Synchronous and Metastatic Papillary and Follicular Thyroid Carcinomas With Unique Molecular Signatures
Synchronous and Metastatic Papillary and Follicular Thyroid Carcinomas With Unique Molecular Signatures
Synchronous and Metastatic Papillary and Follicular Thyroid Carcinomas With Unique Molecular Signatures
DOI 10.1007/s12022-017-9491-6
1
Department of Pathology, The University of Chicago Medical
Center, 5841 South Maryland Ave, Chicago, IL 60637, USA
Case Presentation
2
Division of Molecular Pathology, Department of Pathology, The
University of Chicago Medical Center, 5841 South Maryland Ave,
A 63-year-old euthyroid female with a history of Type 1 dia-
Chicago, IL 60637, USA betes mellitus, hypercholesterolemia, hypertension, and
3
Section of Endocrinology, Department of Medicine, The University
nephrolithiasis presented with flank pain. Although she did
of Chicago Medical Center, 5841 South Maryland Ave, not have a personal history of thyroid disease, her family
Chicago, IL 60637, USA history was notable for maternal thyroidectomy for an uncer-
4
Department of Pathology, St. Mary’s Hospital, 700 South Park St, tain indication and two sisters with hypothyroidism. She had
Madison, WI 53715, USA no radiation exposure and no known genetic predisposition to
10 Endocr Pathol (2018) 29:9–14
tumor development. CT and subsequent MRI identified a 7- cellularity. Definite angioinvasion was not identified. This le-
cm mass centered on the left 11th rib with destruction of the sion was considered follicular thyroid carcinoma.
lateral T11 vertebral body and extension into the epidural Following thyroidectomy, she was treated briefly with
space, causing displacement of the spinal cord. Core needle levatinib, but it was discontinued after seizures likely secondary
biopsy of the spinal lesion showed small colloid-filled folli- to reversible posterior leukoencephalopathy syndrome.
cles with monotonous round to oval nuclei. Cells were posi- Another round of radiation was given to the spine for pain,
tive for TTF-1 and thyroglobulin and negative for calcitonin and the persistent thoracic rib/vertebral lesion was resected
and BRAF, and a diagnosis of metastatic thyroid carcinoma 5 months after thyroidectomy. The spinal lesion showed histo-
was made. She was treated with external beam radiotherapy to logic features similar to prior core biopsy, namely small colloid-
the metastatic lesion, followed by total thyroidectomy with filled follicles with round, bland nuclei and scant cytoplasm
central neck dissection 1 month later. (Fig. 2e, f). The spinal lesion was favored to represent a metas-
The entire thyroid gland was submitted for histologic eval- tasis from the primary right lobe follicular carcinoma. Two
uation. It showed a 1.7-cm tumor in the left lobe with irregular months later, PET scan revealed additional lesions in the liver,
borders and an invasive growth pattern. It was composed of sacrum, and T12 vertebra. The hepatic lesion was resected,
well-developed papillae lined by large cells with eosinophilic radiation was given to the bony lesions, and radioactive iodine
cytoplasm and irregular, wrinkled nuclei with chromatin clear- therapy was administered. Approximately one and a half years
ing and intranuclear cytoplasmic pseudoinclusions (Fig. 1a, following original diagnosis, the patient is alive with disease.
b). A single lymph node in the central neck contained a 1-
mm focus of metastatic carcinoma with papillary growth,
abundant eosinophilic cytoplasm, and pseudoinclusions (Fig. Molecular Testing
2c, d). These foci were considered papillary thyroid carcino-
ma. There was also a 1.1-cm tumor in the right lobe composed Next generation sequencing of the primary left lobe PTC,
of an encapsulated proliferation of cells arranged entirely in primary right lobe FTC, and spinal metastasis was performed
follicles with scant clear to amphophilic cytoplasm and round, using the targeted hybrid capture 1213 gene UCM-OncoPlus
regular nuclei without atypia. Scattered foci of capsular inva- panel [14]. In brief, genomic DNA was isolated from macro-
sion were present, as well as abundant central necrosis (Fig. dissected tumor-enriched FFPE tissue using the QIAamp
2a–d). One mitotic figure was identified per ten high power DNA FFPE Tissue Kit (Qiagen, Valencia, CA) according to
fields, although the necrosis effaced much of the tumor manufacturer’s instructions. Following extraction, DNA was
quantified using the Qubit fluorometric assay (Thermo Fisher fragmented using the Covaris S2 (Covaris, Woburn, MA).
Scientific, Foster City, CA) and further assessed for quantity The fragmented DNA was amplified using the KAPA HTP
and quality using a quantitative PCR assay (hgDNA Library Preparation Kit (Kapa Biosystems) along with a set
Quantitation and QC kit, KAPA Biosystems, Wilmington, of patient-specific indexes (Roche, Indianapolis, IN). The
MA). Library preparation and sequencing were performed as pooled library was captured using a custom SeqCap EZ cap-
previously described for the UCM-OncoPlus Assay [14]. ture panel (Roche) featuring a collection xGen
Briefly, approximately 100 ng Qubit quantified DNA was LockdownProbes (IDT, Coralville, IA) for 1213 genes. The
Tumor type and site Percent tumor BRAF V600E RAS Q61R MSH2 R382H WRN K1087E
in tested sample Allele frequency Allele frequency allele frequency allele frequency
(%) (%) (%) (%) (%)
None reported
None reported
None reported
None reported
was performed across all 1213 genes using the bioinformatics
Metastases
Adenomatous nodules gesting that these may represent germline variants (Table 1).
(1.5 cm, right lobe)
(1.5 cm, left lobe)
Additional tumors
None reported
Discussion
(0.4 cm)
of PTC. This variant is a RAS-driven neoplasm considered to metastasis and follicular histology is associated with 50%
be better classified as FTC in light of the biologic and genetic disease-specific 5-year survival, compared to 70% with
similarities between these two tumors [15]. In our case, al- papillary histology [23]. In this patient, confirming the
though the FTC was small (1.1 cm), it showed extensive cen- metastatic carcinoma as follicular rather than papillary in
tral necrosis with ghost follicles and multiple foci of capsular origin portends a worse prognosis. In summary, the oc-
invasion. The presence of only capsular invasion in the ab- currence of synchronous and metastatic PTC and FTC is
sence of angioinvasion may be compatible with so-called extremely rare, but, in this case, can be proven morpho-
Bminimally invasive^ FTC; however, the presence of tumor logically and genetically to represent two independent
necrosis in follicular neoplasms has been suggested as an in- clonal events with genetics and behaviors unique to the
dicator of aggressive behavior and worsened prognosis in morphologic subtype.
well-differentiated thyroid carcinomas [16]. In this case, the
necrosis represented true tumor necrosis rather than post- Compliance with Ethical Standards
biopsy infarction, as the patient did not undergo previous thy-
Conflict of Interest The authors declare that they have no conflict of
roid FNA.
interest.
Both carcinomas demonstrate mutations characteristic
of classic, well-differentiated papillary and follicular thy- Ethics Approval For this type of study, formal consent is not required.
roid carcinomas. BRAF mutations are present in approx- This article does not contain any studies with human participants or an-
imately 50% of papillary thyroid carcinomas, and, when imals performed by any of the authors.
present, are nearly always the V600E polymorphism
Informed Consent Informed consent was obtained from all individual
[17]. RAS gene mutations are present in follicular neo-
participants in this study.
plasms, including in 40–50% of follicular thyroid carci-
nomas, follicular adenomas, and non-invasive follicular
thyroid neoplasms with papillary-like nuclear features,
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