2023 年 70 巻 2 号 p. 223-228
Anaplastic thyroid carcinoma (ATC) is a highly malignant tumor with invasive nature. Most patients present with locally advanced and/or distant metastatic diseases that are difficult to treat. We report a case of a previously inoperable patient with v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutated ATC. After a trial of neoadjuvant Dabrafenib/Trametinib with immunotherapy, the tumor became operable, and surgical pathology indicated a pathologic complete response (pCR). We also reviewed cases from the literature that utilized neoadjuvant BRAF-directed therapy in ATCs. These cases emphasize that BRAF-and immune-directed therapy is a feasible option in patients with inoperable ATC and may lead to improved outcomes.
ANAPLASTIC THYROID CARCINOMA (ATC) is a rare histological subtype of thyroid cancer (TC), with rapid progression and invasive nature. It comprises 1%–2% of all TCs but accounts for more than 50% of annual disease-related mortality [1, 2]. Traditional ATC treatments include surgery followed by external beam radiation therapy (EBRT) with or without chemotherapy. Despite multimodality therapy, the outcomes remain dismal, with a median survival of 5–12 months [3, 4]. Complete resection has been described as the only effective therapy for ATC, but patients usually present with an invasive neck mass involving critical structures such as the larynx, trachea, esophagus, and great neck vessels, and half of them also have distant metastatic disease [4]. Few curative options have been available in the past for patients with exhausted locoregional therapies or distant metastasis [5]. The median overall survival (OS) is three months for stage IVC disease [6].
Novel therapeutic targets associated with ATC tumorigenesis have been identified with the development of molecular diagnosis. Approximately 40%–70% of ATCs have B-Raf proto-oncogene (BRAF) V600E mutation [7]. A limited number of case series have investigated the role of targeted therapies disrupting the BRAF pathway with a combination of a BRAF inhibitor (Dabrafenib) and MEK inhibitor (Trametinib) in BRAF V600E-mutated ATC [8]. For extensively invasive unresectable primary tumors, which presented in 85%–95% ATC patients, applying Dabrafenib/Trametinib with or without immunotherapy has been described as neoadjuvant therapy to facilitate complete resection with subsequent surgery [9].
However, according to limited literature, none of the previously described patients achieved a pathologic complete response (pCR) confirmed by surgery. We report a patient with locoregionally advanced and distant metastatic BRAF V600E-mutated ATC. The patient has provided informed consent. She was previously deemed inoperable but was later successfully operated on with pCR after a trial of neoadjuvant Dabrafenib/Trametinib with immunotherapy, followed by de-escalation adjuvant therapy. We also present cases from the literature that utilized neoadjuvant BRAF-directed therapy in the setting of inoperable ATC.
The patient was a 65-year-old female with a one-month history of a self-palpable mass in the neck, mild dyspnea but no stridor or hoarseness. She had a history of diabetes mellitus and hypertension. Initial workup yielded a fixed mass at the midline neck on physical examination, while normal serum thyroid-stimulating hormone levels. Neck ultrasound and computed tomography (CT) with contrast showed a large mass with low enhancement from the left thyroid lobe, measuring 6.1 × 4.8 cm. The tumor invaded the sternocleidomastoid muscle, common carotid artery, and internal jugular vein, involving the cricoid cartilage, trachea, and esophagus, with left cervical lymphadenopathy. Tumor thrombus can be observed in the lower parts of the ipsilateral internal jugular vein. Chest CT also demonstrated multiple lung metastases. (Fig. 1A, C and E)
Axial and coronal images from the computed tomography (CT) of the neck and the chest performed before (A, C, E) and after (B, D, F) Dabrafenib/Trametinib with immunotherapy therapy. Arrow in axial images (A) demonstrates tumor invasion of the common carotid artery, Arrow in coronal images (C) demonstrates tumor thrombus in the internal jugular vein. Arrow in chest CT (E) demonstrates the biggest pulmonary metastatic nodule before neoadjuvant treatment, which almost disappeared afterward (F).
Fine needle aspiration (FNA) of the thyroid demonstrated malignant tumor cells that could not be classified through immunohistochemistry (IHC) using the “cell block.” FNA of the suspicious cervical lymph node revealed no metastasis, and the washout thyroglobulin level was <0.04 ng/mL. Then, a core needle aspiration was performed for further pathological diagnosis and molecular testing, revealing a sarcomatoid pattern of ATC with BRAF V600E, TERT promoter, and TP53 point mutations (Fig. 2A). IHC indicated a positive programmed death-ligand 1 (PD-L1) expression (22C3 pharmDx, Agilent Technologies, CA), with a combined positive score (CPS) = 90 (Fig. 2B). The tumor was immunohistochemically positive for vimentin, p63, and Ki-67 index (60%), while negative for CK, CK7, CD20, CD3, TTF1, PAX8, P40, CK5/6, Napsin A, S100, SMA, desmin, myoD1, myogenin, CD5, CD117, and CD34.
(A) Core-needle biopsy of the thyroid nodule showed marked atypical sarcomatoid tumor cells, consistent with anaplastic thyroid carcinoma (ATC) (H&E, ×200); (B) Immunohistochemical staining indicated a positive programmed death-ligand 1 expression.
After the assessment, the patient initially staged IVC, and complete surgical resection of the primary tumor was unlikely. She was started on Dabrafenib/Trametinib (Dabrafenib 150 mg p.o. twice-daily; Trametinib 2 mg p.o. daily), plus PD-1 inhibitor: sintilimab (200 mg, intravenously on day 1 Q3W). After two months of combination therapy, enhanced neck CT showed a significant shrink of the primary tumor and a separation from the carotid. A chest CT revealed that metastatic lung disease had nearly disappeared (Fig. 1B, D and F). The patient’s symptoms improved markedly. She developed a grade 1 rash on her legs, and a transient ischemic stroke which was successfully resuscitated without sequelae. Based on this response, curative resection was offered.
The patient underwent total thyroidectomy, central and left level II–IV neck dissection. The left internal jugular vein and its internal tumor thrombus were removed during neck dissection. The wrapped left recurrent laryngeal nerve was resected en bloc. Gross necrosis could be seen in the resected specimen (Fig. 3A). The histological evaluation indicated no residual tumor cells. Marked fibrosis, extensive histiocytic infiltration, and multifocal and scattered lymphocyte infiltration in and around the tumor bed was highlighted (Fig. 3B).
(A) The resected specimen shows necrotic areas in cut surface; (B) Multifocal and scattered lymphocyte infiltration in and around the tumor bed, without residual tumor cells, was shown microscopically (H&E, ×100).
The patient’s case was presented to the multidisciplinary consultation postoperatively; radiation or chemotherapy was not recommended. Dabrafenib/Trametinib was rejected by the patient probably due to economic reasons. The only adjuvant therapy was sintilimab 200 mg every three weeks. Surveillance scans demonstrate no evidence of disease 12 months after surgery.
Molecular-based multidisciplinary therapies have changed the treatment pattern of untreatable ATC and significantly increased patient survival. Since Cabanillas et al. reported the first use of BRAF- and immune-directed neoadjuvant therapy for managing BRAF-mutated ATC [10], Dabrafenib/Trametinib has been recommended over other systemic therapies by American Thyroid Association Guidelines in BRAF V600E-mutated IVC and unresectable IVB ATC patients due to its outstanding efficacy [7]. According to the author, this is the first report of a pCR case in ATC after neoadjuvant therapy. Furthermore, de-escalation strategies in adjuvant therapy are explored innovatively.
BRAF V600E mutation is a common driver mutation in well-differentiated thyroid cancer. TERT promoter mutations are key transitional steps in tumor evolution; their prevalence is higher in poorly differentiated TCs and ATCs. TP53 mutation is a late-event change that occurs in more than 70% of ATC patients [11]. These typical genetic variations occurred in this patient and promote a progressive dedifferentiation to ATC. Animal experiments proved that transgenic mice harboring BRAF V600E and TP53 mutations developed poorly differentiated thyroid tumors that could be treated with BRAF inhibitor PLX4720. Adding MEK inhibition resulted in a complete MAPK blockade and enhanced antitumor activity compared to single-agent BRAF inhibitors [12]. It has also been shown that PD-1/PD-L1 pathway protein expression was increased in ATC tumors [13]. ATC patients who received targeted therapy with immunotherapy had significantly higher OS than those who received targeted therapy alone [14]. This patient’s tumor highly expressed PD-L1 (CPS = 90) in the initial workup, making her more amenable to immunotherapy.
Dabrafenib/Trametinib, with or without immunotherapy, has been reported in a small number of cases to shrink the tumor burden preoperatively to facilitate ensuing surgery in ATC patients. Table 1 presents a series of ATC case reports that employed neoadjuvant Dabrafenib/Trametinib therapy and their subsequent outcomes. These eight patients were newly diagnosed ATC harboring BRAF V600E mutation, with or without other mutations. The tumors presented with the invasion of adjacent structures such as the larynx, esophagus, or carotid arteries, and satisfactory resection was not possible after the initial evaluation. The patients received Dabrafenib/Trametinib, and two of them were also administered pembrolizumab. The tumor size decreased, and curative resections were offered after a period of 1.6 to 12 months. The procedures included total thyroidectomy and central or lateral neck dissection. One patient received limited resection of esophageal muscularis, while another received laryngotracheal resection with primary anastomosis. Five of the eight patients underwent an R0 resection. Thyroid or lymph node pathology revealed TC with different degrees of differentiation. All patients received combined adjuvant therapy. Two patients died of progressive distant metastases, while the rest were alive at the end of follow-up (7.8–26 months from diagnosis).
| Study reference | Age (years)/Sex | TNM | Preoperative immunotherapy | Residual (R) tumor classification | Resected final pathology | Adjuvant therapy | Clinical outcome |
|---|---|---|---|---|---|---|---|
| Cabanillas et al. [10] | 60/M | T4bN1bM0 | Pembrolizumab | R1 | ATC + PTC | Chemoradiation + D/T + anti-PD1 | Local recurrence 8 weeks after radiation, free of disease at 26 m from diagnosis (20 m after salvage therapy) |
| Wang et al. [9] | 48/F | T4bN1bM0 | None | R0 | ATC + PTC | Chemoradiation + D/T | Died of distant metastases at 14 m from diagnosis (11 m after surgery) |
| 69/F | T4bN1aM0 | None | R1 | ATC + PTC | Chemoradiation | Died of distant metastases nearly 8 m from diagnosis (7 m after surgery) | |
| 58/M | T4bN1bM0 | None | R0 | PDTC + DTC | Chemoradiation + D/T + anti-PD-1 | Free of disease at 20 m from diagnosis (19 m after surgery) | |
| 73/F | T4bN1bM1 | None | R0 | ATC + PTC | D/T + anti-PD-1 | Free of disease at 19 m from diagnosis (6 m after surgery) | |
| 46/F | T4bN1bM1 | Pembrolizumab | R0 | PTC | Chemoradiation + D/T + anti-PD-1 | Free of disease at 12 m from diagnosis (8 m after surgery) | |
| McCrary et al. [15] | 73/M | T4bN1bM1 | None | R0 | ATC + PTC | Chemoradiation + D/T | Complete resection 3 m from diagnosis, follow-up results were not reported |
| Kent et al. [16] | 67/M | T4bN1bM0 | None | R1 | ATC | Chemoradiation + D/T + anti-PD-1 | Free of disease at 21 m from diagnosis (17 m after surgery) |
F, Female; M, Male; ATC, anaplastic thyroid carcinoma; PDTC, poorly-differentiated thyroid carcinoma; PTC, papillary thyroid carcinoma; D/T, Dabrafenib/Trametinib; PD1, programmed death 1; m, months
All cases were reported in the United States, and six out of eight were from The University of Texas MD Anderson Cancer Center. BRAF V600E mutation prevalence was higher in East Asian TC patients than in Western countries [17]. However, there was little or no representation of Asian patients concerning the effectiveness of neoadjuvant therapy in BRAF-mutated ATC. Our limited experience showed that Chinese ATC patients could also respond dramatically to Dabrafenib/Trametinib plus immunotherapy, with tolerable side effects. Moreover, a pCR has been achieved, indicating a probably good prognosis and possibly reducing the strength of follow-up adjuvant therapy.
Adjuvant therapy must be initiated timely due to the rapid progression of ATC. Adjuvant radiation and chemotherapy are commonly recommended to maximize locoregional control and prevent distant metastasis. However, there is no experience to follow for patients with a pCR after neoadjuvant therapy. We suggested a de-escalation therapy with Dabrafenib/Trametinib plus immunotherapy after weighing the uncertain benefit and potential adverse effects of chemoradiation. The patient declined adjuvant target therapy and resumed sintilimab 200 mg every three weeks. Sintilimab is a recombinant humanized anti-PD-1 monoclonal antibody; previous studies have validated its safety and efficacy in other tumor species [18, 19]. This is the first application of sintilimab in thyroid cancer treatment as an alternative anti-PD-1 antibody besides pembrolizumab. Exploring a new paradigm provide patients with more choices. However, the long-term outcome must be verified.
In summary, we reported an ATC case, initially considered inoperable but resected after preoperative Dabrafenib/Trametinib plus anti-PD-1 immunotherapy, resulting in a pCR. Molecular-based multidisciplinary therapies are feasible in ATC patients and can reduce the lesion size or even eliminate it, offering a potential cure for this devastating disease. Further studies, including larger samples and long-time follow-ups, are required to investigate the optimal operation time and proper adjuvant therapy strategy.
None of the authors have any potential conflicts of interest associated with this report.
