Does Every Classical Type of Well-differentiated Thyroid Cancer Have Excellent Prognosis? A Case Series and Literature Review

DISCUSSION

WDTC accounts for 2% of all human carcinomas, and it is estimated that this tumor is responsible for fewer than 0.5% of all cancer deaths.¹⁸ Generally, WDTC is considered a sporadic tumor with excellent prognosis. Local infiltration of WDTC to the surrounding anatomical structures, organs, and soft tissues localized in the neck is also an infrequent occurrence. In our study, the most common infiltrated organ was the trachea (11/14; 78%). The classical type of PTC in a majority of cases is indolent tumor with a 10-year survival of over 95%.¹⁹ One of the most common characteristics of the aggressiveness of the classical type of WDTC is its recurrence. This is observed in 8– 23% of cases.²⁰ Long term follow-up (median 40 months) in our patients demonstrated a high rate of locoregional recurrence in 12/14 (85.71%) individuals, and pulmonary and other distant metastases in 4/14 (28.57%) patients. Some authors say that these patients who had one recurrence subsequently are at a higher risk of multiple recurrences.¹⁸ The mortality of patients with a recurrence of the classical type of WDTC has been estimated at 38– 69%.²¹ In our patients, the mortality rate was 21% (3/14).

Although recently reported data suggest that some types of PTC, such as diffuse sclerosing, insular, tall, or columnar cells, present various stages of aggressiveness,²² in our study, we found that even classical type PTC might present very aggressive features. The same situation concerns the follicular variant of PTC. This estimation has very high clinical value because follicular variants of PTC are very difficult to distinguish from FTC and follicular adenoma. In our study, we identified 4 cases with classical type of FTC, and only in 2 (50%) individuals was malignancy suspected before surgery (categories 2 and 4 of The Bethesda System for Reporting Thyroid Cytopathology). Some authors suggest that the prognosis of WDTCs depends on whether they are invasive or totally encapsulated.²³ In our study, this feature was observed in 78% of patients (11/14), so we agree with some authors’ opinion that, in addition to the histopathological type of WDTC, clinical stage may determine subsequent management after surgery.²³ However, several years ago, some clinical features including histopathological type and subtype or molecular status were not taken into consideration in guideline recommendations for the planning of surgical treatment.²⁴ Currently, the situation has totally changed, and all mentioned features are valuable in the planning of WDTC management.¹⁷ To plan proper surgical treatment, strict diagnosis of WDTC must be established. The crucial point is to detect the most aggressive forms of WDTC, especially within the classical type, which is considered the entity with excellent outcome. Some authors suggest that the prognosis of follicular type PTC is generally similar to that of classical type PTC with the exception of diffuse or multinodular follicular variants. In these cases, more aggressive behavior is usually observed.²² It was estimated that the tall cell variant of PTC is more aggressive than the classical type.²⁵ Bernstein et al observed that in patients with the tall cell variant of papillary thyroid microcarcinoma (PTMC), the spread of cancer outside of the thyroid gland occurred in 33%, whereas it was not observed in any patients with the classical type PTMC.²⁶ In our study, we identified 3 (21%) patients with classical type PTMC, and all of them had aggressive clinical features (Table 1). Sometimes even small tumors may grow very aggressively, with potential for dedifferentiation. Some authors emphasized that some types of PTC must be distinguished from poorly differentiated thyroid cancer. These two extremely different groups of thyroid malignancy have the same growth pattern.²⁵ As opposed to the classical type of PTC, the columnar variant is considered by most authors as the aggressive type, especially in older patients with larger tumors demonstrating diffuse infiltrative growth and extrathyroidal extension.^25,26 However, some studies suggested that when the tumor is encapsulated, the patients have no poorer prognosis than those with classical type PTC.²⁷ In our study, 2 patients had encapsulated tumor at the time of surgery (pT1ma); however, both presented with aggressive features (lymph node and vertebral column metastases) (Figure 2C).

In a small group of patients, even with the aggressive form of WDTC, the diagnosis of malignancy might be estimated postoperatively. In that case, the necessity for completion of primary surgery should be carefully assessed. This evaluation is especially important in the case of PTC, because as we know, more than 25% are multifocal; therefore, they might also be aggressive forms of PTC.⁹ In our study, almost half of the analyzed group (6/14) presented with multifocality as one of the aggressive features (Table 1).

The other aspect increasing the aggressiveness of the classical type of WDTC is the anatomic proximity of the neck organs to the thyroid gland, rendering them vulnerable to infiltration by this tumor. The most common infiltrated anatomical structure is the aerodigestive tract. In our study, we estimated that 71% (10/14) of patients had aerodigestive infiltration. The infiltration of these structures is the major cause of death in patients with aggressive forms of WDTC. In our study, 42% of patients (6/14) presented with dyspnea as the main symptom of aggressiveness of classical type WDTC (Table 1). Though local aggressiveness is rare in the classical type of WDTC, its early diagnosis is of particular importance because of its relatively benign nature and better responsiveness to surgical management. This makes the WDTC neoplasm group one that comprises tumors with various clinical and histopathological features. Although esophageal and laryngotracheal infiltration by WDTC is not a very common clinical situation, it also might be observed. Surgical treatment depends on the local tumor invasion. The surgery may consist of the shave procedure or radical organ resection. When the tumor adheres to local organs such as the larynx, trachea, or esophagus without transmural invasion, the removal of the malignant tissue is recommended as an organ function preservation procedure. In cases of transmural invasion, radical resection is recommended, such as thyroidectomy with leryngectomy.⁸ In our study, we observed (11/14) locoregional infiltration of the adjacent organs and tissues in 78% of patients. Only in 1 case did we have to perform partial resection of the infiltrated organ. In the last 9 cases, the shave procedure was performed without necessity of organ resection. In 10 cases, the infiltrated organ was the trachea; in the other cases, it was the esophagus (1 individual), carotid (2 patients), recurrent laryngeal nerve (3 patients), and muscles (1 patient) (Table 1).

During recent years, some authors have presented cases of aggressive forms of WDTC.²² They described them as quite aggressive and resistant to conventional treatment with surgery and radioiodine therapy. They added that some variants of PTC often present various degrees of aggressiveness from that observed in WDTC to undifferentiated thyroid carcinoma. These cases of WDTC usually present higher rates of metastases, recurrence, resistance to surgical treatment, and 131I therapy.²⁸ Because of these tumors, other treatment methods are involved, including external radiation therapy, standard chemotherapy, and kinase inhibitor drugs such as sorafenib.²² The next very interesting question is, why in some entities of the classical type PTC very aggressive behavior is observed. In the aspect of mentioned features like resistance to surgical treatment and 131 I therapy, some specific molecular mechanisms should be analyzed. Volante et al identified the T1799A missense mutation in 15 Exon of the BRAF gene and rearranged during transfection gene (RET/PTC) rearrangement as the main and dominant genetic cancer pathogenesis mutation in the initiation of PTC.²⁹ The authors noticed that this specific mutation leads to a constitutive activation of the retrovirus-associated DNA sequences (RAS), rapidly accelerated fibrosarcoma (RAF), mitogen-activated protein kinase (MAPK) pathway.²⁹ They described these molecular alterations mainly in diffuse sclerosing variant of PTC, exhibiting a higher frequency of cervical and distant metastases. However, it would be interesting to check the presence and occurrence of these genetic mechanisms in the aggressive entities of the classical type PTC.

One example of the aggressiveness of WDTC is a tumor arising as struma ovarii. This is a rare clinical finding, and proper management remains unclear.³⁰ The majority of studies recommend radical pelvic resection in addition to total thyroidectomy and radioactive iodine ablation. However, others suggest that extensive pelvic surgery and elective thyroidectomy to facilitate radioactive iodine therapy might be reserved for patients with gross extra-ovarian infiltration or distant metastases.³⁰ In this location of the aggressive form of WDTC, radical pelvic resection might be performed, but we cannot carry out radical resection in the classical neck location.