| Abstract|| |
Background: Papillary thyroid microcarcinoma (mPTC) is defined as a tumor with low malignancy potential. Different treatment protocols have been used at different centers for analyzing this tumor which has common recurrence and metastasis rates. Consequently, in 2016, the definition of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was accepted which included the lesions > cm. It is important to explain the clinical course and appropriate treatment options for mPTC and its subtypes. Aims: In this study, we aimed to describe the clinical course of mPTC with and without NIFTP and to determine different risk groups among these subtypes. Material and Methods: We performed microscopic reexamination of about 280 unifocal mPTCs retrieved from our archives between 2007–2018 and analyzed the results of morphological and clinical comparison among these cases that had 0–11-years of clinical follow-up. Results: Among 280 unifocal mPTCs, 127 cases (45.4%) had classical morphology, 58 (20.7%) had NIFTP, 53 (18.9%) had infiltrative pattern, 27 (9.6%) had oncocytic pattern, 12 (4.3%) showed capsular invasion, and 3 (1.1%) showed other morphologies. Seven patients were detected with lymph node metastasis and one with distant metastasis at diagnosis. Lymph node metastasis (recurrence) was postoperatively detected in five patients. All patients with recurrence were women. Moreover, three of these patients were in their 30s and two in 70s. The median diameter of the tumor was 3 mm. Both invasive and noninvasive cases have recurred. Conclusion: Contrary to the results of the previous studies, the results of our study did not confirm the indolent course of mPTC with NIFTP. However, metastasis was detected both at the time of diagnosis and during the postoperative period. The malignancy potential of these tumors may not be low. Therefore, more clinicopathological and molecular studies are needed to determine the biological behavior of mPTC cases with different histology.
Keywords: Clinical comparison, noninvasive follicular thyroid neoplasm with papillary-like nuclear features, papillary thyroid microcarcinoma, unifocal
|How to cite this article:|
Cakir E, Saygin I, Kisioglu S. A comparison between unifocal papillary thyroid microcarcinoma with noninvasive follicular thyroid neoplasm with papillary-like nuclear features and other patterns: A retrospective clinicopathological study. Indian J Pathol Microbiol 2020;63:188-93
|How to cite this URL:|
Cakir E, Saygin I, Kisioglu S. A comparison between unifocal papillary thyroid microcarcinoma with noninvasive follicular thyroid neoplasm with papillary-like nuclear features and other patterns: A retrospective clinicopathological study. Indian J Pathol Microbiol [serial online] 2020 [cited 2020 May 27];63:188-93. Available from: http://www.ijpmonline.org/text.asp?2020/63/2/188/282703
| Introduction|| |
Papillary thyroid microcarcinoma (mPTC) measures ≤1 cm in diameter and is known to show indolent behavior. However, the clinical approaches to these tumors are controversial and different treatment protocols are used at different medical centers. Recently, the term “papillary microtumor” has been chosen to define this variant of papillary thyroid carcinoma. Since it is described as a type of “cancer,” patients are subjected to additional surgery/treatment and frequent follow-ups. On the other hand, mPTC is associated with a 1.0% disease-related mortality rate, 5.0% lymph node metastasis (LNM) rate, and 2.5% distant metastasis rate; hence, some studies recommend the same treatment protocol as papillary thyroid carcinoma for patients with mPTC, if poor prognostic factors are present. According to the updated 2015 American Thyroid Association (ATA) guidelines, unifocal mPTC is defined in the low-risk category, whereas multifocal disease lies in the intermediate-risk category., The local recurrence rate after surgical treatment is 2%–6%.
Recently, similar concerns have also been noted for papillary thyroid carcinomas, which are encapsulated (or well-circumscribed), noninvasive, and of the follicular variant (EFVPTC). Numerous clinical studies involving long-term follow-up have shown that these tumors have a very low risk of LNM and distant metastases with a recurrence rate of less than 1% within the first 15 years. In the literature published in the English language, only two of the 352 EFVPTCs recurred. Incomplete excision was detected in one of the recurred tumors; whereas, in the other case, noninvasive nature of the tumor was suspected. However, these tumors are treated like a classic papillary carcinoma causing anxiety in patients, which in addition to psychological effects, imposes a serious economic burden on the state budget with frequent treatment and follow-up costs. In 2016, Nikiforov et al. conducted an international and multidisciplinary study under the name of “The Endocrine Pathology Working Group.” They published the exclusion criteria as well as major and minor diagnostic criteria for this tumor group and provided a different definition for these tumors, which differ in their genetic and clinical characteristics. EFVPTC was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and this definition was included in the 2017 World Health Organization classification. These tumors are no longer included under the title of “carcinoma” but are rather included under the title of “other encapsulated follicular-pattern thyroid tumors;” therefore, they are not included in the frequent follow-up programs along with radical surgeries and additional treatments.
However, the consensus diagnostic criteria for NIFTP did not involve sub-centimeter lesions. According to the current (February 2019) College of American Pathologists cancer protocol for the thyroid gland, NIFTP is not well-validated in oncocytic, sub-centimeter, and multifocal lesions.
In the literature, very few studies on mPTC with NIFTP have been published. We investigated differences in the clinical outcome of various histological variants in mPTC. We aimed to contribute to the studies that tried to explain whether NIFTP criteria should exclude sub-centimeter lesions. In addition, we wanted to contribute to the determination of the risk factors related to aggressive tumor behavior of mPTC., thereby, determining the prognostic parameters and therapeutic approach.
The present study reviewed the histopathological and clinical data of 280 unifocal patients with mPTC and analyzed the results of comparison among different unifocal mPTCs that also included NIFTP.
| Material and Methods|| |
We performed a retrospective review and microscopic reexamination of mPTCs at our institution between 2007 and 2018. We conducted a computer search to find all cases of thyroid nodules measuring ≤1 cm in diameter. We made a query using the keywords “thyroid,” “papillary,” and “microcarcinoma” and obtained 1,048 cases.
We excluded 744 cases from the study. The exclusion criteria were: (1) consultation slides from external hospitals (we did not have clinical data of this group) (n = 505), (2) multifocal disease (n = 182),(3) additional PTC (n = 49), and (4) additional other tumor (n = 8).
We, as two endocrine pathologists, re-examined 304 cases by recutting them. However, after microscopic reexamination of all the cases, we detected extra microcarcinoma foci and also excluded these cases (n = 24) from our study. Totally, 280 patients with unifocal mPTC, which were our target population, were included in the study [Figure 1].
|Figure 1: Study flow diagram (mPTC: Papillary thyroid microcarcinoma, NIFTP: noninvasive follicular thyroid neoplasm with papillary-like nuclear features)|
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To define mPTC cases with NIFTP, the cases were reviewed using strict NIFTP diagnostic criteria proposed by Nikiforov et al. Tumors, which include well-formed papilla, psammoma bodies, >% solid/trabecular/insular growth pattern, infiltrative border, invasion (capsular or lympho-vascular), necrosis, and mitotic activity (>3 per 10 high-power field), were classified in other groups.
Data of the patients were reevaluated to determine the following parameters: age at diagnosis, gender, tumor size, LNM and distant metastasis at diagnosis, additional treatment (radioactive iodine) (RAI), duration of clinical follow-up, and clinical outcome (recurrence status).
Notably, 6 months after the operation, the patients were evaluated with clinical examination, neck ultrasonography (USG), and thyroglobulin (TG), and anti-TG antibodies measurements. Subsequently, all parameters were obtained annually.
Presence of new LNM was highly suspected in the USG and any increase in the serum TG values or serum anti-TG antibody values 3 months after surgery at a 6-month follow-up were accepted as “recurrence.”
The absence of LNM in high-quality neck USG, low TG values (<0.2 ng/mL), and absence of anti-TG antibodies, 1 month after surgery, at a 6-month follow-up, were accepted as “cure.”
RAI application criteria were as follows: family history, poor prognostic subtypes, radiation exposure to the neck region, extrathyroidal extension (ETE), LNM, and distant metastasis.
| Results|| |
The results were presented in numbers and percentages. The comparison of the clinical and histopathological data between mNIFTP and other types of unifocal mPTC cases is shown in [Table 1].
The characteristics of 280 unifocal mPTC cases were: 127 classical pattern (presence of papillary structures) (45.4%), 53 infiltrative pattern (18.9%), 27 oncocytic pattern (9.6%), 58 well-circumscribed noninvasive follicular pattern (20.7%), 12 capsular invasion (4.3%), and 3 other subtypes (1.1%). ETE and lymphovascular invasion (LVI) were not detected. The consensus diagnostic criteria for NIFTP were used for the 58 patients with the well-circumscribed noninvasive follicular pattern. We termed them micro NIFTP (mNIFTP).
Of the 280 patients, 221 were female (78.9%) and 59 were male (21.1%). The median age was 50 years (12–77 years). The median tumor size was 4 mm (1–10 mm). Data on follow-up period was available for 179 of 280 patients with the median follow-up time being 3 years. Data on TG levels were available for 188 of 280 patients. None of the patients developed a structural disease or an increase in TG or anti-TG antibody levels during follow-up. Seven of 269 patients (2.6%) had LNM at diagnosis: five exhibited a classical pattern, one had mNIFTP, and one had an oncocytic pattern. Only one of the 270 patients (0.4%) had distant metastasis (brachiocephalic lymph node) at diagnosis. According to USG findings of 5 of 183 patients (2.7%), LNM (recurrence) was detected after surgery. One of the two recurred cases had LNM at diagnosis as well, the other one had distant metastasis. RAI was applied to 23 patients.
Two of the five recurred cases were mNIFTP, two were classical type, and one was infiltrative. Three of these patients were in their 30s and two in 70s. All of these patients were women. Among the recurred cases, tumor size was found to be both greater and smaller than 5 mm. Both infiltrative and noninfiltrative cases recurred. In two of these cases, LNM was detected in the 3rd month after the operation, in one patient in the 13th month, in another patient in the 6th month, and in the last patient in the 4th month. We did not find any relationship between the recurrence and patient age, tumor size, morphology, and infiltrative pattern. The characteristics of the recurred cases and the cases with LNM/distant metastasis at diagnosis are shown in [Table 2].
|Table 2: Characteristics of the cases with recurrence and with LNM/distant metastasis at diagnosis|
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Two nodules with mNIFTP (both 3 mm in diameter) were reevaluated with additional recuts. In the examination after the recuts, the papilla-like structure was detected in one (classical-type morphology), whereas the follicular pattern was seen in the other [Figure 2].
|Figure 2: (a) A 3-mm follicular papillary microcarcinoma (mPTC), showing a well-circumscribed border (HE, ×200). (b) A suspected focus for papillae (arrow) (HE, ×400). (c) Another 3-mm mPTC with noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) (HE, ×40). (d) Same lesion showing nuclear enlargement, chromatin clearing, and elongation with scattered grooves (HE, ×400)|
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Among the 58 patients (20.7%) with mNIFTP, 43 were women (74.1%) and 15 were men (25.9%). The median age was 51 years (19–75 years). The median tumor size was 3 mm (1–8 mm). Data on follow-up period was available for 39 of 58 patients, and for five patients (8.6%), it was 1 year, for 24 patients, it was 2–5 years (41.4%), and for 10 patients, it was 6–10 years (17.2%). Data on TG levels were available for 39 of 58 patients. None of the patients developed a structural disease or an increase in TG or anti-TG antibody during the follow-up. One of these patients had LNM at diagnosis. There was no distant metastasis. In two patients, LNM (recurrence) was detected after the operation. RAI was applied to 4 of 57 patients with mNIFTP.
| Discussion|| |
Papillary microcarcinoma is being diagnosed with increasing frequency. However, the clinicopathological characteristics and prognostic significance of mPTC is still controversial. Among mPTCs, some tumors have more indolent behavior than the others. The updated 2015 ATA guidelines classified these tumors into different risk groups., Although it is defined as “indolent,” this tumor is mostly treated with total thyroidectomy/lobectomy and sometimes additional RAI ablation. RAI treatment in our institution is performed using the criteria mentioned above.
It is important to clarify which subtypes of mPTC should be defined as “indolent” and should not be overtreated.
Malignant behavior in mPTC
The crucial point of discussion on mPTC and NIFTP is to determine their aggressive nature. Many studies have been conducted to understand the nature of the aggressive tumor behavior of mPTC. Some groups have studied how to manage risk in cases of mPTC. Following surgical treatment, loco-regional disease recurrence rates are approximately 2%–6%. In a study, Tarasova et al. identified risk of structural disease recurrence across various histological variants in thyroid cancer and mPTC. Pierce EN et al. suggested postoperative RAI thyroid remnant ablation in patients with one or more of the following: multifocal disease, LNM, or capsular or vessel invasion. Moreover, as a result of a study on 445 patients with mPTC, Mercante et al. proposed that capsular invasion without ETE causes aggressive tumor behavior, which requires radical treatment. In addition to these findings, Ito et al. showed that larger tumor size (≥7 mm) or tumor location in the upper region is more likely to be related to LNM. However, we did not find any relationship between tumor size and LNM.
So et al. found subclinical central LNM in 37% of the 551 patients with mPTC, and they recommended that clinicopathological features, such as male sex, tumor multifocality, and ETE, should be considered for the determination of prophylactic central lymph node dissection. In our study, we selected unifocal cases and all of the recurred cases were found in women.
Lu et al. reviewed the data of 1,990 patients and examined the factors significantly associated with neck LNM in mPTC. In addition to findings in the study of So, this study showed that age <45 years, tumor size > mm, bilateral thyroid tumors, and BRAFV600E and TERT mutations were associated with neck LNM. Contrary to studies of Ito and Lu, Wada et al. showed that tumor size did not influence recurrence.
The results of our study suggested that there was no relationship between recurrence and patient age, tumor size, morphology, and infiltrative pattern. However, we did not mention the location of the tumor, whether peripheral or central. Because most of the cases were very small in size and found incidentally. Therefore, microscopically, it was not possible to tell the exact location of a small tumor in a large thyroidectomy material.
The risk factors associated with aggressive tumor behavior of mPTC are still controversial.
Molecular studies on mPTC
Based on the data presented by ATA, there appears to be little role for BRAF mutational testing as an aid to risk stratification of mPTCs; whereas, some studies showed the relationship between BRAF mutation and aggressive tumor behavior of mPTC.,, In a study, RAS mutation was determined in the group with nonaggressive tumors.
Should NIFTP be included in a high-risk group or is it indolent?
In a multicenter study, 65 of the 363 NIFTP cases were associated with mPTC. LNM (micrometastasis) was detected in one patient at a 6-year follow-up (in the mPTC group). There was no LNM or recurrence in patients without mPTC. Canberk et al. showed that 18% of the patients with NIFTP had a bilateral lesion (most of them were malignant); therefore, they emphasized that the opposite lobe should be investigated. According to the results of the study conducted by Parente et al., 6% of patients with NIFTP showed malignant behavior. They suggested that these tumors behave as a “low-risk thyroid cancer” rather than a “benign entity.” Furthermore, ATA recently suggested that an NIFTP diagnosis should not affect the management and follow-up of patients with very low-risk, well-differentiated, and thyroid cancer., It is clear that it is too early even to define NIFTP cases on which many studies were conducted and labeled as “indolent”.
What about the mNIFTP cases?
There are very few studies on this subject. A small number of studies on mPTC with NIFTP may be the reason for NIFTP criteria not being applied to microcarcinomas. In the study conducted by Shafique et al., noninvasive well-circumscribed follicular patterned mPTC was found similar to NIFTP in terms of histology and clinical behavior, whether unifocal or multifocal. In another study, 52 unifocal mPTC cases with NIFTP were compared with invasive follicular variant PTC as the control group. In conclusion, it has been emphasized that mPTC meeting NIFTP criteria has an indolent course, and they should be considered in the spectrum of NIFTP to avoid overtreatment and side-effects.
In our study, metastasis was detected in 13 of 280 patients. Notably, 10 of 122 patients (8.2%) without NIFTP and 3 of 58 patients (5.1%) with NIFTP exhibited metastasis. The metastasis rate of the cases with and without NIFTP is similar. LNM was detected in one of these three metastatic mNIFTP cases at diagnosis and two in the postoperative period. Even though we suspected that only one case included papillary structure, the other two suggested that these tumors also showed aggressive tumor behavior.
| Conclusion|| |
In the studies on mPTC cases with NIFTP, it was emphasized that these tumors have benign behavior like NIFTP., However, the results of our study do not confirm the indolent course of mNIFTP.
In conclusion, first, rigid morphological criteria should be used for the diagnosis of mNIFTP. The patients considered to have NIFTP should be examined in more detail in terms of the presence of papillae, infiltration, and invasion. This nodule is in a pattern that is more malignant. It is possible to overlook the structures of the papillae especially when the microcarcinoma foci are very small. Thyroidectomy or lobectomy material should be examined with many sections to detect “different mPTC foci.”
As in NIFTPs, the potential for malignant behavior in these tumors may not be low.
There is a need for a lot of clinicopathological and molecular studies to determine the biological behavior of mPTC cases with different histologies.
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Conflicts of interest
There are no conflicts of interest.
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Department of Pathology, Faculty of Medicine, Karadeniz Technical University, Ortahisar -61080, Trabzon
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2]