Did President Grant die from too much Oral Sex?

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1 Case 6 Did President Grant die from too much Oral Sex? Lester D. R. Thompson 53 year old man Small nodule noted 2 months ago, just below the angle of the jaw during shaving Non-tender Smokes, drinks and works in the adult film industry FNA performed, with follow-up biopsy 2 History 65 year old man Small nodule noted 2 months ago, just below the angle of the jaw during shaving Non-tender Smokes, drinks and works in the adult film industry FNA performed, with follow-up biopsy 3 4 Oropharyngeal Carcinoma Definition Oropharyngeal squamous cell carcinoma (OPSCC) is a malignant epithelial neoplasm involving the oropharynx which includes: Soft palate Tonsils and adenoids (Waldeyer ring) Uvula Base of tongue Oropharyngeal wall 5 6 Oropharyngx and Thyroid 1

2 Sagittal Axial Environmental Exposure Etiology/Pathogenesis Marijuana use is greater in HPV+ OPSCC Tobacco smoking and alcohol use greater in HPV- OPSCC, but still a major factor in HPV+ OPSCC Infectious Agents High-risk HPV associated with >80% of cases OPSCC HPV 16 is the predominant type Other HPV high-risk types are reported Epidemiology OPSCC increased 1-2% annually in USA males in past 20 years In USA, 225% increase in HPV+ OPSCC between ~13,000 new cases/year in US 9 10 It is a sexually transmitted disease: Higher than average sex history Oral sex, multiple partners Epidemiology Sex: Male (~95%) Age: s Race: Caucasian History of smoking Mostly light or former Presentation Site: Anterior tonsillar pillar and fossa most common Tongue base Presentation Early lesions generally asymptomatic Tonsillar asymmetry Dysphagia Otalgia Trismus Enlarging cervical lymph node Often presenting symptom > 70% of patients present with stage III or IV disease Oropharyngx and Thyroid 2

3 13 14 Imaging Findings Computed tomography (CT) &/or magnetic resonance imaging (MR) for preoperative tumor staging and planning Chest CT or plain film to rule out lung metastases Positron emission tomography (PET) useful particularly when dealing with unknown primary or in evaluating distant metastases Distant metastases uncommon in oral cavity cancer at presentation Oropharyngx and Thyroid 3

4 Cytology Fine needle aspiration of cervical lymph node may be initial biopsy Nonkeratinizing OPSCC show cohesive groups of cells with distinct cell borders and hyperchromatic nuclei Keratinization usually absent or minimal Cellular debris and inflammatory cells May be hypocellular because of cyst formation Serous fluid in cystic lymph node metastasis Distinct from metastatic lymph node with central necrosis Squamous Cell Carcinoma There are 3 major carcinoma types in the upper aerodigestive tract that do not progress through dysplastic precursors Basaloid squamous cell carcinoma Nonkeratinizing squamous carcinoma Lymphoepithelial carcinoma Microscopic Features HPV positive types Oropharyngeal SCC, non-keratinizing Oropharyngeal SCC, keratinizing HPV negative types Oropharyngeal SCC, non-keratinizing Oropharyngeal SCC, keratinizing HPV Detection Methods Show biologically or transcriptionally-active HPV Polymerase chain reaction RT-PCR for high risk E6/E7 mrna In situ hybridization Multiplexed (High risk vs. low risk) Type specific probes Other methods Hybrid capture (cytology samples) Other technologies p16 immunohistochemistry 23 Oncogenesis of HPV E7 p16 Cyclin D1 Rb E2F S-phase p21 ARF p53 MDM2 Apoptosis E6 HPV protein E7 degrades the retinoblastoma protein leading to aberrant overexpression of p16 Courtesy Dr. J. L. Hunt 24 Oropharyngx and Thyroid 4

5 Study # of p16 Positive Patients* Dahlstrand, Anticancer Res 2005 HPV DNA PCR HPV DNA ISH HPV DNA ISH & DNA PCR HPV RNA RTPCR HPV RNA ISH (93%) NP NP NP NP Weinberger, JCO (94%) NP NP NP NP Reimer, Int J Cancer (86%) NP NP NP NP Ang, NEJM NP 192 (93%) NP NP NP Lewis, AJSP NP 139 (74%) Ukpo, AJSP NP 119/157 (75%) 161 (86.1%) NP NP NP NP 147/148 (99%) Schlecht, Mod Pathol NP 6/10 (60%) NP 10 (90.9%) NP Thavaraj, J Clin Pathol NP 75 (83.3%) 88 (97.8%) NP NP Doxtader, Hum Pathol NP 24 (96.0%) NP NP NP Totals /63 (90%) 555/675 (82%) 249/277 (89%) 10/11 (90%) 147/148 (99%) HPV Detection methods Approximately 5% of p16 positive were HPV- However, p16 may be over-expressed by another mechanism Approximately 2% of p16 negative cases were HPV+ p16 is a sensitive marker for transcriptionally active HPV Clone E6H4 (MTM Laboratories) gives best results Must be >70% nuclear & cytoplasmic positive 26 WHO Classification Book-2017 p Microscopic Features HPV-positive OPSCC OPSCC, Nonkeratinizing type (75% of cases) Tumor often seen arising from epithelium of tonsillar crypts rather than overlying epithelium Basaloid oval to spindle-shaped cells with hyperchromatic nuclei and minimal cytoplasm forming trabeculae, sheets, or nests with sharply defined borders Comedo-necrosis frequently present Brisk mitotic rate and numerous scattered apoptotic cells Permeated by lymphocytes Squamous maturation and focal areas of keratinization can be seen but should comprise <10% Oropharyngx and Thyroid 5

6 Microscopic Features HPV-positive OPSCC OPSCC, Hybrid-type (with maturation) Has features of both nonkeratinizing OPSCC and keratinizing SCC Squamous maturation is >10% but < 25% Not all cases show p16 or HPV positivity p Oropharyngx and Thyroid 6

7 37 38 p Microscopic Features HPV-positive OPSCC OPSCC, Lymphoepithelial-like Similar in histology to EBV-related nasopharyngeal carcinoma Syncytial-appearing large tumor cells with indistinct cell borders and vesicular nuclei intermingled with lymphocytes and plasma cells Tumor cells immunoreactive for cytokeratin Positive: p16 (IHC) Negative: EBER (ISH) Oropharyngx and Thyroid 7

8 p16 p OPSCC, Papillary Microscopic Features HPV-positive OPSCC Exceedingly uncommon morphologic variant of SCC that can occur in oropharynx Finger-like projections of cytologically malignant epithelial cells with fibrovascular cores Surface keratinization usually limited Definitive invasive SCC may be difficult to see, particularly on biopsy specimens Up to 2/3 of cases reported to be p16 positive but < 50% positive for high-risk HPV p Oropharyngx and Thyroid 8

9 Microscopic Features HPV-negative OPSCC OPSCC, Keratinizing Exhibits features of conventional-type SCC, including nests of epithelial cells with abundant eosinophilic cytoplasm and welldefined cell borders Frank keratinization present Basaloid morphology not seen p Reaction Positive Negative Positive Negative Tumor Type: p16 and HPV reactions Nonkeratinizing (54%) 98% 2 % 88% 12% Nonkeratinizing with maturation (21%) p16 HPV 84% 16% 74% 26% Keratinizing (25%) Immunohistochemistry p16 strongly positive in HPV-associated OPSCC >70% both nuclear & cytoplasmic staining of tumor cells 19% Normal epithelium is negative or shows minimal patchy staining 81% p16 considered reliable surrogate marker for high risk BE AWARE: p16+ alone DOES NOT equal 21% oropharyngeal carcinoma! 79% There are many lesions that can be p16 positive 54 Oropharyngx and Thyroid 9

10 Treatment & Prognosis Approaches depend on clinical stage Tonsillectomy for small T1 tumors confined to tonsil Radiation therapy, specifically intensity-modulated radiation therapy (IMRT) (including brachytherapy) Concurrent radiotherapy with multiagent chemotherapy Targeted agents such as cetuximab Prognosis HPV-positive OPSCC associated with improved survival outcomes Tumor size and presence of metastases influence p prognosis Prognosis Radiation: HPV+ HPV- 5 year 62% 26% Tobacco use: Decreased survival + Nodal status: Decreased survival Patients can be stratified into deescalation therapies E6 and E7 oncoprotein can be targeted, restoring p53 and retinoblastoma tumor suppressor pathways (degraded by E6/E7) Survival: Radiation vs. Chemotherapy Radiotherapy and Oncology, Volume 103, Issue 1, 2012, Oropharyngx and Thyroid 10

11 Pertinent Issues Do not diagnose OPSCC as in-situ Do not give tumor grades for OPSCC Report: Oropharyngeal squamous cell carcinoma Non-keratinizing; with maturation; or keratinizing types (for clarity) Report p16 as part of the original report 61 Base of Tongue p1662 The most important thing to do: 1. Perform CK5/6 2. Do EBER 3. Report p16 4. Do HPV subtyping Sample Diagnosis Base of tongue, right (biopsy): 1) HPV-associated Oropharyngeal squamous cell carcinoma, non-keratinizing type 2) p16: Strong, diffuse, nuclear and cytoplasmic positive. 64 Tonsil p Oropharyngx and Thyroid 11

12 Sample Diagnosis Tonsil, left (biopsy): 1) HPV-associated Oropharyngeal squamous cell carcinoma, with maturation 2) p16: Strong, diffuse, nuclear and cytoplasmic positive. 67 Nasopharynx 68 Differential Diagnosis Nasopharyngeal Carcinoma Share similar clinical presentation of enlarged cervical lymph node as initial manifestation of disease Lymphoepithelial carcinoma pattern Strong association with EBV EBER in situ hybridization may be helpful in separating occult metastasis from either nasopharynx or oropharynx DO NOT DO EBV LMP! 69 EBER 70 Sample Diagnosis P16 positive cases instead Nasopharynx, right (biopsy): 1) Nasopharyngeal carcinoma, nonkeratinizing type 2) p16: Strong, diffuse, nuclear and cytoplasmic positive 3) EBER: Negative p Oropharyngx and Thyroid 12

13 HPV-associated Neuroendocrine Oropharyngeal carcinoma HPV-associated Neuroendocrine Oropharyngeal carcinoma 73 Synaptophysin p1674 Branchial Cleft Cyst with p16 p Malignant Proliferating Pilar Tumor Diffuse large B-cell lymphoma CD20 p16 p Oropharyngx and Thyroid 13

14 Case #7 Abbreviations in Thyroid Pathology Lester D. R. Thompson 35 y.o. Female Presented with an enlarged right thyroid gland lobe. FNA was performed on a 6.0 cm mass Lobectomy was performed Papillary Thyroid Carcinoma: Follicular Variant Encapsulated Type Replaced by: Noninvasive Follicular Thyroid Neoplasm with Papillary-like like Nuclei (NIFTP) Overall Objectives What is the current management of papillary carcinoma? What are the trends and what can we do differently? Supporting data Recommendations 84 Oropharyngx and Thyroid 14

15 Thyroid Neoplasms: General Considerations Thyroid carcinoma is most common endocrine malignancy (3.8% of all new US cancers; 9 th most common cancer type) Incidence = 62,980 /year 1 per 8 minutes Death rate = 1,890 (annual) (0.3% all deaths) Age = years old Sex = F:M = 3: /100,000 population /year 1.1% will develop thyroid cancer during lifetime WHO Histological Classification of Thyroid Tumours Thyroid carcinomas Papillary carcinoma 8260/3 Follicular carcinoma 8330/3 Poorly differentiated carcinoma Undifferentiated (anaplastic) carcinoma 8020/3 Squamous cell carcinoma 8070/3 Mucoepidermoid carcinoma 8430/3 Sclerosing mucoepidermoid carcinoma with eosinophilia 8430/3 Mucinous carcinoma 8480/3 Medullary carcinoma 8345/3 Mixed medullary and follicular cell carcinomas 8346/3 Spindle cell tumour with thymus-like differentiation 8588/3 Carcinoma showing thymus-like differentiation 8589/3 Thyroid adenoma Follicular adenoma 8330/0 Hyalinizing trabecular tumour 8336/0 Other thyroid tumours Teratoma 9080/1 Primary lymphoma and plasmacytoma Ectopic thymoma 8580/1 Angiosarcoma 9120/3 Smooth muscle tumours Peripheral nerve sheath tumours Paraganglioma 8693/1 Solitary fibrous tumour 8815/0 Follicular dendritic cell tumour 9758/3 Langerhans cell histiocytosis 9751/1 Secondary tumours 97.8% 5-year survival for all thyroid cancers Current Management Lobectomy or Thyroidectomy Pre-op FNA dependent Completion thyroidectomy if any of following: Tumor >4 cm Positive Margins Extrathyroidal extension Macroscopic multifocal disease (not microscopic) Confirmed lymph node metastasis Lymphovascular invasion Version 2, 2015 (07/2015): NCCN Clinical Practice Guidelines Current Management NO completion thyroidectomy only if all are present: Age between years No prior radiation No distant metastases No cervical metastases No extrathyroidal extension Tumor <4 cm No aggressive variant Tall, Columnar, Diffuse sclerosing, poorly Thyroid Papillary Carcinoma: Histologic Types Usual or Conventional types Occult, incidental, microcarcinoma, microscopic Follicular Macrofollicular Oncocytic or oxyphilic Clear cell Biologically Aggressive Variants Diffuse sclerosing Tall cell Columnar cell Insular or Poorly differentiated differentiated Oropharyngx and Thyroid 15

16 Thyroid Papillary Carcinoma: Classic Pathology Macroscopic Majority are solid and solitary May be cystic Encapsulated versus overt invasion Adjacent tissues or extrathyroidal extension (pt3) Fibrosis and calcification may be present Size varies: Occult, incidental, minute, microscopic < 1.0 cm by WHO definition Large: > 5 cm Architectural Vascular or capsular invasion Variable growth patterns Elongated and/or twisted follicles Calcospherites (psammoma bodies) Intratumoral fibrosis Tincture of colloid (bright and rich) & scalloping Crystals or giant cells in the colloid Thyroid Papillary Carcinoma: Classic Morphologic Features Cytomorphologic/Nuclear Enlarged cells (compared to normal thyroid) High nuclear to cytoplasmic ratio Nuclear overlapping, crowding Irregular placement around follicle Nuclear grooving/folding Intranuclear cytoplasmic inclusions Pale chromatin with chromatin margination/condensation and clearing Orphan Annie Nuclei Thyroid Papillary Carcinoma: Classic Morphologic Features Architectural Vascular or capsular invasion Variable growth patterns Elongated and/or twisted follicles Calcospherites (psammoma bodies) Intratumoral fibrosis Tincture of colloid (bright and rich) & scalloping Crystals or giant cells in the colloid Oropharyngx and Thyroid 16

17 Oropharyngx and Thyroid 17

18 Thyroid Papillary Carcinoma: Classic Morphologic Features Cytomorphologic/Nuclear Enlarged cells (compared to normal thyroid) High nuclear to cytoplasmic ratio Nuclear overlapping, crowding Irregular placement around follicle Nuclear grooving/folding/irregular contour Intranuclear cytoplasmic inclusions Pale chromatin with chromatin margination/condensation and clearing Orphan Annie Nuclei Oropharyngx and Thyroid 18

19 NIFTP: Noninvasive Follicular Thyroid Neoplasm with Papillary-like like Nuclei Accepted term at March, 2015 The Endocrine Pathology Society Conference for Re-Examination of the Encapsulated Follicular Variant of Thyroid Papillary Carcinoma in Boston 112 Materials Reviewed All thyroid surgeries performed in 2002 A minimum of 10 years of follow-up 721 cases reviewed All histology slides reviewed 7,977 primary slides 2,022 additional intraoperative, IHC, levels, specials, deepers Follow-up obtained from EMR or direct communication Diagnosis (= 324) Papillary carcinoma: Type/Variant Breakdown # of Cases % of all papillary cases Classical Microscopic Follicular variant Tall cell Diffuse sclerosing Oropharyngx and Thyroid 19

20 Study Design International, multi-disciplinary study of 138 patients with Noninvasive EFVPTC followed for years and 130 patients with invasive EFVPTC followed for 1-18 years collected at 13 sites in 5 countries. Review of digitalized histologic slides by 24 thyroid pathologists from 7 countries. 24 experienced thyroid pathologists (representing 7 countries and 4 continents), two endocrinologists, one surgeon, and one psychiatrist. In addition, a molecular pathologist, a biostatistician, and a thyroid cancer survivor/patient advocate participated in the study Study Materials A total of 268 tumors diagnosed as EFVPTC based on current criteria were contributed by working group pathologists from 13 institutions Potential cases for Group 1 included Noninvasive EFVPTC with no radioiodine (RAI) treatment and at least 10 years of follow-up (n=138). Potential cases for Group 2 included EFVPTC with vascular invasion and/or tumor capsule invasion and 1 year of follow-up (n=130). 8 week series of weekly teleconferences aimed to refine groups 1 and 2 and to achieve consensus 0Study/view.apml Mutations in Papillary Carcinoma and Phenotypical Associations Molecular Alterations Point mutations involving RAS genes about 10% of papillary carcinomas Almost exclusively the follicular variant Seen in NRAS, HRAS, and KRAS genes Strong correlation with More frequent tumor encapsulation Lower rate of lymph node BRAF K601E mutation usually in follicular variant of papillary carcinoma PAX8/PPARγ Usually follicular carcinoma 5% of follicular variant papillary carcinomas Oropharyngx and Thyroid 20

21 Histology Gene Profiles and Histologic Variants Molecular Major Features 1. Encapsulation or clear demarcation 2. Follicular growth pattern (<1% papillae) 3. Nuclear Features of PTC (Score 2 or 3): Enlargement/crowding/ overlapping Elongation Irregular contours Grooves Pseudoinclusions Chromatin clearing Minor Features 1. Dark colloid 2. Irregularly-shaped follicles 3. Intratumoral fibrosis 4. Sprinkling sign 5. Follicles cleft from stroma 6. Multinucleated giant cells within follicles Criteria Features not seen/ Exclusion criteria 1. True papillae >1% 2. Psammoma bodies 3. Infiltrative border (capsular or lymphovascular invasion) 4. Tumor necrosis 5. High mitotic activity (>3/10 HPFs) 6. Cell/morphologic characteristics of other variants of PTC 123 ALGORITHM FOR DIAGNOSIS OF NIFTP Encapsulated or Well-demarcated Yes Capsular and/or Lymphovascular invasion No >30% solid/insular/trabecular and/or >1% true papillary pattern and/or Psammoma bodies identified and/or Tall cell or columnar cell variants No Predominantly follicular pattern Yes Nuclear features of papillary thyroid carcinoma (score 2 or 3) No Yes Yes No Tumor necrosis and/or >3 mitoses/10 HPFs Yes No Yes NIFTP No N O T N I F T P Infiltrative FVPTC EFVPTC or FC with invasion Solid PTC and/or Classical PTC and/or Tall cell or columnar cell variants Classical PTC encapsulated and/or Follicular adenoma Poorly differentiated tumor Follicular adenoma and/or adenomatoid nodule Noninvasive Follicular Thyroid Neoplasm with Papillary-like like Nuclei Surrounded by thick, well formed capsule Capsule may be thinned and attenuated Partially encapsulated and incompletely encapsulated are equivalent Smooth muscle-walled vessels within the fibrosis Oropharyngx and Thyroid 21

22 Partially encapsulated circumscribed Noninvasive Follicular Thyroid Neoplasm with Papillary-like like Nuclei Absent invasion By definition this must be noninvasive No capsular invasion No vascular invasion Must be adequately (completely) sampled Tumor to capsule to parenchyma 3 sections (not blocks) per cm of tumor Capsular invasion Oropharyngx and Thyroid 22

23 Capsular invasion Vascular Invasion Noninvasive Follicular Thyroid Neoplasm with Papillary-like like Nuclei Predominantly follicular pattern of growth Small to medium, round, twisted and elongated follicles Follicles are often a monotonous size and shape (helpful feature) Isolated or rare papillae may be seen Must be 1% of overall tumor volume If >1%, then it is NOT follicular variant Oropharyngx and Thyroid 23

24 Sandison pseudopapillary structure OK Single papillary structure is OK Too many papillary structures Too many papillary structures Noninvasive Follicular Thyroid Neoplasm with Papillary-like like Nuclei Hypereosinophilic colloid Scalloped colloid frequently present Internal, acellular, eosinophilic fibrosis between follicles Dropping substage condenser often creates a bright signal Oropharyngx and Thyroid 24

25 Hypereosinophilic Colloid Colloid scalloping Internal fibrosis Noninvasive Follicular Thyroid Neoplasm with Papillary-like like Nuclei Absent psammoma bodies Absent necrosis No increased mitoses 3 mitoses/10 High Power Fields No other patterns or specific tumor types present Solid, insular, trabecular, morular Oncocytic, tall, columnar Excluded: Tumor Necrosis Excluded: >3 mitoses/10 HPFs Oropharyngx and Thyroid 25

26 Excluded: Solid Pattern Excluded: Oncocytic papillary Excluded: Cribriform-morula Excluded: Tall cell papillary Excluded: Columnar papillary Thyroid Papillary Carcinoma: Encapsulated Follicular variant Must have nuclear features of papillary carcinoma 1 point each = 3; 2 or more is diagnostic Size and shape (1 point) Nuclear enlargement, overlapping, crowding, elongation Nuclear membrane irregularities (1 point) Irregular contours, grooves, pseudoinclusions Chromatin characteristics (1 point) Clearing with margination, glassy nuclei Oropharyngx and Thyroid 26

27 Noninvasive Follicular Thyroid Neoplasm with Papillary-like like Nuclei Diagnosis rests on cytology Size and shape Enlargement, elongation, overlapping/crowding Membrane irregularities Irregular contours, grooves/folds, intranuclear cytoplasmic inclusions Chromatin distribution Chromatin clearing, margination to membrane, glassy nuclei Nuclear score: Sum of three nuclear features (each 0 or 1) Thus, total score will vary between 0 and 3 Nuclear features: 1) Size and Shape Enlargement Elongation Overlapping Absent/insufficiently expressed (0) Present/Sufficient (1) Nuclear score: Sum of three nuclear features (each 0 or 1) Thus, total score will vary between 0 and 3 Nuclear features: Absent/insufficiently expressed (0) Present/Sufficient (1) 1) Size and Shape Enlargement Elongation Overlapping 2) Membrane Irregularities Irregular contours Grooves Intranuclear cytoplasmic inclusions 161 Oropharyngx and Thyroid 27

28 Nuclear score: Sum of three nuclear features (each 0 or 1) Thus, total score will vary between 0 and 3 Nuclear features: Absent/insufficiently expressed (0) Present/Sufficient (1) 1) Size and Shape Enlargement Elongation Overlapping 2) Membrane Irregularities Irregular contours Grooves Intranuclear cytoplasmic inclusions 3) Chromatin Features Chromatin clearing Margination to nuclear membrane Glassy nuclei 165 Slight changes not sufficient to call present! Oropharyngx and Thyroid 28

29 Thyroid Papillary Carcinoma: Encapsulated Follicular Variant How much of the tumor must have nuclear feature? 3 foci per cm of tumor gross measurement This is not well defined or agreed upon May be multifocal within same nodule Oropharyngx and Thyroid 29

30 Papillary carcinoma: Lymphovascular invasion Diagnosis (= 324) # of Cases Absent Present Classical Microscopic FV: Encap/Inv Tall Diffuse sclerosing Number with disease, %, average follow-up for diseased patients p< (chi square 0/149 0% (11.1) 20/ % Follicular Variant Overall 71 cases 25 cases Surgery only Thyroidectomy NO RAI RAI NED NED 11.1 years 10.6 years (9.3) Oropharyngx and Thyroid 30