Mucoepidermoid Carcinoma May Be Devoid of Squamoid Cells by Immunohistochemistry: Expanding the Histologic and Immunohistochemical Spectrum of MAML2- Rearranged Salivary Gland Tumors

Head & Neck, Salivary Gland
Bishop JA, Thompson LDR, Siegele B, Gagan J, Mansour M, Chernock RD, Rooper LM.
Histopathology. 2023 Jan;82(2):305-313. doi: 10.1111/his.14817.
Mucoepidermoid carcinoma (MEC) is historically defined by a mix of squamoid, intermediate, and mucous cells, but we have recently encountered several cases lacking immunoreactivity for squamous markers p40, p63, and CK5/6 despite MAML2 fusions. This study will characterise these unique tumours. Ten MEC were collected arising from the parotid gland (n = 4), submandibular gland (n = 2), nasopharynx (n = 1), base of tongue (n = 1), bronchus (n = 1), and trachea (n = 1). Six tumours were low-grade, two intermediate-grade, one high-grade, and one demonstrated low-grade areas with high-grade transformation. Four cases were oncocytic, four had clear-cell features, two had spindle cell features, and one high-grade MEC had prominent solid, cord-like, and micropapillary features. The tumours were negative for p40 (10/10), p63 (10/10), and CK5/6 (9/9). Targeted RNA sequencing demonstrated CRTC1::MAML2 in five cases, CRTC3::MAML2 in two, and a novel MAML2::CEP126 in the unusual high-grade case. In two cases with insufficient RNA, MAML2 fluorescence in situ hybridisation (FISH) showed rearrangement. Genetically-confirmed MEC may lack overt squamous differentiation by histology and immunohistochemistry. While most cases harboured canonical fusions and fit within the spectra of MEC variants with oncocytic, clear cell, and/or spindle cell features, one had a novel MAML2::CEP126 fusion and unusual morphology. In MEC without squamoid cells, the use of immunohistochemistry may hinder, rather than aid, the correct diagnosis. In such cases, MAML2 analysis is most useful. The historical definition of MEC as a carcinoma with squamoid, intermediate and mucous cells should be revisited.
PubMed ID: 36208053
Article Size: 2.7 MB

Comprehensive Molecular Profiling of Sinonasal Teratocarcinosarcoma Highlights Recurrent SMARCA4 Inactivation and CTNNB1 Mutations

Head & Neck, Sinonasal Tract
Rooper LM, Agaimy A, Gagan J, Simpson RHW, Thompson LDR, Trzcinska AM, Ud Din N, Bishop JA.
Am J Surg Pathol. 2023 Feb 1;47(2):224-233.
Sinonasal teratocarcinosarcoma (TCS) is a rare tumor defined by intermixed neuroepithelial, mesenchymal, and epithelial elements. While its etiology was historically ambiguous, we recently reported frequent SMARCA4 loss by immunohistochemistry, suggesting that TCS might be related to SMARCA4-deficient sinonasal carcinomas. However, other molecular alterations including CTNNB1 mutation have been reported in TCS, and its full genetic underpinnings are unclear. Here, we performed the first comprehensive molecular analysis of sinonasal TCS to better understand its pathogenesis and classification. We collected 30 TCS including 22 cases from our initial study. Immunohistochemical loss of SMARCA4 was seen in 22 cases (73%), with total loss in 18 cases (60%). β-catenin showed nuclear localization in 14 cases (64%) of the subset tested. We selected 17 TCS for next-generation sequencing with enrichment for partial or intact SMARCA4 immunoexpression. We identified inactivating SMARCA4 mutations in 11 cases (65%) and activating CTNNB1 mutations in 6 cases (35%), including 5 cases with both. Of 5 cases that lacked SMARCA4 or CTNNB1 mutation, 2 harbored other SWI/SNF complex and Wnt pathway alterations, including 1 with SMARCB1 inactivation and 1 with concomitant APC and ARID1A mutations, and 3 had other findings, including DICER1 hotspot mutation. These findings confirm that SMARCA4 inactivation is the dominant genetic event in sinonasal TCS with frequent simultaneous CTNNB1 mutations. They further underscore a possible relationship between TCS and sinonasal carcinomas with neuroendocrine/neuroectodermal differentiation. However, while SMARCA4 and β-catenin immunohistochemistry may help confirm a challenging diagnosis, TCS should not be regarded as a molecularly defined entity.
PubMed ID: 36206446
Article Size: 1.6 MB

Alterations in key signaling pathways in sinonasal tract melanoma. A molecular genetics and immunohistochemical study of 90 cases and comprehensive review of the literature.

Head & Neck, Sinonasal Tract
Chłopek M, Lasota J, Thompson LDR, Szczepaniak M, Kuźniacka A, Hińcza K, Kubicka K, Kaczorowski M, Newford N, Liu Y, Agaimy A, Biernat W, Durzyńska D, Dziuba I, Hartmann A, Inaguma S, Iżycka-Świeszewska E, Kato H, Kopczyński J, Michal M, Michal M, Pęksa R, Prochorec-Sobieszek M, Starzyńska A, Takahashi S, Wasąg B, Kowalik A, Miettinen M.
Mod Pathol. 2022 Nov;35(11):1609-1617.
Sinonasal mucosal melanoma is a rare tumor arising within the nasal cavity, paranasal sinuses, or nasopharynx (sinonasal tract). This study evaluated 90 cases diagnosed in 29 males and 61 females with median age 68 years. Most tumors involved the nasal cavity and had an epithelioid morphology. Spectrum of research techniques used in this analysis includes targeted-DNA and -RNA nextgeneration sequencing, Sanger sequencing, fluorescence in situ hybridization and immunohistochemistry. Sinonasal melanomas were commonly driven by RAS (38/90, 42%), especially NRAS (n = 36) mutations and rarely (4/90, 4%) displayed BRAF pathogenic variants. BRAF/RAS mutants were more frequent among paranasal sinuses (10/14, 71%) than nasal (26/64, 41%) tumors. BRAF/RASwild type tumors occasionally harbored alterations of the key components and regulators of Ras-MAPK signaling pathway: NF1 mutations (1/17, 6%) or NF1 locus deletions (1/25, 4%), SPRED1 (3/25, 12%), PIK3CA (3/50, 6%), PTEN (4/50, 8%) and mTOR (1/50, 2%) mutations. These mutations often occurred in a mutually exclusive manner. In several tumors some of which were NRAS mutants, TP53 was deleted (6/48, 13%) and/or mutated (5/90, 6%). Variable nuclear accumulation of TP53, mirrored by elevated nuclear MDM2 expression was seen in >50% of cases. Furthermore, sinonasal melanomas (n = 7) including RAS/BRAF-wild type tumors (n = 5) harbored alterations of the key components and regulators of canonical WNT-pathway: APC (4/90, 4%), CTNNB1 (3/90, 3%) and AMER1 (1/90, 1%). Both, TERT promoter mutations (5/53, 9%) and fusions (2/40, 5%) were identified. The latter occurred in BRAF/RAS-wild type tumors. No oncogenic fusion gene transcripts previously reported in cutaneous melanomas were detected. Eight tumors including 7 BRAF/RAS-wild type cases expressed ADCK4::NUMBL cis-fusion transcripts. In summary, this study documented mutational activation of NRAS and other key components and regulators of Ras-MAPK signaling pathway such as SPRED1 in a majority of sinonasal melanomas.
PubMed ID: 35978013
Article Size: 3.3 MB

GLI1-Altered Soft Tissue Tumors of the Head and Neck: Frequent Oropharyngeal Involvement, p16 Immunoreactivity, and Detectable Alterations by DDIT3 Break Apart FISH

Head & Neck, Oropharynx
Palsgrove DN, Rooper LM, Stevens TM, Shin C, Damm DD, Gagan J, Bridge JA, Thompson LDR, Koduru PR, Bishop JA.
Head Neck Pathol. 2022 Dec;16(4):1146-1156.
BACKGROUND: GLI1 is a transcription factor protein that has recently gained recognition in a morphologically distinct group of epithelioid soft tissue tumors characterized by GLI1 fusions or amplifications. The head and neck region, particularly the tongue, is a common location for GLI1-altered tumors. DDIT3 break apart fluorescence in situ hybridization (FISH), commonly used to identify translocations in myxoid/round cell liposarcoma, has been used as a surrogate test to detect both fusions and amplifications of the 12q13.3 region encompassing DDIT3 and GLI1 gene loci.
METHODS: We herein report 5 cases of GLI1-altered soft tissue tumors. Three arose in the oropharynx (base of tongue/vallecula, tonsil) and two arose in the tongue. Given the frequent oropharyngeal location and epithelioid morphology, p16 immunohistochemistry was performed on cases with available material. Commercially available DDIT3 break apart FISH, custom GLI1 specific FISH, and RNA sequencing were performed on select cases.
RESULTS: Two cases showed amplification using DDIT3 FISH which was confirmed using GLI1 specific FISH. The remaining cases harbored ACTB::GLI1, one of which showed rearrangement of the 12q13.3 region by DDIT3 FISH with absence of amplification by GLI1 specific FISH. STAT6 immunoexpression was positive in the GLI1-amplified cases and negative in the GLI1-rearranged cases while MDM2 expression was positive in the 4 cases tested. CDK4 expression was strong and diffuse in the GLI1-amplified cases. p16 immunohistochemistry showed strong nuclear and cytoplasmic staining in 50-70% of tumor cells in all four tested cases.
CONCLUSIONS: Here we show that GLI1-altered soft tissue tumors are frequently positive for p16 and can occur in tonsillar regions of the oropharynx. As such, positive p16 immunohistochemistry alone cannot be used as evidence for the diagnosis of HPV-related squamous cell carcinoma as strong and diffuse p16 expression may also occur in GLI1-altered soft tissue tumors. Commercially available DDIT3 break apart FISH, which is readily available in many cytogenetic laboratories, may be useful as a sensitive surrogate test for GLI1 fusions and amplifications.
PubMed ID: 35933574
Article Size: 4.8 MB

Retro-orbital alveolar soft-part sarcoma in a 76-year-old female: case report and review of the literature.

Head & Neck, Sinonasal Tract
Dermarkarian CR, Duckwiler G, Thompson LDR, Krantz KB, Feldman KA.
Can J Ophthalmol. 2022 Apr 23:S0008-4182(22)00114-4. doi: 10.1016/j.jcjo.2022.03.007.
Abstract not available. FIRST PARAGRAPH: Alveolar soft part sarcoma (ASPS) is a rare mesenchymal neoplasm that represents less than 1% of all sarcomas. Orbital ASPS is extremely rare, representing only 5%15%of all cases of ASPS.2 The average age at presentation of orbital ASPS is 13.517.8 years. A recent review of the literature suggests there are fewer than 70 documented cases of primary orbital ASPS.
PubMed ID: 35472298
Article Size: <1 MB

Radiotherapy for pediatric adrenocortical carcinoma – Review of the literature

Adrenal, Endocrine
Wiegering V, Riedmeier M, Thompson LDR, Virgone C, Redlich A, Kuhlen M, Gultekin M, Yalcin B, Decarolis B, Härtel C, Schlegel PG, Fassnacht M, Timmermann B.
BACKGROUND AND PURPOSE: Pediatric adrenocortical carcinoma (pACC) is a rare disease with poor prognosis. Publications on radiotherapy (RT) are scarce. This review summarizes the current data on RT for pACC and possibly provides first evidence to justify its use in this setting.
MATERIALS AND METHODS: We searched the PubMed and Embase database for manuscripts regarding RT for pACC.
RESULTS: We included 17 manuscripts reporting on 76 patients treated with RT, after screening 2961 references and 269 full articles. In addition, we added data of 4 unreported pACC patients treated by co-authors. All reports based on retrospective data. Median age at first diagnosis was 11.1 years (70% female); 78% of patients presented with hormonal activity. RT was mostly performed for curative intent (78%). 88% of RT were administered during primary therapy. The site of RT was predominantly the local tumor bed (76%). Doses of RT ranged from 15 to 62 Gy (median 50 Gy). Information on target volumes or fractionation were lacking. Median follow-up was 6,9 years and 64% of the patients died of disease, with 33% alive without disease. In 16 of 48 patients with available follow-up data after adjuvant RT (33%) no recurrence was reported and in 3 of 9 patients palliative RT seemed to induce some benefit for the patient.
CONCLUSIONS: Our first systematic review on RT for pACC provides too few data for any general recommendation, but adjuvant RT in patients with high risk might be considered. International collaborative studies are urgently needed to establish better evidence on the role of RT in this rare malignancy.
PubMed ID: 35601796
Article Size: <1 MB

Outcome for Neoadjuvant Treatment of Parotid Gland Adamantinoma-Like Ewing Sarcoma: Case Report and Review of Literatures

Head & Neck, Salivary Gland
Wei CH, Thompson LDR, Lee K, Chow W, Liang Y.
Int J Surg Pathol. 2022 Oct;30(7):776-783.
BACKGROUND: Adamantinoma-like Ewing sarcoma typically shows t(11;22) EWSR1::FLI1 translocation and complex epithelial differentiation. It poses a diagnostic challenge, especially in the head and neck region, due to its under-recognition and significant histologic overlap with other malignancies. Neoadjuvant and adjuvant treatment information on head and neck Adamantinoma-like Ewing sarcoma is limited.
CASE PRESENTATION: Herein, we report a case of a 78-year-old female with Adamantinoma-like Ewing sarcoma of the parotid gland, including the imaging findings and clinical response to neoadjuvant therapy followed by surgery. The efficacy of neoadjuvant therapy in the treatment of Adamantinoma-like Ewing sarcoma is discussed in the context of a review of pertinent literature.
CONCLUSION: Adamantinoma-like Ewing sarcoma in the head and neck is frequently misdiagnosed as poorly differentiated squamous cell carcinoma or a basaloid salivary gland carcinoma. Adamantinoma-like Ewing sarcoma is a EWS1::FLI1 translocation driven tumor; frequently misdiagnosed on head and neck biopsies as poorly differentiated carcinoma, or squamous cell carcinoma. Ewing sarcoma-specific chemoregimen appears effective for this entity. If diagnosed early, patient may be amenable to neoadjuvant therapy, which may improve surgical and cosmetic outcomes. This is especially important in head and neck regions.
PubMed ID: 35467446
Article Size: 1.9 MB

Sinonasal Tumors With Neuroepithelial Differentiation (Olfactory Carcinoma): Delineation of Their Pathologic and Clinical Features With Insights into Their Relationship to Olfactory Neuroblastoma and Sinonasal Carcinoma

Head & Neck, Sinonasal Tract
Rooper LM, Bishop JA, Faquin WC, Foss RD, Gallia GL, Jo VY, Lewis JS Jr, Nishino M, Stelow EB, Thompson LDR, Wenig BM, Westra WH.
Am J Surg Pathol 2022 Aug 1;46(8):1025-1035.
Olfactory carcinoma is one of many names applied to sinonasal malignancies with histologic similarity to olfactory neuroblastoma (ONB) but cytokeratin expression or gland formation. It is unclear whether these neuroepithelial tumors represent a unified category and if they are separate from ONB and currently-recognized sinonasal carcinomas. This study aims to explore their clinicopathologic characteristics based on a large collective experience. A total of 53 sinonasal tumors with neuroepithelial differentiation were identified affecting 41 men and 12 women, median age 47 years (range: 12 to 82 y). The vast majority arose in the superior nasal cavity and presented at the high Kadish-Morita stage. Frequent histologic findings included (1) lobulated and solid growth, (2) rosettes and/or neurofibrillary stroma, (3) high-grade cytology, (4) complex, often ciliated glands, (5) nonfocal pancytokeratin expression, (6) neuroendocrine pos+itivity, and (7) variable S100-positive sustentacular cells. Twelve patients with available follow-up (48%) developed progressive disease at a median 8 months (range: 0 to 114 mo to progression), and 7 (28%) died of disease. Despite disparate historical terminology, neuroepithelial differentiation is a recurrent and recognizable histologic pattern that is associated with aggressive behavior in sinonasal tumors. While tumors with this phenotype may originate from olfactory mucosa, well-developed epithelial features warrant separation from conventional ONB and neural elements distinguish them from most sinonasal carcinomas. Although their full histogenesis remains uncertain and some heterogeneity may exist, we propose that this pattern is sufficiently distinctive to merit separate recognition as olfactory carcinoma. Use of consistent nomenclature may facilitate greater recognition of tumors with this phenotype and understanding of their pathogenesis and classification.
PubMed ID: 35420559
Article Size: 1.8 MB

Low-grade non-intestinal-type sinonasal adenocarcinoma: a histologically distinctive but molecularly heterogeneous entity

Head & Neck, Sinonasal Tract
Rooper LM, Thompson LDR, Gagan J, Hwang JSG, London NR, Mikula MW, Stevens TM, Bishop JA.
Mod Pathol. 2022 Sep;35(9):1160-1167.
Although low-grade non-intestinal-type sinonasal adenocarcinoma (SNAC) is formally a diagnosis of exclusion defined by the absence of salivary or intestinal differentiation, most tumors in this category comprise a distinctive histologic group that are increasingly thought to derive from seromucinous glands. However, the molecular underpinnings of SNAC remain poorly understood, and it is unclear if diverse genetic alterations recently reported in isolated cases should delineate separate subgroups. This study aims to perform comprehensive evaluation of gene fusions and mutations and their histologic correlates in low-grade SNAC to clarify its pathogenesis and classification. We identified 18 non-intestinal-type SNAC that all displayed characteristic tubulopapillary architecture and low-grade cytology, although several cases had other unique histologic features and 3 showed intermixed high-grade areas. Among tumors stained with S100 protein, SOX10, and DOG1, 86% expressed at least one of these seromucinous markers. Of 17 cases with sufficient RNA or DNA available for analysis, likely oncogenic molecular alterations were identified in 76% of cases, most notably including CTNNB1 p.S33F mutations in 2 cases, concomitant BRAF p.V600E and AKT1 p.E17K mutations in 2 cases, and ETV6::NTRK3, PRKAR1A::MET, FN1::NRG1, and DNAJB1::PRKACA fusions in 1 case each. While tumors with most genetic alterations were histologically indistinguishable, cases with CTNNB1 mutations had intermixed squamoid morules and cases with BRAF and AKT1 mutations showed a myoepithelial cell population and prominent papillary to micropapillary architecture. Overall, these findings confirm previous reports of frequent seromucinous differentiation in low-grade SNAC. However, these tumors display striking molecular diversity with involvement of multiple kinase fusions, leading to frequent activation of signaling cascades including the MAPK pathway. While most genetic alterations are not associated with sufficiently distinctive histologic features to suggest separate classification, biphasic tumors with BRAF p.V600E mutations are more unique and may represent a distinctive subgroup.
PubMed ID: 35322195
Article Size: 6 MB

Update from the 5th 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, Bishop JA.
Head Neck Pathol. 2022 Mar;16(1):1-18. doi: 10.1007/s12105-021-01406-5.
The World Health Organization Classification of Head and Neck Tumours recently published the 5th edition. There are new entities, emerging entities, and significant updates to the taxonomy and characterization of tumor and tumor-like lesions, specifically in this article as it relates to nasal cavity, paranasal sinuses and skull base. Importantly, the number of diagnostic entries has been reduced by creating category-specific chapters for soft tissue, hematolymphoid, melanocytic, neuroectodermal, and metastatic tumors. Bone and salivary gland tumors are also not separately reported in the sinonasal tract, but included in the jaw and salivary gland sections, respectively. Repetition of characteristic entities in each anatomic site was also reduced, instead highlighting only the unique features in each anatomic site. Two new entities (SWI/SNF complex-deficient sinonasal carcinomas and HPV-related multiphenotypic sinonasal carcinoma) will be highlighted in this review, with a discussion of several emerging entities. There is a short description of updated information for all 24 diagnostic entities included in this edition to allow the reader a snapshot of current state of knowledge, but to encourage more investigation and further broaden understanding of these diverse and rare entities.
PubMed ID: 35312976
Article Size: 6.7 MB

Thyroid Follicular Cell-derived Carcinomas in a Background of Multiple Adenomatous Nodules Leading to a Diagnosis of PTEN Hamartoma Tumor Syndrome in an Adult Patient With a Novel RECQL4 Mutation

Endocrine, Thyroid
Liu A, Borges PM, Tay YS, Thompson LDR, Kong MX, Lai J.
Anticancer Res. 2022 Mar;42(3):1481-1485. doi: 10.21873/anticanres.15619.
BACKGROUND: Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a complex disorder. Carriers develop hamartomatous tumors, with an increased risk for developing malignant tumors in multiple organs. Surveillance to facilitate the early detection and treatment of malignancies is extremely important.
CASE REPORT: A 31-year-old male presented with a 10 cm left lobe thyroid gland mass. After fine needle aspiration a left hemithyroidectomy was performed, which demonstrated a minimally invasive follicular thyroid carcinoma (FTC, stage pT3a) and microscopic classical papillary thyroid carcinoma (PTC) in the background of about 50 separate adenomatous nodules (0.2-5 mm). Immunostaining showed loss of PTEN protein in the minimally invasive FTC and in all of the nodules tested, with uninvolved parenchyma serving as an internal control. Kaiser Permanente Northern California (KPNC) Hereditary Cancer Panel, testing for 62 genes, was performed and showed germline mutations in PTEN and RecQ like helicase 4 (RECQL4) genes. Completion thyroidectomy subsequently performed demonstrated about 60 follicular cell-derived adenomatous nodules (0.3-10 mm). Genetic counseling and evaluation documented Cowden syndrome (CS) in the family. Thus, PHTS was confirmed.
CONCLUSION: This report documents synchronous FTC and PTC in a background of multiple follicular adenomatous nodules with a novel RECQL4 mutation in an adult patient with PHTS. As such, documented the loss of PTEN protein in a thyroid gland affected by multiple adenomatous nodules aided in diagnosing PHTS.
PubMed ID: 35220242
Article Size: 1.6 MB

Frankly Invasive Carcinoma Ex-intraductal Carcinoma: Expanding on an Emerging and Perplexing Concept in Salivary Gland Tumor Pathology

Head & Neck, Salivary Gland
McLean-Holden AC, Rooper LM, Lubin DJ, Magliocca KR, Manucha V, Sadow PM, Tobias J, Vargo RJ, Thompson LDR, Heidarian A, Weinreb I, Wenig B, Gagan J, Hernandez-Prera JC, Bishop JA.
Head Neck Pathol. 2022 Sep;16(3):657-669.
Intraductal carcinoma (IDC) of the salivary glands is an uncommon and enigmatic tumor, our understanding of which is rapidly evolving. Recent studies have demonstrated multiple IDC subtypes and consistent gene fusions, most frequently involving RET. Because IDC is a ductal proliferation surrounded by flattened myoepithelial cells, it was previously presumed to be analogous to breast ductal carcinoma in situ, but recent evidence has shown that the myoepithelial cells of fusion-positive IDC harbor the same genetic alterations of the ductal cells and are therefore neoplastic. In addition, there are rare reports of fusion-positive IDC with overt areas of irregular invasion lacking myoepithelial cells, but this phenomenon is not well documented or understood. This study aims to better characterize these frankly invasive carcinoma ex-IDC. All cases of frankly invasive carcinoma ex-IDC were obtained from the authors’ files. Inclusion criteria included a component of concurrent or antecedent IDC and/or a fusion known to be associated with IDC. Immunohistochemistry (S100, SOX10, mammaglobin, androgen receptor, p63, p40) and molecular analysis (targeted RNA sequencing or large panel DNA next generation sequencing) was performed. Clinical follow-up was obtained from medical records. Ten cases of frankly invasive carcinoma ex-IDC were identified. The tumors occurred in 8 men and 2 women ranging from 33 to 82 years (mean, 66.3). All but one case arose in the parotid gland. In 4 cases, the IDC component was intercalated duct type. It was mixed apocrine/intercalated duct in two, and in the remaining 4 cases, no residual IDC was identified. The frankly invasive carcinomas were remarkably heterogeneous, ranging from minimally to widely invasive beyond the confines of the IDC, low-grade to high-grade, with morphologies that varied from duct-forming to those having clear cell or sarcomatoid features, to frankly apocrine. The original diagnoses for these cases were (adeno) carcinoma, not otherwise specified (n = 6), salivary duct carcinoma (n = 3), and secretory carcinoma (n = 1). All cases harbored fusions: NCOA4::RET (n = 6), TRIM33::RET (n = 2), TRIM27::RET (n = 1), and STRN::ALK (n = 1). Clinically, one tumor recurred locally, cervical lymph node metastases occurred in five patients, and distant metastasis later developed in four of these patients. Our findings highlight striking diversity in frankly invasive carcinomas that arise from fusion-positive IDC, a tumor which may serve as a precursor neoplasm like pleomorphic adenoma. These carcinomas vary in their extent of invasion, grade, histologic appearances, and clinical behavior. Importantly, in contrast to pure IDC, which is believed to be indolent, many frankly invasive cases were aggressive. Because RET and ALK fusions are targetable, it is important to recognize the broad spectrum of frankly invasive carcinomas that can arise from IDC, particularly because some cases are completely overrun or recur without any recognizable IDC component. These results suggest fusion analysis may be of clinical benefit on any salivary gland (adeno) carcinoma, not otherwise specified or salivary duct carcinoma.
PubMed ID: 34985683
Article Size: 5 MB

An Imaging Biomarker of Tumor-Infiltrating Lymphocytes to Risk-Stratify Patients with HPV-Associated Oropharyngeal Cancer

Head & Neck, Oral Cavity/Gnathic (Jaw)
Corredor G, Toro P, Koyuncu C, Lu C, Buzzy C, Bera K, Fu P, Mehrad M, Ely KA, Mokhtari M, Yang K, Chute D, Adelstein DJ, Thompson LDR, Bishop JA, Faraji F, Thorstad W, Castro P, Sandulache V, Koyfman SA, Lewis JS, Madabhushi A.
J Natl Cancer Inst. 2022 Apr 11;114(4):609-617. doi: 10.1093/jnci/djab215.
BACKGROUND: HPV-associated oropharyngeal squamous cell carcinoma (OPCSCC) has excellent control rates compared to non-virally associated OPSCC. Multiple trials are actively testing whether de-escalation of treatment intensity for these patients can maintain oncologic equipoise while reducing treatment related toxicity. We have developed OP-TIL, a biomarker that characterizes the spatial interplay between tumor-infiltrating lymphocytes (TILs) and surrounding cells in histology images. Herein, we sought to test whether OP-TIL can segregate stage I HPV-associated OPSCC patients into low-risk and high-risk groups and aid in patient selection for de-escalation clinical trials.
METHODS: Association between OP-TIL and patient outcome was explored on whole slide H&E images from 439 stage I HPV-associated OPSCC patients across six institutional cohorts. One institutional cohort (n = 94) was used to identify the most prognostic features and train a Cox regression model to predict risk of recurrence and death. Survival analysis was used to validate the algorithm as a biomarker of recurrence/death in the remaining five cohorts (n = 345). All statistical tests were 2-sided.
RESULTS: OP-TIL separated stage I HPV-associated OPSCC patients with ≤30 pack-year smoking history into low-risk (2-year disease-free survival [DFS] = 94.2%; 5-year DFS= 88.4%) and high-risk (2-year DFS = 82.5%; 5-year DFS = 74.2%) groups (hazard ratio = 2.56, 95% confidence interval = 1.52-4.32, P < .001), even after adjusting for age, smoking status, T and N-classification, and treatment modality on multivariate analysis for DFS (hazard ratio = 2.27, 95% confidence interval = 1.32-3.94, P = .003).
CONCLUSIONS: OP-TIL can identify stage I HPV-associated OPSCC patients likely to be poor candidates for treatment de-escalation. Following validation on previously completed multi-institutional clinical trials, OP-TIL has the potential to be a biomarker, beyond clinical stage and HPV status, that can be used clinically to optimize patient selection for de-escalation.
PubMed ID: 34850048
Article Size: 1.9 MB

Machine learning methods for automated classification of tumors with papillary thyroid carcinoma-like nuclei: A quantitative analysis

Endocrine, Thyroid
Böhland M, Tharun L, Scherr T, Mikut R, Hagenmeyer V, Thompson LDR, Perner S, Reischl M.
PLoS One. 2021 Sep 22;16(9):e0257635. doi: 10.1371/journal.pone.0257635. eCollection 2021.
When approaching thyroid gland tumor classification, the differentiation between samples with and without “papillary thyroid carcinoma-like” nuclei is a daunting task with high inter-observer variability among pathologists. Thus, there is increasing interest in the use of machine learning approaches to provide pathologists real-time decision support. In this paper, we optimize and quantitatively compare two automated machine learning methods for thyroid gland tumor classification on two datasets to assist pathologists in decision-making regarding these methods and their parameters. The first method is a feature-based classification originating from common image processing and consists of cell nucleus segmentation, feature extraction, and subsequent thyroid gland tumor classification utilizing different classifiers. The second method is a deep learning-based classification which directly classifies the input images with a convolutional neural network without the need for cell nucleus segmentation. On the Tharun and Thompson dataset, the feature-based classification achieves an accuracy of 89.7% (Cohen’s Kappa 0.79), compared to the deep learning-based classification of 89.1% (Cohen’s Kappa 0.78). On the Nikiforov dataset, the feature-based classification achieves an accuracy of 83.5% (Cohen’s Kappa 0.46) compared to the deep learning-based classification 77.4% (Cohen’s Kappa 0.35). Thus, both automated thyroid tumor classification methods can reach the classification level of an expert pathologist. To our knowledge, this is the first study comparing feature-based and deep learning-based classification regarding their ability to classify samples with and without papillary thyroid carcinoma-like nuclei on two large-scale datasets.
PubMed ID: 34550999
Article Size: 3.14 MB

Unexpected Reason for Non-healing Oral Ulcers: Syphilis

Head & Neck, Oral Cavity/Gnathic (Jaw)
Deng F, Thompson LDR, Lai J.
Head Neck Pathol 2022 Jun;16(2):544-549. doi: 10.1007/s12105-021-01348-y.
Syphilis is a sexually transmitted infectious disease caused by Treponema pallidum and characterized by a complex and variable clinical presentation. Cases of unexpected oral syphilis presenting as non-healing ulcers are uncommonly reported. We report 3 cases (one female and two males, aged 35, 35, and 56 years, respectively) in which patients presented with non-healing oral ulcers. Biopsies revealed surface ulceration and a significant neutrophilic infiltrate rather than the more conventional plasma cell infiltrate seen with most reported syphilis infections, potentially leading to an inaccurate diagnosis. Treponema pallidum immunohistochemistry highlighted spirochetes within the epithelium, with additional diagnostic confirmation by serum T. pallidum particle agglutination assay. Sexual history documentation by the clinician with nonspecific oral ulcers is paramount to aiding diagnosis and leading to proper management. Further, it is important to perform immunohistochemistry for T. pallidum in oral biopsies from non-healing ulcers, especially when clinical history raises the differential diagnosis or when other clinical manifestations may support this consideration.
PubMed ID: 34342809
Article Size: 2 MB

Sporadic Neurofibroma of the Tongue Unassociated with Neurofibromatosis Type I: A Clinicopathologic Study of Ten Cases.

Head & Neck, Oral Cavity/Gnathic (Jaw)
Thompson LDR, Koh SS, Lau SK.
2020 Jun;14(2):374-380. doi: 10.1007/s12105-019-01041-1. Epub 2019 May 20.
Neurofibromas rarely occur within the oral cavity and infrequently involve the tongue. The majority of lingual neurofibromas arise in patients affected by neurofibromatosis type 1 (NF1). Neurofibromas of the tongue unassociated with this disorder are exceedingly uncommon. The clinical and pathologic features of 10 cases of sporadic lingual neurofibromas, unassociated with NF1, were evaluated. The patients included six females and four males ranging in age from 30 to 69 years (mean 59 years; median 63 years). An asymptomatic or slowly enlarging lingual mass was the most common clinical presentation. None of the patients were documented to have NF1. Histologically, the tumors were unencapsulated and situated beneath an intact squamous mucosa. The tumors are comprised of spindle cells with wavy nuclei within a collagenous to myxoid stroma. One tumor was characterized by a plexiform growth pattern. The lesional cells were positive for S-100 protein. Clinical follow up, available for all patients, showed no recurrences and no subsequent development of additional clinical manifestations of NF1. Lingual neurofibromas should be distinguished from other peripheral nerve sheath tumors that can affect this anatomic site. This series of cases confirms that sporadic neurofibromas of the tongue may be rarely encountered in patients having no other features of NF1.
PubMed ID: 31111316
Article Size: 2.7 MB

Ossifying Fibroma of Non-odontogenic Origin: A Fibro-osseous Lesion in the Craniofacial Skeleton to be (Re-)considered

Head & Neck, Sinonasal Tract
Baumhoer D, Haefliger S, Ameline B, Hartmann W, Amary F, Cleven A, Klein MJ, Thompson LDR, Harder D, O’Donnell P.
Head Neck Pathol. 2022 Mar;16(1):257-267. doi: 10.1007/s12105-021-01351-3.
In the cranio-facial skeleton, a heterogeneous group of well characterized fibro-osseous lesions can be distinguished. Whereas fibrous dysplasia can affect any skeletal bone, ossifying fibroma and cemento-osseous dysplasia exclusively develop in the cranio-facial region, with most subtypes restricted to the tooth bearing areas of the jaws. Herein we present a series of 20 fibro-osseous lesions that developed mostly in the frontal bone and in the mandible, presenting as expansile intramedullary tumors with a unique histologic appearance and an indolent clinical course. We provide evidence that these tumors are distinct from the categories included in the WHO classification and are therefore currently unclassifiable. The definition of cemento-ossifying fibroma as an odontogenic neoplasm developing only in close proximity to teeth should be re-considered and incorporate also extragnathic lesions as shown here.
PubMed ID: 34173971
Article Size: 3.2 MB

Data set for reporting of carcinoma of the adrenal cortex: Explanations and recommendations of the guidelines from the International Collaboration on Cancer Reporting (ICCR)

Adrenal, Endocrine
Giordano TJ, Berney D, de Krijger RR, Erickson L, Fassnacht M, Mete O, Papathomas T, Papotti M, Sasano H, Thompson LDR, Volante M, Gill AJ.
Hum Pathol. 2021 Apr;110:50-61. doi: 10.1016/j.humpath.2020.10.001. Epub 2020 Oct 12.
Complete resection of adrenal cortical carcinoma (ACC) with or without adjuvant therapy offers the best outcome. Recurrence is common and in individual cases the long term outcome is difficult to predict, making it challenging to personalize treatment options. Current risk stratification approaches are based on clinical and conventional surgical pathology assessment. Rigorous and uniform pathological assessment may improve care for individual patients and facilitate multi-institutional collaborative studies. The International Collaboration on Cancer Reporting (ICCR) convened an expert panel to review ACC pathology reporting. Consensus recommendations were made based on the most recent literature and expert opinion. The data set comprises 23 core (required) items. The core pathological features include: diagnosis according to the current World Health Organization (WHO) classification, specimen integrity, greatest dimension, weight, extent of invasion, architecture, percentage of lipid rich cells, capsular invasion, lymphatic invasion, vascular invasion, atypical mitotic figures, coagulative necrosis, nuclear grade, mitotic count, Ki-67 proliferative index, margin status, lymph node status and pathological stage. Tumors were dichotomized into low grade (<20 mitoses per 10 mm2) and high grade (>20 mitoses per 10 mm2). Additional noncore elements that may be useful in individual cases included several multifactorial risk assessment systems (Weiss, modified Weiss, Lin-Weiss-Bisceglia, reticulin, Helsinki, and AFIP scores/algorithms). This data set is now available through the ICCR website with the hope of better standardizing pathological assessment of these relatively rare but important malignancies.
PubMed ID: 33058949
Article Size: 5.4 MB

Epstein-Barr Virus-Associated Smooth Muscle Tumors of Larynx: A Clinicopathologic Study and Comprehensive Literature Review of 12 Cases

Head & Neck, Larynx
Whaley RD, Thompson LDR.
Head Neck Pathol. 2021 Dec;15(4):1162-1171.
Laryngeal mesenchymal neoplasms are rare, with smooth muscle tumors comprising a small subset. Specifically, Epstein-Barr virus (EBV)-associated smooth muscle tumors are exceptionally rare, lacking a comprehensive evaluation of their clinical and histologic features. Two patients (a 59 year old male and 51 year old female) had received renal transplants 156 and 240 months, respectively prior to onset of laryngeal symptoms. Supraglottic polypoid masses were identified and removed conservatively. Histologically, the tumors were hypercellular, showing alternating light and dark areas, the latter composed of primitive appearing round cells, while a more characteristic spindled tumor cell population was noted in the remaining areas. Cytoplasmic vacuoles were noted adjacent to the nucleus. There was no tumor necrosis or pleomorphism, but increased mitotic figures (11-12/2 mm2) were seen, without atypical forms. The tumor cells were strongly immunoreactive with smooth muscle actin and smooth muscle myosin heavy chain and with Epstein-Barr virus encoded RNA (EBER) by in situ hybridization. These patients were reviewed in the context of a thorough English literature review, which demonstrates a wide age range at presentation without a sex predilection, but with most patients from specific ethnic groups (Chinese, Thai, Pilipino). Three-quarters of patients are part of multifocal disease and the majority are post-renal transplantation patients. Conservative management seems to yield the best overall outcome for these indolent tumors. In conclusion, EBV-associated smooth muscle tumors should be considered in any immunocompromised patient with a head and neck smooth muscle tumor, especially when EBER is documented by in situ hybridization. Conservative management may be employed, even when multifocal tumors are documented.
PubMed ID: 33891274
Article Size: 3 MB

Clinicopathologic and Genomic Characterization of Inflammatory Myofibroblastic Tumors of the Head and Neck: Highlighting a Novel Fusion and Potential Diagnostic Pitfall

Head & Neck, Larynx
Kerr DA, Thompson LDR, Tafe LJ, Jo VY, Neyaz A, Divakar P, Paydarfar JA, Pastel DA, Shirai K, John I, Seethala RR, Salgado CM, Deshpande V, Bridge JA, Kashofer K, Brčić I, Linos K.
Am J Surg Pathol. 2021 Dec 1;45(12):1707-1719.
Inflammatory myofibroblastic tumor (IMT) is a distinctive fibroblastic and myofibroblastic spindle cell neoplasm with an accompanying inflammatory cell infiltrate and frequent receptor tyrosine kinase activation at the molecular level. The tumor may recur and rarely metastasizes. IMT is rare in the head and neck region, and limited information is available about its clinicopathologic and molecular characteristics in these subsites. Therefore, we analyzed a cohort of head and neck IMTs through a multi-institutional approach. Fourteen cases were included in the provisional cohort, but 1 was excluded after molecular analysis prompted reclassification. Patients in the final cohort included 7 males and 6 females, with a mean age of 26.5 years. Tumors were located in the larynx (n=7), oral cavity (n=3), pharynx (n=2), and mastoid (n=1). Histologically, all tumors showed neoplastic spindle cells in storiform to fascicular patterns with associated chronic inflammation, but the morphologic spectrum was wide, as is characteristic of IMT in other sites. An underlying fusion gene event was identified in 92% (n=11/12) of cases and an additional case was ALK-positive by IHC but could not be evaluated molecularly. ALK represented the driver in all but 1 case. Rearrangement of ALK, fused with the TIMP3 gene (n=6) was most commonly detected, followed by 1 case each of the following fusion gene partnerships: TPM3-ALK, KIF5B-ALK, CARS-ALK, THBS1-ALK, and a novel alteration, SLC12A2-ROS1. The excluded case was reclassified as spindle cell rhabdomyosarcoma after detection of a FUS-TFCP2 rearrangement and retrospective immunohistochemical confirmation of rhabdomyoblastic differentiation, illustrating an important diagnostic pitfall. Two IMT patients received targeted therapy with crizotinib, with a demonstrated radiographic response. One tumor recurred but none metastasized. These results add to the growing body of evidence that kinase fusions can be identified in the majority of IMTs and that molecular analysis can lead to increased diagnostic accuracy and broadened therapeutic options for patients.
PubMed ID: 34001695
Article Size: <1 MB

Middle Ear and Temporal Bone Papilloma: A Clinicopathologic Study and Comprehensive Literature Review of 57 Cases

Ear & Temporal Bone, Head & Neck
Thompson LDR.
Head Neck Pathol. 2021 Dec;15(4):1212-1220.
Sinonasal papilloma (SP), formerly Schneiderian papilloma, represents a rare group of benign epithelial neoplasms, most commonly identified in the sinonasal tract, while less frequently identified in the pharynx, lacrimal sac, and middle ear. Within temporal bone sinonasal-type papilloma (TBSP), there seems to be a much higher recurrence and malignant transformation risk than those identified in the sinonasal tract. Based on this clinical report and a review of the cases reported in the English literature, 49% of the 57 cases developed in the setting of concurrent or antecedent sinonasal or nasopharyngeal SP. There is an equal sex distribution (26 females and 31 males), with a broad age range (19-81 years) at presentation (median 56 years; average 54 years). Three patients had bilateral disease. Symptoms include a mass lesion with hearing loss, otitis media, otorrhea, otalgia, and tinnitus, among others. Inverted SP was identified in 42 patients, oncocytic SP in six, and exophytic SP in four (undefined in the remainder). Recurrence was identified in 38 of 49 patients with follow-up (78%), often with multiple recurrences over time, with carcinoma developing in the temporal bone in 19 patients (33%), with males developing carcinoma by a 1.7:1 ratio over females. Surgery was the treatment of choice (radical mastoidectomy) with 6 patients (10%) dead of disease (median 30 months, mean 38 months), while 47 patients were alive at last follow-up: 31 without disease (mean 33 months); 7 with locally recurrent disease (mean 20 months); 9 patients alive but with unknown disease status; and 4 patients without follow-up. In conclusion, TBSP is frequently identified in the setting of concurrent sinonasal tract disease, showing similar histologic features to sinonasal tract counterparts. There is no sex predilection, with patients most commonly presenting in the sixth decade of life. Recurrences are common, with carcinoma developing much more frequently than in sinonasal tract papilloma (33%), but recognizing that carcinoma may be documented in either or both anatomic sites. Overall outcome is excellent, with long term clinical follow-up warranted to manage recurrence or malignant transformation.
PubMed ID: 34021464
Article Size: 1.2 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

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

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

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

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

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

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

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

Frozen section in thyroid gland follicular neoplasms: It’s high time to abandon it!

Endocrine, Thyroid
Sanabria A, Zafereo M, Thompson LDR, Hernandez-Prera JC, Kowalski LP, Nixon IJ, Shaha A, Rodrigo JP, Mäkitie A, Vander Poorten V, Suarez C, Zbären P, Rinaldo A, Ferlito A
Surg Oncol. 2021 Mar;36:76-81. doi: 10.1016/j.suronc.2020.12.005. Epub 2020 Dec 8.
Thyroid nodules are a very common clinical condition. The 2015 American Thyroid Association (ATA) guidelines recommend surgical excision for Bethesda IV nodules. The use of intraoperative frozen section (FS) has been recommended as a strategy to tailor the extent of the initial surgery. We critically evaluated the literature that discusses the utility and cost-effectiveness of FS to make an intraoperative decision in patients with thyroid nodules classified as follicular neoplasm. FS should not be recommended as a routine intraoperative test to assess for malignancy in thyroid follicular patterned lesions due to its low performance; the high number of deferred results; the inability to adequately assess histologically defining features; the improvements in risk stratification guiding total thyroidectomy; and the low cost-effectiveness of FS.
PubMed ID: 33316682
Article Size: 4.5 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

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

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

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

Is thyroid core needle biopsy a valid compliment to fine-needle aspiration?

Endocrine, Thyroid
Pantanowitz L, Thompson LDR, Jing X, Rossi ED.
J Am Soc Cytopathol. Sep-Oct 2020;9(5):383-388. doi: 10.1016/j.jasc.2020.06.003. Epub 2020 Jun 18.
Fine-needle aspiration (FNA) has long been considered the first and an important diagnostic tool in the evaluation of thyroid nodules. The advantages of FNA include simplicity, safety, cost-effectiveness, high diagnostic accuracy, and low complication rate. Nevertheless, limitations associated with FNA include a substantial rate of inconclusive results and indeterminate interpretations. Therefore, core needle biopsy (CNB) of the thyroid gland has been proposed as a complementary or even alternate diagnostic method to evaluate thyroid nodules. Although controversial, a growing number of researchers have reported CNB to be an effective and safe sampling method for thyroid nodules, especially for cases with inadequate or indeterminate FNA yields. Skeptics highlight local pain and bleeding risk. Supporters highlight the potential likelihood of overcoming FNA limitations by obtaining a larger amount of tissue and using architecture and cellular details to guide possible ancillary testing. This review evaluates the indications, advantages, and disadvantages of CNB as compared with FNA of the thyroid gland.
PubMed ID: 32665216
Article Size: 1 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

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

Salivary Gland Pathology: SC and PAC

Thyroid

This 60-minute presentation covers two topics: Secretory carcinoma and Acinic cell carcinoma and how to separate between them; and polymorphous adenocarcinoma: PLGA and Cribriform carcinoma. Produced originally during COVID-19 pandemic when residents were not able to obtain their usual education.
TIP: For sharpest focus, you may need to change YouTube’s default quality settings from Auto to 1080p60. Once you start the video, click the Settings cog icon near the lower right corner of video frame, select Quality and change Auto to 1080p. You should also click the Full Screen icon at the far right.

 

Fungal Prostatitis Due to Endemic Mycoses and Cryptococcus: A Multicenter Case Series

Other Anatomic Sites, Prostate
Epstein DJ, Thompson LDR, Saleem A, Kao CS, Epstein JI.
Prostate. 2020 Jun 22. doi: 10.1002/pros.24034. Online ahead of print.
BACKGROUND: Fungal prostatitis is exceedingly rare with mostly case reports.
METHODS: Electronic medical records at three medical centers were searched for cases of fungal prostatitis due to endemic mycoses and Cryptococcus over the preceding 10 years.
RESULTS: Seven cases were identified from 105 600 prostate biopsies within the Southern California Permanente Medical Group for an incidence of 0.0066%. An additional eight cases were identified from two other health care systems. Excluding four patients without available clinical data, 11 patients were reviewed, most of whom underwent biopsy due to elevated prostate-specific antigen. Four were asymptomatic and the remainder had nonspecific signs or symptoms. All biopsies revealed granulomatous inflammation and fungal organisms. Seven patients had coccidioidomycosis, three patients had cryptococcosis (confirmed in two cases and suspected by organism morphology in the other), and one patient had likely histoplasmosis based on organism morphology. Prolonged antifungal treatment was standard; outcomes were favorable.
CONCLUSION: Fungal prostatitis due to endemic mycoses and Cryptococcus is uncommon and associated with favorable outcomes but generally involves prolonged therapy.
PubMed ID: 32572997
Article Size: 1.6 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

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

Malignant teratomas of the thyroid gland: clinico-radiologic and cytomorphologic features of a rare entity.

Endocrine, Thyroid
Miller DL, Thompson LDR, Bishop JA, Rooper LM, Ali SZ.
J Am Soc Cytopathol. Jul-Aug 2020;9(4):221-231. doi: 10.1016/j.jasc.2020.04.008. Epub 2020 Apr 28.
INTRODUCTION: Primary thyroid gland malignant teratomas are extremely rare and can pose diagnostic challenges on fine needle aspiration (FNA) due to their cytomorphologic heterogeneity. Recent next generation sequencing studies have identified recurrent DICER1 hotspot mutations in these tumors, suggesting that malignant teratomas of the thyroid should be considered a distinct pathological entity. Herein, we review the clinico-radiologic and FNA findings in a series of DICER1 mutated malignant teratomas.
METHODS: We performed a retrospective case review of 9 FNAs from 5 patients with a histologically confirmed malignant teratoma of the thyroid gland from 2 large tertiary care pathology practices.
RESULTS: The patients included 4 females and 1 male, with an average age of 43 years (22-65 years). The nodules were centered within the thyroid gland and ranged from 1.7 to 10 cm in diameter. FNAs of primary thyroid teratomas demonstrate marked cellularity, epithelial proliferations, an absence of colloid, and a predominance of immature spindled cells, representing the mesenchymal and neural ectodermal components of these tumors. The FNA interpretations ranged from atypia of undetermined significance to overtly malignant. Three patients died of their disease and 2 are alive with no evidence of disease.
CONCLUSIONS: Malignant thyroid teratoma is a rare entity with cytomorphologic overlap with other highgrade neoplasms of the thyroid. Recent molecular studies have defined recurrent DICER1 mutations in malignant thyroid teratomas and propose these as a distinct clinicopathological entity. The features described here may be helpful in providing a correct prospective interpretation.
PubMed ID: 32448730
Article Size: 3.7 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

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

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

Recurrent DICER1 Hotspot Mutations in Malignant Thyroid Gland Teratomas: Molecular Characterization and Proposal for a Separate Classification.

Endocrine, Thyroid
Rooper LM, Bynum JP, Miller KP, Lin MT, Gagan J, Thompson LDR, Bishop JA.
Am J Surg Pathol. 2020 Jun;44(6):826-833. doi: 10.1097/PAS.0000000000001430.
Thyroid gland teratomas are rare tumors that span a wide clinicopathologic spectrum. Although benign and immature teratomas arise in infants and young children and generally have good outcomes, malignant teratomas affect adults and follow an aggressive course. This divergent behavior raises the possibility that benign/immature and malignant teratomas are separate entities rather than different grades of a single tumor. However, the histogenesis and molecular underpinnings of thyroid gland teratomas are poorly understood regardless of grade. In this study, we performed next-generation sequencing on 8 thyroid gland teratomas, including 4 malignant, 3 benign, and 1 immature. We identified DICER1 hotspot mutations in all 4 malignant cases (100%) but not in any benign/immature cases (0%). No clinically significant mutations in other genes were found in either group. We also performed immunohistochemistry to characterize the primitive components of malignant teratomas. Not only did all cases consistently contain immature neural elements (synaptophysin and INSM1 positive), but also spindled cells with rhabdomyoblastic differentiation (desmin and myogenin positive) and bland epithelial proliferations of thyroid follicular origin (TTF-1 and PAX8 positive). Although DICER1 mutations have previously been implicated in multinodular hyperplasia and well-differentiated thyroid carcinomas, these findings demonstrate the first recurrent role for DICER1 in primitive thyroid tumors. The combined neural, rhabdomyoblastic, and homologous epithelial elements highlighted in this series of malignant thyroid gland teratomas parallel the components of DICER1-mutated tumors in other organs. Overall, these molecular findings further expand the differences between benign/immature teratomas and malignant teratomas, supporting the classification of these tumors as separate entities.
PubMed ID: 31917706
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