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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 26  |  Issue : 2  |  Page : 131-134

The phenomenon of dedifferentiation: Understanding its effect on the post-operative management of papillary thyroid carcinomas


KIMS Cancer Center, Thiruvananthapuram, Kerala, India

Date of Submission03-Aug-2020
Date of Decision21-Aug-2020
Date of Acceptance30-Sep-2020
Date of Web Publication07-Nov-2020

Correspondence Address:
Dr. Sandeep Babu Bhaskaran Pillai
14 Beaufort Court, West Bridgford, Nottinghamshire, NG2 7TB,United Kingdom

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ksj.ksj_21_20

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  Abstract 


Well-differentiated thyroid cancers are usually managed by total thyroidectomy with or without neck dissection. High-risk patients are followed up using serial thyroglobulin estimation and radioiodine scans. The phenomenon of dedifferentiation is essential to understand the events during post-operative follow-up of these tumours. This article describes the cascade of sequential dedifferentiation, its genetic undercurrents and its impact on the detection and treatment of post-surgical recurrences. New targeted agents aimed at redifferentiation are also discussed.

Keywords: Dedifferentiation, radioiodine therapy, redifferentiation agents, thyroglobulin assay, well-differentiated thyroid cancer


How to cite this article:
Bhaskaran Pillai SB. The phenomenon of dedifferentiation: Understanding its effect on the post-operative management of papillary thyroid carcinomas. Kerala Surg J 2020;26:131-4

How to cite this URL:
Bhaskaran Pillai SB. The phenomenon of dedifferentiation: Understanding its effect on the post-operative management of papillary thyroid carcinomas. Kerala Surg J [serial online] 2020 [cited 2020 Nov 30];26:131-4. Available from: http://www.keralasurgj.com/text.asp?2020/26/2/131/300230




  Introduction Top


Well-differentiated thyroid cancer (WDTC) is among the most curable human malignancies. More than 90% of patients survive beyond 20 years in large case series.[1] Clinicopathologically, they comprise papillary carcinomas (including follicular variant, tall cell, columnar cell, diffuse sclerosing and insular carcinomas) and follicular carcinomas (including Hurthle cell variant).

In routine surgical practice, most patients with WDTC present with swellings in the thyroid region with or without neck nodes. The widespread availability of ultrasound screening has led to a recent trend towards diagnosing subclinical tumours confined to the thyroid, especially in affluent countries.[2] Distant metastases occur only in 1%–15% of WDTCs. Even with locally advanced or metastatic presentation, they are managed with curative intent, especially in patients younger than 55 years.

Normal thyroid follicular cells have a characteristic ability for iodine uptake. WDTCs retain this capacity to a greater extent, thanks to the expression of sodium-iodide symporter along their basolateral membrane.[3] Radioiodine selectively kills usual thyroid cells and thyroid cancer cells without affecting most other cells in the body – a truly targeted therapy aiding in their treatment, follow-up and prognosis.

Residual normal functioning thyroid follicular cells take up most of the radioiodine administered, leaving very little effect on the WDTC cells. Hence, a patient must be made athyreotic (without normal thyroid tissue) for detection and ablation of local and metastatic sites of disease. If the metastases take up radioiodine, a cure is possible in most patients. Forty-five per cent of patients with lung metastases achieved long-term remission, while radioiodine could cure only 9% of bone lesions. The 10-year overall survival was 92% in those patients who achieved remission of metastatic disease after radioiodine treatment.[4]

Thyroglobulin (TG) is a glycoprotein synthesised exclusively by thyroid cells (both normal and malignant).[5] In an athyreotic patient, detectable levels of TG confirm persistent thyroid tissue, most likely a recurrence.[5] A repeat whole-body scintiscanning now will usually demonstrate the site of recurrence, which is treated with either surgery or radioiodine. Elevation of TG is specific for recurrence, but sensitivity of the assay equipment, and interference by anti-TG antibodies should be considered.

Because TG synthesis is thyroid-stimulating hormone (TSH) dependent, TG measurement is thought to be more reliable when the background TSH is higher than 30 mIU/L than while the patient is on suppressive doses of Eltroxin, but this is debatable.[5]

Dedifferentiation is the sequential loss of resemblance to normal histological architecture that occurs with progression of malignant phenotype.[Figure 1] & [Figure 2]. WDTCs have typical cytological features such as nuclear grooving, clearing and inclusions, but they maintain histological resemblance to the thyroid follicle. As the dedifferentiation progresses, the cells lose more of these retained features and become more primitive in structure and function, changing into poorly differentiated and anaplastic cancers.[3]
Figure 1: Normal Thyroid Cell

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Figure 2: Thyroid Cell Dedifferentiation

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Normal thyroid follicular cell has the following functional abilities:[6] They synthesise TG, take up iodine and produce thyroid hormones (iodination of tyrosine residues and coupling). WDTCs retain the first two abilities but cannot synthesise thyroid hormones. As the dedifferentiation progresses, cells lose the capability to hook on iodine, while ability to synthesise TG remains intact for considerably longer periods. Up to two-third of patients with unresectable or metastatic WDTC develop radioiodine refractory disease. Loss of TG synthesis capacity may also eventually occur, and by that time, the cells lose all resemblance to thyroid cells, and attain anaplastic transformation.

Molecular genetics underlying the dedifferentiation process delineates the potential mechanisms for this phenomenon and probable interventions to alter it.[3],[4],[7]

Most WDTCs have mutational activation of MAPK pathway and RET/PTC rearrangements as drivers of oncogenesis; these are early events in tumorigenesis. RET/PTC rearrangements are also early events, typically seen in paediatric and radiation-induced thyroid cancers. These are, however, unrelated to dedifferentiation.

Three mutations are now identified as probable culprits in dedifferentiation. They are PIK3CA via AKT/mTOR pathway, telomerase reverse transcriptase via telomerase reactivation and p53 by loss of ability for cell cycle arrest, apoptosis and DNA repair. These are found in higher frequencies in dedifferentiated cancers as compared to their well-differentiated counterparts. Molecular profiling of high-risk WDTCs to identify the putative markers of anaplastic transformation may be valuable in prognostication and therapy in the future.


  Clinical Relevance of Dedifferentiation Top


After total thyroidectomy, most cases of intermediate- and high-risk WDTC patients undergo radioiodine remnant ablation to render them athyreotic. This enables TG assay and whole-body radioiodine scanning to detect recurrence or metastases. There are five possible scenarios during the routine follow-up of WDTC.[Table 1],[5],[8],[9],[10],[11]
Table 1: Clinical Scenarios

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Scenario 1

In the absence of clinical signs or symptoms of recurrence, if TG assays and radioiodine scans are found to be negative, patients are kept on thyroxine tablets to suppress TSH. Some centres insist on ultrasound to ensure local control, in addition to normal TG levels, absent anti-TG antibodies and negative radioiodine scan. The duration and stringency of follow-up are extremely variable across centres. Delayed recurrences are usual, and many patients require long-term follow-up.

Scenario 2

Fourteen to twenty per cent of patients show TG level above normal at 9–12 months post-ablation follow-up. There may still be residual thyroid tissue, and these patients are continued on Eltroxin suppression for 6 months before re-estimating TG. If TG values are persistently elevated, iodine scan is repeated. Patients with positive scans are given ablative doses of radioiodine, with curative intent.

Scenario 3

Described as the TENIS syndrome,[12] here, the tumour cells start to dedifferentiate and lose their avidity for iodine. The TG is, however, elevated, as the capacity to synthesise TG is only affected further down in the dedifferentiation cascade. Thus, recurrence is confirmed, but it does not show up in iodine scan. Most of such disease can now be localised using PET scanning. Treatment is by surgery or external beam radiotherapy, while some recommend empirical higher dose radioiodine therapy regardless of poor iodine uptake.

Scenario 4

Iodine scan demonstrates disease recurrence, but TG levels are normal. This is counterintuitive because, during dedifferentiation, the TG synthesis ability is lost after losing iodine affinity. In fact, here, TG levels are raised, but anti-TG antibodies interfere with the sensitivity of TG assay. Anti-TG antibodies are exhibited in 10%–25% of cases; hence, anti-TG antibodies should be always measured with TG assays.[13],[14] As these cells remain well differentiated and iodine avid, treatment and outcomes are similar to scenario 2.

Scenario 5

The patient comes with a swelling in the surgical field, but with no elevation of TG levels, and iodine scan shows no activity. Post-operative scarring or lymph collection should be ruled out by guided biopsy or aspiration of the swelling. Rarely, this could even be a dedifferentiated recurrence, with cells losing both iodine uptake ability and TG synthesis.


  Therapeutic Applications Top


Selective iodine affinity of WDTC cells ensures excellent survival outcomes even in fairly advanced disease. Loss of this ability becomes the Achilles heel of treatment, as there are no effective options, once iodine ablation fails.

Resectable iodine non-avid recurrences are managed by surgery, while inoperable cases receive whole-body external beam radiotherapy. Local ablation using percutaneous ethanol injections is attempted when surgery is impossible or too risky.[15],[16]

With iodine-resistant metastatic disease, treatment options were limited to palliative chemotherapy. The small-molecule tyrosine kinase inhibitors such as sorafenib, pazopanib and vandetanib were also tried with limited success.[17]

Tyrosine kinase inhibitors targeting dedifferentiation are promising as they restore the iodine affinity in these tumours. For example, MEK inhibitors like selumetinib (MEK1/MEK2 inhibitor) enable radioiodine ablation of previously non-avid lesions.[18] Selective BRAF inhibitor dabrafenib stimulated iodine uptake in 60 per cent of metastatic cases with BRAF V600E mutations in a recent study.[19]


  Conclusion Top


Dedifferentiation in thyroid cancer is a well-recognised phenomenon by which the normal thyroid follicular cell sequentially loses its functional capabilities and evolves into anaplastic phenotype. It helps to decipher complicated scenarios of post-operative follow-up in WDTC. Manipulation of dedifferentiation by drugs may improve the dismal outcomes in metastatic iodine refractory thyroid carcinomas.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Ito Y, Miyauchi A, Kihara M, Fukushima M, Higashiyama T, Miya A. Overall survival of papillary thyroid carcinoma patients: A single-institution long-term follow-up of 5897 patients. World J Surg 2018;42:615-22.  Back to cited text no. 1
    
2.
Vaccarella S, Franceschi S, Bray F, Wild CP, Plummer M, Dal Maso L. Worldwide thyroid-cancer epidemic? The increasing impact of overdiagnosis. N Engl J Med 2016;375:614-7.  Back to cited text no. 2
    
3.
Liu J, Liu Y, Lin Y, Liang J. Radioactive iodine-refractory differentiated thyroid cancer and redifferentiation therapy. Endocrinol Metab 2019;34:215-25.  Back to cited text no. 3
    
4.
Schlumberger M, Challeton C, De Vathaire F, Travagli JP, Gardet P, Lumbroso JD, et al. Radioactive iodine treatment and external radiotherapy for lung and bone metastases from thyroid carcinoma. J Nucl Med 1996;37:598-605.  Back to cited text no. 4
    
5.
Smallridge RC, Meek SE, Morgan MA, Gates GS, Fox TP, Grebe S, et al. Monitoring TG in a sensitive immunoassay has comparable sensitivity to recombinant human TSH-stimulated TG in follow-up of thyroid cancer patients. J Clin Endocrinol Metab 2007;92:82-7.  Back to cited text no. 5
    
6.
Ringel MD, Anderson J, Souza SL, Burch HB, Tambascia M, Shriver CD, et al. Expression of the sodium iodide symporter and thyroglobulin genes are reduced in papillary thyroid cancer. Mod Pathol 2001;14:289-96.  Back to cited text no. 6
    
7.
Papp S, Asa SL. When thyroid goes bad: A morphological and molecular analysis. Head and Neck Pathol 2015;9:16-23.  Back to cited text no. 7
    
8.
Gasent Blesa JM, Grande Pulido E, Provencio Pulla M, Alberola Candel V, Laforga Canales JB, Grimalt Arrom M, et al. Old and new insights in the treatment of thyroid carcinoma. J Thyroid Res 2010;2010:279468.  Back to cited text no. 8
    
9.
Gallardo E, Medina J, Sanchez JC, Viúdez A, Grande E, Porras I, et al. SEOM clinical guideline in thyroid cancer 2019. ClinTransl Oncology 2020;22:223-35.  Back to cited text no. 9
    
10.
Clark OH, Hoelting T. Management of patients with differentiated thyroid cancer who have positive serum thyroglobulin levels and negative radioiodine scans. Thyroidology 1994;4:501-5.  Back to cited text no. 10
    
11.
Wahba H, El-Hadaad HA, Anter AH, Wafa A. Impact of thyroglobulin on survival and prognosis of differentiated thyroid cancer. J Cancer Therapy 2018;9:706-13.  Back to cited text no. 11
    
12.
Sfar R, Kamoun T, Nouira M, Regaieg H, Ammar N, Charfi H, et al. Differentiated thyroid cancer with thyroglobulin elevation and negative iodine scintigraphy (TENIS Syndrome). Int J Otolaryngol Head Neck Surg 2014;3:149-53.  Back to cited text no. 12
    
13.
Locsei Z, Szabolcs I, Rácz K, Kovács GL, Horváth D, Toldy E. Serum thyroglobulin antibody levels within or near to the reference range may interfere with thyroglobulin measurement. Biochem Med (Zagreb) 2012;22:365-70.  Back to cited text no. 13
    
14.
Spencer CA. Clinical review: Clinical utility of thyroglobulin antibody (TgAb) measurements for patients with differentiated thyroid cancers (DTC). J Clin Endocrinol Metab 2011;96:3615-27.  Back to cited text no. 14
    
15.
Fontenot TE, Deniwar A, Bhatia P, Al-Qurayshi Z, Randolph GW, Kandil E. Percutaneous ethanol injection versus reoperation for locally recurrent papillary thyroid cancer-A systematic review and pooled analysis. JAMA Otorhinology Head Neck Surgery 2015;141:512-8.  Back to cited text no. 15
    
16.
Hay ID, Lee RA, Davidge-Pitts C, Reading CC, Charboneau JW. Long-term outcome of ultrasound guided percutaneous ethanol ablation of selected recurrent neck nodal metastases in 25 patients with papillary carcinomas previously treated by surgery and iodine therapy. Surgery 2013;154:1448-55.  Back to cited text no. 16
    
17.
Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, Bastholt L, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: A randomised, double-blind, phase 3 trial. Lancet 2014;384:319-28.  Back to cited text no. 17
    
18.
Ho AL, Grewal RK, Leboeuf R, Sherman EJ, Pfister DG, Deandreis D, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med 2013;368:623-32.  Back to cited text no. 18
    
19.
Falchook GS, Millward M, Hong D, Naing A, Piha-Paul S, Waguespack SG, et al. BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid cancer. Thyroid 2015;25:71-7.  Back to cited text no. 19
    


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