Ectomesenchymal Chondromyxoid Tumor: A Neoplasm Characterized by Recurrent RREB1-MKL2 Fusions.

Dickson BC, Antonescu CR, Argyris PP, Bilodeau EA, Bullock MJ, Freedman PD, Gnepp DR, Jordan RC, Koutlas IG, Lee CH, Leong I, Merzianu M, Purgina BM, Thompson LDR, Wehrli B, Wright JM, Swanson D, Zhang L, Bishop JA.
Am J Surg Pathol. 2018 Jun 15. [Epub ahead of print]
Ectomesenchymal chondromyxoid tumor is a rare and benign neoplasm with a predilection for the anterior dorsal tongue. Despite morphologic heterogeneity, most cases are characterized by a proliferation of bland spindle cells with a distinctive reticular growth pattern and myxoid stroma. The immunophenotype of these neoplasms is likewise variable; most cases express glial fibrillary acid protein and S100 protein, with inconsistent reports of keratin and myoid marker expression. The molecular pathogenesis is poorly understood; however, a subset of cases has been reported to harbor EWSR1 gene rearrangement. Following identification of an RREB1-MKL2 fusion gene by RNA Sequencing in an index patient, a retrospective review of additional cases of ectomesenchymal chondromyxoid tumors was performed to better characterize the clinical, immunohistochemical, and molecular attributes of this neoplasm. A total of 21 cases were included in this series. A marked predisposition for the dorsal tongue was confirmed. Most cases conformed to prior morphologic descriptions; however, hypercellularity, hyalinized stroma, and necrosis were rare attributes not previously emphasized. The neoplastic cells frequently coexpressed glial fibrillary acid protein, S100 protein, keratin, smooth muscle actin, and/or desmin; a single case was found to contain significant myogenin expression. An RREB1-MKL2 fusion product was identified in 19 tumors (90%), a single tumor (5%) had an EWSR1-CREM fusion product, and the remaining case lacked any known fusion gene by RNA Sequencing. The latter 2 cases subtly differed morphologically from many in the cohort. This series illustrates that recurrent RREB1-MKL2 fusions occur in most, perhaps all, cases of ectomesenchymal chondromyxoid tumor.
PubMed ID: 29912715
Article Size: 1 MB

Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP): Achieving Better Agreement by Refining Diagnostic Criteria

Alves VAF, Kakudo K, LiVolsi V, Lloyd RV, Nikiforov YE, Nosé V, Papotti M, Thompson LDR.
Clinics (Sao Paulo). 2018 May 21;73:e576.
FIRST PARAGRAPH: Over the past decade, improvements in imaging technologies along with greater access to medical care have resulted in the discovery of neoplasms in a much earlier stage. This has contributed to a reduction in cancer mortality. However, an unintended consequence of early detection has been detection of lesions which present at an earlier pathologic stage of development, requiring modification of diagnostic criteria, as well as determining a more appropriate risk stratification to inform management.
PubMed ID: 29791602
Article Size: <1 MB

Measuring Depth of Invasion in Early Squamous Cell Carcinoma of the Oral Tongue: Positive Deep Margin, Extratumoral Perineural Invasion, and Other Challenges.

Berdugo J, Thompson LDR, Purgina B, Sturgis CD, Tuluc M, Seethala R, Chiosea SI.
Head Neck Pathol. 2018 Apr 26. [Epub ahead of print]
The 8th edition of American Joint Committee on Cancer (AJCC 8th) staging manual incorporated depth of invasion (DOI) into pT stage of oral cavity cancer. The aim of this study was to characterize several histological findings that may complicate measurement of DOI in early conventional squamous cell carcinomas (SCC) of the oral tongue: (1) lack of or minimal residual carcinoma following biopsy; (2) positive deep margin; (3) extratumoral perineural invasion (PNI); and (4) lymphatic or vascular invasion. Conventional SCC of the oral tongue (n = 407) with the largest dimension of ≤ 4 cm and with a negative elective cervical lymph node dissection (pN0) were reviewed. A clear plastic ruler was used to measure DOI by dropping a “plumb line” to the deepest point of the invasive tumor from the level of the basement membrane of the normal mucosa closest to the invasive tumor. Examples of identifying reference point on the mucosal surface of oral tongue from which to measure the DOI are illustrated. In the experience of one contributing institution, the residual carcinoma was absent in 14.2% of glossectomies (34/239), while in 4.8% of cases (10/205) there was only minimal residual carcinoma. In 11.5% (21/183) of pT2 cases the deep margin was positive and thus DOI and pT may be underestimated. Of all cases with PNI, extratumoral PNI was identified in 23.1% (31/134) of cases, but represented the deepest point of invasion in only two cases. In one case, lymphatic invasion represented the deepest point of invasion and could have led to upstaging from pT1 to pT2. In conclusion, DOI measurement for SCC of the oral tongue may require re-examination of the diagnostic biopsy in up to 20% of cases due to the absence or only minimal residual carcinoma in glossectomy specimens. In 11.5% of apparently pT2 cases, DOI may be underestimated due to the positive deep margin. Rarely, extratumoral PNI or lymphatic invasion may be the deepest point of invasion. Overall, two issues (absent or minimal residual disease and positive deep margin) may confound DOI measurement in early SCCs of oral tongue.
PubMed ID: 29700721
Article Size: 3 MB

Diagnostic Approach to Fine Needle Aspirations of Cystic Lesions of the Salivary Gland

Pantanowitz L , Thompson LDR, Rossi ED.
Head Neck Pathol. 2018 Mar 9. doi: 10.1007/s12105-018-0904-8. [Epub ahead of print]
Fine needle aspiration (FNA) has diagnostic and therapeutic value in the management of salivary gland cysts. Rendering an accurate diagnosis from an aspirated salivary gland cyst is challenging because of the broad differential diagnosis, possibility of sampling error, frequent hypocellularity of specimens, morphologic heterogeneity, and overlapping cytomorphology of many cystic entities. To date, there have been no comprehensive review articles providing a practical diagnostic approach to FNA of cystic lesions of salivary glands. This article reviews the cytopathology of salivary gland cysts employing 2017 World Health Organization terminology, addresses the accuracy of FNA, and presents The Milan System approach for reporting in cystic salivary gland cases. The utility of separating FNA specimens from salivary gland cysts, based upon the presence of mucin and admixed lymphocytes in cyst fluid is demonstrated. A reliable approach to interpreting FNA specimens from patients with cystic salivary gland lesions is essential to accurately determine which of these patients may require subsequent surgery.
PubMed ID: 29524082
Article Size: 3.5 MB

Dentigerous cyst

Thompson, LD.
Ear Nose Throat J. 2018 Mar;97(3):57.
FIRST PARAGRAPH: A dentigerous cyst is a development cyst that surrounds and envelops the crown of an unerupted tooth, attached at the crown-root (cemento-enamel or cervical) junction. Dentigerous cysts account for about 20% of all odontogenic cysts, developing during a peak age of 10 to 30 years, with a male predilection (3:2). The lesion presents in the mandible (3rd molar region) about twice as often as the maxilla (near maxillary canines).
PubMed ID: 29554396
Article Size: <1 MB

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in thyroid tumor classification.

Kakudo K, El-Naggar AK, Hodak SP, Khanafshar E, Nikiforov YE, Nosé V, Thompson LDR.
Pathol Int. 2018 Apr 19. doi: 10.1111/pin.12673. [Epub ahead of print]
In 2016, a new morphological thyroid tumor entity, noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), was introduced to replace a group of lowrisk tumors known as noninvasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC). Since then, there have been more than 60 publications with a keyword of NIFTP according to a PubMed literature survey on October 28, 2017. These publications cover many aspects on this new tumor entity, cytological diagnosis, ultrasound features, molecular genotyping, clinical management and long-term outcome of NIFTP patients. They supported an indolent nature of NIFTP even in large size (>4 cm) tumors. Under ultrasound examination, NIFTPs are usually in low-suspicion nodules while invasive EFVPTC in intermediate-suspicious nodules and infiltrative FVPTCs in high-suspicion nodules. In FNA cytology, the majority of NIFTP are classified in indeterminate (atypia of uncertain significance/follicular lesion of uncertain significance, follicular neoplasm/suspicious for follicular neoplasm or suspicious for malignancy) categories. The new 4th edition of the World Health Organization (WHO) Classification of Tumours of Endocrine Organs including thyroid tumors was published in 2017 and it incorporated a new chapter on borderline tumors of follicular cell origin. These included hyalinizing trabecular tumor, uncertain malignant potential (UMP), and noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). UMP and NIFTP were incorporated as subchapters in a new chapter of other encapsulated follicular-patterned thyroid tumors (Table 1). Their behavior codes were set as /1 (unspecified, borderline, or uncertain behavior), and not /0 (benign tumors), /2 (carcinoma in situ and grade III intraepithelial neoplasia), or /3 (malignant tumors).
This editorial was written by seven authors, on behalf of all authors of the NIFTP working group, to refine diagnostic criteria for NIFTP in order to improve concordance in the diagnosis and to address several issues with the diagnosis of NIFTP raised in recent publications.
PubMed ID: 29675873
Article Size: <1 MB

Head and Neck Kaposi Sarcoma: Clinicopathological Analysis of 11 Cases.

Agaimy A, Mueller SK, Harrer T, Bauer S, Thompson LDR.
Head Neck Pathol. 2018 Mar 5. [Epub ahead of print]
Kaposi sarcoma (KS) of the head and neck area is uncommon with limited published case series. Our routine and consultation files were reviewed for histologically and immunohistochemically proven KS affecting any cutaneous or mucosal head and neck site. Ten males and one female aged 42-78 years (median, 51 years; mean, 52 years) were retrieved. Eight patients were HIV-positive and three were HIV-negative. The affected sites were skin (n = 5), oral/oropharyngeal mucosa (n = 5), and lymph nodes (n = 3) in variable combination. The ear (pinna and external auditory canal) was affected in two cases; both were HIV-negative. Multifocal non-head and neck KS was reported in 50% of patients. At last follow-up (12-94 months; median, 46 months), most of patients were either KS-free (n = 8) or had ongoing remission under systemic maintenance therapy (n = 2). One patient was alive with KS (poor compliance). Histopathological evaluation showed classical features of KS. One case was predominantly sarcomatoid with prominent inflammation mimicking undifferentiated sarcoma. Immunohistochemistry showed consistent expression of CD31, CD34, ERG, D2-40 and HHV8 in all cases. This is one of the few series devoted to head and neck KS showing high prevalence of HIV-positivity, but also unusual presentations in HIV-negative patients with primary origin in the skin of the ear and the auditory canal. KS should be included in the differential diagnosis of difficult-to-classify spindle cell lesions at this uncommon location.
PubMed ID: 29508130
Article Size: 1.6 MB

An International Interobserver Variability Reporting of the Nuclear Scoring Criteria to Diagnose Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features: a Validation Study

Thompson LDR, Poller DN, Kakudo K, Burchette R, Nikiforov YE, Seethala RR.
Endocr Pathol. 2018 Mar 6. doi: 10.1007/s12022-018-9520-0. [Epub ahead of print]
The aim of the study was to assess interobserver variation in reporting nuclear features of encapsulated follicular variant of papillary thyroid carcinoma, newly reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), based on a proposed standardized scoring system. An education module was individually reviewed as a pre-evaluation teaching guide of the specific features of classical papillary carcinoma, the specific inclusion and exclusion features for the diagnosis of NIFTP, and a catalog of the standardized scoring system of the nuclear features of papillary carcinoma used to reach this diagnosis. Participants subsequently reviewed 30 cases of thyroid lesions previously scored by members of the Endocrine Pathology Society Working Group for the Re-evaluation of the Encapsulated Follicular Variant of Papillary Thyroid Carcinoma. There was one uninvolved reference image to demonstrate fixation, processing, and cell size and one image from each case for scoring, with results recorded for each participant. The location of training (country and program), years as a practicing pathologist, and approximate number of thyroid gland surgical cases diagnosed per year were recorded. The degree of agreement between participants was assessed by kappa statistics, using the individual criteria and the average composite scores of the Working Group as a point of comparison. Using the Nuclear Standardized Scoring System, the interobserver agreement for final diagnosis score was generally excellent: unweighted and weighted kappa values between individual observers ranging from 0.242 to 0.930 (average 0.626). There was significant agreement between observers in reaching an interpretation of the presence or absence of nuclear features to diagnose NIFTP (score 0–1 versus score of 2–3), with California pathologists, 0.63 (median 0.66, SD 0.15); Japanese pathologists, 0.64 (median 0.66, SD 0.16); and UK pathologists, 0.60 (median 0.57, SD 014) compared to the expert panel, 0.70 (median 0.73, SD 0.19). The use of the nuclear scoring system to evaluate the nuclear features of papillary thyroid carcinoma as applied to reach the diagnosis of NIFTP shows a good to substantial interobserver agreement, suggesting that consensus can be reached in diagnosing the nuclear features required for this newly reclassified neoplasm.
PubMed ID: 29508145
Article Size: 2 MB

Induction chemotherapy followed by concurrent chemoradiation versus concurrent chemoradiation alone in the definitive management of p16-positive oropharyngeal squamous cell carcinoma with low-neck or N3 disease

Bhattasalia O, Han J, Thompson LDR, Buchschacher GL Jr, Abdalla IA, Iganeja S.
Oral Oncol. 2018 Mar;78:151-155.
Objective: The addition of induction chemotherapy (ICT) to concurrent chemoradiation (CCRT) has been investigated as a method of improving outcomes among patients with locally advanced head and neck squamous cell carcinoma. Previous studies have consisted of heterogeneous populations with both p16-positive and p16- negative disease and varying extent of nodal disease burden. We evaluated the role of ICT in p16-positive oropharyngeal squamous cell carcinoma (OPSCC) at high-risk of distant failure.
Materials and methods: A retrospective review was conducted of 88 consecutive patients with p16-positive OPSCC with low-neck and/or N3 lymphadenopathy. Among these patients, 44 received ICT followed by CCRT, and 44 received CCRT alone with concurrent agents including Cisplatin, Carboplatin, and Cetuximab. Disease control and survival outcomes were reported after adjusting for age, T stage, N stage, and smoking status.
Results: Median follow-up for surviving patients was 47 (range: 13–115) months. Patients who received CCRT alone were older than those who received ICT (61 years vs. 56 years; p=0.02); the groups were otherwise similarly balanced. 3-year distant metastasis: 38% vs. 18% (adjusted hazard ratio (HR)=0.32 [0.13–0.82]; p=0.02). 3-year progression-free survival: 49% vs. 74% (adjusted HR=0.46 [0.22–0.93]; p=0.03). 3-year overall survival: 67% vs. 83% (adjusted HR=0.48 [0.21–1.12]; p=0.09).
Conclusion: Among patients with p16-positive OPSCC with low-neck and/or N3 lymphadenopathy, ICT followed by CCRT may reduce the risk for distant failure over CCRT alone and lead to improved progression-free survival. Future trials should concentrate on patients at the highest risk of distant metastasis in order to appropriately assess the benefit of ICT.
PubMed ID: 29496043
Article Size: <1 MB

Sinonasal Tract Solitary Fibrous Tumor: A Clinicopathologic Study of Six Cases with a Comprehensive Review of the Literature.

Thompson LDR, Lau SK.
Head Neck Pathol. 2017 Dec 27. [Epub ahead of print]
Solitary fibrous tumors (SFTs) are well recognized in the head and neck region, but rarely arise in the sinonasal tract (SNT). Six primary SNT SFTs were identified in the files of Southern California Permanente Medical Group between 2006 and 2017. The patients included five males and one female ranging in age from 33 to 72 years (mean 52 years), most of whom presented clinically with nasal obstruction. Three tumors involved the nasal cavity alone, one involved the paranasal sinuses, and two involved both the nasal cavity and paranasal sinuses. Histologically, the tumors were characterized by a variably cellular proliferation of cytologically bland spindle cells within a collagenous stroma with prominent interspersed branching vessels. Mitotic activity was low (range 0–2 per 10 high power fields) and there was no evidence of pleomorphism or tumor necrosis. Surface ulceration was noted. By immunohistochemistry, the lesional cells were positive for CD34, STAT6 and bcl-2. Clinical follow up information was available for all patients (range 32–102 months; mean 72 months). There were no recurrences or metastases and all were alive with no evidence of disease at last follow-up. SFTs rarely affect the SNT, but should be considered in the differential diagnosis of SNT mesenchymal lesions. Immunohistochemical expression of STAT6 can aid in diagnosis and separation of SFT from other spindle cell lesions occurring at this anatomic site. In combination with cases reported in the literature, primary SNT SFT behave in an indolent manner with conservative treatment.
PubMed ID: 29282671
Article Size: 4 MB

Epithelial-Myoepithelial Carcinoma: Frequent Morphologic and Molecular Evidence of Preexisting Pleomorphic Adenoma, Common HRAS Mutations in PLAG1-intact and HMGA2-intact Cases, and Occasional TP53, FBXW7, and SMARCB1 Alterations in High-grade Cases.

El Hallani S, Udager AM, Bell D, Fonseca I, Thompson LDR, Assaad A, Agaimy A, Luvison AM, Miller C, Seethala RR, Chiosea S.
Am J Surg Pathol. 2018 Jan;42(1):18-27.
We hypothesized that there is a relationship between the preexisting pleomorphic adenoma [PA]), histologic grade of epithelial-myoepithelial carcinomas (EMCAs), and genetic alterations. EMCAs (n=39) were analyzed for morphologic and molecular evidence of preexisting PA (PLAG1, HMGA2 status by fluorescence in situ hybridization, FISH, and FGFR1-PLAG1 fusion by next-generation sequencing, NGS). Twenty-three EMCAs were further analyzed by NGS for mutations and copy number variation in 50 cancer-related genes. On the basis of combined morphologic and molecular evidence of PA, the following subsets of EMCA emerged: (a) EMCAs with morphologic evidence of preexisting PA, but intact PLAG1 and HMGA2 (12/39, 31%), (b) Carcinomas with PLAG1 alterations (9/39, 23%), or (c) HMGA2 alterations (10/39, 26%), and (d) de novo carcinomas, without morphologic or molecular evidence of PA (8/39, 21%). Twelve high-grade EMCAs (12/39, 31%) occurred across all subsets. The median disease-free survival was 80 months (95% confidence interval, 77-84 mo). Disease-free survival and other clinicopathologic parameters did not differ by the above defined subsets. HRAS mutations were more common in EMCAs with intact PLAG1 and HMGA2 (7/9 vs. 1/14, P<0.001). Other genetic abnormalities (TP53 [n=2], FBXW7 [n=1], SMARCB1 deletion [n=1]) were seen only in high-grade EMCAs with intact PLAG1 and HMGA2. We conclude that most EMCAs arose ex PA (31/39, 80%) and the genetic profile of EMCA varies with the absence or presence of preexisting PA and its cytogenetic signature. Progression to higher grade EMCA with intact PLAG1 and HMGA2 correlates with the presence of TP53, FBXW7 mutations, or SMARCB1 deletion.
PubMed ID: 29135520
Article Size: 1.2 MB

Sinonasal Leiomyosarcoma: Clinicopathological Analysis of Nine Cases with Emphasis on Common Association with Other Malignancies and Late Distant Metastasis.

Agaimy A, Semrau S, Koch M, Thompson LDR.
Head Neck Pathol. 2017 Dec 21. [Epub ahead of print]
Sinonasal tract (SNT) leiomyosarcoma (LMS) is exceedingly rare with < 100 cases reported. Their relationship to retinoblastoma and other malignancies, along with previous irradiation has not been clarified. Routine and consultation cases were reviewed for histologically and immunohistochemically proven SNT LMS. The tumors were tested with antibodies against α-smooth muscle actin, desmin, h-caldesmon, HMB45, S100 protein, Rb1, MDM2, CDK4 and EBV (EBER-ISH). Nine tumors affecting 5 males and 4 females aged 26 to 77 years (median: 48 years) were identified in the maxillary sinus (n = 4), nasal cavity (n = 3) and combined SNT (n = 2). Three patients had previous irradiation (2 for retinoblastoma, 1 for fibrous dysplasia) and 1 patient had chemotherapy and stem cell transplantation for Hodgkin lymphoma. One patient had prostatic adenocarcinoma (prior) and rectal adenocarcinoma (post) to the LMS. All patients with follow-up developed either local recurrences and/or metastases, principally to lung (time to metastasis: 16-156 months, mean 62 months). Histologically, 6 tumors were conventional high-grade LMS, two had glycogen-rich clear cell (PEComa-like) morphology and one was spindle cell low-grade. The latter showed grade 2 in the recurrence and grade 3 in the lung metastases. Two cases showed dedifferentiation to anaplastic pleomorphic (inflammatory MFH-like) phenotype. Immunohistochemistry revealed diffuse expression of at least 2 smooth muscle markers in 8 and only actin in one case/s. All other markers were negative. RB1 loss was observed in 6/8 cases tested. Sinonasal tract leiomyosarcomas are rare aggressive sarcomas that frequently develop in a background of previous cancer therapy (4/9), most frequently irradiation. Their varied morphology underlines the wide differential diagnostic considerations. Long-term survival may be achieved with aggressive multimodal therapy.
PubMed ID: 29270859
Article Size: 2.2 MB

Nasopharyngeal papillary adenocarcinoma.

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

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

Sakagiannis G, Giotakis E, Thompson LDR.
Head Neck Pathol. 2017 Dec 27. [Epub ahead of print]
Localized nasopharyngeal amyloidosis is an extremely rare entity with only 25 cases described in the English and German literature. We present a case series of seven patients with localized nasopharyngeal amyloidosis and combine the findings with a thorough review the literature.
PubMed ID: 29282670
Article Size: 1.2 MB

Pathologic reporting of Tall Cell Variant of Papillary Thyroid Cancer: Have we reached a consensus?

Hernandez-Prera J, Machado R, Asa SL, Baloch ZW, Faquin WC, Ghossein R Md, LiVolsi VA, Lloyd RV, Mete O, Nikiforov YE, Seethala R, Suster S, Thompson LDR, Turk A, Sadow PM, Urken ML, Wenig BM.
Thyroid. 2017 Dec;27(12):1498-1504.
BACKGROUND: Tall cell variant (TCV) is widely believed to be a more aggressive subtype of papillary thyroid carcinoma (PTC). Despite the significance of TCV with respect to risk stratification and therapeutic decision making, its diagnosis is subject to interobserver variability. We aim to determine the level of agreement among expert pathologists in the identification and reporting of TCV.
METHODS: 17 surgical resections for thyroid cancer containing the diagnostic term “tall cell” in their pathology reports and 22 cases diagnosed as classical PTC were selected. Cases were digitalized and 14 expert pathologists reviewed the scanned slides blinded to the original interpretation. Each pathologist designated each case as TCV or not and answered multiple questions about diagnostic histopathologic features of TCV.
RESULTS: The overall strength of agreement for identifying TCV was fair (Fleiss kappa 0.34) and the proportion of observed agreement was 0.70. Fifteen out of twenty-two (68%) cases originally diagnosed as PTC classical variant were re-classified as TCV by at least one expert pathologist. It was noted that four different definitions for TCV were used by the participants based on various combinations of cell height to width (H:W) ratio and the percentage of tumor cells showing that specific ratio. All pathologists agreed that the diagnosis of TCV does not rely solely on a specific H:W ratio.
CONCLUSIONS: Pathologic reporting of TCV varies among pathologists. This disagreement is a result of the lack of unanimous diagnostic criteria and variation in individual pathologists’ interpretations. These discrepancies lead to over- and under-diagnosis of TCV, which has significant implications in patient management. It is imperative to understand this variability in diagnosis TCV as it relates to risk stratification and interpretation of clinical studies related to this histologic subtype of PTC. Further studies are needed to reach consensus on the diagnostic criteria of TCV.
PubMed ID: 29020884
Article Size: <1 MB

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features: a review for pathologists.

Seethala RR, Baloch ZW, Barletta JA, Khanafshar E, Mete O, Sadow PM, LiVolsi VA, Nikiforov YE, Tallini G, Thompson LD.
Mod Pathol. 2018 Jan;31(1):39-55.
The rising incidence of papillary thyroid carcinoma is linked in part to inclusion of noninvasive follicular variant of papillary thyroid carcinoma. Despite its designation as carcinoma, noninvasive follicular variant of papillary thyroid carcinoma appears to be exceptionally indolent, often over treated by current treatment practices. Additionally, criteria for diagnosis have historically been subjective and challenging. Recently, an international multidisciplinary collaborative group performed a clinicopathologic survey of such cases with extended follow-up and concluded based on the outcome data that a revision in nomenclature was warranted, proposing ‘Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP).’ This monograph is a synopsis and guide for pathologists on NIFTP and focuses on histologic features, including inclusion and exclusion criteria used to define NIFTP, as well as grossing guidelines, reporting practices, and potential diagnostic limitations.
PubMed ID: 29052599
Article Size: 1.5 MB

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

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

Ear fetal rhabdomyoma.

Thompson LD.
Ear Nose Throat J. 2017 Sep;96(9):358.
FIRST PARAGRAPH: Rhabdomyomas are a group of benign tumors that show skeletal muscle differentiation. They are divided into cardiac and extracardiac types with the extracardiac type divided into adult, fetal, and genital types. The fetal type is separated into myxoid and intermediate types. There is a predominance in the head and neck of both the fetal and adult types. The fetal type is commonly seen in newborns and early childhood, with a moderate male predominance (2:1).
PubMed ID: 28931187
Article Size: <1 MB

Improving margin revision: Characterization of tumor bed margins in early oral tongue cancer.

Prabhu AV, Sturgis CD, Lai C, Maxwell JH, Merzianu M, Hernandez-Prera JC, Purgina B, Thompson LDR, Tuluc M, Yang X, Seethala RR, Ferris RL, Chiosea SI.
Oral Oncol. 2017 Dec;75:184-188.
OBJECTIVES: To improve margin revision, this study characterizes the number, fragmentation, and orientation of tumor bed margins (TBM) in patients with pT1-2 pN0 squamous cell carcinoma (SCC) of the oral tongue.
MATERIALS AND METHODS: Pathology reports (n=346) were reviewed. TBM parameters were indexed. In Group 1 patients all margins were obtained from the glossectomy specimen and there were no TBM. In Revision Group/Group 2 (n=103), tumor bed was sampled to revise suboptimal margins identified by examination of the glossectomy specimen. In Group 3 (n=124), TBM were obtained before examination of the glossectomy specimen.
RESULTS AND CONCLUSIONS: Fewer TBMs were obtained per patient in Group 2 compared to Group 3 (57/103, 55% of patients with <3 vs. 117/124, 94%, ≥3 TBMs, respectively). The new margin surface was more frequently indicated in Group 2 compared to Group 3 (59/103, 57%, vs. 19/124, 15%, p<.001). If glossectomy specimen margins are accepted as the reference standard, then the TBM was 15% sensitive in Group 2 (95% confidence interval [CI], 7-29) and 32% sensitive in Group 3 (95% CI, 15-55). TBM fragmentation (23/103, 22% vs. 42/124, 34%) and frozen vs. permanent discrepancies (8/103, 3% vs. 3/124, 2%) were similar between Groups 2 and 3. The new margin surface was not indicated in 6 of 11 cases with discrepant frozen vs. permanent pathology findings, precluding judgment on final margin status. To facilitate the assessment of final margins, TBM should be represented by one tissue fragment with a marked new margin surface.
PubMed ID: 29074194
Article Size: <1 MB

Sinonasal Tract Alveolar Rhabdomyosarcoma in Adults: A Clinicopathologic and Immunophenotypic Study of Fifty-Two Cases with Emphasis on Epithelial Immunoreactivity.

Thompson LDR, Jo VY, Agaimy A, Llombart-Bosch A, Morales GN, Machado I, Flucke U, Wakely PE Jr, Miettinen M, Bishop JA.
Head Neck Pathol. 2017 Sep 5. [Epub ahead of print]
Sinonasal tract (SNT) alveolar rhabdomyosarcoma (ARMS) are frequently misdiagnosed, especially in adults. Fifty-two adult (≥18 years) patients with SNT ARMS were reviewed and characterized by immunohistochemistry and molecular studies. Twenty-six females and 26 males (18-72 years; mean 43.2 years), presented after a short duration (mean 2.6 months) with a large (mean 5.5 cm) destructive nasal cavity mass, involving multiple contiguous paranasal sites (n = 46) and with cervical adenopathy (n = 41). The tumors showed an alveolar, nested to solid growth pattern below an intact, but often involved (n = 9) epithelium with frequent necrosis (n = 37), destructive bone invasion (n = 30), and lymphovascular invasion (n = 25). The neoplastic cells were dyshesive and dilapidated, with crush artifacts. Rhabdoid features (n = 36) and tumor cell multinucleation (n = 28) were common. Mitotic counts were high (mean 17/10 HPFs). The neoplastic cells showed the following immunohistochemical positive findings: desmin (100%), myogenin (100%), MYOD1 (100%), MSA (96%), SMA (52%), CAM5.2 (50%), AE1/AE3 (36%); other positive markers included S100 protein (27%), CD56 (100%), synaptophysin (35%), and chromogranin (13%). Overall, 54% show epithelial marker reactivity. Molecular studies showed FOXO1 translocations (81%) with PCR demonstrating PAX3 in 72.7% tested. Patients presented with high stage (IV 24; III 26) and metastatic disease (lymph nodes n = 41; distant metastases n = 25) (IRSG grouping). Surgery (n = 16), radiation (n = 41) and chemotherapy (n = 45) yielded an overall survival of 36.1 months (mean; range 2.4-286); 18 alive without disease (mean 69.6 months); 7 alive with disease (mean 11.0 months); 1 dead without disease (63.7 months); and 26 dead with disease (mean 18.5 months). SNT ARMS frequently present in adults as a large, destructive midline mass of short symptom duration, with high stage disease. The alveolar to solid pattern of growth of cells with rhabdoid-plasmacytoid features suggests the diagnosis, but epithelial immunohistochemistry markers are present in 54% of cases, leading to misdiagnosis as carcinomas if muscle markers are not also performed. Overall survival of 36.1 months is achieved with multimodality therapy, but 64% have incurable disease (16.9 months). Mixed anatomic site (p = 0.02) was a significant adverse prognostic indicator, while stage (0.06) and tumor size >5 cm (0.06) approached marginal significance.
PubMed ID: 28875443
Article Size: 4 MB

Metastases to the Parathyroid Glands: A Comprehensive Literature Review of 127 Reported Cases.

Bauer JL, Toluie S, Thompson LDR.
Head Neck Pathol. 2017 Sep 5. [Epub ahead of print]
Metastases to the head and neck organs are uncommon, potentially representing the initial presentation of an occult malignancy. Single case reports and small series report metastases to the parathyroid gland, but there is no large review of the literature on secondary tumors involving the parathyroid glands. A review of the English literature between 1950 and 2017 was performed of all metastases or secondary involvement of the parathyroid glands. One hundred and twenty-seven cases of metastatic tumors were reported, although potentially significantly unrepresented in autopsy series (parathyroid glands are not routinely examined) and due to reporting bias. Women were affected more commonly than men (5.8:1; 99 vs. 17, respectively), with a mean age at presentation of 58.5 years, when reported. The most common primary sites of malignancies that metastasized to the parathyroid glands were breast carcinomas (66.9%, n = 85), melanoma (11.8%, n = 15), and lung carcinoma (5.5%, n = 7), with carcinomas representing 86.6% of metastases. Metastases were nearly always identified as part of widely metastatic disease, with only five (3.2%) cases reported as isolated metastases. Tumor-to-tumor metastases comprised 5.5% of all metastases to the parathyroid glands (metastases to parathyroid adenoma). A significant clinical finding of metastases to the parathyroid glands was the development of deranged calcium homeostasis, well beyond the 9 (7.2%) cases with primary parathyroid gland disease present. Although concurrent conditions (renal disease; bone metastases) may partially affect calcium metabolism, the onset of calcium derangement seemed to coincide with parathyroid gland metastases and not systemic disease. In summary, metastases to the parathyroid glands are uncommon, potentially under-recognized in patients who have otherwise widely metastatic tumors. Women are affected more often than men, with breast carcinomas (66.9%) and melanoma (11.8%) the most common primary tumors. Calcium homeostasis is affected, probably as a result of parathyroid gland parenchymal destruction.
PubMed ID: 28875280
Article Size: 1.1 MB

Ectopic Hamartomatous Thymoma: A Review Of The Literature With Report Of New Cases And Proposal Of A New Name: Biphenotypic Branchioma.

Sato K, Thompson LDR, Miyai K, Kono T, Tsuda H.
Head Neck Pathol. 2017 Sep 6. [Epub ahead of print]
Ectopic hamartomatous thymoma (EHT) is a rare benign neoplasm of the lower neck suggesting branchial origin. Despite use of the term thymoma in the nomenclature, there is no evidence of thymic origin or differentiation. It affects middle-aged adults with a remarkable male predominance. To date less than 80 cases have been reported in the English literature. We present here two additional cases of EHT. The first is a benign case in a 31-year-old man, showing typical histological features. The second is a malignant case in a 70-year-old woman, showing intraductal carcinoma arising in intimate association with an EHT. These cases are presented in the context of a review of cases reported in the English literature. The exact origin has not been identified, but is considered to be of branchial apparatus, creating a quandary about the best terminology. Recently, the designation “branchial anlage mixed tumor” or “thymic anlage tumor” were proposed, but do not quite reflect the true nature of the neoplasm. To avoid taxonomic confusion, international consensus on terminology is desired. As this entity is a neoplasm that shows dual mesoderm and endoderm derivation/differentiation, we propose a new name “biphenotypic branchioma.”
PubMed ID: 28879635
Article Size: 2 MB

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

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

Non-Neoplastic Diseases of the Head and Neck, (1st series, Vol. 11)

AFIP Atlas of Nontumor Pathology: Non-Neoplastic Diseases of the Head and Neck

Bruce M. Wenig, MD • Esther L. B. Childers, MD • Mary S. Richardson, MD • Raja R. Seethala, MD • Lester D.R. Thompson, MD


  • Hardcover: 491 pages
  • Publisher: ARP Press; 1st edition (2017)
  • Language: English
  • ISBN-10: 1-9334-77-37-7
  • ISBN-13: 978-1-933477-37-4
  • Product Dimensions: approx. 8.75 x 1.125 x 11 inches

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Nasopharyngeal Angiofibroma: A Clinical, Histopathological and Immunohistochemical Study of 42 Cases with Emphasis on Stromal Features.

Sánchez-Romero C, Carlos R, Díaz Molina JP, Thompson LDR, de Almeida OP, Rumayor Piña A.
Head Neck Pathol. 2017 May 15. [Epub ahead of print]
Nasopharyngeal angiofibroma is a benign but aggressive tumor of unknown etiology, typically occurring in adolescent males. It is described as a rare neoplasm; however, the prevalence seems to have geographic differences. All cases referred to our head and neck clinical and pathology service were reviewed. Most of the patients presented at an advanced stage. The clinical and radiographic features are presented and discussed. Histologically, the tumor shows a highly vascular fibrous proliferation with characteristic plump, angulated and stellate cells, categorized as fibroblasts. Immunohistochemistry was performed on 42 cases to further elucidate the nature of these cells. The stromal cells expressed vimentin and factor XIIIa, the latter expressed most commonly in the giant stellate cells. Inflammation was almost exclusively present in peripheral subepithelial areas. Mast cells were abundant, even in the absence of other inflammatory cells. Lymphatics were observed principally in peripheral regions. Proliferating cells (Ki-67 reactive) were restricted to endothelial cells.
PubMed ID: 28508272
Article Size: 3 MB


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

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

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

Neuroendocrine tumors of the larynx.

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

Hailey-Hailey disease.

Thompson LD.
Ear Nose Throat J. 2016 Sep;95(9):370.
FIRST PARAGRAPH: Hailey-Hailey disease is a genodermatosis characterized by incomplete penetrance of an autosomal dominant disorder with defects in the ATP2C1 gene. Patients present with well-demarcated, erythematous plaques that often show crusting. The plaques may be vegetative, commonly associated with a distinct malodor. There may be associated burning or itching. While intertriginous areas are most commonly affected, the neck is also frequently involved. There is a natural remission and exacerbation cycle, with heat, moisture, and trauma the most common exacerbating factors. The lesions may be managed by corticosteroids or antibiotics, along with retinoids for severe disease.
PubMed ID: 27657314
Article Size: <1 MB

Secretory carcinoma.

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

Thyroglossal duct cyst.

Thompson LD.
Ear Nose Throat J. 2017 Feb;96(2):54-55.
FIRST PARAGRAPH: Embryologically, the thyroglossal duct develops as the thyroid anlage descends from the foramen cecum at the base of the tongue to its final resting point in the pretracheal inferior midline neck. The duct usually involutes, but persistence may give rise to a clinical cyst. Thyroglossal duct remnant cysts (TGDCs) are one of the most common neck lesions seen clinically, showing a bimodal age distribution in the first and fifth decades, and identified in approximately 2.2/100,000 population at risk each year. While there is an equal sex distribution, males tend to predominate in pediatric patients while females predominate among adults.
PubMed ID: 28231361
Article Size: <1 MB

Ossifying fibroma of the maxilla and sinonasal tract: Case series

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

Thyroglossal Duct Cyst Carcinomas in Pediatric Patients: Report of Two Cases with a Comprehensive Literature Review

Thompson LD, Herrera HB, Lau SK.
Head Neck Pathol. 2017 Dec;11(4):442-449.
Thyroglossal duct cyst (TGDC) carcinomas are rarely encountered in the pediatric population. The clinical behavior of these tumors in the pediatric setting is unclear and management is not well defined. Two cases of pediatric thyroglossal duct cyst carcinoma were identified in a review of all thyroglossal duct cysts diagnosed over a ten year period. These two cases were analyzed along with 57 cases of thyroglossal duct cyst carcinoma affecting patients less than 21 years of age compiled from the English literature. Fifty-nine patients (36 females, 23 males) aged 6–20 years (mean 15.0 years) were identified. All presented with an anterior midline neck mass, which was typically mobile and non-tender. The average tumor size was 2.6 cm. Histologically, all tumors were papillary thyroid carcinomas arising in a background of a thyroglossal duct cyst. The tumors exhibited a papillary, follicular, or mixed architecture with classical papillary thyroid carcinoma nuclear features. Soft tissue extension was present in 16 cases. All patients were managed surgically with a Sistrunk procedure, with additional thyroidectomy performed in 29 patients, combined with a lymph node dissection (n = 15), or a Sistrunk and lymph node dissection (n = 5). All patients were stage I at presentation, with 11 showing lymph node metastases. Postoperative radioactive iodine was employed in 20 patients. A papillary carcinoma of the thyroid gland was reported in four of the patients who had concurrent/subsequent thyroidectomies. Recurrences were reported in four patients, with distant metastases in one patient, who died of disease (13 months). Follow up data was available for 45 patients, with an overall mean follow-up of 54.5 months. All patients were alive, with the exception of one who died with disease. TGDC carcinomas in pediatric patients is associated with a good overall prognosis, best managed by Sistrunk procedure alone, with selected lymph node dissection if clinically indicated.
PubMed ID: 28293858
Article Size: 1.5 MB

Update From the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Tumours of the Ear.

Thompson LD.
Head Neck Pathol. 2017 Mar;11(1):78-87. doi: 10.1007/s12105-017-0790-5. Epub 2017 Feb 28.
The 2017 fourth edition of the World Health Organization Classification of Tumours, specifically as it relates to the ear (Chap. 9), has several changes. Importantly, the number of entities has been significantly reduced by omitting tumors or lesions if they do not occur exclusively or predominantly at this site or if they are discussed in detail elsewhere in the book. These entities include: embryonal rhabdomyosarcoma, osteoma, exostosis, angiolymphoid hyperplasia with eosinophilia, Schneiderian papilloma, inverted papilloma, lipoma of the internal auditory canal, hemangioma, hematolymphoid tumors, and secondary tumors. Paraganglioma was included in the neck chapter. New entries include otosclerosis and cholesteatoma, while refinements to nomenclature, classification and criteria were incorporated into the ceruminous gland tumors and epithelial tumors of the middle and inner ear. Specifically, the middle and inner ear were combined, as practical limitations of origin and imaging make a definitive separation artificial. The classification reflects the state of current understanding for these uncommon entities, with this update only highlighting selected entities that were the most significantly changed.
PubMed ID: 28247225
Article Size: 4.6 MB

Laryngeal Dysplasia, Squamous Cell Carcinoma, and Variants

Thompson, LDR.
Surg Pathol Clin. 2017 Mar;10(1):15-33.
Squamous cell carcinoma (SCC) is a malignant epithelial tumor showing evidence of squamous differentiation. It is the most common malignancy of the larynx, with several variants (verrucous, exophytic or papillary, spindle-cell, basaloid, acantholytic, adenosquamous) recognized, with well-established precursor lesions. Dysplasia is now separated into only low-grade and high-grade categories. Each SCC variant has unique cytomorphologic features and histologic differential diagnoses that are important to consider, as management and outcomes are different.
PubMed ID: 28153131
Article Size: 13 MB

Small round blue cell tumors of the sinonasal tract: a differential diagnosis approach.

Thompson LD.
Mod Pathol. 2017 Jan;30(s1):S1-S26. doi: 10.1038/modpathol.2016.119.
One of the most challenging diagnostic categories within tumors of the sinonasal tract is the small round blue cell tumors. Biopsies are usually small and limited, resulting in considerable diagnostic difficulty for practicing surgical pathologists. These tumors share several overlapping histologic and immunophenotypic findings while also showing considerable variation within and between cases. Specific tumor site of origin, imaging findings, and clinical findings must be combined with the histology and pertinent ancillary studies if the correct diagnosis is to be reached. Discrimination between neoplasms is critical as there are significant differences in therapy and overall outcome. It is important to have a well developed differential diagnosis for this category of tumors, where each of the diagnoses is considered, evaluated, and either confirmed or excluded from further consideration. In an undifferentiated tumor, showing a small round blue cell morphology, using the mnemonic ‘MR SLEEP’ helps to highlight tumors to consider: melanoma, mesenchymal chondrosarcoma, rhabdomyosarcoma, sinonasal undifferentiated carcinoma, squamous cell carcinoma (including NUT carcinoma), small cell osteosarcoma, lymphoma, esthesioneuroblastoma (olfactory neuroblastoma), Ewing sarcoma/primitive neuroectodermal tumor, pituitary adenoma, and plasmacytoma. A panel of pertinent immunohistochemistry studies, histochemistries and/or molecular tests should aid in reaching a diagnosis, especially when taking the pattern and intensity of reactions into consideration.
PubMed ID: 28060373
Article Size: 4 MB

Template for Reporting Results of Biomarker Testing of Specimens From Patients With Thyroid Carcinoma.

Chiosea S, Asa SL, Berman MA, Carty SE, Currence L, Hodak S, Nikiforov YE, Richardson MS, Seethala RR, Sholl LM, Thompson LD, Wenig BM, Worden F; Members of the Cancer Biomarker Reporting Committee, College of American Pathologists.
Arch Pathol Lab Med. 2017 Apr;141(4):559-563.
The College of American Pathologists offers these templates to assist pathologists in providing clinically useful and relevant information when reporting results of biomarker testing. The College regards the reporting elements in the templates as important elements of the biomarker test report, but the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice.
The College developed these templates as educational tools to assist pathologists in the useful reporting of relevant information. It did not issue them for use in litigation, reimbursement, or other contexts. Nevertheless, the College recognizes that the templates might be used by hospitals, attorneys, payers, and others. The College cautions that use of the templates other than for their intended educational purpose may involve additional considerations that are beyond the scope of this document.
Completion of the template is the responsibility of the laboratory performing the biomarker testing and/or providing the interpretation. When both testing and interpretation are performed elsewhere (e.g., a reference laboratory), synoptic reporting of the results by the laboratory submitting the tissue for testing is also encouraged to ensure that all information is included in the patient’s medical record and thus readily available to the treating clinical team.
PubMed ID: 27681332
Article Size: 83 KB

Thyroglossal Duct Cyst Carcinomas: A Clinicopathologic Series of 22 Cases with Staging Recommendations

Thompson LD, Herrera HB, Lau SK.
Head Neck Pathol. 2017 Jun;11(2):175-185.
Carcinomas arising from thyroglossal duct remnant cysts (TGDCs) are rare, without well-defined management and staging criteria. All TGDCs (n = 685) diagnosed between 2005 and 2015 were retrospectively reviewed, with 22 carcinomas identified (3.2 % incidence). Twenty-two patients (17 females, 5 males), aged 12-64 years (mean 39.9 years; median 39 years) were identified. An anterior, superior midline neck mass was the presenting symptom in all patients. A cancer diagnosis [all papillary thyroid carcinoma (PTC)] was made after the Sistrunk procedure (SP), with a Bethesda Category V or VI classification preoperatively by fine needle aspiration in 5 of 12 cases tested. A SP was performed in all patients, with total thyroidectomy concurrently (n = 4) or subsequently (n = 12). A selected neck dissection was performed in 5 patients, with metastases found in 3. Of the patients who had a thyroidectomy, synchronous PTC was identified in 6 (thus, 6 of 22 patients had synchronous thyroid gland primaries). This supports an origin from extra-thyroidal remnants (cyst origin) rather than metastatic tumor from a thyroid gland primary. Follow-up radioactive iodine therapy was performed in 13 patients. Metastatic disease to local lymph nodes 57 months after presentation was seen in 1 patient, with all others alive and disease free (mean 3.8 years; range 0.4-10.8 years). The TGDCs ranged from 0.8 to 5 cm (mean 2.3 cm), while the PTCs ranged from 0.1 to 3.8 cm (mean 1.4 cm). All of the tumors were classical PTC, showing a sclerotic and infiltrative pattern, with a capsule present in 11. Lymphovascular invasion was detected in 11; margins were positive in 6. Using currently defined criteria, the patients were separated into AJCC stage group I (n = 21) or II (n = 1). However, if extension into the adipose tissue (n = 11), skeletal muscle (n = 10), or perineural/perivascular tissues (n = 10) were used to stage the patients, interpreted to represent the equivalent of “extrathyroidal extension” (n = 13) as defined for thyroid gland primaries, there would be 15 group I and 7 group III cases. All seven group III patients were ≥45 years. Three of four patients with lymph node metastasis also showed soft tissue extension. In conclusion, TGDC carcinomas (TGDCCa) are uncommon, with all classical PTC. For “microcarcinomas” (≤1 cm), conservative management can be used for patients <45 years (i.e., Sistrunk procedure only); for >1 cm tumors, and due to the high incidence of concurrent papillary carcinoma and higher stage at presentation in older patients, completion thyroidectomy is recommended for patients ≥45 years. Thus, even though a good prognosis can be expected for PTC developing in TGDCs, staging is advocated to more appropriately match therapeutic interventions.
PubMed ID: 27704385
Article Size: 2.5 MB

Myeloid sarcoma of the breast soft tissue following allogeneic bone marrow transplantation

Chou JL, Thompson LD.
J Case Rep Images Oncology 2016;2:71–73.
FIRST PARAGRAPH: A 47-year-old female presented with high-risk myelodysplastic syndrome (MDS) without detectable cytogenetic abnormality from the bone marrow specimen. Initially, she received azacytidine while awaiting bone marrow transplantation (BMT). After successful allogeneic BMT from a mismatched related donor, she received post-transplant care including management of transplant-related toxicity and skin manifestations of graft versus host disease (GVHD) in a designated BMT center. Subsequent bone marrow showed no evidence of MDS, and she is currently free from GVHD.
Article Size: <1 MB

Inter-Observer Variation in the Pathologic Identification of Extranodal Extension in Nodal Metastasis from Papillary Thyroid Carcinoma

Du E, Wenig BM, Su HK, Rowe ME, Haser GC, Asa SL, Baloch Z, Faquin WC, Fellegara G, Giordano T, Ghossein R, LiVolsi VA, Lloyd R, Mete O, Ozbek U, Rosai J, Suster S, Thompson LD, Turk AT, Urken ML.
Thyroid. 2016 Jun;26(6):816-9.
Background: Extranodal extension (ENE) in lymph node metastases has been shown to worsen the prognosis of papillary thyroid cancer (PTC). Despite the clinical significance of ENE, there are no stringent criteria for its microscopic diagnosis, and its identification is subject to inter-observer variability. The objective of this study was to determine the level of agreement among expert pathologists in the identification of ENE in PTC cases.
Methods: Eleven expert pathologists from the United States, Italy, and Canada were asked to review 61 scanned slides of representative permanent sections of PTC specimens from Mount Sinai Beth Israel Medical Center in New York. Each slide was evaluated for the presence of ENE. The pathologists were also asked to report the criteria they use to identify ENE.
Results: The overall strength of agreement in identifying ENE was only fair (j = 0.35), and the proportion of observed agreement was 0.68. The proportions of observed agreement for the identification of perinodal structures (fat, nerve, skeletal, and thick-walled vessel involvement) ranged from 0.61 to 0.997.
Conclusions: Overall agreement for the identification of ENE is poor. The lack of agreement results from both variation in pathologists’ identification of features and disagreement on the histologic criteria for ENE. This lack of concordance may help explain some of the discordant information regarding prognosis in clinical studies when this feature is identified.
PubMed ID: 27089928
Article Size: <1 MB

Subsets of Salivary Duct Carcinoma Defined by Morphologic Evidence of Pleomorphic Adenoma, PLAG1 or HMGA2 Rearrangements, and Common Genetic Alterations

Chiosea SI, Thompson LD, Weinreb I, Bauman JE, Mahaffey AM, Miller C, Ferris RL, Gooding WE.
Cancer. 2016 Oct 15;122(20):3136-3144. doi: 10.1002/cncr.30179. Epub 2016 Jul 5.
BACKGROUND: The authors hypothesized that histogenetic classification of salivary duct carcinoma (SDC) could account for de novo tumors and those with morphologic or molecular evidence (pleomorphic adenoma gene 1 [PLAG1], high-mobility group AT hook 2 [HMGA2] rearrangement, amplification) of pleomorphic adenoma (PA).
METHODS: SDCs (n = 66) were reviewed for morphologic evidence of PA. PLAG1 and HMGA2 alterations were detected by fluorescence in situ hybridization (FISH). PLAG1-positive tumors were tested by FISH for fibroblast growth factor receptor 1 (FGFR1) rearrangement. Thirty-nine tumors were analyzed using a commercial panel for mutations and copy number variations in 50 cancer-related genes.
RESULTS: On the basis of combined morphologic and molecular evidence of PA, 4 subsets of SDC emerged: 1) carcinomas with morphologic evidence of PA but intact PLAG1 and HMGA2 (n = 22); 2) carcinomas with PLAG1 alteration (n = 18) or 3) HMGA2 alteration (n = 12); and 4) de novo carcinomas, without morphologic or molecular evidence of PA (n = 14). The median disease-free survival was 37 months (95% confidence interval, 28.4-45.6 months). Disease-free survival and other clinicopathologic parameters did not differ for the subsets defined above. Combined Harvey rat sarcoma viral oncogene homolog/phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit α (HRAS/PIK3CA) mutations were observed predominantly in de novo carcinomas (5 of 8 vs 2 of 31 tumors; P = .035). Erb-B2 receptor tyrosine kinase 2 (ERBB2) copy number gain was not observed in de novo carcinomas (0 of 8 vs 12 of 31 tumors; P = .08). Tumor protein 53 (TP53) mutations were more common in SDC ex pleomorphic adenomas than in de novo carcinomas (17 of 31 vs 1 of 8 tumors; P = .033).
CONCLUSIONS: The genetic profile of SDC varies with the absence or presence of pre-existing PA and its cytogenetic signature. Most de novo SDCs harbor combined HRAS/PIK3CA mutations and no ERBB2 amplification.
PubMed ID: 27379604
Article Size: <1 MB

Cervical Lymph Node Metastasis in Adenoid Cystic Carcinoma of the Larynx: A Collective International Review

Coca-Pelaz A, Barnes L, Rinaldo A, Cardesa A, Shah JP, Rodrigo JP,, Suárez C,, Eloy JA, Bishop JA, Devaney KO, Thompson LD, Wenig BM, Strojan P, Hamoir M, Bradley PJ,, Gnepp DR,, Silver CE, Slootweg PJ, Triantafyllou A, Vander Poorten V,, Williams MD, Skálová A, Hellquist H, Teymoortash A, Medina JE, Robbins KT, Pitman KT, Kowalski LP, de Bree R, Mendenhall WM, Takes RP, Ferlito A.
Adv Ther. 2016 Apr;33(4):553-79.
Adenoid cystic carcinoma (AdCC) of the head and neck is a well-recognized pathologic entity that rarely occurs in the larynx. Although the 5-year locoregional control rates are high, distant metastasis has a tendency to appear more than 5 years post treatment. Because AdCC of the larynx is uncommon, it is difficult to standardize a treatment protocol. One of the controversial points is the decision whether or not to perform an elective neck dissection on these patients. Because there is contradictory information about this issue, we have critically reviewed the literature from 1912 to 2015 on all reported cases of AdCC of the larynx in order to clarify this issue. During the most recent period of our review (1991-2015) with a more exact diagnosis of the tumor histology, 142 cases were observed of AdCC of the larynx, of which 91 patients had data pertaining to lymph node status. Eleven of the 91 patients (12.1%) had nodal metastasis and, based on this low proportion of patients, routine elective neck dissection is therefore not recommended.
PubMed ID: 27084720
Article Size: <1 MB

Update on follicular variant of papillary thyroid carcinoma with an emphasis on new terminology: noninvasive follicular thyroid neoplasm with papillary-like nuclear features

Thompson, LDR.
Diagnostic Histopathology 2016.
The most common papillary thyroid carcinoma (PTC) variant is the follicular variant, representing w30% of all PTCs. The tumour is most common in middle aged (4th e 5th decades) women, who usually present with a single dominant nodule (about 3 cm). By definition, follicular architecture must be the dominant finding, while demonstrating the nuclear features of PTC. Papillary structures are <1% of volume, while necrosis, increased mitoses (>3/10 high power fields) and psammoma bodies are absent. The tumour category is divided into “encapsulated/well demarcated” and “invasive” types. The nuclear features include enlarged, elongated and overlapping nuclei; membrane irregularities (irregular contours, grooves and pseudoinclusions); chromatin clearing, margination and glassy nuclei. When the tumour is encapsulated/well demarcated without invasion, demonstrating the other inclusion and exclusion criteria, the new name of “Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features” (NIFTP) is used, a tumour that requires no additional treatment.
PubMed ID: n/a
Article Size: 8.4 MB

A Clinicopathologic Series of 685 Thyroglossal Duct Remnant Cysts

Thompson LD, Herrera HB, Lau SK.
Head Neck Pathol. 2016 Dec;10(4):465-474. Epub 2016 May 9.
The clinical features of thyroglossal duct remnant cysts (TGDC) have been well described, however the histopathologic aspects of these lesions have not been addressed in a detailed manner. In particular, there has been no large community practice based series evaluating TGDC histologically compared with management outcomes. A retrospective review of all TGDC diagnosed between 2005 and 2015 was performed. Six hundred eighty-five patients were identified (344 males; 341 females). Age at presentation was bimodal (first and fifth decades) and ranged from 0.8 to 87 years (mean 31.3 years). Males predominate in children (150:111); females in adults (230:194). Patients presented most frequently with a mobile midline neck mass in an infrahyoid location. An associated skin fistula (n = 67) was twice as common in pediatric as adult patients. The average cyst size was 2.4 cm (range 0.4-9.9 cm) by imaging studies and 2.6 cm (range 0.2-8.5 cm) by pathologic examination; pediatric patients had smaller cysts (mean 2.1 cm) than adults (mean 2.8 cm). Histologically, 257 (38 %) TGDC were lined by respiratory epithelium alone, 68 (10 %) squamous epithelium alone, 347 (51 %) exhibited both respiratory and squamous epithelium, and 13 (1 %) had no identifiable epithelial lining. Four hundred eighty-four (71 %) TGDC had associated thyroid gland tissue present within the cyst wall (n = 282), skeletal muscle (n = 71), adipose tissue (n = 34), or a combination of these sites (n = 97). The hyoid bone was identified in 647 (grossly and/or histologically), and absent in 38. Surgical management consisted of Sistrunk procedure (n = 647), cystectomy (n = 31), or thyroidectomy/thyroid lobectomy (n = 7). Treatment related complications were observed in 6 patients, which included vocal cord damage, seroma, and hematoma. Recurrences developed in 20 (3 %) patients, 14 of whom were managed initially by cystectomy. Papillary thyroid carcinoma was identified in 22 (3.2 %) TGDC. In summary, TGDC show a bimodal peak in the 1st and 5th decades, commonly presenting as a midline cervical lesion below the hyoid bone, associated with a skin fistula in 10 %. Histologically TGDC are most commonly lined by a combination of respiratory and squamous epithelium. Thyroid gland tissue is identified in 71 % of cases (0.45 cm mean size), although not limited to the cyst wall, but present in the surrounding soft tissues. Rare TGDC may harbor malignancy (3.2 %). TGDC are most effectively managed by Sistrunk procedure rather than excision, which carries low rates of complications (1 %) and recurrence (3 %).
PubMed ID: 27161104
Article Size: 2.7 MB

Ear and temporal bone meningioma

Thompson, LD.
Ear Nose Throat J. 2016 Apr-May;95(4-5):146.
FIRST PARAGRAPH: Meningiomas account for 30% of all intracranial neoplasms, but primary extracranial (ectopic) meningiomas of the ear and temporal bone are less common, accounting for about 10% of all ear and temporal bone tumors. Meningiomas are derived from the arachnoid cap cells, also called pacchionian bodies.
PubMed ID: 27140011
Article Size: <1 MB

Ninety-four cases of encapsulated follicular variant of papillary thyroid carcinoma: A name change to Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features would help prevent overtreatment

Thompson, LD.
Mod Pathol. 2016 Jul;29(7):698-707.
Encapsulated follicular variant of papillary thyroid carcinoma is a common thyroid gland cancer, with a highly indolent behavior. Recently, reclassification as a non-malignant neoplasm has been proposed. There is no comprehensive, community hospital based longitudinal evaluation of encapsulated follicular variant of papillary thyroid carcinoma. Ninety-four cases of encapsulated follicular variant of papillary thyroid carcinoma were identified in a review of all thyroid gland surgeries performed in 2002 within the Southern California Permanente Medical Group. All histology slides were reviewed and follow-up obtained. Seventy-five women and nineteen men, aged 20-80 years (mean 45.6 years), had a single (n=61), multiple (same lobe; n=20), or bilateral (n=13) tumor(s), ranging in size from 0.7 to 9.5 cm in diameter (mean 3.3 cm). Histologically, all cases demonstrated a well-formed tumor capsule, with capsular and/or lymphovascular invasion in 17 and no invasion in 77 cases. Lymph node metastases were not identified. The tumors had a follicular architecture, without necrosis or 43 mitoses/10 high-power fields (HPFs). Classical papillary thyroid carcinoma nuclear features were seen in at least three HPFs per 3mm of tumor diameter, including enlarged, elongated, crowded, and overlapping nuclei, irregular nuclear contours, nuclear grooves, and nuclear chromatin clearing. Lobectomy alone (n=41), thyroidectomy alone (n=34), or completion thyroidectomy (n=19) was the initial treatment combined with post-op radioablative iodine in 25 patients. All patients were without evidence of disease after a median follow-up of 11.8 years. Encapsulated follicular variant of papillary thyroid carcinoma showed benign behavior, supporting conservative surgery alone and reclassification of these tumors to Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP).
PubMed ID: 27102347
Article Size: <1 MB

Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma: A Paradigm Shift to Reduce Overtreatment of Indolent Tumors.

Nikiforov YE, Seethala RR, Tallini G, Baloch ZW, Basolo F, Thompson LD, Barletta JA, Wenig BM, Al Ghuzlan A, Kakudo K, Giordano TJ, Alves VA, Khanafshar E, Asa SL, El-Naggar AK, Gooding WE, Hodak SP, Lloyd RV, Maytal G, Mete O, Nikiforova MN, Nosé V, Papotti M, Poller DN, Sadow PM, Tischler AS, Tuttle RM, Wall KB, LiVolsi VA, Randolph GW, Ghossein RA.
JAMA Oncol. 2016 Aug 1;2(8):1023-9.
IMPORTANCE: Although growing evidence points to highly indolent behavior of encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC), most patients with EFVPTC are treated as having conventional thyroid cancer.
OBJECTIVE: To evaluate clinical outcomes, refine diagnostic criteria, and develop a nomenclature that appropriately reflects the biological and clinical characteristics of EFVPTC.
DESIGN, SETTING, AND PARTICIPANTS: International, multidisciplinary, retrospective study of patients with thyroid nodules diagnosed as EFVPTC, including 109 patients with noninvasive EFVPTC observed for 10 to 26 years and 101 patients with invasive EFVPTC observed for 1 to 18 years. Review of digitized histologic slides collected at 13 sites in 5 countries by 24 thyroid pathologists from 7 countries. A series of teleconferences and a face-to-face conference were used to establish consensus diagnostic criteria and develop new nomenclature.
MAIN OUTCOMES AND MEASURES: Frequency of adverse outcomes, including death from disease, distant or locoregional metastases, and structural or biochemical recurrence, in patients with noninvasive and invasive EFVPTC diagnosed on the basis of a set of reproducible histopathologic criteria.
RESULTS: Consensus diagnostic criteria for EFVPTC were developed by 24 thyroid pathologists. All of the 109 patients with noninvasive EFVPTC (67 treated with only lobectomy, none received radioactive iodine ablation) were alive with no evidence of disease at final follow-up (median [range], 13 [10-26] years). An adverse event was seen in 12 of 101 (12%) of the cases of invasive EFVPTC, including 5 patients developing distant metastases, 2 of whom died of disease. Based on the outcome information for noninvasive EFVPTC, the name “noninvasive follicular thyroid neoplasm with papillary-like nuclear features” (NIFTP) was adopted. A simplified diagnostic nuclear scoring scheme was developed and validated, yielding a sensitivity of 98.6% (95% CI, 96.3%-99.4%), specificity of 90.1% (95% CI, 86.0%-93.1%), and overall classification accuracy of 94.3% (95% CI, 92.1%-96.0%) for NIFTP.
CONCLUSIONS AND RELEVANCE: Thyroid tumors currently diagnosed as noninvasive EFVPTC have a very low risk of adverse outcome and should be termed NIFTP. This reclassification will affect a large population of patients worldwide and result in a significant reduction in psychological and clinical consequences associated with the diagnosis of cancer.
PubMed ID: 27078145

Inter-Observer Variation in the Pathologic Identification of Minimal Extrathyroidal Extension in Papillary Thyroid Carcinoma.

Su HK, Wenig BM, Haser GC, Rowe ME, Asa SL, Baloch Z, Du E, Faquin WC, Fellegara G, Giordano T, Ghossein R, LiVolsi VA, Lloyd R, Mete O, Ozbek U, Rosai J, Suster S, Thompson LD, Turk AT, Urken ML.
Thyroid. 2016 Apr;26(4):512-7.
BACKGROUND: Extrathyroidal extension (ETE) is a significant prognostic factor in papillary thyroid carcinoma (PTC). Minimal extrathyroidal extension (mETE) is characterized by involvement of the sternothyroid muscle or perithyroid soft tissue, and is generally identified by light microscope examination. Patients with mETE, identified pathologically, are automatically upstaged to pT3. However, the prognostic implications of mETE have been a source of controversy in the literature. Moreover, there is also controversy surrounding the identification of mETE on pathological specimens. The objective of this study was to determine the level of agreement among expert pathologists in the identification of mETE in PTC cases.
METHODS: Eleven expert pathologists from the United States, Italy, and Canada were asked to perform a review of 69 scanned slides of representative permanent sections of PTC specimens. Each slide was evaluated for the presence of mETE. The pathologists were also asked to list the criteria they use to identify mETE.
RESULTS: The overall strength of agreement for identifying mETE was slight (κ = 0.14). Inter-pathologist agreement was best for perithyroidal skeletal muscle involvement (κ = 0.46, moderate agreement) and worst for invasion around thick-walled vascular structures (κ = 0.02, slight agreement). In addition, there was disagreement over the constellation of histologic features that are diagnostic for mETE, which affected overall agreement for diagnosing mETE.
CONCLUSIONS: Overall agreement for the identification of mETE is poor. Disagreement is a result of both variation in individual pathologists’ interpretations of specimens and disagreement on the histologic criteria for mETE. Thus, the utility of mETE in staging and treatment of PTC is brought into question. The lack of concordance may explain the apparent lack of agreement regarding the prognostic significance of this pathologic feature.
PubMed ID: 26953223
Article Size: <1 MB