e. Parathyroid glands, if identified (give laterality and/or location, if known)
f. Description of other tissues
g. Results of intraoperative consultation
b. Descriptive features
c. Size(s) (Note D)
d. Extracapsular thyroid extension (Note D)
3. Margins, as appropriate
4. Regional lymph nodes
b. Location, if possible
5. Tissue submitted for microscopic evaluation
c. Tumor capsule in toto, as appropriate
d. Noninvolved thyroid
f. All lymph nodes, if submitted
g. Other lesions
h. Parathyroid tissue, if identified
i. Frozen section tissue fragment(s) (unless saved for special studies)
j. Other tissue(s) (specify)
k. Special circumstance: prophylactic thyroidectomy (familial medullary carcinoma or MEN syndrome) (Note F)
6. Special studies (specify) (eg, histochemistry, immunohistochemistry, morphometry, DNA analysis [specify type])
C. Microscopic Evaluation
a. Histologic type(s) (Note C)
b. Multicentricity, if present
d. Extent of invasion (Note D)
(1) capsular invasion: location and extent (minimally vs widely) (Note C)
(2) venous/lymphatic vessel invasion, if present (note extent: minimally vs widely) (Note C)
(3) extrathyroid capsular extension (Note D)
(4) Invasion of tissue(s) adjacent to thyroid (specify)
2. Margin(s), as appropriate (Note E)
3. Lymph nodes
b. Number involved by tumor
(1) location, if possible
(2) extranodal extension, if present
4. Additional pathologic findings, if present
a. Nodular goiter
c. Therapy-related changes
d. Adenomatous (hyperplastic, adenomatoid) nodules/adenoma
5. Other tissues/organs (eg, parathyroid tissue; give laterality and/or location, if known)
6. Results/status of special studies (specify)
7. Distant metastasis (specify site)
a. Correlation with intraoperative consultation, as appropriate
b. Correlation with other specimens, as appropriate
c. Correlation with clinical information, as appropriate
A. Specimen Adequacy
The specimen adequacy criteria should be followed regardless of radiologic and clinical findings. A widely used criterion for specimen adequacy requires 6 or more groups of follicular cells with 10 to 20 cells per group on 2 different slides. Paucicellular specimens with abundant colloid almost always correspond to colloid nodules, but rarely papillary cancers may have these findings. Specimens with inadequate numbers of follicular cells and scant (or no) colloid should be interpreted as nondiagnostic. Paucicellular specimens having limited numbers of follicular cells showing some features of malignancy should be interpreted as suspicious. Although specimens showing only abundant proteinacous material, histiocytes, and/or hemosiderin can be interpreted as cyst contents such specimens have a low risk of representing a malignancy, but a higher risk than otherwise benign adequate specimens. It should be recognized that cystic malignancies may rarely present with cytologic findings that are similar to those of benign cysts. Guidelines for fine-needle aspiration (FNA) of the thyroid have been published.1
Guidelines for the Microscopic Evaluation of Specimen Adequacy1
Number of Follicular Cells
Adequate for interpretation, diagnosis depends on cellular features
Scanty or Absent
Few follicular, numerous histocytes
Nondiagnostic. Recommend repeat after 3 months, possible under ultrasound guidance.##,###
# One should be cautious in rendering a diagnosis of colloid nodule in a specimen which shows watery colloid, macrophages, and few follicular cells, because aspirates of papillary carcinoma with extensive cystic degeneration may also give rise to specimens with abundant colloid-like material, macrophages, and few follicular cells. If malignant cells, irrespective of the number, are positively identified in an aspirate, a malignant diagnosis should be made. However, if small numbers of follicular cells show atypical features short of overt malignancy, a “suspicious” diagnosis or a repeat aspiration may be suggested. The pathologist should discuss these findings with the clinician before rendering a “suspicious” diagnosis on a paucicellular specimen. In the majority of cases, a definite diagnosis of malignancy can be reached in an ultrasound guided repeat FNA.
## The report should contain a qualifier stating that the interpretation is limited by the paucity of follicular cells.
### Occasionally, a cystic papillary carcinoma may present a similar pattern. Check for residual solid areas, and re-aspirate if palpable. The risk of malignancy is higher in large (greater than 4 cm) lesions and those that increase in size despite therapy.
B. Fine-Needle Aspiration (FNA) Diagnostic Categories
Nodular goiter, Hyperplastic nodule, Thyroiditis
Follicular neoplasm, Hürthle cell neoplasm
Rule out / Suggestive of neoplasm
See Note C; Follicular and Hürthle cell carcinoma cannot be reliably diagnosed with FNA.
C. Histologic Type
The histologic classification published by the World Health Organization (WHO) is recommended by the protocol and shown below.2-4
The diagnosis of follicular carcinoma or Hürthle cell carcinoma depends on the identification of capsular and/or blood vessel invasion. Blood vessels should be of venous caliber and be located outside the tumor, within, or immediately outside the capsule. Encapsulated follicular tumors with vascular invasion have potential for metastasis.5 Tumor cells should be attached to the vessel wall and protrude into the lumen. Encapsulated follicular tumors with invasion of the capsule may have potential for metastasis, although this is still controversial.
“Minimally invasive” follicular carcinoma refers to lesions with no vascular invasion. “Angioaggressive” follicular carcinoma refers to those tumors in which vascular invasion is identified. “Widely invasive” follicular and Hürthle cell carcinomas are those tumors with grossly apparent invasion of thyroid and/or soft tissue.
According to the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC), staging of thyroid cancer depends primarily on the histologic type.6,7 Thus, there are specific TNM stage groupings for papillary and follicular carcinomas that are stratified by age, and separate stage groupings not stratified by age for medullary carcinomas and undifferentiated carcinomas. Hürthle cell tumors are staged the same as follicular carcinomas. Undifferentiated or anaplastic carcinomas are always assigned stage IV. Age is not a prognostically important consideration for medullary or undifferentiated carcinomas. Tumor size and lymph node status are also considered in the TNM classification.
All categories may be subdivided: (a) solitary tumor, (b) multifocal tumor. With multifocal tumors, the largest one is used for classification. The lymph nodes must be specifically identified to classify regional node involvement.
Primary Tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumor 2 cm or less in greatest dimension limited to the thyroid
T2 Tumor more than 2 cm but not more than 4 cm in greatest dimension limited to the thyroid
T3 Tumor more than 4 cm in greatest dimension limited to the thyroid or any tumor with minimal extrathyroidal extension (eg, extension to sternothyroid muscle or perithyroid soft tissues)
T4a Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus or recurrent laryngeal nerve
T4b Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels.
All anaplastic carcinomas are considered T4 tumors T4a Intrathyroidal anaplastic carcinoma—surgically resectable
By AJCC/UICC convention, the designation “T” refers to a primary tumor that has not been previously treated. The symbol “p” refers to the pathologic classification of the TNM, as opposed to the clinical classification, and is based on gross and microscopic examination. pT entails a resection of the primary tumor or biopsy adequate to evaluate the highest pT category, pN entails removal of nodes adequate to validate lymph node metastasis, and pM implies microscopic examination of distant lesions. Clinical classification (cTNM) is usually carried out by the referring physician before treatment during initial evaluation of the patient or when pathologic classification is not possible.
Pathologic staging is usually performed after surgical resection of the primary tumor. Pathologic staging depends on pathologic documentation of the anatomic extent of disease, whether or not the primary tumor has been completely removed. If a biopsied tumor is not resected for any reason (eg, when technically unfeasible) and if the highest T and N categories or the M1 category of the tumor can be confirmed microscopically, the criteria for pathologic classification and staging have been satisfied without total removal of the primary cancer.
Regional Lymph Nodes (N) (see Note G)
NX Regional nodes cannot be assessed
N0 No regional lymph node metastasis
N1a Nodal metastases to Level VI (pretracheal, paratracheal and prelaryngeal/Delphian) lymph nodes
N1b Metastases to unilateral, bilateral, or contralateral cervical or superior mediastinal lymph nodes
Distant Metastasis (M)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
Papillary or Follicular Carcinoma
Under 45 Years of Age 45 Years or Older
Stage I Any T Any N M0 T1 N0 M0
Stage II Any T Any N M1 T2 N0 M0
Stage III T3 N0 M0
T1 N1a M0
T2 N1a M0
T3 N1a M0
Stage IVA Any T# Any N M0
Stage IVB T4b Any N M0
Stage IVC Any T Any N M1
# Except T4b.
Medullary Carcinoma (Any Age)
Stage I T1 N0 M0
Stage II T2 N0 M0
T3 N0 M0
Stage III T1 N1a M0
T2 N1a M0
T3 N1a M0
Stage IVA T4a N0 M0
T4a N1a M0
T1 N1b M0
T2 N1b M0
T3 N1b M0
T4a N1b M0
Stage IVB T4b Any N M0
Stage IVC Any T Any N M1
Undifferentiated Carcinoma (All Cases - Stage IV)
Stage IVA T4a Any N M0
Stage IVB T4b Any N M0
Stage IVC Any T Any N M1
For identification of special cases of TNM or pTNM classifications, the “m” suffix and “y,” “r,” and “a” prefixes are used. Although they do not affect the stage grouping, they indicate cases needing separate analysis.
The “m” suffix indicates the presence of multiple primary tumors in a single site and is recorded in parentheses: pT(m)NM.
The “y” prefix indicates those cases in which classification is performed during or following initial multimodality therapy (ie, neoadjuvant chemotherapy, radiation therapy, or both chemotherapy and radiation therapy). The cTNM or pTNM category is identified by a “y” prefix. The ycTNM or ypTNM categorizes the extent of tumor actually present at the time of that examination. The “y” categorization is not an estimate of tumor prior to multimodality therapy (ie, before initiation of neoadjuvant therapy).
The “r” prefix indicates a recurrent tumor when staged after a documented disease-free interval, and is identified by the “r” prefix: rTNM.
The “a” prefix designates the stage determined at autopsy: aTNM.
Residual Tumor (R)
Tumor remaining in a patient after therapy with curative intent (eg, surgical resection for cure) is categorized by a system known as R classification, shown below.
RX Presence of residual tumor cannot be assessed
R0 No residual tumor
R1 Microscopic residual tumor
R2 Macroscopic residual tumor
For the surgeon, the R classification may be useful to indicate the known or assumed status of the completeness of a surgical excision. For the pathologist, the R classification is relevant to the status of the margins of a surgical resection specimen. That is, tumor involving the resection margin on pathologic examination may be assumed to correspond to residual tumor in the patient and may be classified as macroscopic or microscopic according to the findings at the specimen margin(s).
By AJCC/UICC convention, vessel invasion (lymphatic or venous) does not affect the T category indicating local extent of tumor unless specifically included in the definition of a T category. In all other cases, lymphatic and venous invasion by tumor are coded separately as follows:
Lymphatic Vessel Invasion (L)
LX Lymphatic vessel invasion cannot be assessed
L0 No lymphatic vessel invasion
L1 Lymphatic vessel invasion
Venous Invasion (V)
VX Venous invasion cannot be assessed
V0 No venous invasion
V1 Microscopic venous invasion
V2 Macroscopic venous invasion
Few published studies have addressed the influence of margin status and patient outcome. Most surgeons, endocrinologists, and nuclear medicine specialists require knowledge of positive margins, ie, tumor extending to surgical resection edge. While this makes intuitive sense and it is recommended that a positive margin be mentioned in the final pathology report, data on the effect of positive margins and outcome in large series of patients with long-term follow-up is not available.
Similarly, a few authors refer to the value of measuring distance of tumor to closest resection margin since some therapists modify dose of postoperative radioiodine depending on closeness of margins.8 Since data on the prognostic import of close margins as an independent variable or even co-variable is lacking, assessment and reporting of this information is not currently recommended.
F. Prophylactic Total Thyroidectomy
In patients with familial medullary carcinoma (familial MTC, MEN 2 or variants) and in whom germline mutations in RET proto-oncogene are present, prophylactic total thyroidectomy is performed based on positive mutational analysis.9 Many of the thyroidectomy specimens appear grossly normal. In such cases, serial blocking of the gland is required to document the extent of C-cell hyperplasia and to assess for micromedullary carcinoma.10 These blocks should be taken in a superior to inferior direction for each lobe, and the isthmus should be submitted separately. This serial sectioning of the thyroid is performed because C-cells are restricted to a zone deep within the middle to upper thirds of the lateral lobes. The extreme upper and lower poles of each lobe and the isthmic regions are generally devoid of C-cells. Immunostains for calcitonin and CEA may be required to assess extent of C-cell disease.
G. Special Procedures for Lymph Nodes
At the current time, no additional special techniques should be used other than routine histology for the assessment of nodal metastases. Immunohistochemistry and polymerase chain reaction (PCR) to detect isolated tumor cells are considered investigational techniques at this time.
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