Evaluation of differentiated and variant thyroid carcinomas (2023)

The incidence of thyroid cancer is increasing worldwide, primarily due to the increased use of ultrasound body imaging followed by fine needle aspiration (FNAB) of incidentally detected thyroid nodules.¹

Papillary thyroid carcinoma (PTC), a type of differentiated thyroid cancer (DTC), is solely responsible for the increased²accounts for nearly 90% of all thyroid cancers.^{2, 3}Another important factor was the increased recognition of follicular variant papillary thyroid carcinoma (FVPTC) from the PTC variant. However, a proportion of these cases were recently recognized as tumors of very low malignant potential, so they were reclassified from carcinoma to neoplasia. This article discusses some of the newer nomenclatures for differentiated thyroid carcinomas and current issues in evaluating important disease claims.

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Thyroid cancer can arise from the follicular or perifollicular C cells of the thyroid gland. Differentiated thyroid carcinoma (DTC) is derived from follicular cells and includes papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), and variants of both. These cancers generally have an excellent prognosis, with 10-year survival rates greater than 90% to 95%.³Poorly differentiated thyroid cancers, which are likely to arise from PTC or FTC, have worse outcomes, with 10-year survival rates of about 50%. Anaplastic thyroid cancer, one of these cancers, is a rare but aggressive, undifferentiated thyroid follicular cell tumor with a survival rate of less than 10% after five years.⁴

Differentiated Thyroid Cancers

PTC histology is characterized by a papillary growth pattern. Warts are tongue-shaped structures with one or two layers of tumor cells surrounding a well-defined fibromuscular core. Vesicles are usually absent. The nuclei of malignant cells appear large, oval, clustered, and overlapping, and may contain powdery, hypodense chromatin, pseudoinclusions, or nuclear striations (also called "orphan eyes of Annie"). PTC is generally not encapsulated.

PTC is also often multifocal, due to spread of lymph within the thyroid or field shift, with the development of synchronous tumors that are locally invasive and may spread to local lymph nodes in the neck. Up to 10% of cases at the time of diagnosis may also have long-distance spread, with local lungs and bones being common.

A scoring system based on tumor size and shape, membrane irregularities, and chromatin characteristics is used to make the diagnosis of PTC.

Histopathology of follicular thyroid carcinoma – a promising subtype showing follicular architecture

Diagnosis of Differentiated Thyroid Cancer

When thyroid cancer is suspected, an ultrasound scan is done, followed by fine-needle aspiration of the thyroid nodule. Microscopic examination of the cells allows the pathologist to recognize the typical testicular changes associated with PTC.

However, with follicular tumors, the pathologist cannot distinguish between a benign follicular adenoma and a malignant CFT before surgery. For the diagnosis of FTC, examination of the thyroid lobe after surgery is necessary to identify the tumor capsule and assess vascular invasion.

Fine needle aspiration of papillary thyroid carcinoma with cancer cells showing the typical appearance of Orphan Annie's eyes

staging and prognosis

There are several systems for issuing DTCs. Each uses a baseline dataset that typically includes age at diagnosis, primary tumor size, extent of local extrathyroidal invasion, and presence or absence of distant metastases. However, there are enough differences between the systems that they are not interchangeable. The TNM system shown in Table 1 appears to be the best for predicting disease-related mortality.⁵

The results, step by step, are very similar for PTC and FTC. PTC mortality increases gradually with age, starting around age 35. Using the age limit of 55 years seems to be the most reliable way of categorization of risk.⁶Follicular cell-derived thyroid cancers, however, exhibit a spectrum of biological behavior ranging from papillary microcarcinoma in the elderly, which generally has an excellent prognosis, to highly lethal anaplastic thyroid cancer, which has a survival rate of 10% to 20%. % survival after one year.

PTC and FTC subtypes have a significant impact on results. Excellent results are associated, for example, with non-invasive encapsulated FTC and follicular variant papillary thyroid carcinoma (FVPTC). The more aggressive variants - poorly differentiated thyroid carcinoma, tall cell variant, studded variant and columnar cell variant - tend to perform worse. Several other histological features, such as perineural invasion, multifocal disease, and high mitotic frequency, may also influence prognosis. However, these histologic features are not included in the American Joint Committee on Cancer (AJCC) grading system because there are no absolute cutoff points.

Tables 1 and 2 illustrate the AJCC classification system,⁷which is based on TNM parameters (tumor, lymph node, metastases) (Table 1) and uses the age limit of 55 years for prognostic subgroups (Table 2). The pathologic staging of tumors is based on the results of surgery for extrathyroidal spread and the pathology of the surgical specimen. Lymph node involvement and spread of distant metastases can only be detected by radioactive iodine scans, which are performed one to three months after surgery.

In addition to staging at the time of diagnosis, the American Thyroid Association⁸also recommends further staging to predict recurrence risk, disease survival risk, and modify the risk estimate based on response to treatment. Factors such as serum thyroglobulin four to six weeks after the first surgery, calculated thyroglobulin doubling time, radioactive iodine uptake, and FDG uptake avidity on PET scans may also influence prognosis.

Table 1
AJCC TNM staging for PTC, FTC, poorly differentiated, Hurthle, and anaplastic thyroid cancer

Source: AJCC Manual of Cancer Staging, 8th edition

Table 2
AJCC prognostic staging groups for differentiated thyroid cancer (PTC and FTC) by age with TNM staging

Source: AJCC Manual of Cancer Staging, 8th edition

Most CDT patients do not die from it: long-term cancer-related mortality is less than 5%.³Numerous studies confirm that mortality from DTC gradually increases with age, but even older patients (over 65 years) in the SEER database still have a 95% five-year survival rate.

Tumor size is important for prognosis. Tumors less than 1.5 cm in size are commonly cured, but mortality increases with tumor size. The 20-year mortality rate for tumors 2.0 cm to 3.9 cm, for example, is 6% and increases to 50% for tumors 7.0 cm or larger.⁹Regional lymph node involvement is also an important adverse factor, particularly in the case of T4 tumors or M1 disease. However, low-volume nodules have little effect on survival, especially at younger ages (<45 years), as they can be successfully removed with radioactive iodine therapy.

PTC vesicular variant (FVPTC)

There are more than 10 variants of PTC,¹⁰including follicular variants (more common), tall cells (more aggressive), island, incus and diffuse sclerosing (Table 3). FVPTC, which accounts for 30% to 40% of all cases,¹¹it has a follicular rather than papillary architecture, and malignant follicular cells exhibit the characteristics of PTC.

There are two main subtypes of FVPTC: encapsulated (EFVPTC), which represents the majority of FVPTC, and non-encapsulated or infiltrative (NFVPTC). These two subtypes have distinctly different clinical and biological behaviors. They also differ in their molecular profiles, with the BRAF V600E mutation seen in infiltrating tumors and the RAS mutation in areola tumors.

Two-thirds of cases of infiltrative FVPTC have lymph node involvement, while EFVPTC rarely (5%) involves lymph nodes. EFVPTC may also show signs of invasion of the tumor capsule, blood vessels within the capsule, or adjacent thyroid tissue. Minimal capsular invasion slightly increases the risk of recurrence, but lymphatic and/or blood vessel invasion - especially extensive (>4 foci) - significantly increases the risk of recurrence, dissemination and mortality.

A significant number of FVPTCs are neither fenced nor infiltrated, but partially fenced or well demarcated. They have a similar molecular profile to EFVPTC, with the RAS mutation present in almost half of the cases (46%) and no BRAF V600E mutation.

Table 3
PTC variants¹²

Source: Fourth Edition WHO Classification of Thyroid Tumors.

Non-invasive follicular thyroid cancer with papillary nuclear features (NIFTP)

In the last 20 to 30 years, the incidence of encapsulated thyroid tumors has increased two to three times and now represents 10% to 20% of all thyroid cancer cases in Europe and North America. These tumors are usually indolent and, after limited surgery (removal of the affected lobe rather than the entire thyroid), very rarely recur or spread to distant sites. To avoid overdiagnosis and overtreatment, in 2017 the classification of these tumors was downgraded from cancer to cancer.

In 2016, an international working group of thyroid pathologists established by the National Cancer Institute presented the results of a study of 109 patients diagnosed with EFVPTC.¹³During a median follow-up of 13 years, these patients had no episodes of relapse or spread. However, this was not the case for patients with invasive FVPTC. Based on these results, the working group recommended that EFVPTC be called "non-invasive follicular thyroid carcinoma with papillary nucleus features" (NIFTP).

This nomenclature and classification change was later accepted by the World Health Organization (WHO) and was included in the 4th edition of the WHO Classification of Tumors of Endocrine Organs, published in 201714. NIFTPs are now usually treated by removing a lobe of the thyroid gland and omitting treatment with radioactive iodine.

The diagnosis of NIFTP is based on the strict inclusion and exclusion criteria shown in Table 4. The assessment of whether a tumor is non-invasive or invasive cannot be made until the tumor and surrounding capsule are removed by lobectomy. The pathologist must carefully examine the entire bursa to determine whether there has been tumor cell invasion or lymphatic vessel invasion. Therefore, the diagnosis can only be made after the operation and not before the operation.

The average size of NIFTP is 3 cm, but they can range from microtumors (<1 cm) to up to 10 cm. They can also be multifocal or affect both lobes and can be found in a thyroid containing an invasive tumor.

From a critical illness (CI) claim evaluation perspective, it is important to be aware that not all EFVPTC cases were downgraded from cancer to NIFTP. Strict criteria for diagnosing NIFTP emphasize that well-defined tumors must not infiltrate the capsule or adjacent thyroid gland.

Table 4
NIFTP inclusion and exclusion criteria¹³

Source: Nikorow et al. Nomenclature review of follicular encapsulated variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of benign tumors.

Evaluation of EFVPTC complaints

Case 1: EFVPTC not meeting NIFTP criteria

• History: A 25-year-old man presented with a persistent, unresponsive nodule 4-5 cm in diameter in the right lobe of the thyroid. There were no palpable lymph nodes in the neck. After the multidisciplinary team (MDT) discussed the USG and fine needle aspiration cytology results, the patient's right thyroid lobe was removed.

• PathologyThe general anatomopathological examination revealed a well-circumscribed lesion that extended throughout the right lobe, measuring 45 x 35 x 26 mm. Microscopy showed that it was an encapsulated vesicular lesion consisting mainly of microbubbles, many of which contained a colloid, and that there were some residual warts. The capsule was relatively thin and in two blocks (sections) there was a suspicion of possible capsular invasion. Vascular infiltration was also suspected in several blocks.

• provisional diagnosis:EFVPTC limited to the thyroid with a lumen of 0.1 mm. There were no lymph nodes present. Stage: pT3a and R0 (light margins).

  The case was also referred to a thyroid specialist pathologist, who agreed that the tumor was a well-demarcated areola. The pathologist noted that there were multiple foci of FVPTC but did not think there was evidence of vascular invasion. However, there were some epithelial components extending into the fibrous capsule but not penetrating it.

• Application: Multifocal EFVPTC with tumor cells in a capsule, but without vascular invasion. Stage: pT2 NX MX and R0.

MDT recommended completion of thyroidectomy followed by treatment with radioactive iodine. Pathological examination of the left lobe showed no cancer.

Key points for assessing a serious illness claim:

• The tumor had a complete capsule (i.e. capsule). Note that the presence of a capsule does not exclude invasive cancer.

• O tumor era multifocal.

• According to the specialists, no vascular invasion was found.

• There were tumor foci in the capsule (this excludes the diagnosis of NIFTP).

• Size does not distinguish between NIFTP and invasive thyroid cancer, as NIFTP can be 4 cm or larger in up to 5% of cases.

• Treatment was as for invasive thyroid cancer.

This case was considered a valid request for severe disease, as the cancer showed signs of invasion with involvement of the tumor capsule.

Case 2: FVPTC partially closed

• History: A 36-year-old woman with a history of multinodular goiter and thyrotoxicosis presented with a persistent nodule on the left side of her neck following a strep throat. Ultrasonography revealed an indeterminate, heterogeneous, well-defined nodule in the left thyroid lobe measuring 18 x 10 mm.

  Fine needle aspiration cytology showed papillary clusters of cubic to columnar cells supported by fibrovascular stroma. The testes had characteristics suspicious for PTC. She underwent surgery to remove the left lobe of her thyroid gland.

• Pathology: General pathology revealed a 15 x 12 x 22 mm nodule close to the surface of the thyroid. Microscopy showed a partially encapsulated follicular variant of papillary thyroid carcinoma. The capsule was fibrous and poorly demarcated in places. The cells showed overlapping nuclei with grooves and inclusions. Vascular invasion was suspected because several foci of intracapsular cells intermingled with the vessels, but interpretation was complicated by granulation tissue reaction to previous fine needle aspiration. There was no clear evidence of vascular invasion. There was also no evidence of capsular invasion or extension beyond the thyroid gland. The tumor extended 0.22 mm from the thyroid capsule.

• Application: Partially surrounded and clearly demarcated FVPTC with suspected vascular invasion, but no capsular involvement. Stage: pT2 (22mm) NX MX.

  Based on the suspicion of vascular invasion, the remaining right lobe of the thyroid gland was removed and radioactive iodine was administered. Right lobe pathology was negative for cancer.

Key points for assessing a serious illness claim:

• The capsule was incomplete and poorly defined in areas, therefore partially encircled.
• The tumor was demarcated and there were no signs of diffuse infiltration.
• There was no invasion of the capsule.
• Vascular invasion was suspected because several foci of intracapsular cells were mixed with the vessels. Interpretation was compromised by the sequelae of fine needle aspiration with granulation tissue (scarring/scarring).
• Treatment was as for a high-risk tumor, with completion of thyroidectomy and radioactive iodine therapy.

This case was accepted as a valid claim of serious illness because it was reasonable to conclude that there was vascular invasion into the tumor capsule.

Case 3: FVPTC not encapsulated

Case 4: Neoplasms of uncertain malignancy potential

• History: A 41-year-old woman presented with a 4-cm nodule on the left side of her thyroid. She had previously undergone a right hemithyroidectomy for a benign lesion 24 years earlier. Ultrasonography was indeterminate and fine needle aspiration cytology did not distinguish between a follicular tumor and a benign lesion. The pathologist was also of the opinion that papillary thyroid carcinoma could not be ruled out. She underwent surgery to remove the remaining left lobe of her thyroid gland.

• Pathology: The general anatomopathological examination showed a well-defined nodular lesion measuring 27 x 33 mm. Microscopy confirmed a circumscribed, closed nodule with densely packed vesicles and a predominantly microbubble growth pattern. There was a well-formed thick fibrous capsule and no cytological features suggestive of papillary carcinoma. There were also three separate small nodules outside the capsule with a similar appearance to the main tumor nodule, suspected to have spread beyond the capsule, although extensive examination of the capsule showed no growth within the capsule. The background thyroid tissue was observed to have a vaguely nodular appearance, and some nodules appeared morphologically similar to the main nodule, albeit at some distance from it. Extracapsular nodules may represent background compressed nodular hyperplasia.

  The tumor was confined to the thyroid and free of a 0.1 mm surgical margin. No lymphatic infiltration was observed and all three lymph nodes were clear.

  The report noted that, in the worst case, the appearance can be consistent with minimally invasive follicular carcinoma, intermediate stage pT2 N0. The case was referred to a pathologist specialized in thyroid.

• Application:After discussion among MDT members, the surgeon wrote that this tumor is best described as "a tumor of unknown malignant potential", but some features fit the diagnosis of minimally invasive thyroid cancer. This was therefore taken as the final working diagnosis.

Key points for assessing a serious illness claim:

• The tumor was an encapsulated lesion with three separate nodules of similar appearance outside the tumor capsule in the adjacent thyroid gland.

• Although the capsule was intact, it was considered reasonable to assume that these nodules represented invasive spread within the thyroid gland. Although the pathologist could not see the capsule invasion, the entire capsule could not be evaluated in detail, so it was possible to miss the area of ​​invasion.

• The final decision on the claim was consistent with the MDT's decision that it was a minimally invasive cancer.

This case highlights the difficulty of making a clear diagnosis, even for an experienced thyroid pathologist. Leading physicians, including the MDT (surgeon, pathologist, radiologist, and oncologist), considered clinical findings and pathology to make a final diagnosis and decide on a treatment plan. In case of doubt about the pathological diagnosis, they can also request the opinion of a regional or national specialist.

For follicular thyroid tumors like this case, the WHO classification system recognizes that there are tumors of "unknown malignant potential", which describes the uncertainty of the biological behavior of these tumors. The recognized types are:

• Follicular tumors of uncertain malignant potential

• Well-differentiated tumors of uncertain malignant potential

summary

For DTC IC claims, assessment of cancer invasion depends on assessment of tumor capsule, vascular invasion, and local spread to adjacent thyroid and lymph nodes.

EFVPTCs that meet strict inclusion and exclusion criteria defined by an international panel of expert pathologists are now known as NIFTP. Classifying these tumors by tumor means recognizing that many cases are non-invasive tumors with an excellent prognosis and therefore can be safely treated with limited surgery. This will allow these patients to avoid the complications associated with removal of the entire thyroid gland and radioactive iodine therapy. From an insurance perspective, these cancers generally do not meet the strict definition of "cancer" set out in most IC policy provisions. However, these cases need to be carefully reviewed to ensure an accurate and fair determination.