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Noninvasive follicular thyroid neoplasm with papillary-like nuclear features

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Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a newly reclassified tumor that was previously referred to by the name of noninvasive encapsulated follicular variant of papillary thyroid carcinoma. This new tumor category in thyroid gland pathology will help to decrease overtreatment of an essentially indolent, although not entirely benign tumor. It will be included in the new World Health Organization Classification of Endocrine Organ Tumours due out in 2017.

Classification

Definition of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): A noninvasive neoplasm that arises from the thyroid follicular cells (cells that normally make thyroid hormone), showing a predominantly follicular growth pattern and with nuclear features of papillary thyroid carcinoma. There are several specific inclusion and exclusion criteria (see below). When these are met, this tumor has an extremely low malignant potential.[1]

Abbreviations:

NIFTP: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features

EFVPTC: Encapsulated follicular variant of papillary thyroid carcinoma.

PTC: Papillary thyroid carcinoma.

Signs and symptoms

The clinical presentation of the patients is identical to other thyroid tumors, where there is usually a painless, asymptomatic, mobile thyroid gland nodule or enlargement. Depending on the size, additional symptoms of hoarseness, difficulty swallowing or other compression symptoms may be experienced. For nearly all cases, the patients do not have any thyroid hormone dysfunction (hyperthyroidism: excess hormone; or hypothyroidism: low hormone levels).

Diagnosis

Imaging findings

Clinical evaluation is usually done with ultrasound studies, which will usually show a solid, well demarcated mass, often showing limited shadowing (hypoechoic). Depending on the specific character on ultrasound and other clinical findings, a fine needle aspiration is often performed.

Fine needle aspiration

This involves taking a thin needle and inserting into the nodule (mass), and creating slides that are then interpreted by a cytopathologist. These tumors are associated with a great degree of difficulty in interpretation, with a relatively high false negative (saying there is no tumor when there is one) and a low true predictive value (when something is present, the ability to accurate predict that it is a neoplasm). ([2][3][4][5][6]} There are several classification systems, but The Bethesda System for Reporting Thyroid Cytopathology: Recommended Diagnostic Categories [7] suggests that most tumors are classified in follicular neoplasm (Bethesda Category IV) or atypia of undetermined significance/follicular lesion of undetermined significance (Bethesda category III), with about 70% in this group. But, if molecular studies are applied to the fine needle aspiration material, an RAS mutation is the most commonly identified.[8] It is very important to realize then, that this new diagnostic category is one for tissue that has been removed by surgery only (surgical pathology diagnosis). Since there are overlapping nuclear features with the invasive follicular variant of papillary thyroid carcinoma, an accurate preoperative fine needle aspiration diagnosis is unreliable. At present, this new tumor will be included in the differential diagnosis for any indeterminate/atypical categories as well as a few tumors that will be reported as malignant on FNA.

Pathology findings

Size

Tumors can be quite variable in size, ranging from as small as 0.7 cm up to 10 cm, although in generally the tumors are about 2–4 cm.[1][9] The definition used >1 cm, but supporting studies have used the criteria for smaller tumors. However, for the present, tumors should be >1 cm. Most tumors are seen in just one lobe of the thyroid gland (unifocal), but multicentric tumors (same lobe or opposite lobe) can be seen in up to 38% of cases.[9]

Histologic features

Several specific features must be identified for the tumor to be classified in this new category, while exclusion criteria should also be evaluated.

1) Encapsulated or partially encapsulated. The tumors are usually very well delimited or circumscribed, with the majority encapsulated, surrounded by a well formed fibrous connective tissue capsule.

Thyroid NIFTP tumor capsule

2) Complete absence of invasion of any kind in a tumor that has been thoroughly and carefully evaluated with the whole capsule of the lesion sampled.

There is no evidence of invasion of this well formed fibrous connective tissue capsule, helping to support a diagnosis of NIFTP.

3) Predominantly follicular pattern of growth. Papillary structures must represent <1% of the overall tumor volume. Further, solid, insular or trabecular architecture must be <30% of the overall tumor for this category to still be used. Colloid (the material that thyroid follicular cells create) is easily identified throughout.

4) Must have the characteristic nuclear features of papillary thyroid carcinoma, although sometimes they are patchy in distribution without all of the tumor showing the features. The nuclear features can be divided into three main categories:

  • Nuclear size and shape: nuclear enlargement, nuclear elongation, and nuclear overlapping and crowding. Loss of nuclear polarity, with nuclei at the lumen, middle or basal zone of the cells is also a helpful finding.
    NIFTP tumor shows specific nuclear features of papillary thyroid carcinoma.
  • Nuclear membrane irregularities: irregular nuclear contours, nuclear grooves and folds, “rat-bites” or demi-lune formations, and the presence of intranuclear cytoplasmic inclusions.
    The nuclear features of papillary thyroid carcinoma, but within an encapsulated neoplasm: NIFTP
  • Nuclear chromatin characteristics: nuclear chromatin clearing, often with condensation or margination along the nuclear membranes resulting in accentuated nuclear margins, glassy nuclei, or fine, even delicate powdery nuclear chromatin.

The exclusion criteria:

1) Any invasion.

2) The presence of any other papillary thyroid carcinoma variant (examples would include tall cell; columnar cell; cribriform morular; diffuse sclerosing, etc).

3) True papillary structures (a fibrovascular core surrounded by neoplastic cells) in greater than 1% of the tumor volume.

4) Psammoma bodies. These are calcified remnants of papillary structures, and thus if a psammoma body is present anywhere within the tumor (in the correct location), then NIFTP cannot be diagnosed.

5) Tumor necrosis: If there is true tumor necrosis not associated with a fine needle aspiration.

6) Increased mitoses: If there are ≥3 mitoses per 10 high power fields, then this category cannot be used.

Genetic profile

This tumor shows a very high association with other follicular-pattern tumors, with 'RAS mutations the most commonly identified. However, PPARγ and THADA gene fusions, and BRAF K601E mutations may be seen on occasion.[1][8][10][11] BRAF V600E mutations and RET gene fusions that are commonly seen in classical type papillary carcinoma are not seen in this tumor.

Management

Lobectomy or surgical removal of one half of the thyroid gland that contains the nodule is currently all that seems to be required. However, it is important to realize that many clinical circumstances come into play when deciding about surgery options. If there are compression symptoms, cosmetic issues, hoarseness or other factors in the patients clinical history (family risk factors, previous radiation for a different disorder, etc), then a total thyroidectomy may be the prudent management. However, no additional surgery is necessary. Further, radiation therapy given as radioactive iodine is not necessary as it does not change the overall patient outcome, while potentially associated with side effects. The American Thyroid association released guidelines on thyroid tumor management: 2015 ATA Guidance on Differentiated Thyroid Cancer http://online.liebertpub.com/doi/abs/10.1089/thy.2015.0020, which can be used as a guide for overall management.[12]

Outcomes

As long as the whole tumor was removed, and the whole periphery of the tumor has been evaluated by the pathologist (all tumor to capsule to parenchyma or tumor to parenchyma if no capsule is present, must have been examined microscopically) who is able to document there is no capsular or lymphovascular invasion, then the risk of recurrence or other adverse events is extremely low, essentially much less than 1% within the first 15 years after surgery.[1][9] It is very important that the whole tumor be completely removed (no tumor left in the neck and no tumor present at the margin of the surgery) to make certain that a local recurrence does not develop.[13]

Epidemiology

The tumor is not new, it is just newly reclassified. Thus, the new name for the tumor means that tumors previously diagnosed as noninvasive encapsulated follicular variant of papillary thyroid carcinoma will now be classified with the new terminology. Overall, about 20% of all thyroid gland "cancers" would now be classified as NIFTP.[14][15] However, it is important to note that in Japan specifically, the diagnostic criteria and nomenclature for these tumors has been different, and so the incidence of this tumor type is different. The majority of patients are females (3-4:1 F:M), affecting a wide age range of patients, although most present during the 4th to the 6th decades of life.[1][9]

History

Patients in the distant past with this lesion would have been regarded as showing features of a benign lesion, a follicular adenoma. However, over time and with additional evaluation and molecular testing these lesions came to be regarded as showing features of a papillary thyroid carcinoma because of the papillary carcinoma type nuclei. Thus, the "follicular variant" of a tumor that normally shows a papillary architecture and papillary nuclear features was named. Over the years, those cases that do not show invasion of either the capsule of the tumor or the vessels in the capsule, have been show to behave in an indolent fashion, with only rare reported cases of metastatic disease. Over a multiyear time frame, an international consensus project was undertaken to re-define the pathological criteria for encapsulated follicular variant of papillary thyroid carcinoma. Based on rigorous review of the literature and a multicentre review of many cases with long term follow up (a minimum of 10 years) together with molecular analysis for some tumors this working group has identified that tumors previously classified as encapsulated follicular variant of papillary carcinoma, without any evidence of capsular or vascular invasion, provided that the entire periphery of the tumor (capsule if encapsulated or periphery if well circumscribed) has been sampled, can be reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features. There are several major inclusion and exclusion criteria.[1]

For the consensus the tumors had to be: more than 1 cm in size; no vascular or capsular invasion in an adequately sampled tumor, no other invasive tumors in the gland, no radioablative iodine treatment and at least 10 years of follow-up.

All cases were available using the following url: http://image.upmc.edu:8080/NikiForov%20EFV%20Study/view.apml

References

  1. ^ a b c d e f "Nomenclature Revision for encapsulated follicular variant of papillary thyroid carcinoma: A Paradigm Shift to Reduce Overtreatment of Indolent Tumors". JAMA Oncol. 14 April 2016. doi:10.1001/jamaoncol.2016.0386. PMID 27078145. {{cite journal}}: Unknown parameter |authors= ignored (help)
  2. ^ "Follicular variant of papillary thyroid carcinoma: a comparative study of histopathologic features and cytology results in 141 patients". Endocr Pract. March 2001. PMID 11421549. {{cite journal}}: Unknown parameter |authors= ignored (help)
  3. ^ "Clinical presentations and outcomes of surgical treatment of follicular variant of the papillary thyroid carcinomas". Jpn J Clin Oncol. November 2006. PMID 17000702. {{cite journal}}: Unknown parameter |authors= ignored (help)
  4. ^ "Preoperative RAS mutational analysis is of great value in predicting follicular variant of papillary thyroid carcinoma". Biomed Res Int. 12 January 2015. doi:10.1155/2015/697068. PMID 25648502. {{cite journal}}: Unknown parameter |authors= ignored (help)CS1 maint: unflagged free DOI (link)
  5. ^ "Follicular variant of papillary thyroid carcinoma: clinical-pathological characterization and long-term follow-up". Cancer J. July 2006. PMID 16925971. {{cite journal}}: Unknown parameter |authors= ignored (help)
  6. ^ "Cytological features of "non-invasive follicular thyroid neoplasm with papillary-like nuclear features" and their correlation with tumor histology". Hum Pathol. 13 April 2016. doi:10.1016/j.humpath.2016.03.014. PMID 27085556. {{cite journal}}: Unknown parameter |authors= ignored (help)
  7. ^ "The Bethesda System For Reporting Thyroid Cytopathology". Am J Clin Pathol. November 2009. doi:10.1309/AJCPPHLWMI3JV4LA. PMID 19846805. {{cite journal}}: Unknown parameter |authors= ignored (help)
  8. ^ a b "Integrated genomic characterization of papillary thyroid carcinoma". Cell. 23 October 2014. doi:10.1016/j.cell.2014.09.050. PMID 25417114. {{cite journal}}: Unknown parameter |authors= ignored (help)
  9. ^ a b c d "Ninety-four cases of encapsulated follicular variant of papillary thyroid carcinoma: A name change to Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features would help prevent overtreatment". Mod Pathol. 22 April 2016. doi:10.1038/modpathol.2016.65. PMID 27102347. {{cite journal}}: Unknown parameter |authors= ignored (help)
  10. ^ "Molecular pathogenesis and mechanisms of thyroid cancer". Nat Rev Cancer. March 2013. doi:10.1038/nrc3431. PMID 23429735. {{cite journal}}: Unknown parameter |authors= ignored (help)
  11. ^ "Molecular genotyping of papillary thyroid carcinoma follicular variant according to its histological subtypes (encapsulated vs infiltrative) reveals distinct BRAF and RAS mutation patterns". Mod Pathol. September 2010. doi:10.1038/modpathol.2010.112. PMID 20526288. {{cite journal}}: Unknown parameter |authors= ignored (help)
  12. ^ "2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer". Thyroid. January 2016. doi:10.1089/thy.2015.0020. PMID 26462967. {{cite journal}}: Unknown parameter |authors= ignored (help)
  13. ^ "Risk stratification of follicular variant of papillary thyroid carcinoma". Thyroid. March 2013. doi:10.1089/thy.2012.0369. PMID 23025507. {{cite journal}}: Unknown parameter |authors= ignored (help)
  14. ^ "The increase in thyroid cancer incidence during the last four decades is accompanied by a high frequency of BRAF mutations and a sharp increase in RAS mutations". J Clin Endocrinol Metab. February 2014. doi:10.1210/jc.2013-2503. PMID 24248188. {{cite journal}}: Unknown parameter |authors= ignored (help)
  15. ^ "Association of BRAF V600E mutation with poor clinicopathological outcomes in 500 consecutive cases of papillary thyroid carcinoma". J Clin Endocrinol Metab. November 2007. PMID 17785355. {{cite journal}}: Unknown parameter |authors= ignored (help)

Further reading

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