Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards

ASCO University
Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 10, 2016 9:13 AM

User Instructions: Welcome to the Molecular Oncology Tumor Board Series! This educational initiative is a collaboration between the American Society of Clinical Oncology (ASCO), College of American Pathologists (CAP), and Association for Molecular Pathology (AMP).

A new case will be presented each month with discussions led by an expert pathologist and medical oncologist. Submit your hypothetical patient cases for consideration in an upcoming Molecular Oncology Tumor Board discussion forum.

This month’s topic is led by Drs. Raja Seethala (University of Pittsburgh) and Francis Worden (University of Michigan).

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Please see attached for supplemental resources related to the case.

Attached:
PDF icon References_August 2016 MOTB.pdf

Comments

13021

ASCO University
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 10, 2016 9:26 AM

Patient Case #1

Age/Sex:  57 y.o. female

Medical History:  The patient presents with a 4 month history of increasing odontophagia, dysphagia, and changes in breathing while sleeping. One month ago, she developed left-sided otalgia.  The patient was seen by her primary care physician and given antibiotics for an acute upper respiratory tract infection.  She returned two weeks later without resolution of her symptoms. Her physical exam now reveals a fixed, non-tender level II lymph node in her left neck.  The remainder of her exam is unremarkable.  The patient is then referred to an otolaryngologist for further work up and evaluation.
 
Past Medical History: Unremarkable for any major medical problems

Co-morbidities:  None

Social History: She is a married attorney, a non-smoker, and consumes alcohol infrequently.
 
Family History: Her mother had a history of breast cancer 10 years ago.
 
Physical Exam: Oral cavity normal to inspection, mild erythema in the posterior pharynx. Neck: palpable, fixed level II lymph node in her left neck. Chest: clear CVS: RRR Abdomen: benign

13026

ASCO University
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 10, 2016 9:27 AM

Discussion Question

  1. What is the next step in the work up of this patient?
  2. What additional imaging studies should be ordered?

13031

Anis Toumeh, MD
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 10, 2016 11:13 AM

This clinical presentation is highly suspicous of carcinoma of the head and neck. The clinical charecterestics of the left neck node (fixed, non tender) indicate higher liklihood of malignancy than an infection/inflammatory; especially with no response after a course of antibiotics. The development of odynophagia and dysphagia could indicate the oropharynx as a primary site. Pathological examination of the left neck node is indicated.

High resolution CT scan of the neck with contrast or MRI with contrast are reasonable choices. Full ENT evaluation with triple endoscopy and random / targeted biopsies will help evaluate other areas of involvement/primary site. Imaging of the chest is indicated if she is having respiratory complaints (cough, SOB, hemoptysis etc). Evaluation of the thyroid is reasonable. 

13036

Francis P. Worden, MD
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 12, 2016 10:09 AM

Course Faculty Response

  1. A referral to ENT for direct laryngoscopy and biopsy is the next step for this patient.  The patient is staged with a T3, N1 tumor based on tumor size and the involvement of a single lymph node in the neck.  Regarding additional imaging, a full body PET scan, blood work including a comprehensive panel, CBC with differential and platelets, and magnesium, and a referral to dentistry is appropriate.
Mayer Gorbaty, MD
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 14, 2016 9:04 AM

1.Is the PET/CT scan instead of a conventional contrast enhanced CT scan or in addition?

2.  Is the PET/CT scan recommended for all stages of H/N cancer or only for certain ones?

Thanks for your response.

13041

ASCO University
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 12, 2016 10:17 AM

Patient Case #1 Update

Images/Scans:  CT neck: Lobulated mass noted in the tongue base projecting into the vallecula. Enlarged lingual tonsils bilaterally encompass the entire extent of the tongue and cross the midline. Enlarged lymph node seen on the left side of the neck. This level 2A lymph node measures approximately 3 cm in its craniocaudal axis and approximately 15 mm in its short axis dimensions.

Pathology: non-keratinizing  squamous cell carcinoma.

Image 1
Image 2

 

13046

ASCO University
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 12, 2016 10:21 AM

Discussion Question

2. What additional testing should be ordered on the pathology specimen following biopsy? How reliable is p16 staining?

13051

Anis Toumeh, MD
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 12, 2016 10:32 AM

Determining HPV status on the tumor is very important, from a prognostic point of a view and also in case the patient is eligible for an ongoing trial. 

My question here is what should we do with discordant p16 staining and HPV by PCR? 
Raja Seethala
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 14, 2016 1:49 PM

Course Faculty Response

Thank you for the question Dr. Toumeh.

P16 is a surrogate marker of transcriptionally active HPV status.  It generally performs very well at oropharyngeal sites, and does not generally need to be backed up by a more specific method.  

If p16 is positive, and HPV testing by a more specific methodology happens to have been performed (i.e. for clinical trial purposes) and is negative, this patient would have to be considered HPV negative.  However there are some caveats.  The main assumption would be that the HPV specific methodology "worked" and was able to detect low levels of viral DNA or E6/E7 mRNA.  With PCR/RT-PCR or other nucleic acid testing, this is usually not an issue.  HPV DNA in situ hybridization, however, may not perform well at low viral copy numbers and interpretation can be technically challenging.   

Conversely the situation where p16 is negative and HPV testing is positive can be a bit more complicated.  While technically HPV positive - this may be a misrepresentation of the actual tumor biology.  HPV infection does not always mean that that virus is oncogenic or transcriptionally active -and p16 negativity may then suggest that the HPV is not involved in the oncogenesis of the tumor.

13066

Raja Seethala
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 15, 2016 9:07 AM

Course Faculty Response

2. Immunohistochemistry for p16.  Within the oropharynx, particularly Waldeyer ring, non-keratinizing morphology in conjunction with diffuse strong nuclear and cytoplasmic p16 positivity (>75% of lesional cells) is very sensitive and specific for high risk HPV-driven carcinoma.   It must be noted that this “non-keratinizing” morphology recapitulates the appearance of normal tonsillar crypt.  Roughly ¼ of cases may show focal keratinization or maturation, just like tonsillar crypt epithelium.  As such it is actually a “well differentiated tumor,” with respect to site of origin.  Using the term “poorly differentiated” is thus incorrect.   Similarly using the term “basaloid” is discouraged since “basaloid squamous cell carcinoma” is a separate distinctive histologic variant that is actually more aggressive at most head and neck subsites.  The ease of testing, interpretation and performance with this anatomic site make additional testing largely unnecessary.  Equivocal p16 staining (i.e. less than 75% of tumor cell) would necessitate more HPV-specific testing (i.e. DNA, RNA-ish, or PCR).

13071

Francis P. Worden, MD
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 15, 2016 9:09 AM

Course Faculty Response

2. The patient’s biopsy confirms squamous cell carcinoma (non-keratinizing) and is p16 +.  Given the large number of cases of p16+ disease involving the oropharynx, we can safely say that p16+ disease represents an HPV-driven disease and no confirmatory stains are needed.

13076

ASCO University
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 15, 2016 9:12 AM

Patient #1 Case Update

Type of Tumor:  Base of tongue

Image 3

Relevant Markers:  p16 (+)

Prior Treatment History/Response: None

13081

ASCO University
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 15, 2016 9:14 AM

Discussion Questions

3. What are the treatment options for this patient? 

4. What follow up is recommended upon completion of treatment?

13056

Francis P. Worden, MD
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 15, 2016 2:32 PM

Course Faculty Response

Thank you for the questions Dr. Mayer Gorbaty.

1. A PET scan should be done in conjunction with a diagnostic CT of the neck and the chest.
2. The CT/PET is recommended for patients with locally advanced disease and is not necessarily required for patients with early stage disease whose treatment is amenable to single modality therapy with either surgery or radiation therapy.  We use PET to assess response to chemoradiatiion in locally advanced SCCHN three months after the completion of radiation.

13091

Francis P. Worden, MD
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 17, 2016 8:20 AM

Course Faculty Response

3. Given the size of the patient’s tumor, surgery, although can be considered, is not the treatment of choice. Rather, an organ preservation approach with chemotherapy (cisplatin 100 mg/m2 every 21 days) with radiation (70 Gy—2 Gy fractions over 35 treatments) would be the most logical choice for treatment.  Cetuximab and radiation can also be considered. However, there is not yet definitive, prospective data to suggest that cetuximab and radiation is equivalent to cisplatin and radiation.
4. PET imaging should be conducted three months following the completion of chemotherapy and radiation therapy to assess for complete response.  Serial fiberscopic laryngcopy examinations may also be warranted at the discretion of the patient’s otolaryngologist.  Serial imaging beyond the first post chemoradiation PET is generally not warranted.  Supportive care services with a nutritionist, pain specialist, and speech and swallowing specialists are also warranted.

13096

ASCO University
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 17, 2016 8:27 AM

Patient Case #2

Age/Sex: 42 y.o. male

Medical History:  The patient presents with a 4 month history of a right neck mass.  He first noted the neck mass upon shaving and states the size of the mass decreased after two months, but since then it has started to grow and feels more firm.

Past Medical History: hypertension, peptic ulcer disease

Social History: He is a married construction worker; tobacco use since age 15 and a 13 pack-year smoking history. Social drinker.

Family History: Non-contributory.

Physical Exam: Oral cavity normal to inspection with soft base of tongue. Neck: palpable, fixed, level II lymph node in his left neck ~ 3 cm in diameter. Chest: clear CVS: RRR Abdomen: benign

Type of Tumor:  Unknown primary

Relevant Markers:  p16 (+)

Image 4

Prior Treatment History/Response: None

Images/Scans/Pathology:  CT-PET: 2.9 cm right level II lymph node with intense uptake and SUV max of 12.9. Subtle asymmetric uptake in the R posterior base of tongue (normal variation).   No distant disease.
 
Pathology:  Diagnostic FNA and core biopsy: Moderately differentiated keratinizing invasive squamous cell carcinoma

13101

ASCO University
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 17, 2016 8:29 AM

Discussion Questions

1. What work up is recommended to evaluate for the primary site of disease?  What additional tumor marker should be considered?
2. Does positive p16 staining confirm cancer somewhere within the oropharynx?

13106

Raja Seethala
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 19, 2016 1:34 PM

Course Faculty Response

  1. Pathologic evaluation of the neck node should be performed (by fine needle aspiration or core biopsy).  Cystic non-keratinizing morphology is typical of metastases from HPV related tumors.  However, EBV-driven nasopharyngeal tumors are also non-keratinizing.  However, both sites also may give rise to keratinizing metastases as seen here.  Both testing for Epstein Barr virus RNA (EBER) and HPV would appropriate to help pinpoint the site of the primary.  P16 positivity alone in this context may not be sufficient to confirm HPV status, particularly with keratinizing morphology in the metastasis.  More specific HPV testing is required. 
  2. No.  See above.  Other mechanisms for p16 overexpression (i.e. Rb mutation/deletion or alterations in related proteins).

13111

Francis P. Worden, MD
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 19, 2016 1:36 PM

Course Faculty Response

  1. This patient should be referred to a qualified head and neck surgeon for an evaluation.  The patient should undergo a fiberoptic evaluation followed by a fine needle aspiration (FNA) of the lymph node.  The patient should also undergo a CT of the chest and a whole body PET scan.  This patient has evidence of a positive level II lymph node, which requires that he undergo simple tonsillectomies, a direct laryngoscopy for biopsies of the base of tongue, and nasopharynx if no obvious primary is seen on examination.  Since one node is positive for squamous cell carcinoma, the patient should undergo a modified radical neck dissection followed by radiation, with or without chemotherapy.  Chemotherapy would be given if there is evidence of extranodal extension.  The FNA of the lymph node returned as squamous cell carcinoma.  The specimen should be stained for Epstein Barr virus and HPV (p16) to evaluate for nasopharyngeal or oropharyngeal cancers.  
  2. No. 

13116

ASCO University
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 19, 2016 1:40 PM

Patient Case #2 Update

Surgical pathology specimen (following neck dissection):  Moderately to Poorly differentiated keratinizing invasive squamous cell carcinoma, HPV-

Image 5

Image 6

13121

ASCO University
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 19, 2016 1:42 PM

Discussion Questions

3. From what site(s) is the primary tumor arising?

4. What are the treatment options for this patient? 

 

13126

Konstantinos Arnaoutakis, MD
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 19, 2016 1:52 PM

Can this patient avoid the neck dissection and receive chemotherapy and radiation only as an alternative option?
Francis P. Worden, MD
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 23, 2016 8:01 PM

Thank you Dr. Konstantinos Arnaoutakis for the question.

This patient has N1 disease. For such patients, surgical extirpation with neck dissection is recommended followed by radiation therapy. Chemotherapy would not be considered unless the pathologic specimen reveals extracapsular or extranodal extension. Chemoradiotherapy upfront is indicated only for patients with N2/N3 disease followed by neck dissection if there is evidence of residual tumor or there is evidence of possible disease on post-treatment imaging

13131

Raja Seethala
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 23, 2016 9:18 AM

Course Faculty Response

3. This tumor may still be arising from the oropharynx (a non-HPV related SCC), though other sites are considerations as well.  Lower neck lymph nodes would necessitate consideration of laryngeal/hypopharyngeal primary sites.  Cutaneous site of origin is an often underappreciated occult site of primary.  

13136

Francis P. Worden, MD
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 23, 2016 9:20 AM

Course Faculty Response

3. In this case, the oropharynx (base of tongue/tonsil) or possibly nasopharynx would most likely be the sites of the primary disease.  Lower lymph nodal basin (IV and V) would be more indicative of a laryngeal primary head and neck cancer.

4. This patient most likely has a primary tonsil cancer which is tobacco related, hence the negative p16 staining (HPV negative) and keratinizing nature of his squamous cell tumor.  He should undergo radiation to the primary and contralateral neck as well as radiation to his oropharynx and nasopharynx (reduced dosage) given that he has a true head and neck cancer of unknown primary.   Chemotherapy would be added if he has evidence of extranodal extension or in his lymph node. Otherwise, he should receive radiation therapy alone.

13146

Raja Seethala
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 24, 2016 1:13 PM

Course Faculty Summary

Case 1

  • Invasive squamous cell carcinoma of tonsil (oropharynx) has a prototypically non-keratinizing morphology.
  • "Poorly differentiated” and “basaloid” are not appropriate terms for HPV driven tonsillar carcinomas
  • Diffuse and strong P16 staining is a robust marker of HPV status at this site.  

Case 2

  • Squamous cell carcinoma of unknown primary can be localized by a combination of imaging (PET, CT) and pathologic assessment for virally driven (EBV, and HPV) phenotypes
  • P16 alone may not be as robust a marker for HPV-driven tumors and should generally be backed up with a more specific testing

13151

Francis P. Worden, MD
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 24, 2016 1:15 PM

Course Faculty Summary

Case 1

  • Squamous cell carcinoma of the tonsil (oropharynx)
  • PET scans and CT scans of the chest are required for patient with lymph involvement of the neck
  • Requires p16 staining to check for the presence of HPV; p16 staining for the presence of HPV is only reliable for patients with oropharyngeal primaries.
  • Treatment is dependent on stage (stage I or II: surgery or radiation; stage III or IV: chemotherapy and radiation therapy)
  • PET imaging is performed 3 months post chemoradiation

Case 2

  • Squamous cell carcinoma of unknown primary in the head and neck
  • All patients must see a qualified head neck surgeon for a complete evaluation and diagnostic work up.
  • FNA biopsies positive for squamous cell carcinoma should be stained for HPV and EBV to evaluate for possible oropharyngeal or nasopharyngeal primaries
  • P16 staining outside the oropharynx can be unreliable. Moreover, the staining may be positive for p16 and not be involving the oropharynx as other factors or knockout drivers can inhibit Rb (retinoblastoma) protein causing subsequent elevations in 16. Hence, confirmatory testing for HPV is required.
  • Unknown primary surgeries are treated usually with neck dissection if the primary disease is not found followed by radiation therapy with or without chemotherapy depending on the presence or lack of extranodal extension noted on the pathologic evaluation of the lymph nodes.

13156

ASCO University
Re: Head and Neck Cancer (August 2016): Molecular Oncology Tumor Boards
Aug 24, 2016 1:19 PM

Thank you to Drs. Seethala and Worden for leading the discussion of this case and also to all of those who contributed to the conversation! The forum is now closed to further comments but users have the opportunity to claim credit on ASCO University by clicking here.

Please check back in mid-September for a new case in this series related to colorectal cancer.    

Have an interesting case in mind? Submit your hypothetical patient cases for consideration in an upcoming Molecular Oncology Tumor Board discussion forum.

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