Thyroid (November 2015): Molecular Oncology Tumor Boards

ASCO University
Nov 04, 2015 10:35 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. This month’s topic is led by Drs. Jennifer Brown (University of Arkansas) and Manisha Shah (Ohio State University).

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Supplemental resources related to the case are attached for reference.




ASCO University
Re: Thyroid (November 2015): Molecular Oncology Tumor Boards
Nov 04, 2015 10:41 AM

Patient Case

A 58 year old previously healthy male presents with papillary thyroid cancer (PTC) with metastasis to lungs, neck/chest lymph nodes and possibly bone.

03/2011: He presented with a large mass in his right neck and had lost 30 lbs. He had a fine needle aspiration (FNA) that was diagnosed as PTC. 

03/2011: He underwent total thyroidectomy; central/lateral neck dissection.  The pathology demonstrated a multifocal and bilateral papillary thyroid carcinoma (PTC) (Image 1:  Most of the tumor showed this appearance with papillary architecture and invasive growth). The largest focus measured 1.3 cm and extensive extra-thyroidal extension and vascular invasion were identified.   There were 7/40 nodes positive for metastatic disease in the central (1/3) and lateral neck (1/6 level II, 4/17 in level III and 1/9 level IV). The largest node measured 7.5 cm and showed extranodal extension.  The tumor was extensively sampled and did not show any areas of anaplastic transformation. There were focal areas within the tumor that showed an unusual morphologic appearance [Image 2:  Focal areas of the showed this appearance, with discoheision of the tumor cells]. There was a background of Hashimoto's thyroiditis. 

06/2011: The patient was treated with radioactive iodine (RAI) 131-I with 150 mCi after thyroid hormone withdrawal. The posttreatment scan showed uptake in the thyroid bed.  CT chest showed bilateral sub-centimeter lung nodules without any uptake.

04/2012: The patient felt another lump in his lateral neck. Ultrasound guided FNA was positive for PTC. He underwent a repeat selective neck dissection of right level II. He had 1/7 nodes positive for PTC, measuring 2 cm and extracapsular spread was noted. 

11/2012: Serum Tg 480 ng/mL(TSH 0.02)  

12/2012: Patient felt another lump in his lateral neck. Ultrasound guided FNA was positive for PTC. He had another neck dissection. Path showed 4/8 nodes positive for PTC and a soft tissue focus measuring 3.5 cm.  

02/2013: Serum Tg 300 ng/mL (TSH 0.01)

02/2013: 2nd dose of RAI 200 mCi with negative post-treatment scan.  

03/2013: CTs neck/chest showed 3.8 cm mediastinal LAP, right hilar 2.5 cm LAP, sclerotic lesion in T7 spine.

Co-morbidities: HTN, Hyperlipidemia, CAD, s/p coronary stents 2009.


ASCO University
Re: Thyroid (November 2015): Molecular Oncology Tumor Boards
Nov 04, 2015 10:42 AM

Discussion Questions

1.    Does this tumor have a variant morphology and is it significant clinically? 

2.    What are the diagnostic/staging studies at this point?

3.    What are treatment options for this patient?

4.    Which tumor gene mutational analysis, if any, might aid in choosing therapy?



Taofeek Kunle Owonikoko, MD, PhD, MS
Re: Thyroid (November 2015): Molecular Oncology Tumor Boards
Nov 04, 2015 3:09 PM

Areas of tall cell morphology seen on the high power field. This histologic variant is associated with more aggressive biological behavior and lack of iodine uptake.

A PET scan in this patient with iodine non-avid disease and elevated thyroglobulin may be helpful to fully quantify the extent of the disease.

With progressive disease in a patient with iodine refractory thyroid cancer such as this index case, targeted agents otherwise called kinase inhibitors will be an appropriate next line of therapy.

Molecular testing for mutation in B-Raf gene is frequently cehcked in thyroid cancer and may be associated with some differences in outcome after surgical resection. The utility of this test in a patient with advanced iodine refractory disease is still under investigation both as a way to improve the efficacy of kinase inhibitors and to resensitize thyroid cancers to radioactive iodine.


Apar Kishor Ganti, MD
Re: Thyroid (November 2015): Molecular Oncology Tumor Boards
Nov 04, 2015 9:02 PM

This appears to be a tall cell variant of papillary thyroid carcinoma, which usually has a more aggressive behavior. Since the tumor is rapidly growing and is no longer radio-iodine avid, as evidenced by the negative post-treatment uptake scan, treatment would include a targeted agent. Lenvatinib, vandetanib and sorafenib can improve PFS in these patients. BRAF mutations are often seen in PTC, there are clinical trials underway to evaluate the efficacy of vemurafenib in PTC.


Peter Sadow
Re: Thyroid (November 2015): Molecular Oncology Tumor Boards
Nov 06, 2015 10:45 AM

Actually, the lesion shown here would be currently classified, if this is truly representative of the overall tumor, as a Hobnail Variant of papillary thyroid carcinoma. These lesions, which often show tall cell features, as described by other participants, have this characteristic finding of secretory changes (blebs of cytoplasm at the apex of the cells and cells shaped like great toes). Lubitz CC et al. Thyroid. 2014 Jun;24(6):958-65. (Hobnail variant of papillary thyroid carcinoma: an institutional case series and molecular profile). These are most frequently associated with BRAFV600E mutations. However, they are also associated with aggressive morphologic features, as is seen in this case, and frequent recurrence. As others have mentioned, these tumors (much like tall cell variants and classical types) do much better when complete tumor resection is noted. It is unclear how responsive these tumors may be to treatments, such as vemurafanib, and may be precursor lesions for evolution to high grade malignancy and anaplastic malignancies, which may acquire additional mutations in p53 or beta catenin.


Jennifer Hunt
Re: Thyroid (November 2015): Molecular Oncology Tumor Boards
Nov 09, 2015 11:17 AM

Course Faculty Response

The areas shown in the image are demonstrating the hobnail variant of papillary carcinoma. This variant is relatively rare, but has been reported to have a worse prognosis. Usually to make a diagnosis of a variant, the majority of the tumor should have these features. In this case, only focal areas showed these features.

Biopsies of the mediastinal lymph nodes and possibly the lung lesions and spine lesion would be able to easily distinguish metastatic papillary carcinoma from other potential tumor mimickers.  With this patient’s history, fine needle aspiration biopsies could be performed and stained with thyroglobulin and TTF-1 to illustrate the thyroid origin even if the cells were not characteristic of PTC.  If a lung primary was also in the differential diagnosis, additional stains could be added, such as napsin and p63, which should be negative in metastatic papillary carcinoma.

The majority of papillary thyroid carcinomas are positive for BRAF gene mutation V600E. There are a number of different types of assays that are commercially available to test for the BRAF mutation, including gene sequencing and other PCR-based approaches. There is also an immunohistochemical stain available to detect mutant BRAF.  Though therapy directed against BRAF is not the first-line approach in a patient with PTC, in this case, a BRAF mutation opens up therapeutic options with this patient’s widely metastatic disease.


Manisha H. Shah, MD
Re: Thyroid (November 2015): Molecular Oncology Tumor Boards
Nov 09, 2015 11:22 AM

Course Faculty Response

FDG-PET scan can be done for staging of this patient.  CT scan of abd/pelvis should be considered to rule out liver/lower spine/pelvic metastasis if PET scan is not performed.  MRI of brain may be considered.  MRI of thoracic spine can be done if patient is symptomatic as it is better than CT scan for reviewing extent of spine met including it is extension into spinal canal and presence/degree of spinal cord compression.

Several treatment options exist:
1.) Sorafenib or Lenvatinib as both TKIs are approved by FDA in United States and by EMA in Europe
2.) If the patient is asymptomatic, Wait and watch with close follow up in 3 months with CTs neck/chest/tumor marker is also an option
3.) If tumor is BRAF-mutation positive, BRAF-targeted therapy on clinical trial.  Alternatively, if it is RAS-mutation positive, MEK-inhibitor trial


ASCO University
Re: Thyroid (November 2015): Molecular Oncology Tumor Boards
Nov 09, 2015 11:30 AM

Patient Case Update

An FNA of the lung lesion and mediastinal lymph node biopsies showed metastatic PTC.

A BRAF gene mutation analysis performed on the lung lesions showed a typical BRAF V600E mutation (Image 3:  The tumor showed the characteristic point mutation indicated by the arrow).

BRAF mutation positive

ECOG PS-good

March 2013-April 2015:  The patient was treated with systemic TKI therapy with sorafenib 400 mg PO BID; 20% shrinkage; Robust serum Tg response.  The patient had HTN, Hand foot syndrome, diarrhea, weight loss that needed dose reduction to 400 mg qAM/200 mg qPM at 3 months (Hand
food syndrome) and subsequently to 200 mg PO BID at 14 months (weight loss).  In April 2015, the patient developed progressive disease with increase in size in mediastinal LAP (2.4 cm to 4.5 cm) but only mild increase in hilar LN (2.0 cm to 2.5 cm) and stable lung and bone mets.


ASCO University
Re: Thyroid (November 2015): Molecular Oncology Tumor Boards
Nov 12, 2015 1:07 PM

Discussion Questions
1.    Does the history raise any other concerns in terms of the pathology diagnosis?
2.    What are therapy options at this point?


Jennifer Hunt
Re: Thyroid (November 2015): Molecular Oncology Tumor Boards
Nov 16, 2015 11:34 AM

Course Faculty Response

Secondary resistance to TKI is well known so a progressive disease at about two years into TKI therapy is not unusual.  However, a concern could be raised about the potential for anaplastic transformation in mediastinal LN that grew at rapid rate than other metastatic lesions.  Adequate histologic sampling of the original tumor resection would be essential to exclude this possibility.

Similar treatment options as previously outlined can be considered except sorafenib.  External beam radiation for palliation can be considered if patient  is symptomatic from progressive mediastinal LAP.


Manisha H. Shah, MD
Re: Thyroid (November 2015): Molecular Oncology Tumor Boards
Nov 16, 2015 11:38 AM

Course Faculty Response

On April 2015 that patient started on lenvatinib PO 24 mg/day.  The patient developed HTN, severe mouth sores, diarrhea. Dose reduction to 20 mg/day.  Partial response per RECIST v1.1 at 4-month f/up and patient remains on such therapy at 6-months now with maintained PR.


Jennifer Hunt
Re: Thyroid (November 2015): Molecular Oncology Tumor Boards
Nov 18, 2015 11:23 AM

Course Faculty Summary

The tumor is a conventional papillary carcinoma with a component of hobnail variant. It is BRAF V600E positive, which is common for conventional type papillary carcinoma.  Adequate sampling of bulky large tumors with metastatic disease should help ensure that a minor component of anaplastic carcinoma is not missed. Diagnosis of subsequent metastatic papillary carcinoma foci (if needed), can usually be made by minimally invasive biopsy techniques such as core biopsies or fine needle aspiration, depending on the location.  



Manisha H. Shah, MD
Re: Thyroid (November 2015): Molecular Oncology Tumor Boards
Nov 18, 2015 11:39 AM

Course Faculty Summary

Patient with RAI refractory PTC (measurable ds; RECIST PD; no symptoms) treated with surgery, RAI x 2.  Progressive disease in mediastinum/lungs/possible bone with biopsy proven PTC with BRAF mutation. Sorafenib with minor response; pt treated with lenvatinib with partial response.  Both TKIs required dose reduction.  Future option will include BRAF-targeted therapy on clinical trial.


ASCO University
Re: Thyroid (November 2015): Molecular Oncology Tumor Boards
Nov 18, 2015 11:44 AM

Thank you to Drs. Hunt and Shah 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 CME credit on ASCO University by clicking here.

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