivary glands (LECSG) are rare neoplasms, reported in endemic populations (southeastern Chinese) with a strong Epstein-Barr virus (EBV) association. A retrospective series comparing EBV status within an ethnically diverse population (endemic vs. non-endemic patients) has not been reported. Sixteen LECSG were equally distributed between males (n = 8) and females (n = 8) with a median age of 54 years (range 18 to 85 years) at initial diagnosis. Ten patients were white, 4 Asian, and 2 black. The patients typically presented with swelling or mass for an average of 11.6 months. Tumors affected only major salivary glands: parotid (n = 13); submandibular (n = 3). Tumors were an average of 2.9 cm (range 1.5 to 5.8 cm). Nine of 16 (56%) patients had cervical lymph node metastases at presentation. No patients had nasopharyngeal or oropharyngeal tumors. Microscopically, the tumors were widely infiltrative, characterized by large polygonal to spindled cells arranged in a syncytial, lattice-like network in a background of lymphoplasmacytic cells. The neoplastic cells showed an open-vesicular nuclear chromatin to a more basaloid-morphology, the latter showing hyperchromatic nuclei and less cytoplasm, while nearly all of the cases had associated lymphoepithelial lesions/sialadenitis. By in situ hybridization, 8 of 16 cases had a strong, diffuse EBER expression (4 of 4 Asians; 4 of 12 non-Asians), while with immunohistochemistry all cases tested were pan-cytokeratin, CK5/6 and p63 reactive; none of the cases tested were p16 reactive. All patients were managed with wide or radical excision, 4 with concurrent chemoradiation, and 6 with radiation alone. Distant metastasis (lung, brain, and bone) developed in 2 patients. Overall follow-up (mean 3.8 years) revealed 12 patients alive and 2 dead, none with evidence of disease (mean 4.3 years); one white male alive with disease at 1.9 years, and one Asian female dead of disease at 4.2 years; both of these latter patients had Group IV stage disease. High stage (Group IV) patients had a shorter mean survival than lower stage patients: 3.1 versus 4.8 years, respectively. In conclusion, LECSG are uncommon primary neoplasms. Concurrent lymphoepithelial lesions may help suggest a primary tumor. The tumors, irrespective of race or ethnicity, may express
PubMed ID: 32462279
Article Size: 3.6 MB

Orbit Solitary Fibrous Tumor: A Proposed Risk Prediction Model Based on a Case Series and Comprehensive Literature Review.

Head & Neck, Sinonasal Tract
Thompson LDR, Liou SS, Feldman KA.
Head Neck Pathol. 2021 Mar;15(1):138-152. doi: 10.1007/s12105-020-01184-6. Epub 2020 Jun 11.
Solitary fibrous tumors (SFTs) of the orbit are rare. In order to further characterize the clinical and pathologic features of solitary fibrous tumor arising at this anatomic site, 12 cases of orbital SFTs were analyzed in conjunction with a review of 263 cases reported from the English literature in order to develop a risk prediction model. SFTs of the orbit were equally distributed between males (n = 5) and females (n = 7) with a mean patient age of 46.8 years (median 44.5 years; range 18-76 years) at initial diagnosis. The patients typically presented with swelling or mass around the orbit, with proptosis (n = 10), ptosis (n = 5), and visual changes (n = 6). Tumors were orbital (n = 10) or upper eyelid (n = 2). Mean tumor size was 2.5 cm (median 2.6 cm). Microscopically, the tumors were characterized by cytologically bland spindle cells with patternless growth, hypocellular and hypercellular areas, variable amounts of collagen, and ectatic, branching blood vessels. By immunohistochemistry, all cases had a strong nuclear STAT6 expression. All patients were initially managed with excision or biopsy, three with presurgical embolization. The two patients with biopsy only had persistent disease (mean 37.2 months), but a third patient developed distant bone metastasis at 86.9 months. Overall mean follow-up was 73.1 months: 9 patients are alive or dead without disease (mean 77.9 months), two patients with persistent disease, and one patient with metastatic disease at last follow-up (102 months). Incorporating cases sufficiently reported in the literature, a risk prediction model based on age > 45 years, tumor size > 3 cm, tumor necrosis, mitoses of > 4/2 mm2, moderate to high cellularity, and moderate to severe pleomorphism allows for risk stratification for the development of local recurrence and distant metastasis. In conclusion, orbital SFTs are rare, but can be reliably diagnosed based on the presence of characteristic morphologic features and STAT6 immunohistochemistry. Orbital tumors tend to show a higher frequency of local recurrence than distant metastasis, which can be predicted by a risk stratification model unique to orbital tumors. With late disease common, long term clinical follow-up is recommended.
PubMed ID: 32529350
Article Size: 3.2 MB

Recurrent Loss of SMARCA4 in Sinonasal Teratocarcinosarcoma

Head & Neck, Sinonasal Tract
Rooper LM, Uddin N, Gagan J, Brosens LAA, Magliocca KR, Edgar MA, Thompson LDR, Agaimy A, Bishop JA.
Am J Surg Pathol. 2020 Oct;44(10):1331-1339. doi: 10.1097/PAS.0000000000001508.
Molecular analysis has reshaped the landscape of high grade sinonasal tumors by defining novel entities and identifying recurrent mutations in established tumor types. However, sinonasal teratocarcinosarcoma (TCS), a rare and aggressive tumor with intermixed teratomatous, carcinomatous, and sarcomatous elements, remains poorly understood. The multiphenotypic differentiation of TCS has engendered persistent controversy about its histogenesis and leads to diagnostic overlap with several other malignancies. In this study, we evaluated the molecular underpinnings of TCS to clarify its pathogenesis and diagnosis. We performed SMARCA4 immunohistochemistry (IHC) on 22 TCS and 153 other sinonasal tumors. We identified loss of SMARCA4 expression in 18 TCS (82%), including 15 (68%) with complete loss and 3 (14%) with partial loss. Although we also identified partial SMARCA4 loss in 1 of 8 SMARCB1-deficient sinonasal carcinomas (13%), SMARCA4 was intact in all other sinonasal carcinomas and neuroendocrine tumors. We then selected 3 TCS with complete SMARCA4 loss by IHC for a targeted next-generation sequencing panel that included 1425 cancer-related genes. We confirmed biallelic somatic inactivation of SMARCA4 without other known oncogenic mutations in these 3 cases. Overall, these findings suggest that SMARCA4 inactivation may be the dominant genetic event in TCS, expanding understanding of this gene’s role in sinonasal tumorigenesis. They also raise the possibility that TCS is on a diagnostic spectrum with the newly described SMARCA4-deficient sinonasal carcinoma, blurring the lines between established and emerging sinonasal entities. In addition, SMARCA4 IHC may provide a useful adjunct for confirming a diagnosis of TCS in limited material.
PubMed ID: 32520761
Article Size: 1 MB

Lobular to Lobule: Metastatic Breast Carcinoma to Olfactory Neuroblastoma

Head & Neck, Sinonasal Tract
Swimley KM, Di Palma S, Thompson LDR.
Head Neck Pathol. 2021 Jun;15(2):642-648. doi: 10.1007/s12105-020-01199-z. Epub 2020 Jul 13.
Tumor-to-tumor metastasis (TTM) is a rare, but well-described phenomenon occurring in patients with multiple synchronous or metachronous primary malignancies. Olfactory neuroblastoma (ONB) is a rare malignant, neuroectodermal sinonasal tract tumor that occurs within the ethmoid sinus involving the cribriform plate. Very few cases of ONB have been documented to metastasize to other primary malignancies, but the reverse scenario is exceptional. During an evaluation for anosmia, a right nasal polyp was identified on imaging and endoscopy in a 66-year-old woman, with a polypectomy performed. Histologic examination showed classical features of a low-grade olfactory neuroblastoma, but within the tumor were isolated epithelioid cells which were strongly pancytokeratin immunoreactive. Review of the clinical history revealed lobular breast carcinoma treated 10 years earlier. Further evaluation with immunohistochemistry showed strong and diffuse nuclear estrogen and progesterone receptor reactivity, along with GATA3. These results confirmed TTM of an invasive lobular breast carcinoma to ONB. By employing a limited immunohistochemistry panel for all small round blue cell tumors that includes pancytokeratin, p40, S100 protein, SOX10, synaptophysin, desmin, CD99, and CD45, one is able to more accurately diagnose the classical tumor types, while also showing potentially unusual tumor features or exceptionally rare events like metastatic lobular breast carcinoma to ONB.
PubMed ID: 32661671
Article Size: 2 MB

Low-Grade Fibromyxoid Sarcoma of the Head and Neck: A Clinicopathologic Series and Review of the Literature

Head & Neck, Neck
Cowan ML, Thompson LD, Leon ME, Bishop JA.
Head Neck Pathol. 2016 Jun;10(2):161-6.
Low-grade fibromyxoid sarcoma (LGFMS) is a deceptively bland malignancy with potential for late recurrence and metastasis, which usually occurs in the deep soft tissues of the extremities and trunk. Most LGFMSs harbor a characteristic gene fusion of FUS-CREB3L2, and recently MUC4 immunostaining has been found to be highly sensitive and specific for the diagnosis. We present a dedicated series of head and neck LGFMS, including the first reported laryngeal case, as well as a review of reported head and neck cases. The surgical pathology archives of our three institutions were searched for cases of LGFMS arising within the head and neck, and four cases were identified. The H&E slides were reviewed, and immunohistochemistry were performed for pancytokeratin, p63, p40, EMA, S100 protein, β-catenin, actin, CD34, and MUC4. The patients were 6, 43, 45, and 73 years old (mean 41.8 years) and included three males and one female. The tumors were located in the posterior cervical spine, facial skin, mandible, and larynx. The tumors were treated with surgical excision, and all four had histologic features typical for LGFMS including alternating myxoid and fibrous areas with prominent curvilinear vasculature. All tumors were MUC4 positive (100%), 2/4 (50%) were p63 positive, 1/4 (25%) showed focal EMA positivity; all 4 were negative for pancytokeratin, p40, S100 protein, β-catenin, actin, and CD34. LGFMS is a low grade sarcoma that rarely develops in the head and neck. Due to its rarity, a pathologist may not consider LGFMS in the differential diagnosis of spindle cell neoplasms within the head and neck. Immunohistochemical staining is helpful, but stains should be selected carefully to avoid misdiagnosis.
PubMed ID: 26276044
Article Size: 1.4 MB
 

Salivary Intraductal Carcinoma Arising within Intraparotid Lymph Node: A Report of 4 Cases with Identification of a Novel STRN-ALK Fusion

Head & Neck, Salivary Gland
Rooper LM, Thompson LDR, Gagan J, Oliai BR, Weinreb I, Bishop JA.
Head Neck Pathol. 2021 Mar;15(1):179-185. doi: 10.1007/s12105-020-01198-0. Epub 2020 Jul 13.
Intraductal carcinoma (IDC) is a rare salivary gland tumor that is considered analogous to ductal carcinoma in-situ of the breast, demonstrating a complex neoplastic epithelial proliferation surrounded by a continuous layer of presumed non-neoplastic myoepithelial cells. It is subcategorized into intercalated duct, apocrine, and hybrid subtypes based on morphologic and immunohistochemical features, with frequent NCOA4-RET and TRIM27-RET fusions, respectively, seen in intercalated duct and hybrid tumors. However, as an expanding clinicopathologic spectrum of IDC has been documented, controversy has emerged as to whether this tumor type is best defined by its intraductal growth pattern or distinctive molecular and immunophenotypic differentiation. Here, we further explore the nature of IDC by evaluating four cases that arose within intraparotid lymph nodes. These intercalated-duct phenotype tumors with diffuse S100 protein expression demonstrated a crowded and complex epithelial proliferation arranged in cystic, cribriform, and micropapillary architecture, surrounded by an intact myoepithelial cell layer, and were completely intranodal. Of two tumors with tissue available for molecular analysis, one demonstrated a NCOA4-RET fusion and one harbored a STRN-ALK fusion that is novel to IDC. Not only does the intranodal presence of IDC present a challenging differential diagnosis, but the complex nature of this proliferation within lymph node tissue raises questions as to whether the myoepithelial component of IDC is actually non-neoplastic in nature. Furthermore, identification of a STRN-ALK fusion expands the genetic spectrum of IDC and adds to evidence of an emerging role for ALK in salivary gland tumors. Further attention to the nature of the myoepithelial cells and documentation of alternate fusion events in IDC may inform continued discussion about its appropriate classification.
PubMed ID: 32661669
Article Size: 2.2 MB

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

Head & Neck, Salivary Gland
Skálová A, Banečkova M, Thompson LDR, Ptáková N, Stevens TM, Brcic L, Hyrcza M, Michal M Jr, Simpson RHW, Santana T, Michal M, Vaněček T, Leivo I.
Am J Surg Pathol. 2020 Oct;44(10):1295-1307. doi: 10.1097/PAS.0000000000001535.
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.
PubMed ID: 32675658
Article Size: 1.1 MB

Data Set for the Reporting of Pheochromocytoma and Paraganglioma: Explanations and Recommendations of the Guidelines from the International Collaboration on Cancer Reporting (ICCR).

Head & Neck, Staging
Thompson LDR, Gill AJ, Asa SL, Clifton-Bligh RJ, de Krijger RR, Kimura N, Komminoth P, Lack EE, Lenders JWM, Lloyd RV, Papathomas TG, Sadow PM, Tischler AS.
Hum Pathol. 2021 Apr;110:83-97. doi: 10.1016/j.humpath.2020.04.012. Epub 2020 May 11.
SUMMARY BACKGROUND AND OBJECTIVES: The International Collaboration on Cancer Reporting (ICCR) is a not-for-profit to develop evidence-based, internationally agreed-upon standardized data sets for each anatomic site, to be used throughout the world. Providing global standardization of pathology tumor classification, staging, and other reporting elements will lead to improved patient management and enhanced epidemiological research.
METHODS: Pheochromocytoma and paraganglioma are uncommon and are frequently overlooked in registry data sets. Malignant criteria have previously been defined only when there was metastatic disease.
RESULTS: With recent recognition of a significant inheritance association and the development of risk stratification tools, this data set was created in order to obtain more meaningful outcomes and management data, using similar criteria across the global pathology community. Issues related to key core and non-core elements, especially clinical hormonal status, familial history, tumor focality, proliferative fraction, adverse or risk stratification features, and ancillary techniques, are discussed in the context of daily application to these types of specimens.
CONCLUSIONS: The ICCR data set, developed by an international panel of endocrine organ specialists, establishes a pathology-standardized reporting guide for pheochromocytoma and paraganglioma.
PubMed ID: 32407815
Article Size: 7 MB

Extragonadal Non-gestational Choriocarcinoma with Tonsillar Presentation.

Head & Neck, Oropharynx
Payne T, Di Palma S, Walker D, Dakin J, Thompson LDR.
Head Neck Pathol. 2021 Sep;15(3):1047-1053. doi: 10.1007/s12105-020-01245-w.
Extragonadal non-gestational choriocarcinoma is a rare but well-described phenomenon occurring in patients with midline germ cell tumors. Choriocarcinoma (ChC) is an aggressive neoplasm usually developing in women as a rare complication of pregnancy. In male patients ChC occurs in the testes, usually as a component of mixed germ cell tumors. Very few patients develop extragonadal choriocarcinoma with the tumor occurring in midline locations, such as the mediastinum, retroperitoneum, and central nervous system (mostly pineal gland). Non-midline choriocarcinoma can occur in the lung, gastrointestinal tract, and breast, sometimes blended with another primary malignancy. A midline choriocarcinoma manifesting as a head and neck malignancy is exceptional. During an evaluation of multiple enlarged cervical lymph nodes suspected to be lymphoma in a 72-year-old man, a core biopsy was taken from one of the left neck lymph nodes which histologically showed a necrotic malignancy with strong diffuse pancytokeratin staining. After an initial interpretation of metastatic carcinoma, further samples were taken from both tonsils and from a right level 5 neck lymph node. Histologically, all samples contained the same tumor, showing profound pleomorphism and multinucleated syncytial-type giant cells. A panel of immunohistochemistry studies were performed, including β-human chorionic gonadotropin, with positive findings leading to a diagnosis of extragonadal non-gestational choriocarcinoma.
PubMed ID: 33128732
Article Size: 2 MB

The Myoepithelial Cells of Salivary Intercalated Duct-type Intraductal Carcinoma Are Neoplastic: A Study Using Combined Whole-slide Imaging, Immunofluorescence, and RET Fluorescence In Situ Hybridization.

Head & Neck, Salivary Gland
Bishop JA, Rooper LM, Sangoi AR, Gagan J, Thompson LDR, Inagaki H.
Am J Surg Pathol. 2021 Apr 1;45(4):507-515. doi: 10.1097/PAS.0000000000001605.
Intraductal carcinoma (IDC) is a salivary gland tumor currently believed to be analogous to breast ductal carcinoma in situ, consisting of a complex neoplastic epithelial proliferation surrounded by a continuous layer of myoepithelial cells presumed to be native and non-neoplastic. Recent molecular insights have shown that there are at least 3 different types of IDC: (1) intercalated duct-like, with frequent NCOA4-RET fusions; (2) apocrine, with multiple mutations similar to salivary duct carcinoma; and (3) mixed intercalated duct-like and apocrine with frequent RET fusions, especially TRIM27-RET. Recent observations (eg, IDC occurring in lymph nodes) have challenged the notion that the myoepithelial cells of IDC are non-neoplastic. Five IDCs with known RET fusions by RNA sequencing were retrieved from the authors’ archives, including 4 intercalated duct-like IDCs with NCOA4-RET, and 1 mixed intercalated duct-like/apocrine IDC with TRIM27-RET. A panel of immunohistochemistry antibodies (S100 protein, p63 or p40, mammaglobin, smooth muscle actin, calponin, androgen receptor) was tested. To precisely localize RET split-positive cells, each case was subjected to sequential retrieval of whole-slide imaging data of hematoxylin and eosin (HE) staining, immunofluorescence staining for calponin, and fluorescence in situ hybridization (FISH) for RET. Because NCOA4-RET is an inversion difficult to visualize on conventional RET FISH, a novel 3-color FISH technique was utilized to demonstrate it clearly. In all 5 cases, the proliferative ducts were completely surrounded by a layer of myoepithelial cells that were positive for p63 or p40, smooth muscle actin, and calponin. Using combined HE, calponin immunofluorescence, and RET FISH imaging, the positive signals were unmistakably identified in both calponin-negative ductal cells and peripheral, calponin-positive myoepithelial cells in all 5 cases. Utilizing combined HE, calponin immunofluorescence, and RET FISH imaging, we demonstrated that IDCs with RET fusions harbored this alteration in both the ductal and myoepithelial cells. This is compelling evidence that the myoepithelial cells of IDC are not mere bystanders, but are rather a component of the neoplasm itself, similar to other biphasic salivary gland neoplasms like pleomorphic adenoma and epithelial-myoepithelial carcinoma. This finding raises questions about the appropriate terminology, classification, and staging of IDC.
PubMed ID: 33086236
Article Size: <1 MB

Proliferative Verrucous Leukoplakia: An Expert Consensus Guideline for Standardized Assessment and Reporting

Head & Neck, Oral Cavity/Gnathic (Jaw)
Thompson LDR, Fitzpatrick SG, Müller S, Eisenberg E, Upadhyaya JD, Lingen MW, Vigneswaran N, Woo SB, Bhattacharyya I, Bilodeau EA, Carlos R, Islam MN, Leon ME, Lewis JS Jr, Magliocca KR, Mani H, Mehrad M, Purgina B, Richardson M, Wenig BM, Cohen DM.
Head Neck Pathol. 2021 Jun;15(2):572-587. doi: 10.1007/s12105-020-01262-9. Epub 2021 Jan 7.
The many diverse terms used to describe the wide spectrum of changes seen in proliferative verrucous leukoplakia (PVL) have resulted in disparate clinical management. The objective of this study was to produce an expert consensus guideline for standardized assessment and reporting by pathologists diagnosing PVL related lesions. 299 biopsies from 84 PVL patients from six institutions were selected from patients who had multifocal oral leukoplakic lesions identified over several years (a minimum follow-up period of 36 months). The lesions demonstrated the spectrum of histologic features described in PVL, and in some cases, patients developed oral cavity squamous cell carcinoma (SCC). An expert working group of oral and maxillofacial and head and neck pathologists reviewed microscopic features in a rigorous fashion, in combination with review of clinical photographs when available. The working group then selected 43 single slide biopsy cases for whole slide digital imaging (WSI) review by members of the consensus conference. The digital images were then reviewed in two surveys separated by a washout period of at least 90 days. Five non-PVL histologic mimics were included as controls. Cases were re-evaluated during a consensus conference with 19 members reporting on the cases. The best inter-observer diagnostic agreement relative to PVL lesions were classified as “corrugated ortho(para)hyperkeratotic lesion, not reactive” and “SCC” (chi-square p = 0.015). There was less than moderate agreement (kappa < 0.60) for lesions in the “Bulky hyperkeratotic epithelial proliferation, not reactive” category. There was ≥ moderate agreement (> 0.41 kappa) for 35 of 48 cases. This expert consensus guideline has been developed with support and endorsement from the leadership of the American Academy of Oral and Maxillofacial Pathology and the North American Society of Head and Neck Pathologists to recommend the use of standardized histopathologic criteria and descriptive terminology to indicate three categories of lesions within PVL: (1) “corrugated ortho(para)hyperkeratotic lesion, not reactive;” (2) “bulky hyperkeratotic epithelial proliferation, not reactive;” and (3) “suspicious for,” or “squamous cell carcinoma.” Classification of PVL lesions based on a combination of clinical findings and these histologic descriptive categories is encouraged in order to standardize reporting, aid in future research and potentially guide clinical management.
PubMed ID: 33415517
Article Size: 2.33 MB

Prognostic impact of retropharyngeal lymphadenopathy in early-stage HPV-associated oropharyngeal cancer: Implications for staging optimization

Head & Neck, Oropharynx
Bhattasali O, Torres FA, Kang HK, Thompson LDR, Abdalla IA, McNicoll MP, Lin A, Ryoo JJ, Chen J, Iganej S.
Oral Oncol. 2021 Mar;114:105147. doi: 10.1016/j.oraloncology.2020.105147. Epub 2021 Jan 16.
FIRST PARAGRAPH: Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is established as a disease with generally favorable outcomes, particularly when contrasted to other head and neck squamous cell carcinomas which are commonly associated with heavy alcohol and tobacco use [1,2]. Prior cancer staging systems did not accurately prognosticate outcomes for HPV-associated OPSCC. Consequently, the American Joint Committee on Cancer (AJCC) 8th edition staging system reclassified HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) as its own entity and adapted the risk-stratification system proposed by the ICON-S group for this cohort of patients [3].
PubMed ID: 33460883
Article Size: 1 MB

Lymphoepithelial Carcinoma of Salivary Glands.

Head & Neck, Salivary Gland
Thompson LDR, Whaley RD.
Surg Pathol Clin. 2021 Mar;14(1):75-96. doi: 10.1016/j.path.2020.09.009.
Lymphoepithelial carcinoma of salivary glands (LECSG) is an uncommon neoplasm. This article summarizes the findings of 438 cases in a review of the literature. Concurrent lymphoepithelial lesions may suggest a primary tumor. The tumor shows a nonkeratinizing carcinoma intimately associated with a rich lymphohistiocytic infiltrate, destroying adjacent salivary gland tissue. Irrespective of race or ethnicity, the tumors usually express Epstein-Barr virus, with Epstein-Barr virus encoded small RNA (EBER) and/or latent membrane protein-1 (LMP-1), although a subset does not. There is an overall good prognosis of about 80% at 5 years.
PubMed ID: 33526225
Article Size: 16.2 MB

Sclerosing Polycystic Adenoma.

Head & Neck, Salivary Gland
Bishop JA, Thompson LDR.
Surg Pathol Clin. 2021 Mar;14(1):17-24. doi: 10.1016/j.path.2020.09.004.
Sclerosing polycystic adenoma (SPA) is the more appropriate name for sclerosing polycystic adenosis. SPA is an uncommon salivary gland lesion with a constellation of unusual histologic findings that were originally interpreted as analogous to breast fibrocystic changes. The histologic findings in SPA include fibrosis, cystic alterations, apocrine metaplasia, and proliferations of ducts, acini, and myoepithelial cells in variable proportions. Because of its unusual mixed histology, SPA may be confused with a variety of lesions, ranging from reactive conditions to benign or even malignant neoplasms. The features of SPA are reviewed, with an emphasis on resolving its differential diagnosis.
PubMed ID: 33526220
Article Size: 8.25 MB

Emerging Entities and New Diagnostic Markers for Head and Neck Soft Tissue and Bone Tumors

Head & Neck, Neck
Franchi A, Thompson LDR, Hernandez-Prera JC, Agaimy A, Williams MD, Mikkelsen LH, Bishop JA, Willems SM, Hellquist H, Ferlito A.
Adv Anat Pathol. 2021 May 1;28(3):139-149. doi: 10.1097/PAP.0000000000000295.
Bone and soft tissue tumors of the head and neck are relatively uncommon tumors that often represent a diagnostic challenge because of the wide range of entities that must be considered in the differential diagnosis. Over the past few years, classification of bone and soft tissue tumors has evolved primarily because of substantial contributions from molecular genetics, with the identification of new markers that are increasingly used to complement histopathologic findings in the routine diagnostic workup. This review focuses on the recently described mesenchymal tumors that preferentially involve the head and neck region, with a focus on the most relevant novel immunohistochemical and molecular findings, including gene fusions and mutations, that can help in the diagnosis and in the assessment of clinical behavior.
PubMed ID: 33559990
Article Size: 1.1 MB

Algorithmic Approach to Fibroinflammatory Sinonasal Tract Lesions.

Head & Neck, Sinonasal Tract
Thompson LDR.
Head Neck Pathol. 2021 Mar;15(1):120-129. doi: 10.1007/s12105-020-01272-7. Epub 2021 Mar 15.
Fibroinflammatory lesions of the sinonasal tract are one of the most common head and neck lesions submitted to surgical pathology. When the fibroinflammatory pattern represents the lesion (i.e., not surface reactive ulceration), an algorithmic approach can be useful. Separated into reactive, infectious, and neoplastic, and then further divided based on common to rare, this logical progression through a series of differential considerations allows for many of these lesions to be correctly diagnosed. The reactive lesions include chronic rhinosinusitis and polyps, granulomatosis with polyangiitis, and eosinophilic angiocentric fibrosis. Infectious etiologies include acute invasive fungal rhinosinusitis, rhinoscleroma, and mycobacterial infections. The neoplastic category includes lobular capillary hemangioma, inflammatory myofibroblastic tumor, and NK/T-cell lymphoma, nasal type. Utilizing patterns of growth, dominant cell types, and additional histologic features, selected ancillary studies help to confirm the diagnosis, guiding further clinical management.
PubMed ID: 33723762
Article Size: 3 MB

Salivary Mucinous Adenocarcinoma Is a Histologically Diverse Single Entity With Recurrent AKT1 E17K Mutations: Clinicopathologic and Molecular Characterization With Proposal for a Unified Classification.

Head & Neck, Salivary Gland
Rooper LM, Argyris PP, Thompson LDR, Gagan J, Westra WH, Jordan RC, Koutlas IG, Bishop JA.
Am J Surg Pathol. 2021 Oct 1;45(10):1337-1347. doi: 10.1097/PAS.0000000000001688.
Mucin-producing salivary adenocarcinomas were historically divided into separate colloid carcinoma, papillary cystadenocarcinoma, and signet ring cell carcinoma diagnoses based on histologic pattern, but have recently been grouped together in the adenocarcinoma not otherwise specified category. It is currently unclear if these tumors represent 1 or more distinct entities and how they are related to well-circumscribed papillary mucinous lesions with recurrent AKT1 E17K mutations that were recently described as salivary intraductal papillary mucinous neoplasm. Here, we sought to evaluate the clinicopathologic and molecular features of salivary mucinous adenocarcinomas to clarify their classification. We identified 17 invasive mucin-producing salivary adenocarcinomas, 10 with a single histologic pattern, and 7 with mixed patterns. While most tumors demonstrated papillary growth (n=15), it was frequently intermixed with colloid (n=6) and signet ring (n=3) architecture with obvious transitions between patterns. All were cytokeratin 7 positive (100%) and cytokeratin 20 negative (0%). Next-generation sequencing performed on a subset demonstrated recurrent AKT1 E17K mutations in 8 cases (100%) and TP53 alterations in 7 cases (88%). Of 12 cases with clinical follow-up (median: 17 mo), 4 developed cervical lymph node metastases, all of which had colloid or signet ring components. Overall, overlapping histologic and immunohistochemical features coupled with recurrent AKT1 E17K mutations across patterns suggests that mucin-producing salivary adenocarcinomas represent a histologically diverse single entity that is closely related to tumors described as salivary intraductal papillary mucinous neoplasm. We propose a unified mucinous adenocarcinoma category subdivided into papillary, colloid, signet ring, and mixed subtypes to facilitate better recognition and classification of these tumors.
PubMed ID: 33739781
Article Size: 1 MB

Computerized tumor multinucleation index (MuNI) is prognostic in p16+ oropharyngeal carcinoma: A multi-site validation study.

Head & Neck, Oropharynx
Koyuncu CF, Lu C, Bera K, Zhang Z, Xu J, Andrea Toro Castaño P, Corredor G, Chute D, Fu P, Thorstad WL, Faraji F, Bishop JA, Mehrad M, Castro PD, Sikora AG, Thompson LDR, Chernock RD, Lang Kuhs KA, Luo J, Sandulache VC, Adelstein DJ, Koyfman S, Lewis JS Jr, Madabhushi A.
J Clin Invest. 2021 Apr 15;131(8):e145488. doi: 10.1172/JCI145488.
BACKGROUND: p16 positive oropharyngeal squamous cell carcinoma (OPSCC) patients are potentially cured with definitive treatment. However, there are currently no reliable biomarkers of treatment failure in p16 positive OPSCC. Pathologist-based visual assessment of tumor cell multinucleation has been shown to be independently prognostic of disease-free survival in p16 positive OPSCC. However, its quantification is time-intensive, subjective, and at risk of interobserver variability.
METHODS: We present a deep learning-based metric, the multi-nucleation index (MuNI), for prognostication in p16 positive OPSCC. This approach quantifies tumor multi-nucleation from digitally scanned hematoxylin eosin (H&E)-stained slides. Representative H&E whole slide images from 1,094 previously untreated p16 positive OPSCC patients were acquired from six institutions for optimizing and validating MuNI.
RESULTS: MuNI was prognostic for disease-free (DFS), overall (OS), or distant metastasis-free (DMFS) survival in p16 positive OPSCC with HRs of 1.78(95%CI:1.37-2.30), 1.94(1.44-2.60), and 1.88(1.43-2.47), respectively, independent of age, smoking status, treatment type, and T/N-categories in multivariable analyses. It was also prognostic for DFS, OS, and DMFS in OPSCC patients at stages I and III.
CONCLUSIONS: MuNI holds promise as a low-cost, tissue non-destructive, H&E stain based digital biomarker test for counseling, treatment, and surveillance of p16 positive OPSCC patients. These data support further confirmation of MuNI in prospective trials.
PubMed ID: 33651718
Article Size: 7.84 MB