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Juhlin. Cancer Drug Resist 2020;3:992-1000 I http://dx.doi.org/10.20517/cdr.2020.66 Page 993

modalities for ATCs are urgently needed, studies regarding therapeutic agents specifically targeting defective
MMR in dedifferentiated thyroid carcinoma could be pursued.

Keywords: DNA repair, mismatch repair, P53, thyroid carcinoma, dedifferentiation, anaplastic thyroid carcinoma,
clone, treatment

INTRODUCTION
Anaplastic thyroid carcinoma: a clinical background
[1,2]
Although rare, anaplastic thyroid carcinoma (ATC) is a highly lethal form of thyroid cancer . Patients
are usually in the older span and often present with dramatic symptoms such as a rapidly growing neck
[3]
mass, dyspnea, and/or hoarseness . The diagnosis is usually pinpointed after cytological examinations
of fine needle biopsy material, in which highly pleomorphic and undifferentiated tumor cell aggregates
[3]
are demonstrable . The tumor is often metastasized at original presentation, and the current treatment
modalities in such cases are mostly palliative in nature, with debulking surgery and combinations of radio-
and chemotherapy (cisplatin or doxorubicin), as well as tyrosine kinase inhibitors constituting the most
common approaches in the clinical setting [1,2,4-8] . Less than 5% of patients with distant metastases survive
more than five years; however, the chance of cure is higher if the patient only exhibits localized disease
[7]
without regional or distant involvement . Notably, long-term survival of ATC patients with disseminated
disease have also been described, of which some have been treated with tyrosine kinase inhibitors, while
rare cases with spontaneous remission also have been reported [9,10] .

Clonal evolution of ATCs
ATCs have traditionally been thought to develop along two separate paths: (1) de novo, without evidence of
a pre-existing, well-differentiated thyroid carcinoma [WDTC, including papillary thyroid carcinoma; PTC
and follicular thyroid carcinoma (FTC)]; or (2) as dedifferentiated forms of pre-existing WDTCs through
an inter-stage poorly differentiated thyroid carcinoma (PDTC) [Figure 1]. The de novo theory builds on
the fact that patients with ATCs do not always display clinical or histological evidence of an associated
WDTC, but as always in medicine - “absence of evidence is not evidence of absence”. As ATCs are highly
proliferative lesions with an infiltrative growth pattern and associated inflammation, destruction of nearby
tissues could in theory mask the presence of a WDTC in certain cases - making the de novo concept less
persuasive. Moreover, differentiated forms of thyroid cancers are histologically present in the majority of
ATC cases reported in larger studies from multi-center institutions, suggesting a linkage between these
[11]
tumor forms . Arguing in favor of the de novo hypothesis, previous cytogenetic analyses have pinpointed
[12]
wide-spread aneuploidy among ATCs, while concurrently observed WDTCs were largely diploid .
Although this study vaguely suggests that the tumors might have evolved from different mother clones, a
tumoral evolution from WDTC to ATC via progressive genomic instability could not be excluded either.

The advent of high-throughput next-generation sequencing (NGS) techniques such as whole-exome and
whole-genome sequencing (WES/WGS) has revolutionized molecular biology, and also increased our
understanding of thyroid cancer dedifferentiation tremendously. By recent NGS studies, the mutational
landscapes of PDTCs and ATCs have been partly deciphered, and the results indicate that a large
proportion of cases exhibit common driver mutations normally seen in WDTCs [13,14] . For example, two
the most common recurrent mutations seen in PDTCs and ATCs are the V600E BRAF mutation as well as
hotspot RAS mutations, which are mutually exclusive in ATCs (BRAF or RAS). Those mutations are also
frequently observed in PTCs (BRAF and RAS) and FTCs (RAS). The occurrence of similar driver mutations
in WDTCs and dedifferentiated forms of thyroid cancer could argue in favor for the chained progression
theory, but does not fully exclude the de novo hypothesis either. As additional genetic events are seen in