Abstract
Summary
We report a 61-year-old male patient without personal history of thyroid carcinoma or radiation exposure. In 2011, he presented with a cervical mass whose biopsy diagnosed a papillary thyroid carcinoma (PTC) in a lymph node metastasis (LNM). Total thyroidectomy with lymphadenectomy of central and ipsilateral compartment was performed. Histopathology identified a 2 mm follicular variant of PTC and LNM in 25/25 lymph nodes. The patient was treated with 150 mCi of radioactive iodine (RAI), followed by levothyroxine suppressive therapy. In 2016, a retrotracheal mass was diagnosed, suggesting local recurrence; patient was submitted to surgical excision and RAI therapy (120 mCi). Due to seizures, in 2019, a brain CT was performed that diagnosed brain metastases. The patient underwent debulking of the main lesion. Histopathology analysis confirmed a metastatic lesion with variated morphology: classical PTC and follicular pattern and hobnail and tall cell features. Molecular analysis revealed BRAFV600E in LNM at presentation and BRAFV600E and TERT promoter (TERTp) mutations in the recurrent LNM and brain metastasis. Based upon this experience we review the reported cases of subcentimetric PTC with brain metastases and discuss the molecular progression of the present case.
Learning points
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Papillary microcarcinoma (PMCs) usually have very good prognosis with low impact on patient survival.
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PMCs presenting in elderly patients with LNM at diagnosis may carry a guarded outcome.
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Brain metastasis although rare indicate aggressive phenotypic features.
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Patient risk stratification of PMCs based on histopathological analysis and genetic testing may have a significant impact on prognosis providing therapeutic markers, that may predict disease progression and overall outcome.
Background
Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy (80–90% of thyroid cancer) (1, 2). Generally, this tumor is characterized by an indolent behavior. It carries good prognosis with survival rates at 10 years exceeding 90–95% (3). PTC measuring 10 mm or less in diameter was defined as papillary thyroid microcarcinoma (PMC) and an active debate questioning if size ‘per se’ could be considered a diagnostic feature is ongoing. In the upcoming 5th edition of the World Health Organization classification of thyroid neoplasms this distinction will be eliminated (2, 4). For the sake of simplicity along this work, we will keep the designation PMC for <1 cm PTC. The incidence of PMCs is increasing and represents approximately 50% of PTC, with a mortality rate of nearly 0.1% at 10 years (5, 6). Aggressive disease develops in approximately 3.8% of patients (5). The presence of metastatic disease at initial presentation is known to carry worse prognosis (7). Lungs and bones are typical locations of distant metastases (8). Brain metastases are very rare (0.8–1.3%) and suggest a more aggressive behavior (9).
In PMCs, histological subtyping of primary tumor or lymph node metastases (LNM) is rarely evaluated, due to PMC’s low clinical aggressiveness and its uncertain prognostic meaning (5). This size-defined variant comprises all histological PTC subtypes, and a wide molecular and biological heterogeneity (6, 10). Ghossein et al. pointed out the importance of LNM subtyping in PMC patients’ prognosis regarding a more accurate risk stratification due to known aggressive variants such as tall cell and hobnail variants of PTC (11). Concerning molecular status, PMCs do not evidence a substantial difference in prevalence of BRAF mutation and RET/PTC rearrangement, in comparison to PTC >1 cm (6). It was advanced that nearly 0.05% of PMCs with BRAFV600E progress to aggressive disease (10). TERT promoter (TERTp) mutations may be present in <10% of PMCs and relate with unfavorable prognosis (12). It was advanced that molecular markers such as BRAF and TERTp mutations combined with histological analysis can have a predictive value for distant metastasization and overall prognosis (12, 13, 14, 15). The occurrence and clinical relevance of the observed histological and molecular alteration in PMCs remain unclear.
Case presentation
A 61-year-old male patient without personal history of thyroid carcinoma or previous radiation exposure presented, in 2011, with a dull cervical mass adherent to muscle planes and without other associated symptoms. The patient was submitted to a cervical lesion excisional biopsy that showed PTC LNM. Total thyroidectomy and lymph node dissection of central and ipsilateral cervical compartments was performed. Histopathology analysis diagnosed a 2 mm partially encapsulated PTC displaying a predominantly follicular pattern. The PMC was localized in the central part of the lobe and there were no signs of vascular invasion. Metastases were detected in 25 out of 25 lymph nodes (LN) harvested, the largest LN measured 35 mm and displayed extranodal extension. The tumor was staged as pT1aN1bM0, according to the 8th AJCC edition (16) and high risk, according to the ATA stratification (17). The patient received 150 mCi of radioactive iodine (RAI) and TSH was suppressed bellow 0.1 ng/mL. At first-year evaluation, the patient had an excellent response to treatment. At second year of follow-up, thyroglobulin (Tg) levels started to increase (Fig. 1). From 2013 until 2016 patient had rising TGB levels fulfilling indeterminate biochemical response (TGB <10 ng/mL in stimulation and no evidence of structural disease in cervical US). In 2016, TGB rise to incomplete biochemical response (16.02 ng/mL in stimulation) and since there was still no evidence of structural disease in cervical US, an FDG PET/CT scan was performed. A retrotracheal mass was identified in the PET-CT scan, suggesting local recurrence. Cervical ultrasound did not evidence any structural disease. A cervical and thoracic CT scan was performed to better characterize the aforementioned lesion (Figs 2A and B).
Patient thyroglobulin (ng/mL) evolution during follow-up.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 4; 10.1530/EDM-23-0025
Detection of disease recurrence; A) Thoracic and B) Cervical CT demonstrating a retro-tracheal lymph node of 3 cm.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 4; 10.1530/EDM-23-0025
The patient was submitted to surgical excision of the cervical lesion, followed by therapy with 120 mCi RAI. The post-RAI scintigraphy showed no focal abnormal uptake and stimulated serum TGB level was undetectable (0.83 ng/mL) (Fig. 1). Histological analysis found metastatic tissue extensively occupying the LN. In 2017, the patient started to experience asthenia and lack of strength in the lower limbs. An FDG-PET/CT scan revealed focal pathological uptake in lungs and dorsal lumbar spine (data not shown). A magnetic resonance imaging (MRI) exhibited infiltrative lesions in D9, D11, S1, and S2, highly suggestive of distant metastases. The patient received 190 mCi of RAI. In this period, suppressed TGB levels increased from 0.83 to 8 mg/dL (Fig. 1). In November 2019, patient presented seizures at the Emergency Room and underwent a brain CT scan and MRI that diagnosed multiple brain lesions (Figs. 3A and B). At this time, the suppressed TGB level was 42 mg/dL (Fig. 1) with negative anti-thyroglobulin antibodies.
Brain metastasis detection in 2019. (A) Brain CT scan showing brain metastases. (B) Brain MRI showing brain main metastasis.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 4; 10.1530/EDM-23-0025
The patient underwent debulking of the main lesion. Histopathological analysis confirmed PTC metastases. He underwent whole-brain radiotherapy. In May 2021, the patient deceased, due to disease progression.
Investigation
Histological and molecular characterization of retrieved specimens was performed to ascertain lesions’ histological subtyping and genetic analysis. There was no remaining material available from the subcentimetric primary PMC.
Histopathological analysis of collected LNM at diagnosis revealed the presence of classical PTC, follicular variant of PTC, and hobnail variant of PTC, as depicted in Fig. 4A. In the retrotracheal recurrence, tall cell variant PTC was also detected along with the previous aspects (Fig. 4B). In the brain metastasis samples, it was detected papillae lined by malignant thyrocytes characterized by a hobnail component (Fig. 4C), as well as a component with clear cell cytoplasm and PTC nuclear features (Fig. 4D).
Microscopic analysis of LNM (A, B, C) and brain metastasis (D) (H&E-stained slides). (A) Micropapillary structures (left) and tail like/tear-drop/hobnail shape malignant thyrocytes (right) revealed the areas of hobnail variant PTC in LNM metastasis present at diagnosis. (B) Thin papillary structures lined by tall cell (3:1 or 2:1 ratio) indicating tall cell variant PTC emerging in the retrotracheal metastases (recurrence). (C) Brain metastasis depicting hobnail component. (D) Brain metastasis – papillary structures lined by malignant thyrocytes characterized by clear cell cytoplasm and PTC nuclear features. Scale bars: 50 μm.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 4; 10.1530/EDM-23-0025
Samples retrieved from LNM at first diagnosis (2011), first recurrence (2016), and brain distant metastases (2019) were studied for p53 expression, Ki-67 index and the most frequent molecular alterations associated with thyroid carcinoma: BRAF, RAS (NRAS, HRAS, and KRAS), and TERTp mutations (Table 1).
Molecular analysis of the retrieved specimens.
| Lesion/Year | Samples, n | Status | TERTp# | BRAF# |
|---|---|---|---|---|
| LNM/2011 | 13 | WT | 12 | 1 |
| Mut | 0 | 12 | ||
| LNM/2016 | 6 | WT | 0 | 0 |
| Mut* | 6 | 5 | ||
| BM/2019 | 7 | WT | 0 | 0 |
| Mut** | 7 | 7 |
No RAS (N-, H-, K-RAS) mutations were detected in any lesion.
*5 out of 6 samples presented BRAFV600E and -124G>ATERTp simultaneous mutation; **7 out of 7 samples presented BRAFV600E and -124G>ATERTp simultaneous mutation; #Not all the samples gave result for the genetic analysis.
BM, brain metastases; LNM, lymph node metastases; Mut, mutated; WT, wild-type.
In LNM present at diagnosis, p53 staining was faint and present in rare and disperse cells, with strong and more extensive reactivity in the focus of hobnail component (Fig. 5A). The overall Ki-67 index was very low (<0.5%) (Fig. 5B). Molecular analysis of the DNA extracted from these samples demonstrated the presence of BRAFV600E mutation. No alterations were detected in RAS genes or TERTp.
Immunohistochemical analysis of p53 expression and Ki-67 index in LNM present at diagnosis (A and B, respectively) and in brain metastases (C and D, respectively). (A) p53 staining was present in the hobnail thyrocytes that lined the early LNM while being negative in the remaining of the lesion. (B) The hobnail variant presented to be negative for Ki-67 staining. (C) p53 staining was weak and rather disperse in the brain metastasis; however, some areas with more frequent p53-positive cells were found, as the one depicted. (D) Brain metastases showed higher Ki-67 index, in which <10% Ki-67-positive cells were homogeneously present in all the lesion.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 4; 10.1530/EDM-23-0025
Retrotracheal cervical recurrence revealed the presence of tall cell variant of PTC in addition to the other morphologic manifestations found at diagnosis (Fig. 4B). The p53 staining of this lesion was faint and disperse; however, the Ki-67 index was higher (~5%), when comparing to the first LNM, and was mostly localized in the periphery of tumor rather that in the center. Molecular analyses demonstrated the coexistence of BRAFV600E and TERTp mutations in all the successful analyzed samples.
Brain metastases were mainly constituted by hobnail variant of PTC (with a minority of classical features) and also showed areas with clear cells (Fig. 4D). p53 expression was faint and disperse (Fig. 5C). Ki-67 index was higher (< 10%) and more widespread than in the previous lesions (Fig. 5D). Like the retrotracheal lesions, brain metastases showed coexistent BRAFV600E and TERTp mutations. No RAS mutations were detected.
Discussion
According to the existing literature, PMCs have mild biological behavior and good prognosis in most patients (5). It is important to distinguish asymptomatic (or incidental) PMC, that carry an excellent prognosis and may undergo active surveillance, from clinically recognized PMCs with LNM at diagnosis, whose prognosis is similar to PTC >1 cm and are not indicated for active surveillance (5). Clinical features that associate with increased risk of adverse outcome remain controversial. Size larger than 5–7 mm has been associated with increased rate of LNM and increased recurrence (11). The presence of clinical LNM at initial presentation is recognized as an important prognostic factor that may lead to a more aggressive course (5). In PMCs, distant metastases are rarely reported (7), and only a minority of that correspond to brain metastases (0.8–1.3%) that carry a worse outcome (9).
Nearly 25% of PMCs develop local LNM recurrence, but rarely develop distant metastases (0.5%) (7). Therefore, it is of major importance to maintain follow-up of patients who present tumors with aggressive features. TGB is used in thyroid carcinoma surveillance as the primary biochemical marker for patient monitoring (17). TGB serum level is high in almost all metastatic thyroid disease, helping in cancer progression detection (18). Sometimes TGB level is the initial sign indicating secondary disease and leading to local or distant metastasis diagnosis (Fig. 1). In this case the patient did not evidence clinical or imaging disease, at the first year evaluation after surgery. At this time, stimulated TGB was <1 mg/dL (excellent response), leading toward a favorable outcome (17). At the second year of follow-up, TGB levels started to increase. In 2016, TGB level reached incomplete biochemical response level, which led to a cervical mass diagnosis in PET-CT scan, confirming the presence of locoregional recurrence. According to ATA classification (17), disease recurrence is identified in 67–75% of high-risk patients and high-risk features may harbor a recurrence risk more than 10 years after initial treatment (17, 19). According to existing studies, persistence is more frequent and associated with a worse outcome than recurrence (17, 19, 20).
The primary tumor in this case was a central parenchymal 2 mm follicular variant of PTC, which presented together some high-risk features, namely, age at diagnosis (61 years), male gender, extensive LNM at presentation with largest LNM >30 mm, and extranodal extension. Central parenchymal PMCs <5 mm have been considered as the most indolent ones. It has been described that the LNM size has a better correlation with the outcome than primary tumor size (5).
We consider that histological subtyping of primary tumor and LNM is important, since aggressive variants have worse prognosis (21). The heterogeneous histology demonstrating classic, hobnail features along with follicular variant of PTC present in the initial LNM may highlight the potential locoregional recurrence and distant metastasization. PMCs with distant metastasis are rarely reported. We performed a literature search regarding this subject since 2010 and realized that distant metastasis in PMCs was reported in 24 patients and brain metastases was reported in only five patients (Table 2).
Clinicopathological features of PMC distant metastasis reported cases.
| No | Study | Age (years), gender | Tumor size (cm) | Histological variant | pN | Metastatic site |
|---|---|---|---|---|---|---|
| 1 | Lecumberi et al. (22) | 65, F | 0.2 | Sclerosing | − | Brain |
| 2 | Xu et al. (23) | 46, F | 0.3 | Follicular | + | Brain, lung |
| 3 | Saito et al. (24) | 70, F | 0.8 | NA | − | Lung |
| 4 | Kozu et al. (25) | 70, M | NA | Classical | NA | Lung |
| 5 | Zheng et al. (26) | 53, F | 0.6 | NA | − | Bone |
| 6 | Kaseda et al. (27) | 66, F | NA | Infiltrative follicular | NA | Lung |
| 7 | Kawai et al. (28) | 70, M | 1 | NA | + | Lung |
| 8 | Jeon et al. 2016 (29) | 51, F | 0.8 | Classical | + | Lung |
| 9 | Jeon et al. (29) | 31, F | 0.9 | Infiltrative follicular | + | Lung |
| 10 | Jeon et al. (29) | 55, F | 0.9 | Tall cell | + | Bone, lung |
| 11 | Jeon et al. (29) | 59, F | 1 | Classical | + | Bone, lung |
| 12 | Jeon et al. (29) | 73, F | 1 | Classical | + | Lung |
| 13 | Jeon et al. (29) | 54, F | 0.8 | Classical | + | Lung |
| 14 | Jeon et al. (29) | 63, F | 0.8 | Classical | + | Bone, lung |
| 15 | Jeon et al. (29) | 46, F | 0.7 | Infiltrative follicular | + | Bone, lung |
| 16 | Jeon et al. (29) | 65, M | 0.6 | Columnar cell | + | Brain, lung |
| 17 | Jeon et al. (29) | 58, F | 0.6 | Solid | + | Brain, lung |
| 18 | Jeon et al. (29) | 60, F | 0.8 | Classical | + | Bone, lung |
| 19 | Jeon et al. (29) | 63, F | 0.9 | Classical | + | Bone, lung |
| 20 | Hu et al. (30) | 70, F | 0.8 | NA | − | Lung |
| 21 | Hu et al. (30) | 29, F | 0.9 | NA | − | Lung |
| 22 | Hitu et al. (31) | 58, F | NA | Classical | − | Muscle |
| 23 | Shawky et al. (32) | 59, M | 0.3 | Follicular | − | Brain |
| 24 | Shimizu et al. (7) | 64, M | 0.9 | Classical | − | Lung |
NA, not available; pN, pathological cervical lymph node metastases.
Particularly, some biological commonalities have been shown in both poorly differentiated thyroid carcinoma and hobnail variant of PTC, owing to a shared morphological formation ‘hobnail pattern’ in both types of tumors. This supports the idea of previous studies, that presence of this pattern inside the tumor might facilitate ‘epithelial-to-mesenchymal transition’ mechanism, which in turn leads to tumor progression, local invasion, and distant metastasis, as in the current case (33), underlined by the recently published literature (3, 21).
Some authors propose the use of Ki-67 index and/or p53 immunostaining as an indicator of high-risk thyroid carcinomas, like in other cancers (34). In our results, p53 presented a faint and limited expression, compatible with a wild-type status, except in the hobnail component where we noted a more intense and widespread expression of p53, as previously described (34). The Ki-67 index was very low in synchronous LNM, increasing in recurrent lesions. It was advanced that the combination of TERT promoter/BRAFV600E mutations and Ki-67 may be clinically useful predicting PTC recurrence (34).
Molecular analysis in PMCs is still under debate. Nevertheless, aggressive tumor behavior can be associated with recently investigated biological characteristics. The alteration more often presents in PMC, associated with locoregional recurrence, is BRAFV600E mutation (14). BRAF mutations are detected in nearly 50% of PTC, but only 10% of these cases have unfavorable clinical outcomes (13, 14). This mutation itself does not contribute to the increase in risk mortality and should be considered in the context of high-risk features (17). BRAFV600E mutation, associated with some clinicopathological risk factors, has shown to increase the risk of disease recurrence in both classical PTCs and PMCs (17). More recently described, the presence of TERTp mutation confers an unfavorable outcome in thyroid cancer (12). TERTp mutations are more frequent in older, male patients with local recurrent disease and presenting distant metastases and have been defined as a late event in thyroid tumorigenesis adding a functional advance toward PMC aggressiveness (12). In the present case, it was not possible to analyze the primary tumor. However, we verified that the LNM samples retrieved at diagnosis only presented BRAFV600E mutation. Notably recurrent LNM and brain metastasis acquired TERTp mutation, in line with the role of TERTp in thyroid cancer progression. There are data regarding an association between the coexistence of these two mutations and clinically aggressive disease (14, 15). The prevalence of BRAF and TERTp mutations coexistence is 7.7% and has revealed to increase the risk of locoregional recurrence and development of distant metastases (13, 35). Currently, there are no risk stratification systems that encompass tumors’ molecular profile (17). Thus, the presence of TERTp mutation is emerging as an independent predictor of mortality (12, 17). In this case, the coexistence of BRAFV600E and TERTp mutations added a worse prognosis that is consistent with recent published studies (12, 13, 14, 15, 35, 36).
The present case highlights the important role of several high-risk factors paradoxically in a very small PTC: man, age >55, extensive large and locally invasive LNM at presentation, coexistence of PTC variants associated to guarded prognosis in LNM and brain metastases and TERTp mutation. Altogether, the aforementioned factors highlight the importance of patient stratification even when the primary tumor is a PMC. Patients with high recurrence risk may benefit from analysis of oncogenic driver mutation (namely, BRAFV600E and TERTp mutation) as an adjunct to recognize disease recurrence earlier and initiate systemic therapy. This case provides evidence to stress the interest of studying morphologically, immunohistochemically and molecularly subcentimetric PTCs in order to progress in the prognosis of challenging cases.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.
Funding
This work was funded by Programa Operational Regional do Norte and cofunded by European Development Fund under the project ‘The Porto Comprehensive Cancer Center’ with the reference NORTE-01-0145-FEDER-072678 and NORTE-01-0145-FEDER-000051 – Consórcio. PORTO.CCC – Porto.Comprehensive Cancer Center. ET was funded by the FCT PhD grant SFRH/BD/143458/2019.
Patient consent
Every effort was made to contact the next of kin of the deceased patient to obtain consent but in vain. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of CHVNG/E (Project investigation 30/2016, January 28, 2016, Comissão de Ética do Centro Hospitalar de Vila Nova de Gaia/Espinho).
Author contribution statement
A Amado: conceptualization, writing (original draft preparation); E Teixeira: methodology, formal analysis, investigation; S Canberk: methodology, formal analysis, investigation; S Macedo: methodology, formal analysis; B Castro: data curation; H Pereira: data curation; J Varanda: data curation; S Graça: named physician of the patient, supervision; A Tavares: supervision; C Soares: named physician of the patient, supervision; M J Oliveira: named physician of the patient, supervision; M Oliveira: supervision; P Soares: writing (review and editing, resources, project administration, funding acquisition, supervision; M S Simões: conceptualization, writing (review and editing), supervision; A A Povoa: conceptualization, writing (review and editing), named physician of the patient, supervision. All authors read and agreed to the final version of the manuscript.
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