Micrometastasis and Isolated Tumor Cells in Oral Squamous Cell Carcinoma: Refining Nodal Staging with Emerging Technologies

Head & Neck, Neck, Oral Cavity/Gnathic (Jaw)
Mp S, Rao KN, Thompson LDR, Rodrigo JP, de Bree R, Stenman G, Schilling C, Rinaldo A, Robbins KT, Nadal A, Agaimy A, Simpson RHW, Ferlito A.
Head Neck Pathol. 2025 Sep 2;19(1):106. doi: 10.1007/s12105-025-01839-2.
PURPOSE: Cervical lymph node metastasis significantly influence prognosis in oral squamous cell carcinoma (OSCC), guiding staging, treatment decisions, and overall survival. Sentinel lymph node biopsy (SLNB) offers a minimally invasive approach for early detection of subclinical nodal metastasis, including micrometastases (0.2–2 mm) and isolated tumor cells (ITCs, < 0.2 mm). Despite its success in melanoma and breast cancer, the clinical relevance of micrometastases and ITCs in OSCC remains incompletely defined. This narrative review explores the biological significance, diagnostic challenges, and emerging strategies for detecting micrometastasis and ITCs in OSCC, aiming to inform their potential role in refining staging systems and treatment algorithms.
METHODS: We performed a comprehensive literature review of SLNB in OSCC, examining data on histopathological detection techniques, molecular markers, artificial intelligence (AI), and radiomics-based tools that enhance diagnostic sensitivity and specificity for occult metastases. Results While current guidelines in some countries endorse SLNB for early-stage OSCC, integration of micrometastasis and ITC data into staging remains inconsistent. Studies suggest that ITCs represent early metastatic events with variable prognostic significance. Advanced techniques such as step-serial sectioning, immunohistochemistry, and molecular diagnostics—including ctDNA, gene-expression profiling, and AI-assisted pathology—have shown promise in improving detection accuracy. However, robust prospective data are lacking, and a consensus on the management of minimal nodal disease is yet to be reached.
CONCLUSION: Accurate identification and interpretation of micrometastasis and ITCs in OSCC represent an evolving frontier in head and neck oncology. Future staging systems should incorporate these elements supported by standardized protocols and high-level evidence. The integration of AI, molecular diagnostics, and radiomics holds the potential to enhance risk stratification and personalize surgical decision-making, reducing overtreatment while ensuring oncologic safety.
PubMed ID: 40892342
Article Size: 1.7 MB

AFIP Atlas: Tumors of the Upper Aerodigestive Tract, Ear, and Jaw (5th Series, Vol. 22)

Books
AFIP Atlas: Tumors of the Upper Aerodigestive Tract, Ear, and Jaw

Justin A. Bishop, MD • William C. Faquin, MD, PhD • James S. Lewis, Jr., MD • Susan Müller, DMD, MS • Lester D.R. Thompson, MD • John M. Wright, DDS, MS

  • Hardcover: 886 pages
  • Publisher: ARP Press; 1st edition, 5th Series, Volume 22 (2025)
  • Language: English
  • ISBN-13: 978-1-933477-61-9

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Sinonasal Teratocarcinosarcoma: A Case Report in a 13-Year-Old Male.

Head & Neck, Sinonasal Tract
Ma Y, Galambos C, Garrington T, Toland A, Guzman S, Samedi V, Thompson LDR.
Pediatr Dev Pathol. 2025 May 16:10935266251342073. doi: 10.1177/10935266251342073. Online ahead of print.
Teratocarcinosarcoma is rare malignant sinonasal neoplasm with immature and malignant endodermal, mesodermal, and neuroepithelial elements resembling immature teratoma, commonly with SMARCA4 loss or activating CTNNB1 mutation. The carcinoma component may be either squamous or adenocarcinoma and the mesenchymal component may be composed of spindle cells, cartilage, bone, smooth muscle, or skeletal muscle. Due to the uncommon nature of this malignancy, there are frequently diagnostic difficulties that result in management problems. Herein we report a teratocarcinosarcoma arising in the nasal cavity of a 13-year-old boy with CTNNB1 activating mutation and copy number variations by next-generation sequencing along with an abnormal karyotype. This tumor must be included in the differential of neoplasms with immature elements, more likely seen in pediatric patients.
PubMed ID: 40380792
Article Size: <1 MB

World Health Organization Classification of Tumours: Endocrine and Neuroendocrine Tumours, 5th Edition

Books
WHO Classification of Tumours: Endocrine and Neuroendocrine Tumours, 5th EditionCurrent 5th Edition

Edited by the WHO Classification of Tumours Editorial Board
(Lester D. R. Thompson, MD, Board Member, co-editor and contributor)

  • Publisher: World Health Organization (IARC); 5th Edition (2025)
  • Pages: 608
  • Language: English
  • ISBN-13: 978-92-832-4524-7

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WHO Classification of Tumours of Endocrine Organs, (4th Edition, 2017)4th Edition
World Health Organization Classification of Tumours -- Pathology & Genetics: Tumours of Endocrine Organs, (3rd Edition, 2004)3rd Edition

The impact of histopathology on prognosis of squamous cell carcinoma of the larynx: can we do better?

Head & Neck, Larynx
Zidar N, Thompson LDR, Agaimy A, Stenman G, Hellquist H, Nadal A, Mäkitie AA, Fernando L, Strojan P, Ferlito A.
Virchows Arch. 2025 Jul;487(1):13-32. doi: 10.1007/s00428-025-04082-w. Epub 2025 Mar 27.
Despite decades of progress, laryngeal squamous cell carcinoma (SCC) is still associated with significant morbidity and mortality worldwide. Additional biomarkers are needed to apply precision medicine and predict the clinical course. We reviewed and summarised routinely reported histopathologic features (e.g. subtypes of laryngeal SCC) along with promising potential biomarkers not yet routinely assessed using international guidelines. These include extra- vs intratumoural vascular and perineural invasion, tumour budding, depth of invasion, and tumour-infiltrating lymphocytes. We also address the problem of specimen quality and type (open approach vs endoscopic surgery) and the related limitations. High-risk human papillomavirus infection is another controversial issue to be discussed, being rare in laryngeal SCC, with an indeterminate prognostic significance and less reliable p16 overexpression as a surrogate marker of HPV infection. Further studies are warranted to address the applicability and to see which of the described parameters may help to better stratify patients with laryngeal SCC and should therefore be included in the pathology report.
PubMed ID: 40140089
Article Size: 5.7 MB

Angiomyolipomatous Lesions of the Nasal Cavity (Sinonasal Angioleiomyoma with Adipocytic Differentiation): A Multi-Institutional Immunohistochemical and Molecular Study

Head & Neck, Sinonasal Tract
Jones VM, Thompson LDR, Pettus JR, Green DC, Lefferts JA, Shah PS, Tsongalis GJ, Sajed DP, Guilmette JM, Lewis JS, Fisch AS, Tafe LJ, Kerr DA.
Head Neck Pathol. 2024 Oct 14;18(1):93. doi: 10.1007/s12105-024-01700-y.
PURPOSE: Mesenchymal neoplasms composed of vascular, smooth muscle, and adipocytic components are uncommon in the nasal cavity. While angioleiomyoma (AL) is a smooth muscle tumor in the Head & Neck WHO classification, it is considered of pericytic origin in the Skin as well as Soft Tissue and Bone classifications. For nasal AL with an adipocytic component, the terms AL with adipocytic differentiation and angiomyolipoma (AML) have been applied, among others. AML is a type of perivascular epithelioid cell tumor (PEComa), most often arising in the kidney, sometimes associated with the tuberous sclerosis complex (TSC). It is uncertain whether nasal cavity AML and AL are best considered hamartomas or neoplasms, as their genetics are largely unexplored.
METHODS: We performed a multi-institutional retrospective study of nasal cavity mesenchymal lesions. Patient demographics, clinical histories, and histologic and immunohistochemical findings were collected. DNA and RNA were extracted from formalin-fixed, paraffin-embedded tissue and analyzed by SNP-based chromosomal microarray, targeted RNA fusion sequencing, and whole-exome sequencing.
RESULTS: Fifteen lesions (3-42 mm) were identified, predominantly in male (87%) patients with a median age of 60. Patients typically presented with obstructive symptoms, and none had a history of TSC. One AL was a recurrence from six years prior; 11 cases showed no recurrence (median 4.7 years, range: 0.88-12.4). Morphologically, 11 AML contained 30-80% smooth muscle, 10-25% vasculature, and 2-60% adipose tissue, while four AL contained 70-80% smooth muscle and 20-30% vasculature. Other histologic observations included ulceration, thrombosis, inflammation, myxoid change, senescent nuclei, and extramedullary hematopoiesis; no well-developed epithelioid cell morphology was identified. Immunohistochemically, all cases were positive for smooth muscle markers (actin, desmin, and/or caldesmon) and negative for melanocytic markers. Molecular analysis revealed loss of 3p and 11q in a single AML. No other known pathogenic copy number or molecular alterations were seen, including in TSC1/2, TFE3, or NOTCH2.
CONCLUSION: Nasal cavity AML lacks morphologic, immunophenotypic, and genetic features of PEComa family AML. The significant histologic overlap between nasal AML and AL without distinguishing molecular features in either entity suggests “sinonasal angioleiomyoma with adipocytic differentiation” may be the most appropriate terminology for hybrid vascular and smooth muscle lesions containing adipocytic components.
PubMed ID: 39281855
Article Size: 2 MB

Hiding in plain sight: NUT carcinoma is an unrecognized subtype of squamous cell carcinoma of the lungs and head and neck

Head & Neck, Sinonasal Tract
Luo J, Bishop JA, DuBois SG, Hanna GJ, Sholl LM, Stelow EB, Thompson LDR, Shapiro GI, French CA.
Nat Rev Clin Oncol. 2025 Apr;22(4):292-306. doi: 10.1038/s41571-025-00986-3. Epub 2025 Feb 3.
In the past two decades, treatment for non-small-cell lung cancers (NSCLCs) and head and neck squamous cell carcinoma (HNSCC) has advanced considerably, owing largely to the characterization of distinct oncological subtypes, the development of targeted therapies for each subtype and the advent of immunotherapy. Data emerging over the past two decades suggest that NUT carcinoma, a highly aggressive malignancy driven by a NUT fusion oncoprotein and arising in the lungs, head and neck, and rarely in other sites, is a squamous cell carcinoma (SCC) based on transcriptional, histopathological, cell-of-origin and molecular characteristics. NUT carcinoma has an estimated incidence of 1,400 cases per year in the United States, surpassing that of some rare NSCLC and HNSCC subtypes. However, NUT carcinoma is currently not recognized as an SCC of the lungs or head and neck. The orphan classification of NUT carcinoma as a distinct entity leads to a lack of awareness of this malignancy among oncologists and surgeons, despite early diagnosis being crucial for this cancer type with a median survival of only ~6.5 months. Consequently, NUT carcinoma is underdiagnosed and often misdiagnosed, resulting in limited research and progress in developing effective treatments in one of the most aggressive forms of lung and head and neck cancer. With a growing number of targeted agents that can potentially be used to treat NUT carcinoma, improved recognition through reclassification and inclusion of NUT carcinoma as a squamous NSCLC or an HNSCC when arising in these locations will accelerate the development of effective therapies for this disease. Thus, in the Perspective, we propose such a reclassification of NUT carcinoma as an SCC and discuss the supporting evidence.
PubMed ID: 39900969
Article Size: 2.4 MB

Uncommon Fibroinflammatory Sinonasal Tract Lesions: Granulomatosis with Polyangiitis, Eosinophilic Angiocentric Fibrosis, and Rosai–Dorfman Disease

Head & Neck, Sinonasal Tract
Thompson LDR.
Surg Pathol Clin. 2024 Dec;17(4):549-560. doi: 10.1016/j.path.2024.07.007. Epub 2024 Aug 16.
Fibroinflammatory lesions of the sinonasal tract include inflammatory polyps (chronic rhinosinusitis), various infious sarcoidosis, and NK/T-cell lymphoma as examples of the most commonly encountered lesions. However, the differential diagnosis includes several less frequently encountered entities, such as granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiits (Churg-Strauss), eosinophilic angiocentric fibrosis considered part of IgG4-related disease, and Rosai-Dorfman disease. This review focuses on these latter entities providing an update on clinical, laboratory, imaging, histology, and ancillary testing employed to reach an actionable
diagnosis.
PubMed ID: 39489548
Article Size: 8 MB

Laryngectomy Margin Assessment: A Little Help From a Template.

Head & Neck, Larynx
Zaccarini DJ, Thompson LDR.
Adv Anat Pathol. 2024 Oct 31. doi: 10.1097/PAP.0000000000000471.
Laryngectomy margin assessment is an important part of patient care and can affect outcomes. There is no standard approach to grossing laryngectomy specimens, with variations in the published guidelines. A uniform approach to margin assessment may be helpful to improve patient care and future research. At the very least, sampling of all mucosal margins (arytenoid area, hypopharyngeal, and anterior epiglottis) and tracheal margin should be performed. Sampling of soft tissue margins may be delegated to the pathologist, and contingent on the tumor extent into soft tissue. If a tracheostomy is present, skin and soft tissue margins should be sampled from the stoma. This review provides a template for laryngectomy margin assessment and can be used as a guideline as to which margins should be assessed.
PubMed ID: 39482281
Article Size: <1 MB

Carcinomas of the Nasal Cavity and Paranasal Sinuses Histopathology Reporting Guide. 2nd edition.

Head & Neck, Staging
Bishop JA, Agaimy A, Bal M, Franchi A, Gallia GL, Kahn S, Rooper L, Stelow E, Weinreb I, Helliwell T, Thompson LDR.
The dataset has been developed for the reporting of resection and biopsy specimens of mucosal malignancies originating in the nasal cavities and paranasal sinuses. Malignancies at the border of skull base are included. Neuroendocrine neoplasms are also included.
Melanomas, lymphomas, sarcomas, olfactory neuroblastoma and haematolymphoid tumours are not included. Bone and soft tissue tumours are dealt with in separate ICCR datasets.
Neck dissections and nodal excisions are dealt with in a separate ICCR dataset, and this dataset should be used in conjunction, where applicable.
This dataset is intended for use for primary cancer resections. For resections of recurrent disease, the reporting guide may be used pragmatically although some data elements may be not applicable nor assessable.
PubMed ID: n/a
Article Size: <1 MB

Carcinomas of the Hypopharynx, Larynx and Trachea Histopathology Reporting Guide. 2nd edition.

Head & Neck, Staging
Zidar N, Bal M, Chernock RD, Dahlstrom JE, Perez-Ordonez B, Strojan P, Helliwell T, Thompson LDR.
International Collaboration on Cancer Reporting; Sydney, Australia. ISBN: 978-1-922324-46-7.
The dataset has been developed for the reporting of resection and biopsy specimens of invasive epithelial malignancies of the larynx, hypopharynx and trachea. Salivary-type malignancies arising from minor mucoserous glands of the hypopharynx and larynx should be recorded in this dataset.
Mucosal melanoma is presented in a separate ICCR dataset. Lymphomas and sarcomas are not included. Malignancies arising at other sites in the head and neck region, and neck dissections and nodal excisions are dealt with in separate ICCR datasets which may be used, as appropriate, in conjunction with this dataset.
Where more than one anatomically or histologically distinct primary tumour occur, a separate dataset should be completed for each tumour.
This dataset is intended for use for primary cancer resections. For resections of recurrent disease, the reporting guide may be used pragmatically but some data items may be not applicable or not assessable.
PubMed ID: n/a
Article Size: 1 MB

Malignant Odontogenic Tumours Histopathology Reporting Guide. 2nd edition.

Head & Neck, Staging
Odell EW, Baumhoer D, Gomez R, Hunter KD, Mosqueda-Taylor A, Richardson MS, Wright J, Helliwell T, Thompson LDR.
International Collaboration on Cancer Reporting; Sydney, Australia. ISBN: 978-1-922324-50-4.
The dataset has been developed for the reporting of excision biopsy and resection specimens for malignant primary odontogenic (carcinoma and sarcoma) tumours. For resections of recurrent disease, the reporting guide may be used pragmatically although some data elements may be not applicable nor assessable. Malignant neoplasms arising in the nasal cavity and paranasal sinuses, oral cavity, salivary glands, trachea, pharynx and larynx are dealt with in separate ICCR datasets. Non-odontogenic bone, soft tissue and lymphoma protocols are also dealt with in separate ICCR datasets. In addition, neck dissections and nodal excisions are dealt with in a separate ICCR dataset, and this dataset should be used in conjunction, where applicable.
This dataset is intended for use for primary cancer resections.
PubMed ID: n/a
Article Size: <1 MB

Carcinomas of the Major Salivary Glands Histopathology Reporting Guide. 2nd edition.

Head & Neck, Staging
Thompson LDR, Bishop JA, Hyrcza MD, Ihrler S, Leivo I, Nagao T, Rupp NJ, Skalova A, Stenman G, Vander Poorten V, van Herpen C, Helliwell T.
International Collaboration on Cancer Reporting; Sydney, Australia. ISBN: 978-1-922324-51-1.
The dataset has been developed for the reporting of primary cancer resection and biopsy specimens of malignancies arising from the major salivary glands (parotid, submandibular and sublingual glands). For resections of recurrent disease, the reporting guide may be used pragmatically although some data elements may be not applicable nor assessable. Melanomas, lymphomas, and sarcomas are dealt with in separate ICCR datasets. Minor salivary gland malignancies arising in the oral cavity, nasal cavity and paranasal sinuses, larynx, hypopharynx, trachea, nasopharynx, oropharynx, gnathic bones, and ear-temporal bone specimens are staged according to their anatomical sub-site and are dealt with in separate ICCR datasets. Minor salivary gland tumours are rare with insufficient quality evidence currently to support a separate dataset, recognising this is a limitation. Further, the ICCR follows Union for International Cancer Control (UICC) guidance for staging, and the major salivary gland system is not applicable to minor salivary glands. The notes on histological typing and grading in this dataset may be used to inform reporting of minor salivary gland malignancies. In addition, neck dissections and nodal excisions are dealt with in a separate dataset, and this dataset should be used in conjunction, where applicable.
This dataset is based on histology, but if cytology is the only material available, we recommend using the ‘other’ box in the operative procedure section to record appropriate information.
For bilateral tumours, a separate dataset should be completed for each tumour.
PubMed ID: n/a
Article Size: <1 MB

Carcinomas of the Nasal Cavity and Paranasal Sinuses Histopathology Reporting Guide. 2nd edition.

Thyroid
Bishop JA, Agaimy A, Bal M, Franchi A, Gallia GL, Kahn S, Rooper L, Stelow E, Weinreb I, Helliwell T, Thompson LDR.
International Collaboration on Cancer Reporting; Sydney, Australia. ISBN: 978-1-922324-52-8.
The dataset has been developed for the reporting of resection and biopsy specimens of mucosal malignancies originating in the nasal cavities and paranasal sinuses. Malignancies at the border of skull base are included. Neuroendocrine neoplasms are also included.
Melanomas, lymphomas, sarcomas, olfactory neuroblastoma and haematolymphoid tumours are not included. Bone and soft tissue tumours are dealt with in separate ICCR datasets.
Neck dissections and nodal excisions are dealt with in a separate ICCR dataset, and this dataset should be used in conjunction, where applicable.
This dataset is intended for use for primary cancer resections. For resections of recurrent disease, the reporting guide may be used pragmatically although some data elements may be not applicable nor assessable.
PubMed ID: n/a
Article Size: <1 MB

Carcinomas of the Oropharynx and Nasopharynx Histopathology Reporting Guide. 2nd edition.

Head & Neck, Staging
Chernock RD, Badoual C, Faquin WC, Hernandez-Prera J, Iyer NG, Katabi N, O’Sullivan B, Robinson M, Willems S, Helliwell T, Thompson LDR.
International Collaboration on Cancer Reporting; Sydney, Australia. ISBN: 978-1-922324-47-4.
The dataset has been developed for the reporting of resection and biopsy specimens of the oropharynx and nasopharynx. For resections of recurrent disease, the reporting guide may be used pragmatically although some data elements may be not applicable nor assessable. The protocol applies to all primary carcinomas (including of minor salivary glands) of the nasopharynx and oropharynx, the latter including the base of tongue, tonsils, tonsillar fossa, tonsillar pillars, soft palate, posterior and lateral walls, and uvula. Although rare, neuroendocrine tumours (NET) and neuroendocrine carcinomas (NEC) are also included. It does not apply to recurrent disease but may be used for residual disease after prior therapy (see below). Lymphomas, sarcomas, and mucosal melanomas are not included. Malignancies arising at other sites in the head and neck region, and neck dissections and nodal excisions are dealt with in separate datasets which may be used, as appropriate, in conjunction with this dataset.
When a biopsy specimen is the only specimen ever received, elements specific to the biopsy should be reported, recognising elements applicable to surgically resected tumours cannot be reliably completed. Although multiple synchronous and metachronous primary oropharyngeal squamous cell carcinomas (SCC) are uncommon and are usually of the same high risk human papillomavirus (HPV) type, there is no data to suggest that they are not simply separate primary tumours. Thus, for oropharyngeal carcinomas, each distinct focus should be considered a separate primary tumour, and should receive its own separate dataset. However, for nasopharyngeal tumours, even if the tumour appears to be multifocal clinically and pathologically, these are regarded and treated as a single primary.
PubMed ID: n/a
Article Size: <1 MB

Ear and Temporal Bone Tumours Histopathology Reporting Guide. 2nd edition.

Head & Neck, Staging
Thompson LDR, Gupta R, Low H, Magliocca K, Sandison A, Helliwl T.
International Collaboration on Cancer Reporting; Sydney, Australia. ISBN: 978-1-922324-53-5.
The dataset has been developed for the reporting of resection and biopsy specimens of the ear and temporal bone. It includes only primary tumours of the external auditory canal, middle and inner ear, including both benign and malignant entities (specifically due to anatomic confines and management alternatives which may require significant, destructive or disfiguring surgery).
By definition, all malignancies of the external ear (pinna, concha, scaphoid, lobe, etc., such as squamous cell carcinoma (SCC), basal cell carcinoma, pleomorphic dermal sarcoma, Merkel cell carcinoma and melanoma) are separately covered by the ICCR Skin Datasets. Primary parotid gland malignancies with direct extension in to the ear canal are excluded; the ICCR Carcinomas of the major salivary glands dataset should be used. Haematolymphoid neoplasms are also excluded from this dataset.
Neck dissections and nodal excisions are dealt with in a separate dataset, and this dataset should be used in conjunction, where applicable.
For bilateral tumours, a separate dataset should be completed for each tumour.
This dataset is intended for use for primary tumour resections. For resections of recurrent disease, the reporting guide may be used pragmatically although some data elements may be not applicable nor assessable.
PubMed ID: n/a
Article Size: 1 MB

Carcinomas of the Oral Cavity Histopathology Reporting Guide. 2nd edition.

Head & Neck, Staging
Müller S, Day TA, Griffith CC, Magliocca KR, Mori T, Richardson MS, Sloan P, Tilakaratne WM, Zain RB, Helliwell T, Thompson LDR.
International Collaboration on Cancer Reporting; Sydney, Australia. ISBN: 978-1-922324-45-0.
The dataset has been developed for the reporting of resection and excisional biopsy specimens of malignancies of the oral cavity, including mucosal lip and tongue (mucosal carcinomas, minor salivary gland malignancies, and neuroendocrine tumours). For resections of recurrent disease, the reporting guide may be used pragmatically although some data elements may be not applicable nor assessable. Incisional biopsies and other biopsy specimens are not included in this dataset. Mucosal melanoma, lymphomas and sarcomas are dealt with in separate ICCR datasets. In addition, neck dissections and nodal excisions are dealt with in a separate ICCR dataset, and this dataset should be used in conjunction, where applicable.
For additional independent (multicentric) tumours, complete a separate dataset for each.
PubMed ID: n/a
Article Size: 1 MB

Mucosal Melanomas of the Head and Neck Histopathology Reporting Guide. 2nd edition.

Staging
Williams MD, Fitzpatrick S, Franchi A, Kakkar A, Patel S, Yamazaki N, Helliwell T, Thompson LDR
International Collaboration on Cancer Reporting; Sydney, Australia. ISBN: 978-1-922324-48-1.
The dataset has been developed for the reporting of resection and biopsy specimens of mucosal melanoma arising in the nasal cavity and paranasal sinuses, oral cavity, nasopharynx, oropharynx, larynx and hypopharynx. All other malignancies are dealt with in separate ICCR datasets, specifically cutaneous melanoma is separately reported.
Direct extension of a cutaneous primary into a mucosal site should be excluded and would not be reported in this dataset. Metastatic melanoma to a head and neck mucosal site is also excluded. If there are overlapping sites, clinical centring of the tumour should determine the dataset to be completed. If a primary tumour extends to involve the contralateral side, the tumour is still considered a unifocal tumour, but involving multiple, contiguous sites. It should be noted that for limited biopsies the pathologist may not be able to complete all of the elements in the ICCR dataset.
Neck lymph node dissections and excisions are dealt with in a separate dataset, and this dataset should be used in conjunction, where applicable.
This dataset is intended for use for primary cancer resections. For resections of recurrent disease, the reporting guide may be used pragmatically although some data elements may be not applicable nor assessable.
PubMed ID: n/a
Article Size: <1 MB

Nodal Excisions and Neck Dissection Specimens for Head and Neck Tumours Histopathology Reporting Guide. 2nd edition.

Staging
Bullock M, Carlson DL, Fonseca I, Katabi N, Taylor SM, Thavaraj S, Williams MD, Helliwell T, Thompson LDR.
International Collaboration on Cancer Reporting; Sydney, Australia. ISBN: 978-1-922324-49-8.
The dataset has been developed for the reporting of lymph node resections from patients with primary carcinomas and mucosal melanomas of the head and neck. This excludes nodal resections for lymphoma and sarcomas. It is not intended for use in reporting lymph node core biopsy or fine needle aspirations. Carcinomas covered by the dataset include sinonasal tract, nasopharnx, oral cavity, oropharynx, hypopharynx, larynx and trachea, salivary glands (major and minor), and ear and temporal bone. Neuroendocrine tumours (grade 1, 2 and 3) and neuroendocrine carcinomas are also included in this dataset, along with musical melanoma and cutaneous carcinomas (except Merkel cell carcinoma). For resections of recurrent disease, the reporting guide may be used pragmatically although some data elements may be not applicable nor assessable. This dataset is to be used in conjunction with other ICCR datasets in the Head and Neck Series. Lymph node excisional biopsies or neck dissections may precede, accompany, or follow the biopsy or resection of a primary tumour. Concurrent reporting of the lymph node and primary tumour dataset elements – ideally in the same report – is preferable, as it provides clinicians with the most comprehensive information for tumour stage categorisation.
PubMed ID: n/a
Article Size: 1 MB

Unusual PEComa With PRCC::TFE3 Fusion Mimicking Sinonasal Tract Melanoma.

Head & Neck, Sinonasal Tract
Lasota J, Thompson LDR, Chłopek M, Kowalik A, Miettinen M.
Appl Immunohistochem Mol Morphol. 2024 Aug 1;32(7):322-325. doi: 10.1097/PAI.0000000000001211. Epub 2024 Jul 9.
BACKGROUND: We report a nasal cavity unusual perivascular epithelioid cell tumor (PEComa) mimicking mucosal melanoma.
METHODS: Immunohistochemistry was performed using BenchMark Ultra and panel of antibodies. The Ion Torrent platform and Ion AmpliSeq cancer hotspot panel were utilized for DNA genotyping. Target-specific RNA libraries for the detection of fusion transcripts were constructed using Archer Universal RNA Reagent Kit v2 and Archer FusionPlex Solid Tumor panel and sequenced on the MiSeqDx instrument.
RESULTS: The tumor, diagnosed in 46-year-old female, was composed of spindle cells, and lacked pigmentation. Immunohistochemically, it showed a patchy HMB-45 positivity. Other melanocytic markers (S100 protein, Melan-A, SOX10) were negative. The tumor cells were weakly positive for KIT (CD117) while negative for smooth muscle actin, pancytokeratin cocktail (AE1/AE3), and synaptophysin. Diagnosis of primary sinonasal tract mucosal melanoma was favored. Additional molecular studies detected PRCC::TFE3 fusion as the sole genetic change, and suggested the diagnosis of unusual PEComa. Previously, TFE3 fusions were reported in a subset of PEComas but not in melanomas, while PRCC involvement has only been documented once in an ocular PEComa. Immunohistochemistry revealed strong nuclear TFE3 expression concordant with the molecular findings.
CONCLUSIONS: This report emphasis the importance of molecular testing in the differential diagnosis between PEComa and melanoma, especially when the tumor arises in a site typical of melanoma but showing an unusual morphology and immunophenotype. The detection of TFE3 fusion transcripts suggested the diagnosis of SNT PEComa, although it cannot be excluded that this and similar tumors represent a distinct diagnostic category.
PubMed ID: 38975712
Article Size: <1 MB

Isosexual precocious pseudopuberty during mitotane treatment in a child with adrenocortical carcinoma: A case report

Adrenal, Endocrine
Riedmeier M, Antonini SRR, Benoit C, Deal C, Martin F, de Figueiredo BC, Gonc EN, Hartel C, Idkowiak J, Kurlbaum M, de Krijger RR, Ribeiro RC, Del Rivero J, Schlegel PG, Thompson LDR, Yalcin B, Wiegering V.
Pediatric Hematology Oncology Journal, Volume 9, Issue 2, June 2024, Pages 74-77, ISSN 2468-1245, https://doi.org/10.1016/j.phoj.2024.03.005.
BACKGROUND: Mitotane is employed as adjuvant therapy in managing adrenocortical carcinoma in pediatric patients. While various adverse effects, such as estrogen-like manifestations, are well-documented in adults, there is limited knowledge regarding pediatric-specific toxicity. This report details an uncommon case of isosexual precocious pseudopuberty induced during childhood due to the estrogen-like effects of mitotane.
CASE REPORT: A 2.8-year-old female diagnosed with adrenocortical carcinoma (pT4 pN0 M0) underwent adjuvant treatment with mitotane and cytotoxic chemotherapy following incomplete resection (tumor stage III). Approximately eight months into mitotane treatment, she exhibited signs of puberty (Tanner stage 2), including progressive breast development, uterine enlargement, vaginal discharge, and an advancement of bone age by nearly two years. Gonadotrophin-dependent puberty and endogenous estrogen production were ruled out. The precocious pseudopuberty was attributed to previously reported estrogen-like effects of mitotane therapy. Subsequent administration of the aromatase inhibitor anastrozole in combination with mitotane led to a reduction in clinical signs of puberty.
CONCLUSIONS: Monitoring for estrogen-like effects of mitotane is crucial, particularly in pre-pubertal children, to avert potentially irreversible changes associated with precocious pseudopuberty.
PubMed ID: tbd
Article Size: <1 MB

Seven Steps to Financial Health.

Articles, Medical Techniques
Thompson LDR, Thompson PA.
Head Neck Pathol. 2024 Apr 18;18(1):30. doi: 10.1007/s12105-024-01640-7.
Physicians and dentists have a very limited exposure to personal financial management and yet find themselves in the top 10% of earners in the United States of America. Education loans, practice expenses, and high standards of living obligate them to be good financial stewards to succeed financially. Anecdotal personal experience and review. The article establishes seven steps to implement as medical/dental students, interns, residents, or practicing doctors to move towards financial health and security. The steps include (1) saving enough; (2) good debt management; (3) being tax savvy; (4) obtaining the correct insurance; (5) making wise investments; (6) if choosing to marry, avoid divorce; and (7) keeping track with periodic progress assessment. Each of these steps contains several components that can aid and guide physicians and dentists in their financial arc of development over their professional career and into retirement, considering generational wealth transfer or charitable donation as ultimate goals. This brief guide is based on my own financial journey to achieve long-term financial independence: start early, use simple tax deferred investments without chasing trends while keeping fees down, live within your means, and adequately insure your income.
PubMed ID: 38635068
Article Size: 4 MB

Metastatic cutaneous squamous cell carcinoma accounts for nearly all squamous cell carcinomas of the parotid gland

Head & Neck, Salivary Gland
Bradley PJ, Stenman G, Thompson LDR, Skálová A, Simpson RHW, Slootweg PJ, Franchi A, Zidar N, Nadal A, Hellquist H, Williams MD, Leivo I, Agaimy A, Ferlito A.
Virchows Arch. 2024 Jul;485(1):3-11. doi: 10.1007/s00428-024-03798-5. Epub 2024 Apr 17.
Primary squamous cell carcinoma of the parotid gland (pSCCP) has long been recognized as a separate entity and is included in the WHO classifications of salivary gland tumors. However, it is widely accepted among head and neck pathologists that pSCCP is exceptionally rare. Yet, there are many publications describing series of pSCCP and data from SEER and other cancer register databases indicate erroneously an increasing incidence of pSCCP. Importantly, pSCCP and metastatic (secondary) squamous cell carcinoma to the parotid gland (mSCCP) have nearly identical histological features, and the diagnosis of pSCCP should only be made after the exclusion of mSCCP. Moreover, all of the histological diagnostic criteria proposed to be in favor of pSCCP (such as, for example, dysplasia of ductal epithelium) can be encountered in unequivocal mSCCP, thereby representing secondary growth along preexistent ducts. Squamous cell differentiation has also been reported in rare genetically defined primary parotid carcinomas, either as unequivocal histological squamous features (e.g., NUT carcinoma, mucoepidermoid carcinoma), by immunohistochemistry (e.g., in NUT carcinoma, adamantinoma-like Ewing sarcoma, basal-type salivary duct carcinoma, mucoepidermoid carcinoma), or a combination of both. Another major issue in this context is that the International Classification of Diseases (ICD) coding system does not distinguish between primary or metastatic disease, resulting in a large number of patients with mSCCP being misclassified as pSCCP. Immunohistochemistry and new molecular biomarkers have significantly improved the accuracy of the diagnosis of many salivary gland neoplasms, but until recently there were no biomarkers that can accurately distinguish between mSCCP and pSCCP. However, recent genomic profiling studies have unequivocally demonstrated that almost all SCCP analyzed to date have an ultraviolet light (UV)-induced mutational signature typical of mSCCP of skin origin. Thus, mutational signature analysis can be a very useful tool in determining the cutaneous origin of these tumors. Additional molecular studies may shed new light on this old diagnostic and clinical problem. This review presents a critical view of head and neck experts on this topic.
PubMed ID: 38630141
Article Size: 2 MB

Ten Ways to Improve Getting a Scientific Manuscript Accepted.

Articles, Medical Techniques
Thompson LDR.
Head Neck Pathol. 2024 Mar 19;18(1):22. doi: 10.1007/s12105-024-01617-6.
BACKGROUND: Scientific publication is the cornerstone to academic and private practice advancement in patient management and outcomes. Writing a manuscript requires a certain discipline and skill set that can be achieved with diligence and hard work.
METHODS: Anecdotal and review.
RESULTS: Several factors must be considered in scientific writing and journal manuscript submission and acceptance. Choosing where to submit the manuscript; understanding the instructions to authors; disclosing ethically; formatting correctly; never plagiarizing; supplying high quality appropriate images; creating meaningful tables; curating a pertinent but thorough bibliography; having valid, supported conclusions; and respecting timelines.
CONCLUSIONS: A discussion of relevant components in manuscript writing and journal submission to improve your chances of acceptance.
PubMed ID: 38503984
Article Size: 2.3 MB

International consensus on mitotane treatment in pediatric patients with adrenal cortical tumors: Indications, therapy, and management of adverse effects.

Adrenal, Endocrine
Riedmeier M, Antonini SRR, Brandalise S, Costa TEJB, Daiggi CM, de Figueiredo BC, de Krijger RR, De Sá Rodrigues KE, Deal C, Del Rivero J, Engstler G, Fassnacht M, Fernandes Luiz Canali GC, Molina CAF, Gonc EN, Gültekin M, Haak HR, Guran T, Hendriks A EJ, Idkowiak J, Kuhlen M, Malkin D, Meena JP, Pamporaki C, Pinto E, Puglisi S, Ribeiro RC, Thompson LDR, Yalcin B, Van Noesel M, Wiegering V.
Eur J Endocrinol. 2024 Mar 30;190(4):G15-G24. doi: 10.1093/ejendo/lvae038.
OBJECTIVE: Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects.
METHODS: A Delphi method with three rounds of questionnaires within the pACC expert consortium of the international network groups ENSAT-PACT and ICPACT was used to create 21 final consensus statements.
RESULTS: We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stage III and IV and with incomplete resection/tumor spillage. For stage II patients mitotane is not generally indicated.The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50 mg/kg/d (1500 mg/m²/d) which can be increased up to 4000 mg/m2/d. Blood levels should range between 14-20 mg/L Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2 to 4 weeks), along with evaluation and assessment of laboratory values are required.
CONCLUSIONS: Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts.
PubMed ID: 38552173
Article Size: <1 MB

Recurrent Wnt Pathway and ARID1A Alterations in Sinonasal Olfactory Carcinoma.

Head & Neck, Sinonasal Tract
Rooper LM, Agaimy A, Bell D, Gagan J, Gallia GL, Jo VY, Lewis JS Jr, London NR, Nishino M, Stoehr R, Thompson LDR, Din NU, Wenig BM, Westra WH, Bishop JA.
Mod Pathol. 2024 Feb 16;37(5):100448. doi: 10.1016/j.modpat.2024.100448.
Sinonasal tumors with neuroepithelial differentiation, defined by neuroectodermal elements reminiscent of olfactory neuroblastoma (ONB) and epithelial features such as keratin expression or gland formation, are a diagnostically challenging group that have never formally been included in sinonasal tumor classifications. Recently, we documented that most of these neuroepithelial neoplasms have distinctive histologic and immunohistochemical findings and proposed the term olfactory carcinoma to describe these tumors. However, the molecular characteristics of olfactory carcinoma have not yet been evaluated. In this study, we performed targeted molecular profiling of 23 sinonasal olfactory carcinoma to further clarify their pathogenesis and classification. All tumors included in this study were composed of high-grade neuroectodermal cells that were positive for pankeratin and at least one specific neuroendocrine marker. A significant subset of cases also displayed rosettes and neurofibrillary matrix, intermixed glands with variable cilia, peripheral p63/p40 expression, and S100 protein-positive sustentacular cells. Recurrent oncogenic molecular alterations were identified in 20 tumors, including Wnt pathway alterations affecting CTNNB1 (n=8) and PPP2R1A (n=2), ARID1A inactivation (n=5), RUNX1 mutations (n=3), and IDH2 hotspot mutations (n=2). Overall, these findings do demonstrate the presence of recurrent molecular alterations in olfactory carcinoma, although this group of tumors does not appear to be defined by any single mutation. Minimal overlap with alterations previously reported in ONB also adds to histologic and immunohistochemical separation between ONB and olfactory carcinoma. Conversely, these molecular findings enhance overlap between olfactory carcinoma and sinonasal neuroendocrine carcinoma. A small subset of neuroepithelial tumors might better fit into the superseding molecular category of IDH2-mutant sinonasal carcinoma. At this point, sinonasal neuroendocrine and neuroepithelial tumors may best be regarded as a histologic and molecular spectrum that includes core groups of ONB, olfactory carcinoma, neuroendocrine carcinoma, and IDH2-mutant sinonasal carcinoma.
PubMed ID: 38369189
Article Size: 6 MB

Video Gallery – Lester’s Pathology Lectures

Medical Techniques, Videos

Scroll further down to see more of videos of my pathology lectures.

 

Branchioma: immunohistochemical and molecular genetic study of 23 cases highlighting frequent loss of retinoblastoma 1 immunoexpression.

Head & Neck, Neck
Bradová M, Thompson LDR, Hyrcza M, Vaněček T, Grossman P, Michal M Jr, Hájková V, Taheri T, Rupp N, Suster D, Lakhani S, Nikolov DH, Žalud R, Skálová A, Michal M, Agaimy A.
Virchows Arch. 2024 Jan;484(1):103-117. doi: 10.1007/s00428-023-03697-1.
Branchioma is an uncommon benign neoplasm with an adult male predominance, typically occurring in the lower neck region. Different names have been used for this entity in the past (ectopic hamartomatous thymoma, branchial anlage mixed tumor, thymic anlage tumor, biphenotypic branchioma), but currently, the term branchioma has been widely accepted. Branchioma is composed of endodermal and mesodermal lineage derivatives, in particular epithelial islands, spindle cells, and mature adipose tissue without preexistent thymic tissue or evidence of thymic differentiation. Twenty-three branchiomas were evaluated morphologically. Eighteen cases with sufficient tissue were assessed by immunohistochemistry, next-generation sequencing (NGS) using the Illumina Oncology TS500 panel, and fluorescence in situ hybridization (FISH) using an RB1 dual-color probe. All cases showed a biphasic morphology of epithelial and spindle cells with intermingled fatty tissue. Carcinoma arising in branchioma was detected in three cases. The neoplastic cells showed strong AE1/3 immunolabeling (100%), while the spindle cells expressed CD34, p63, and SMA (100%); AR was detected in 40-100% of nuclei (mean, 47%) in 14 cases. Rb1 showed nuclear loss in ≥ 95% of neoplastic cells in 16 cases (89%), while two cases revealed retained expression in 10-20% of tumor cell nuclei. NGS revealed a variable spectrum of likely pathogenic variants (n = 5) or variants of unknown clinical significance (n = 6). Loss of Rb1 was detected by FISH in two cases. Recent developments support branchioma as a true neoplasm, most likely derived from the rudimental embryological structures of endoderm and mesoderm. Frequent Rb1 loss by immunohistochemistry and heterozygous deletion by FISH is a real pitfall and potential confusion with other Rb1-deficient head and neck neoplasms (i.e., spindle cell lipoma), especially in small biopsy specimens.
PubMed ID: 37962685
Article Size: 4.2 MB

Predictive value of tumor budding in head and neck squamous cell carcinoma: an update

Head & Neck, Larynx
Chiesa-Estomba CM, Thompson L, Agaimy A, Zidar N, Simpson RHW, Franchi A, Rodrigo JP, Mäkitie AA, Almangush A, Leivo I, Ferlito A.
Virchows Arch. 2023 Oct;483(4):441-449.
Head and neck squamous cell carcinoma forms an anatomically and functionally complex group of malignancies. The signifcant local aggressiveness and frequent regional relapses motivate ongoing research to identify more reliable and sensitive prognostic and predictive biomarkers. One emerging area of cancer biology is the evaluation of tumor budding at the advancing invasive front of various types of epithelial cancers. Recent studies suggest that tumor budding is a relatively common phenomenon in cancer progression and that it may have important prognostic implications for patients due to its potential to provide valuable insights into the biology and clinical behavior of head and neck cancer. In this review, we aim to provide information about tumor budding in head and neck squamous cell carcinoma. Thus, we hope to shed light on the complex biology of these malignancies, as well as aiding diagnostic, classifcation, and better characterization and thereby, looking for new avenues for improving patient outcomes.
PubMed ID: 37642731
Article Size: <1 MB

Lester’s Tips on Photoshop for Pathology Images

Medical Techniques, Videos

International consensus statement on allergy and rhinology: Sinonasal tumors

Head & Neck, Sinonasal Tract
Kuan EC, Wang EW, Adappa ND, Beswick DM, London NR Jr, Su SY, Wang MB, Abuzeid WM, Alexiev B, Alt JA, Antognoni P, Alonso-Basanta M, Batra PS, Bhayani M, Bell D, Bernal-Sprekelsen M, Betz CS, Blay JY, Bleier BS, Bonilla-Velez J, Callejas C, Carrau RL, Casiano RR, Castelnuovo P, Chandra RK, Chatzinakis V, Chen SB, Chiu AG, Choby G, Chowdhury NI, Citardi MJ, Cohen MA, Dagan R, Dalfino G, Dallan I, Dassi CS, de Almeida J, Tos APD, DelGaudio JM, Ebert CS, El-Sayed IH, Eloy JA, Evans JJ, Fang CH, Farrell NF, Ferrari M, Fischbein N, Folbe A, Fokkens WJ, Fox MG, Lund VJ, Gallia GL, Gardner PA, Geltzeiler M, Georgalas C, Getz AE, Govindaraj S, Gray ST, Grayson JW, Gross BA, Grube JG, Guo R, Ha PK, Halderman AA, Hanna EY, Harvey RJ, Hernandez SC, Holtzman AL, Hopkins C, Huang Z, Huang Z, Humphreys IM, Hwang PH, Iloreta AM, Ishii M, Ivan ME, Jafari A, Kennedy DW, Khan M, Kimple AJ, Kingdom TT, Knisely A, Kuo YJ, Lal D, Lamarre ED, Lan MY, Le H, Lechner M, Lee NY, Lee JK, Lee VH, Levine CG, Lin JC, Lin DT, Lobo BC, Locke T, Luong AU, Magliocca KR, Markovic SN, Matnjani G, McKean EL, Meço C, Mendenhall WM, Michel L, Na’ara S, Nicolai P, Nuss DW, Nyquist GG, Oakley GM, Omura K, Orlandi RR, Otori N, Papagiannopoulos P, Patel ZM, Pfister DG, Phan J, Psaltis AJ, Rabinowitz MR, Ramanathan Jr M, Rimmer R, Rosen MR, Sanusi O, Sargi ZB, Schafhausen P, Schlosser RJ, Sedaghat AR, Senior BA, Shrivastava R, Sindwani R, Smith TL, Smith KA, Snyderman CH, Solares CA, Sreenath SB, Stamm A, Stölzel K, Sumer B, Surda P, Tajudeen BA, Thompson LDR, Thorp BD , Tong CCL , Tsang RK , Turner JH , Turri-Zanoni M, Udager AM, van Zele T, VanKoevering K, Welch KC, Wise SK , Witterick IJ, Won TB, Wong SN, Woodworth BA, Wormald PJ, Yao WC, Yeh CF, Zhou B, Palmer JN
Int Forum Allergy Rhinol. 2024 Feb;14(2):149-608. doi: 10.1002/alr.23262.
BACKGROUND: Sinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represents a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and presents 48 thematic and histopathology-based topics spanning the field.
METHODS: Sinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represents a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and presents 48 thematic and histopathology-based topics spanning the field.
RESULTS: The ICNST document consists of 4 major sections: general principles, benign neoplasms and lesions, malignant neoplasms, and quality of life and surveillance. It covers 48 conceptual and/or histopathology-based topics relevant to sinonasal neoplasms and masses. Topics with a high level of evidence provided specific recommendations, while other areas summarized the current state of evidence. A final section highlights research opportunities and future directions, contributing to advancing knowledge and community intervention.
CONCLUSIONS: As an embodiment of the multidisciplinary and collaborative model of care in sinonasal neoplasms and masses, ICSNT was designed as a comprehensive, international, and multidisciplinary collaborative endeavor. Its primary objective is to summarize the existing evidence in the field of sinonasal neoplasms and masses.
PubMed ID: 37658764
Article Size: 4.33 MB

HN-CLEAR: Head and Neck Consensus Language for Ease and Reproducibility, a Multidisciplinary Consensus Mechanism for Head and Neck Pathology

Head & Neck, Staging
Gupta R, Bal M, Bishop JA, Hunter KD, Magliocca K, Seethala RR, Thompson LDR, Weinreb I, Angelos P, Beadle B, Bell RB, Clark JR, Ferris R, Huang SH, Hayes DN, Ladwa R, Yang J, Cipriani NA, Nelson BL, Sadow PM, Lewis JS.
Head Neck Pathol. 2023 Sep;17(3):877-880. doi: 10.1007/s12105-023-01570-w.
Background (first paragraph) only: The head and neck region harbors a diverse range of tissue types and pathologies in close anatomical proximity. It also includes some of the most common human malignancies such as squamous cell carcinoma of the skin and aerodigestive tract while also including infections, inflammatory disorders, and many rare entities such as salivary gland and odontogenic neoplasms. The head and neck brings together pathologists with diverse training and sub-specialty backgrounds including head and neck, maxillofacial, endocrine pathology, dermatopathology, cytopathology, and other subspecialists as well as general surgical pathologists. The broad range of diagnostic terminologies and prognostic issues that influence patient management in head and neck pathology are further confounded by overlapping and confusing terminology and lack of robust evidence in many areas. Uniform and evidence-based diagnostic and prognostic terminologies are needed to inform the treatment of patients and support the design of clinical trials, epidemiological and fundamental research, cancer registries for education and preventive strategies, and assist policy makers in the allocation of health care resources.
PubMed ID: 37486534
Article Size: <1 MB

Machine learning driven index of tumor multinucleation correlates with survival and suppressed anti-tumor immunity in head and neck squamous cell carcinoma patients

Head & Neck, Oropharynx
Koyuncu CF, Frederick MJ, Thompson LDR, Corredor G, Khalighi S, Zhang Z, Song B, Lu C, Nag R, Sankar Viswanathan V, Gilkey M, Yang K, Koyfman SA, Chute DJ, Castro P, Lewis JS Jr, Madabhushi A, Sandulache VC.
Oral Oncol. 2023 Aug;143:106459. doi: 10.1016/j.oraloncology.2023.106459.
Objectives: Matching treatment intensity to tumor biology is critical to precision oncology for head and neck
squamous cell carcinoma (HNSCC) patients. We sought to identify biological features of tumor cell multinucleation,
previously shown by us to correlate with survival in oropharyngeal (OP) SCC using a machine
learning approach.
Materials and methods: Hematoxylin and eosin images from an institutional OPSCC cohort formed the training set
(DTr). TCGA HNSCC patients (oral cavity, oropharynx and larynx/hypopharynx) formed the validation set (DV ).
Deep learning models were trained in DTr to calculate a multinucleation index (MuNI) score. Gene set enrichment
analysis (GSEA) was then used to explore correlations between MuNI and tumor biology.
Results: MuNI correlated with overall survival. A multivariable nomogram that included MuNI, age, race, sex, T/
N stage, and smoking status yielded a C-index of 0.65, and MuNI was prognostic of overall survival (2.25,
1.07–4.71, 0.03), independent of the other variables. High MuNI scores correlated with depletion of effector
immunocyte subsets across all HNSCC sites independent of HPV and TP53 mutational status although the correlations
were strongest in wild-type TP53 tumors potentially due to aberrant mitotic events and activation of
DNA-repair mechanisms.
Conclusion: MuNI is associated with survival in HNSCC across subsites. This may be driven by an association
between high levels of multinucleation and a suppressive (potentially exhausted) tumor immune microenvironment.
Mechanistic studies examining the link between multinucleation and tumor immunity will be required
to characterize biological drivers of multinucleation and their impact on treatment response and outcomes.
PubMed ID: 37307602
Article Size: 2.5 MB

Assessing Oral Epithelial Dysplasia Risk for Transformation to Cancer: Comparison Between Histologic Grading Systems Versus S100A7 Immunohistochemical Signature-based Grading.

Head & Neck, Oral Cavity/Gnathic (Jaw)
Darling MR, Hwang JTK, Dickson BJ, Cutz JC, Salama S, McCord C, Pritzker KPH, Mock D, Thompson LDR.
Appl Immunohistochem Mol Morphol. 2023 Jul 1;31(6):399-405.
While a 3-tier oral epithelial dysplasia grading system has been utilized for decades, it is widely recognized as a suboptimal risk indicator for transformation to cancer. A 2-tier grading system has been proposed, although not yet validated. In this study, the 3-tier and 2-tier dysplasia grading systems, and an S100A7 immunohistochemical signature-based grading system were compared to assess prediction of risk of transformation to oral cancer. Formalin-fixed, paraffin-embedded biopsy specimens with known clinical outcomes were obtained retrospectively from a cohort of 48 patients. Hematoxylin and eosin-stained slides were used for the 2- and 3-tier dysplasia grading, while S100A7 for biomarker signature-based assessment was based on immunohistochemistry. Inter-observer variability was determined using Cohen’s kappa (K) statistic with Cox regression disease free survival analysis used to determine if any of the methods were a predictor of transformation to oral squamous cell carcinoma. Both the 2- and 3-tier dysplasia grading systems ranged from slight to substantial inter-observer agreement (Kw between 0.093 to 0.624), with neither system a good predictor of transformation to cancer (at least P=0.231; (P>>>0.05). In contrast, the S100A7 immunohistochemical signature-based grading system showed almost perfect inter-observer agreement (Kw=0.892) and was a good indicator of transformation to cancer (P=0.047 and 0.030). The inherent grading challenges with oral epithelial dysplasia grading systems and the lack of meaningful prediction of transformation to carcinoma highlights the significant need for a more objective, quantitative, and reproducible risk assessment tool such as the S100A7 immunohistochemical signature-based system.
PubMed ID: 37249075
Article Size: 0.5 MB

High Grade Differentiated Follicular Cell-Derived Thyroid Carcinoma Versus Poorly Differentiated Thyroid Carcinoma: A Clinicopathologic Analysis of 41 Cases

Endocrine, Thyroid
Thompson LDR
Endocr Pathol. 2023 Jun;34(2):234-246.
Criteria overlap for separating between malignant follicular epithelial cell-derived thyroid gland neoplasms with high grade features of increased mitoses and tumor necrosis but lacking anaplastic histology. Patterns of growth, nuclear features, tumor necrosis, and various mitotic index cutoffs are suggested, but a reproducible Ki-67-based labeling index has not been established. Forty-one cases diagnosed as poorly differentiated thyroid carcinoma (PDTC) or high grade differentiated follicular cell-derived thyroid carcinoma (HGDFCDTC) were reviewed, with histologic features, mitotic figure counts, and Ki-67 labeling index reviewed on cases within Southern California Permanente Medical Group from 2010 to 2021 to establish any potential outcome differences. There were 17 HGDFCDTC (nine papillary thyroid carcinoma; eight oncocytic follicular thyroid carcinoma), median age 64 years, affecting nine females and eight males. Tumors were large (median, 6.0 cm), usually unifocal (n = 13), with only one tumor lacking invasion. Tumor necrosis was present in all; median mitotic count was 5/2 mm2 (median Ki-67 labeling index 8.3%). Three patients had metastatic disease at presentation, with additional metastases in four patients (41.2% developed metastases); 11 were without evidence of disease (median 21.2 months); with the remaining six patients alive (n = 4) or dead (n = 2) with metastatic disease (median 25.8 months). Criteria associated with an increased risk of developing metastatic disease: widely invasive tumors; age ≥ 55 years; male; advanced tumor size and stage; extrathyroidal extension; but not increased mitotic rate or higher labeling index. There were 24 PDTC, median age 57.5 years, affecting 13 females and 11 males. Tumors were large (median, 6.9 cm), with 50% part of multifocal disease, with three tumors lacking invasion. Insular/trabecular/solid architecture was seen in all tumors; tumor necrosis was present in 23; and median mitotic count was 6/2 mm2 (median Ki-67 labeling index 6.9%). Five patients had metastatic disease at presentation, with additional metastases in 3 patients (29.2% developed metastases); 16 were without evidence of disease (median, 48.1 months); with the remaining 8 patients alive (n = 3) or dead (n = 5) with metastatic disease (median, 22.4 months). Criteria associated with an increased risk of developing metastatic disease: widely invasive tumors; male; advanced tumor size and stage; extrathyroidal extension; but not increased mitotic rate or higher labeling index. HGDFCDTC shows tumor necrosis, a median Ki-67 labeling index of 8.3%, with a high percentage (41%) of patients developing metastatic disease. Extent of invasion (non-invasive, minimally invasive, angioinvasive, widely invasive) correlates strongly with developing metastatic disease. PDTC presents at a slightly younger age, with large tumors, often in a background of multifocal tumors, with tumor necrosis nearly always seen, a median Ki-67 labeling index of 6.9%, with 29% of patients developing metastatic disease. Separation between groups is meaningful as early metastatic disease is relatively common, but mitotic counts/labeling indices are not different between the groups nor able to potentially risk stratify development of metastatic disease.
PubMed ID: 37195480
Article Size: 2.5 MB

IgG4-related sclerosing thyroiditis (Riedel-Struma): a review of clinicopathological features and management

Endocrine, Thyroid
Czarnywojtek A, Pietrończyk K, Thompson LDR, Triantafyllou A, Florek E, Sawicka-Gutaj N, Ruchała M, Płazinska MT, Nixon IJ, Shaha AR, Zafereo M, Randolph GW, Angelos P, Al Ghuzlan A, Agaimy A, Ferlito A.
Virchows Arch. 2023 Aug;483(2):133-144.
We present a thorough review of the literature on Riedel thyroiditis (RT) with emphasis on aetiology, diagnosis and management, using the PubMed, Sinomed, and China National Knowledge Infrastructure databases. Although the exact aetiology of RT remains obscure, the histopathological features are consistent with a localized form of IgG4-related systemic disease (IgG4-RSD). Nevertheless, IgG4-RSD as a systemic fibroinflammatory disorder per se rarely affects the thyroid in the context of multiorgan manifestations. The initial diagnosis of RT is based on clinical history and imaging, but confirmation by histopathological examination is mandatory. In contrast to the historical surgical approach, glucocorticosteroid therapy is currently considered first line therapy, in line with the RT currently being viewed as a manifestation of, or analogous to, IgG4-RSD. For disease relapse, immunomodulatory agents (azathioprine, methotrexate, rituximab) can be used.
PubMed ID: 37204493
Article Size: 1.6 MB

Salivary Gland Secretory Carcinoma: Clinicopathologic and Genetic Characteristics of 215 Cases and Proposal for a Grading System

Head & Neck, Salivary Gland
Baněčková M, Thompson LDR, Hyrcza MD, Vaněček T, Agaimy A, Laco J, Simpson RHW, Di Palma S, Stevens TM, Brcic L, Etebarian A, Dimnik K, Majewska H, Stárek I, O’Regan E, Salviato T, Helliwell T, Horáková M, Biernat W, Onyuma T, Michal M, Leivo I, Skalova A.
Am J Surg Pathol. 2023 Jun 1;47(6):661-677.
Salivary gland secretory carcinoma (SC), previously mammary analog SC, is a low-grade malignancy characterized by well-defined morphology and an immunohistochemical and genetic profile identical to SC of the breast. Translocation t(12;15)(p13;q25) resulting in the ETV6::NTRK3 gene fusion is a characteristic feature of SC along with S100 protein and mammaglobin immunopositivity. The spectrum of genetic alterations for SC continues to evolve. The aim of this retrospective study was to collect data of salivary gland SCs and to correlate their histologic, immunohistochemical, and molecular genetic data with clinical behavior and long-term follow-up. In this large retrospective study, we aimed to establish a histologic grading scheme and scoring system. A total of 215 cases of salivary gland SCs diagnosed between 1994 and 2021 were obtained from the tumor registries of the authors. Eighty cases were originally diagnosed as something other than SC, most frequently acinic cell carcinoma. Lymph node metastases were identified in 17.1% (20/117 cases with available data), with distant metastasis in 5.1% (6/117). Disease recurrence was seen in 15% (n=17/113 cases with available data). The molecular genetic profile showed ETV6::NTRK3 gene fusion in 95.4%, including 1 case with a dual fusion of ETV6::NTRK3 and MYB::SMR3B. Less frequent fusion transcripts included ETV6::RET (n=12) and VIM::RET (n=1). A 3-tiered grading scheme using 6 pathologic parameters (prevailing architecture, pleomorphism, tumor necrosis, perineural invasion (PNI), lymphovascular invasion (LVI), and mitotic count and/or Ki-67 labeling index) was applied. Grade 1 histology was observed in 44.7% (n=96), grade 2 in 41.9% (n=90), and grade 3 in 13.5% (n=29) of cases. Compared with low-grade and intermediate-grade SC, high-grade tumors were associated with a solid architecture, more prominent hyalinization, infiltrative tumor borders, nuclear pleomorphism, presence of PNI and/or LVI, and Ki-67 proliferative index >30%. High-grade transformation, a subset of grade 2 or 3 tumors, seen in 8.8% (n=19), was defined as an abrupt transformation of conventional SC into high-grade morphology, sheet-like growth, and a tumor lacking distinctive features of SC. Both overall survival and disease-free survival (5 and 10 y) were negatively affected by tumor grade, stage, and TNM status (each P<0.0001). SC is a low-grade malignancy with predominantly solid-microcystic growth patterns, driven by a gene fusion, most commonly ETV6::NTRK3. There is a low risk for local recurrence and a good overall long-term survival, with a low risk for distant metastasis but a higher risk for locoregional lymph node metastasis. The presence of tumor necrosis, hyalinization, PNI and/or LVI, and positive resection margins correlate with higher tumor grade, less favorable prognosis, and increased mortality. The statistical results allowed us to design a 3-tiered grading system for salivary SC.
PubMed ID: 37070739
Article Size: 2.3 MB

Prognostic value of the Weiss and Wieneke (AFIP) scoring systems in pediatric ACC – a mini review

Adrenal, Endocrine
Riedmeier M, Thompson LDR, Molina CAF, Decarolis B, Härtel C, Schlegel PG, Fassnacht M, Wiegering V.
Endocr Relat Cancer. 2023 Mar 8;30(4):e220259. doi: 10.1530/ERC-22-0259. Print 2023 Apr 1.
Histopathological differentiation in pediatric adrenocortical carcinoma (pACC) is difficult and clinical prediction and stratification scores are not evaluated yet. Therefore, this review aims to summarize current evidence on the value and accuracy of the two commonly used scoring systems (Weiss/Armed Forces Institute of Pathology (AFIP)) pACC. On this base, one might be able to evaluate if patients may benefit from a unique scoring system. For this, we performed a systematic review of the published literature and included 128 patients in our analysis. The majority (72%) of the pACCs had a good clinical course. The follow-up time ranged from 0 to 420 months with a mean age of 5.6 years at diagnosis. Patients with a good clinical course were younger (mean 4.8 years) than patients with a poor outcome (mean 7.6 years). Comparing the two scoring systems, the specificity of the Weiss score was very low (25%), whereas the sensitivity was 100%. According to the AFIP score, specificity (77%) was higher than the Weiss score, whereas the sensitivity of the AFIP score was minimal lower with 92%. Age differences were recognizable as the specificity was lower in infants <4 years (20%) than in older children (32%). In contrast, the specificity of the AFIP score was higher in infants <4 years (82%) than in older age groups (76%). Summarizing our results, we could show that the Weiss score is not a suitable tool for the prediction of malignancy in pACC in comparison with the AFIP score, but further efforts may seek to ensure early and accurate stratification through augmented scoring.
PubMed ID: 3675331
Article Size: <1 MB

Top Ten Differentials to Mull Over for Head and Neck Myoepithelial Neoplasms

Head & Neck, Salivary Gland
Thompson LDR, Xu B.
Head Neck Pathol. 2023 Mar 16. doi: 10.1007/s12105-022-01502-0. Online ahead of print.
BACKGROUND: Myoepithelial neoplasms of the salivary gland are benign or malignant neoplasms composed exclusively of neoplastic myoepithelial cells. These tumors, including the benign myoepithelioma and the malignant counterpart myoepithelial carcinoma, exhibit a wide range of cytomorphologic features and architectural patterns.
METHODS: Review.
RESULTS: Myoepithelial cells can be epithelial, plasmacytoid, clear cell, spindle cell, and/or oncocytic cell, arranging as trabeculae, solid sheets, nests, cords, and/or single cells. A stromal component is commonly but not universally present, Therefore, their differential diagnoses are quite broad, including salivary gland neoplasms especially those with a myoepithelial component, plasmacytoma, melanoma, and various mesenchymal tumors.
CONCLUSION: In this review, we summarize the characteristic histologic features, useful immunohistochemical panel, and common molecular alterations of myoepithelial tumors and their top differential diagnoses. A logical stepwise algorithmic approach and an immunohistochemical panel to include multiple myoepithelial markers are essential to establish the correct diagnosis.
PubMed ID: 36928733
Article Size: 5.2 MB

Adenoid Cystic Carcinoma With Striking Tubular Hypereosinophilia: A Unique Pattern Associated With Nonparotid Location and Both Canonical and Novel EWSR1::MYB and FUS::MYB Fusions

Head & Neck, Salivary Gland
Weinreb I, Rooper LM, Dickson BC, Hahn E, Perez-Ordonez B, Smith SM, Lewis JS Jr, Skalova A, Baněčková M, Wakely PE Jr, Thompson LDR, Rupp NJ, Freiberger SN, Koduru P, Gagan J, Bishop JA.
Am J Surg Pathol. 2023 Apr 1;47(4):497-503. doi: 10.1097/PAS.0000000000002023. Epub 2023 Mar 15.
The classification of salivary gland tumors is ever-evolving with new variants of tumors being described every year. Next-generation sequencing panels have helped to prove and disprove prior assumptions about tumors’ relationships to one another, and have helped refine this classification. Adenoid cystic carcinoma (AdCC) is one of the most common salivary gland malignancies and occurs at all major and minor salivary gland and seromucous gland sites. Most AdCC are predominantly myoepithelial and basaloid with variable cribriform, tubular, and solid growth. The luminal tubular elements are often less conspicuous. AdCC has largely been characterized by canonical MYB fusions, with MYB::NFIB and rarer MYBL1::NFIB. Anecdotal cases of AdCC, mostly in nonmajor salivary gland sites, have been noted to have unusual patterns, including squamous differentiation and macrocystic growth. Recently, this has led to the recognition of a subtype termed “metatypical adenoid cystic carcinoma.” Another unusual histology that we have seen with a wide range of architecture, is striking tubular hypereosinophilia. The hypereosinophilia and luminal cell prominence is in stark contrast to the vast majority of AdCC that are basaloid and myoepithelial predominant. A total of 16 cases with tubular hypereosinophilia were collected, forming morular, solid, micropapillary, and glomeruloid growth, and occasionally having rhabdoid or Paneth-like cells. They were subjected to molecular profiling demonstrating canonical MYB::NFIB (5 cases) and MYBL1::NFIB (2 cases), as well as noncanonical EWSR1::MYB (2 cases) and FUS::MYB (1 case). The remaining 6 cases had either no fusion (3 cases) or failed sequencing (3 cases). All cases were present in nonmajor salivary gland sites, with seromucous glands being the most common. These include sinonasal tract (7 cases), laryngotracheal (2 cases), external auditory canal (2 cases), nasopharynx (1 case), base of tongue (2 cases), palate (1 case), and floor of mouth (1 case). A tissue microarray of 102 conventional AdCC, including many in major salivary gland sites was examined for EWSR1 and FUS by fluorescence in situ hybridization and showed that these novel fusions were isolated to this histology and nonmajor salivary gland location. In summary, complex and striking tubular hypereosinophilia and diverse architectures are present within the spectrum of AdCC, particularly in seromucous gland sites, and may show variant EWSR1/FUS::MYB fusions.
PubMed ID: 36920022
Article Size: 1.06 MB

Recurrent IDH2 Mutations in Salivary Gland Striated Duct Adenoma Define an Expanded Histologic Spectrum Distinct From Canalicular Adenoma

Head & Neck, Salivary Gland
Rooper LM, Agaimy A, Assaad A, Bal M, Eugene H, Gagan J, Nonogaki H, Palsgrove DN, Shah A, Stelow E, Stoehr R, Thompson LDR, Weinreb I, Bishop JA.
Am J Surg Pathol. 2023 Mar 1;47(3):333-343.
Striated duct adenoma (SDA) is a rare salivary gland neoplasm defined by histologic similarity to normal striated ducts. However, doubt persists about whether SDA represents a genuine entity distinct from canalicular adenoma and if a malignant counterpart exists. This study aims to evaluate the molecular underpinnings of SDA to clarify its pathogenesis and classification. We identified 10 SDA and 2 tumors called low-grade adenocarcinoma not otherwise specified that were retrospectively recognized to resemble SDA. All cases showed recurrent histologic features including (1) discrete monophasic tubules, (2) tall columnar eosinophilic cells, (3) monotonous oval nuclei, and (4) scant fibrous stroma, and most were positive for S100 protein (91%), SOX10 (80%), and CK7 (80%). Although 1 case was previously called adenocarcinoma based on interdigitation with normal acini, this pattern was also seen in some SDA, and likely does not indicate malignancy; the significance of growth surrounding nerve in 1 other case is less clear. Targeted sequencing identified IDH2 R172X mutations in all 8 cases with sufficient tissue, with positivity for IDH1/2 mutation-specific immunohistochemistry in 9 cases stained. In contrast, 5 canalicular adenomas lacked IDH2 mutations or other oncogenic alterations. Overall, IDH2 R172X mutations are a defining feature of SDA that, in combination with its recognizable pathologic profile, confirm it is a unique entity separate from canalicular adenoma. IDH1/2 mutation-specific immunohistochemistry may provide a convenient tool to facilitate diagnosis. Both morphology and IDH2 mutations raise parallels between SDA and breast tall cell carcinoma with reverse polarity.
PubMed ID: 36510691
Article Size: 2.14 MB

A Subset of Salivary Intercalated Duct Lesions Harbors Recurrent CTNNB1 and HRAS Mutations: A Molecular Link to Basal Cell Adenoma and Epithelial-Myoepithelial Carcinoma?

Head & Neck, Salivary Gland
McLean AC, Rooper LM, Gagan J, Thompson LDR, Bishop JA.
Head Neck Pathol. 2023 Jun;17(2):393-400. doi: 10.1007/s12105-022-01513-x.
BACKGROUND: Intercalated duct lesions (IDLs) are benign salivary gland proliferations that resemble normal intercalated ducts and are subdivided into hyperplastic, adenoma or hybrid types depending on circumscription. While IDLs were historically regarded as non-neoplastic, frequent association with basal cell adenoma (BCA) and epithelial-myoepithelial carcinoma (EMC) has raised the possibility that they are neoplastic precursors.
METHODS: In this study, we performed β-catenin immunohistochemistry and targeted molecular analysis on IDLs to clarify their pathogenesis.
RESULTS: We identified 15 IDLs from the parotid glands of eight men and six women with a median age of 65 years (range 42-85 years). These lesions included nine hyperplastic, three adenoma, and three hybrid types. Nuclear β-catenin localization was present in 7 of 13 lesions tested (54%). Next generation sequencing was successfully completed in 12 IDLs, of which seven (58%) had likely oncogenic mutations. These included three recurrent CTNNB1 mutations in hyperplastic (n = 2) and hybrid (n = 1) lesions and two recurrent HRAS hotspot mutations in adenomas.
CONCLUSION: Despite substantial heterogeneity, these findings confirm that a majority of IDLs are genuinely neoplastic, and some demonstrate molecular overlap with both BCA and EMC, supporting their theorized role as precursors to these tumors. Nevertheless, no oncogenic drivers were present in a significant subset of cases, suggesting that some IDLs may be truly reactive and hyperplastic. As such, IDL appear to represent a diverse morphologic and molecular spectrum that include both neoplastic and hyperplastic lesions. Reconsideration of the boundary between IDL and BCA in the future may be necessary to simplify classification.
PubMed ID: 36480093
Article Size: 2 MB

Analysis of KRAS, BRAF, and EGFR mutational status in respiratory epithelial adenomatoid hamartoma (REAH)

Head & Neck, Sinonasal Tract
Guimarães LM, Vieira TDS, De Marco LA, Thompson LDR, Gomes CC.
J Oral Pathol Med 2023 Jul;52(6):548-553.
BACKGROUND: Respiratory epithelial adenomatoid hamartoma (REAH) is a sinonasal glandular overgrowth arising from the surface respiratory epithelium and invaginating into the stroma. Clinically, it appears as a polypoid mass that may cause nasal obstruction, anosmia, and epistaxis. The presence of cartilaginous and/or osseous areas move the lesion to a chondro-osseous respiratory epithelial (CORE) hamartoma subtype. Scattered small seromucinous glands may be observed between typical REAH glands and when it is the only feature, it represents seromucinous hamartoma (SH). The molecular pathogenesis of REAH has been poorly explored and remains unclear. Given that KRAS, BRAF, and EGFR mutations have been detected in a variety of sinonasal tumors, we aimed to assess these mutations in REAH and SH.
METHODS: Ten REAH (including one CORE subtype), in addition to two SH cases, were Sanger sequenced by standard techniques. The targeted regions included KRAS exons 2-4 (encompassing hotspots codons 12, 13, 61, and 146), BRAF exons 11 and 15 (spanning the V600 codon), and EGFR exons 19 and 20.
RESULTS: All REAH and SH samples showed wild-type sequences for KRAS, BRAF, and EGFR genes.
CONCLUSION: Our results demonstrate a lack of KRAS, BRAF, or EGFR pathogenic variants with further evaluation of REAH and SH needed to elucidate driver genetic events.
PubMed ID: 36504219
Article Size: 6.2 MB

Salivary Gland Intraductal Carcinoma: How Do 183 Reported Cases Fit Into a Developing Classification.

Head & Neck, Salivary Gland
Thompson LDR, Bishop JA.
Adv Anat Pathol. 2023 Mar 1;30(2):112-129.
Salivary gland intraductal carcinoma (IDC) is a very uncommon group of neoplasms. Many names, variations in diagnostic criteria, and newly observed molecular findings (including NCOA4::RET, TRIM27::RET, HRAS point mutations, and PIK3CA pathway alterations) have generated further confusion in being able to recognize and categorize this group of tumors. Different histologic appearances and patterns of growth suggest there is more than one tumor category, with intercalated duct, apocrine, oncocytic, and hybrid features seen. Frankly destructive invasion further complicates the category, as the name “intraductal” would suggest an “in situ” neoplasm. Recent evidence on fusion-positive IDC demonstrates the same molecular underpinnings in both the ductal and the myoepithelial cells, which aids in further separating these tumors. This article summarizes the historical group of 183 neoplasms classified under the umbrella of IDC and highlights the unique histologic, immunohistochemistry, and molecular features that may further guide nomenclature standardization and harmonization.
PubMed ID: 36040027
Article Size: 1.4 MB

Image analysis reveals differences in tumor multinucleations in Black and White patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma

Head & Neck, Oropharynx
Koyuncu CF, Nag R, Lu C, Corredor G, Viswanathan VS, Sandulache VC, Fu P, Yang K, Pan Q, Zhang Z, Xu J, Chute DJ, Thorstad WL, Faraji F, Bishop JA, Mehrad M, Castro PD, Sikora AG, Thompson LDR, Chernock RD, Lang Kuhs KA, Wasman JK, Luo JR, Adelstein DJ, Koyfman SA, Lewis JS Jr, Madabhushi A.
Cancer 2022 Nov 1;128(21):3831-3842. doi: 10.1002/cncr.34446. Epub 2022 Sep 6.
BACKGROUND: Understanding biological differences between different racial groups of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) patients, who have differences in terms of incidence, survival, and tumor morphology, can facilitate accurate prognostic biomarkers, which can help develop personalized treatment strategies.
METHODS: This study evaluated whether there were morphologic differences between HPV-associated tumors from Black and White patients in terms of multinucleation index (MuNI), an image analysis-derived metric that measures density of multinucleated tumor cells within epithelial regions on hematoxylin–eosin images and previously has been prognostic in HPV-associated OPSCC patients. In this study, the authors specifically evaluated whether the same MuNI cutoff that was prognostic of overall survival (OS) and disease-free survival in their previous study, TTR, is valid for Black and White patients, separately. We also evaluated population-specific cutoffs, TB for Blacks and TW for Whites, for risk stratification.
RESULTS: MuNI was statistically significantly different between Black (mean, 3.88e–4; median, 3.67e–04) and White patients (mean, 3.36e–04; median, 2.99e–04), with p = .0078. Using TTR, MuNI was prognostic of OS in the entire population with hazard ratio (HR) of 1.71 (p = .002; 95% confidence interval [CI], 1.21–2.43) and in White patients with HR of 1.72 (p = .005; 95% CI, 1.18–2.51). Population-specific cutoff, TW, yielded improved HR of 1.77 (p = .003; 95% CI, 1.21–2.58) for White patients, whereas TB did not improve risk-stratification in Black patients with HR of 0.6 (p = .3; HR, 0.6; 95% CI, 0.2–1.80).
CONCLUSIONS: Histological difference between White and Black patient tumors in terms of multinucleated tumor cells suggests the need for considering population-specific prognostic biomarkers for personalized risk stratification strategies for HPV-associated OPSCC patients.
PubMed ID: 36066461
Article Size: 6 MB

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