Case report
A 62-year-old woman presented with complaints of a painless hoarseness
and a palpable right lymph node. Laryngoscopy initially showed right
recurrent nerve paralysis, and an ill-defined tumor mass was found in
the right thyroid lobe using ultrasound. A computed tomography (CT) scan
revealed that the tumor measured over 60 mm replacing the thyroid lobe
and extended into the strap muscles compressing the trachea (Figure 1a).
Multiple metastases into cervical lymph nodes and lung were also
observed in the CT scan. Furthermore, after a fine needle aspiration
biopsy, an anaplastic or poorly differentiated carcinoma was strongly
suspected. After the diagnosis of poorly differentiated carcinoma,
lenvatinib, a multi-receptor tyrosine kinase inhibitor, was used as a
first-line treatment. During lenvatinib administration, a liver
metastasis was detected in a CT scan that gradually progressed (Figure
1b). To prevent spontaneous intra-tumoral hemorrhage in the liver
metastasis and a life-threatening tracheal invasion at the primary site,
both primary and metastatic lesions were surgically resected.
Postoperative pathology reported that CD5, p40, p63, and c-Kit were
highly expressed, whereas TTF-1 and PAX8 expression were negative in the
tumor tissue, concluding that the tumor was a metastatic ITTC (Figure 1c
& 1d). The patient’s treatment strategy was switched from lenvatinib
administration to scheduled hypofractionated radiotherapy (45 Gy in 15
fractions) followed by weekly paclitaxel administration. However, the
patient discontinued paclitaxel treatment because of paclitaxel-induced
severe side effects. After a failure of chemoradiotherapy, her liver
metastasis re-emerged and rapidly progressed.
To explore more effective and optimal treatments for this metastatic
ITTC, after obtaining the informed consent from the patient, we
investigated the specific genetic mutation profile within the liver
metastatic lesion using NGS-based cancer mutation analysis. The specific
genetic mutations in metastatic ITTC were shown in Table 1. Among those
mutations, focal copy number amplifications in CD274 andPDCDILG2 , which are encoding PD-L1 and PD-L2 as immune checkpoint
proteins, were detected. Abundant expression of PD-L1 protein was also
found on most of the tumor cells by conventional immunohistochemistry
(IHC) (Figure 2), suggesting that an immune checkpoint signaling pathway
is associated with tumor progression in metastatic ITTC.
We subsequently visualized the spatial distribution of
PD-L1+ tumor cells and
PD-1+CD3+ T cells in the metastatic
ITTC using multiplex IHC. Interestingly, the number of tumor cells
expressing PD-L1 was higher in the marginal area than that in the tumor
nest (Figure 3a). Intra-tumoral and stromal distribution of
PD-1+CD3+ T cells was also observed
in the metastatic ITTC (Figure 3a). Next, we examined whether
CD3+CD8+ T cells, a cytotoxic
subtype of T cells, express PD-1 in metastatic ITTC by using Image
cytometry and multiplex IHC. Interestingly, 41.86 %
CD3+CD8+T cells expressed PD-1 on
their membranes (Figure 3b and 3c). Moreover, we evaluated PD-1
expression on CD3+CD8+ T cells in
the tumor nest and in the marginal and stromal areas. The number of
PD-1+CD3+CD8+ T
cells tended to be higher in the tumor nest and the marginal area than
that in the stromal area (Figure 3d). These data indicated the existence
of immunosuppression via a PD-1/PD-L1 pathway in the metastatic ITTC,
and a PD-1/PD-L1 pathway could be therapeutically targeted.
Given our immune data, we made the treatment decision to administer
pembrolizumab to block the PD-1/PD-L1 pathway in this case. However, the
patient’s liver metastasis rapidly progressed, leading to a
deterioration of her physical condition. Pembrolizumab was then no
longer an option for controlling the metastatic ITTC, and the patient
died because of her liver metastasis.