doi:10.1507/endocrj.EJ21-0388

Original

Pathological diagnosis of general rules for thedescription of thyroid cancer by Japanese Society ofThyroid Pathology and Japan Association of Endocrine
Surgery
Hiroshi Kamma1), Kaori Kameyama2), Tetsuo Kondo3), Yoshiaki Imamura4), Masahiro Nakashima5),
Tomohiro Chiba6) and Mitsuyoshi Hirokawa7)
1)

Department of Pathology, Kyorin University, Tokyo 181-8611, Japan
Department of Pathology, Showa University Northern Yokohama Hospital, Yokohama 224-8503, Japan3)
Department of Human Pathology, University of Yamanashi, Yamanashi 409-3898, Japan
4)
Division of Diagnostic Pathology/Surgical Pathology, University of Fukui Hospital, Fukui 910-1193, Japan
5)
Department of Tumor and Diagnostic Pathology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan
6)
Division of Pathology, the Cancer Institute, Japan Foundation for Cancer Research, Tokyo 135-8550, Japan
7)
Department of Diagnostic Pathology and Cytology, Kuma Hospital, Kobe 650-0011, Japan
2)

Abstract. The Japanese Society of Thyroid Pathology and the Japan Association of Endocrine Surgeons developed the eighth
edition of the General Rules for the Description of Thyroid Cancer (GRDTC) in December 2019. This article describes thepathological diagnosis of the GRDTC, which has been improved through repeated revisions based on the experience ofJapanese pathologists and translated into English to introduce the Japanese diagnostic standard to foreign countries. In thisedition of the GRDTC, the histopathological classification and descriptions differ in some respects from those of the fourth
edition of the World Health Organization (WHO) classification as revised in 2017. For example, the GRDTC does not adopt
the concept of borderline lesions (FT-UMP, WDT-UMP, and NIFTP) of the WHO, taking into consideration the popular
histological criteria accepted by Japanese pathologists. The cytological reporting system of the GRDTC was partly modified
from the Bethesda system in 2015. It has an additional cyst fluid category separated from the unsatisfactory category that has
been demonstrated to be useful in Japan. This translated edition makes it easy to submit Japanese clinicopathological studiesof thyroid tumors in an international journal. We also wish to contribute to the improvement, standardization, andglobalization of the pathological diagnosis of thyroid tumors.
Key words: the General Rules for the Description of Thyroid Cancer (GRDTC), the World Health Organization (WHO),
Thyroid tumors, Pathological diagnosis, Cytology

THE PATHOLOGICAL classification of general rules
for the description of thyroid cancer (GRDTC) [1] hasbeen improved through repeated revisions based on theexperience of Japanese pathologists, although it funda‐
mentally follows an international standard. In the eighth
edition, the histological classification of the pathologicaldiagnosis was partly changed according to the revised

World Health Organization (WHO) classification in 2017[2]. The Japanese classification of GRDTC does not
adopt the concept of borderline lesions (FT-UMP, WDTUMP, and NIFTP) of the WHO, considering the popular
histological criteria accepted by Japanese pathologists,
and a detailed commentary is described to establish
consistency between the two classifications. For theSubmitted Jun. 25, 2021; Accepted Aug. 15, 2021 as EJ21-0388
Released online in J-STAGE as advance publication Sep. 15, 2021

(thyroid) carcinoma; ATC, anaplastic (thyroid) carcinoma; MTC,
medullary (thyroid) carcinoma; HTT, hyalinizing trabecular tumor;
GRDTC, General rules for the description of thyroid cancer (8thedition); WHO, WHO classification (4th edition); FT-UMP, follicu‐
lar tumor of uncertain malignant potential; WDT-UMP, welldifferentiated tumor of uncertain malignant potential; NIFTP,
noninvasive follicular thyroid neoplasm with papillary-like nuclear
features.

Correspondence to: Hiroshi Kamma, M.D., Department of Pathol‐ogy, School of Medicine, Kyorin University, 6-20-2 Shinkawa,
Mitakashi,Tokyo 181-8611, Japan.
E-mail: hkamma@ks.kyorin-u.ac.jp
Abbreviations: PTC, papillary (thyroid) carcinoma; FTC, follicular(thyroid) carcinoma; FTA, follicular (thyroid) adenoma; WDTC,
well-differentiated thyroid carcinoma; PDTC, poorly differentiated©The Japan Endocrine Society

2Fig. 1

Kamma et al.

(a) Sagittal section. (b) Horizontal section.

definition of poorly differentiated carcinoma, thestandard of the previous WHO classification is usedinstead of the restrictive Turin standard. In contrast, an
encapsulated angioinvasive subtype is added to follicular
carcinoma according to the WHO classification.
The reporting system for cytological diagnosis fol‐
lowed the previous edition of the GRDTC. The GRDTC
system was partly modified from the Bethesda system in2015 [3] and it has been demonstrated to be useful in Japan.
We wish to contribute to the improvement, standardi‐
zation, and globalization of the pathological diagnosis of
thyroid tumors for all pathologists, physicians, andresearchers engaged in thyroid cancer.

Handling of the Thyroid Excision
Specimen
Fixation
Surgically-removed thyroid specimens are immedi‐
ately immersed in a fixative (neutral buffered, 10% for‐malin solution). If the specimen is a large mass, it could
be carefully cut before fixation to avoid disturbing thepathological examination.
Incision
The fixed thyroid gland is cut in a sagittal section (Fig.
1a) and sliced every 3–5 mm. It could be cut in a hori‐zontal section (Fig. 1b) to examine the lesions in relation
to the surrounding tissues and in comparison with theradiologic images.

Fig. 2Cutting and gross examination
Slice an oval tumor and make many specimens to wellinspect the border.

undesirable to place the entire excised thyroid gland in adecalcifying agent.
2) When a follicular carcinoma is suspected macro‐scopically, it is desirable to cut out many areas, espe‐
cially of the tumor capsule, because vascular invasion isobserved in and beneath the capsule.
3) For apparent malignant tumors, it is necessary to
prepare specimens including attached organs such as themuscles.
4) It is necessary to prepare specimens of all the para‐thyroid glands and lymph nodes that are attached to thesample.

Histological Classification
Gross examination and cutting
The sectioned surfaces, property and border of tumors
should be inspected carefully in the surrounding tissues
and strap muscles, and appropriate sites are cut as speci‐
mens of enough number (Fig. 2).
1) Calcified lesions should not be cut forcibly, but are
divided, if possible. The calcified specimens are placedin a decalcifying agent and cut after decalcification. It is

Thyroid tumors are mainly classified as 1. benign
tumors, 2. malignant tumors, 3. other tumors, 4. unclassi‐
fied tumors, and 5. tumor-like lesions (Table 1). A
benign tumor is only a follicular adenoma. Malignant
tumors are classified as papillary, follicular, poorly
differentiated, anaplastic, medullary carcinomas, or
lymphoma respectively.

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Pathological diagnosis of GRDTCTable 1

Histological classification of thyroid tumors

1. Benign tumors
a. Follicular adenoma

8,330/0

Variants
1) Follicular adenoma, oxyphilic cell (oncocytic) variant

8,290/0

2) Follicular adenoma, clear cell variant

8,330/0

2. Malignant tumors
a. Papillary carcinoma

8,260/3

Variants
1) Papillary carcinoma, follicular variant

8,340/3

2) Papillary carcinoma, macrofollicular variant

8,340/3

3) Papillary carcinoma, oxyphilic cell (oncocytic) variant

8,342/3

4) Papillary carcinoma, diffuse sclerosing variant

8,350/3

5) Papillary carcinoma, tall cell variant

8,344/3

6) Papillary carcinoma, solid variant

8,260/3

7) Papillary carcinoma, cribriform variant

8,260/3

8) Papillary carcinoma, hobnail variant

8,260/3

9) Other variants

8,260/3

b. Follicular carcinoma

8,330/3

Subtypes according to invasive pattern
1) Follicular carcinoma, minimally invasive

8,335/3

2) Follicular carcinoma, encapsulated angioinvasive

8,339/3

3) Follicular carcinoma, widely invasive

8,330/3

Variants
1) Follicular carcinoma, oxyphilic cell (oncocytic) variant

8,290/3

2) Follicular carcinoma, clear cell variant

8,330/3c. Poorly differentiated carcinoma

8,337/3d. Anaplastic carcinoma

8,020/3

e. Medullary carcinoma

8,345/3

f. Mixed medullary and follicular cell carcinoma

8,346/3

g. Lymphoma

9,590/3

3. Other tumors
a. Hyalinizing trabecular tumor

8,336/1

b. Columnar cell carcinoma

8,344/3

c. Mucinous carcinoma

8,480/3

d. Mucoepidermoid carcinoma

8,430/3

e. Intrathyroid thymic carcinoma (ITTC)

8,589/3

f. Spindle cell tumor with thymus‒like differentiation (SETTLE)

8,588/3

g. Squamous cell carcinoma

8,070/3

h. Sarcomas

8,800/3

i. Others
j. Secondary (metastatic) tumors
4. Unclassified tumors
5. Tumor‒like lesions
a. Adenomatous goiterb. Amyloid goiterc. Cyst

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Kamma et al.

Description of Histological Types
Benign tumors
Follicular adenoma
Follicular adenoma (FTA) is a benign tumor derived
from the follicular epithelium and it is encapsulated by afibrous capsule. The neoplastic cells are almost uniform
in size and form, and mainly proliferate in a follicularpattern. It does not demonstrate capsular invasion, vascu‐
lar invasion, or distant metastasis.
FTAs are usually solitary, proliferate to compress theneighborhood thyroid tissue, and are encapsulated by afibrous capsule. The capsule of the FTA covers the entire
circumference, although the thickness varies for eachcase. The capsule is occasionally calcified and ossified.
Capsular connective tissue does not usually extend or
separate into tumors.
The tumor cells are relatively monotonous in size andshape within one tumor, although they may have cubic,
columnar, and polyhedral shapes. There is a rare case ofoutstanding signet-ring cells.
Although the large and small follicles are mixed, thepredominant growth pattern is a small follicular struc‐ture. FTA may show a papillary structure in some cases,
although it does not show the characteristic nuclear
features of papillary carcinoma. When FTAs are accom‐
panied by hyperthyroidism (toxic adenoma or hyper‐
functioning adenoma), the neoplastic cells are highlycolumnar, and papillary structures and absorption
vacuoles are partly seen.
FTAs usually have a narrow stroma and rich capillary
vessels among follicles. FTAs are sometimes locallyaccompanied by secondary changes such as edema, fi‐
brosis, hyalinization, hemorrhage, calcification, cartilagi‐
nous and bone metaplasia, and cyst formation. There arerare cases of stromal adipose tissue (lipoadenoma) andmucin deposition (FTA, mucinous type).
Lesions previously diagnosed as papillary adenoma
are now considered either FTAs showing papillary struc‐ture, adenomatous goiter with marked papillary structure,and encapsulated papillary carcinoma. Therefore, thediagnosis of papillary adenomas is currently obsolete.
Variants
1) Follicular adenoma, oxyphilic cell (oncocytic)
variant
An oxyphilic FTA is a tumor consisting mainly of
acidophilic cells (more than 75%) and is called a Hürthle
cell adenoma. Macroscopically, it is brownish and occa‐
sionally has a scar at the center. Neoplastic cells haveabundant acidophilic granular cytoplasm and often
hyperchromatic nuclei. The nuclei are occasionally large,
pleomorphic, and have clear nucleoli. An oxyphilic FTA
is distinguished from an oxyphilic-type papillary carci‐noma, in which the nucleus shows characteristics of pap‐
illary carcinoma. The cytoplasmic characteristic of thistumor originates from the abundant mitochondria.
2) Follicular adenoma, clear cell variant
A clear cell FTA is an FTA in which all or most of thecells have a clear cytoplasm. Cytoplasmic clearing
depends on mitochondrial ballooning, accumulation of
fat or glycogen, and retention of thyroglobulin. This
tumor should be differentiated from the metastasis ofclear cell type follicular carcinoma, adenoma of the para‐thyroid gland, and renal cell carcinoma.
Appendix* Follicular adenoma with bizarre nuclei
FTA with bizarre nuclei shows severe structural andcellular/nuclear atypia. This tumor reveals neither capsu‐
lar nor vascular invasion, although it often shows more
severe atypia than ordinary follicular carcinoma.

Malignant tumors
Papillary carcinoma
Papillary carcinoma (PTC) is a malignant follicularcell-derived tumor with a set of distinctive nuclear fea‐tures. Although the basic structure of PTC is papillary, it
is interspersed to various degrees with neoplastic folli‐cles. An exclusively follicular growth pattern is occa‐
sionally observed. Therefore, the cardinal morphologicalfeatures of PTC are not dependent on histological struc‐ture, such as papillary or follicular, but on cytologicalfindings, especially nuclear features.
The nuclei of PTC cells are large and show irregular
contours, and there are few mitotic figures. Typical
nuclear features include overlapping nuclei, groundglass-like nuclei, nuclear grooves, and intranuclear cyto‐
plasmic (pseudo-)inclusions. Overlapping nuclei, which
lie one upon another, are mainly found in the papillary
structures. Ground glass-like nuclei indicate a paleappearance due to finely textured, evenly distributed
chromatin. The nuclear grooves are found parallel to thelong axis. Because intranuclear cytoplasmic inclusions
constitute deep cytoplasmic invaginations into the
nucleus, they are the same as cytoplasmic coloring. Intra‐
nuclear cytoplasmic inclusions are observed in othertumors such as medullary carcinoma. The cytoplasm of
PTC is slightly or moderately eosinophilic, and squa‐mous metaplasia is occasionally observed.
Papillary structures seen in PTC are irregularly
arranged with a fibrovascular core, which is edematousin some cases. On the other hand, papillary structures
observed in adenomatous goiter, follicular adenoma, etc.,
do not contain fibrovascular cores. Psammoma bodies(laminated micro-calcified foci) are frequently found inlymphatic channels or within the stroma. Hyalinizationor calcium deposition is occasionally detected within the

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Pathological diagnosis of GRDTC

abundant stroma. Cystic change is occasionally observed
and accompanied by only a few PTC cells.
PTC may be accompanied by poorly differentiatedcarcinoma components, such as solid/trabecular/insular
growth patterns. In addition, PTC may include an ana‐
plastic carcinoma component with highly pleomorphic
and isolated cells. If a PTC case consists predominantlyof a poorly differentiated carcinoma component (>50%),
it should be diagnosed as poorly differentiated carci‐
noma. On the other hand, a PTC case including an ana‐
plastic carcinoma component should be classified asanaplastic carcinoma regardless of its predominancy.
Variants
1) Papillary carcinoma, follicular variant
Although the nuclear features are analogous to thoseof PTC, this variant shows an exclusively follicular
growth pattern without a papillary structure. The encap‐
sulated follicular variant of PTC has a fibrous capsuleand mild cellular atypia. Therefore, the main differential
diagnosis of encapsulated follicular variant of PTC is afollicular tumor with a fibrous capsule.
2) Papillary carcinoma, macrofollicular variant
This variant consists of large follicles containing col‐loids with nuclear features of PTC. The differential diag‐nosis of this variant includes follicular adenoma or
adenomatous goiter.
3) Papillary carcinoma, oxyphilic cell (oncocytic)
variant
This variant is characterized by the presence of acido‐
philic and granular cytoplasm with nuclear features ofPTC (nuclear grooves, intranuclear cytoplasmic inclu‐
sions, etc.) and distinct nucleoli.
4) Papillary carcinoma, diffuse sclerosing variant
This variant is characterized by diffuse involvement of
one or both thyroid lobes without a dominant nodule. It
occurs mainly in young patients. Tumor cells have a pro‐pensity to invade numerous intrathyroidal dilated lym‐
phatic spaces with dense stromal fibrosis and extensive
lymphocytic infiltration. Squamous metaplasia of tumor
cells and psammoma bodies is frequently observed.
5) Papillary carcinoma, tall cell variant
This variant tends to occur in elderly patients withextrathyroidal extension and vascular invasion. It con‐sists of elongated tall cells that are more than three times
taller than their width. Because tall cell areas are fre‐quently present in conventional PTCs, tall cells accountfor more than 50% of all tumor cells for the diagnosis of
this variant.
6) Papillary carcinoma, solid variant
This variant predominantly consists of solid and/or
trabecular growth patterns with nuclear features of PTC(>50%). In cases of marked nuclear pleomorphism, highmitotic count, or tumor cell necrosis, it is regarded as a5poorly differentiated carcinoma.
7) Papillary carcinoma, cribriform variant
This variant can occur in both familial and sporadic
forms. The familial form is characterized by multifocal
thyroid nodules in patients with familial polyposiscoli. Young women are affected more frequently. Histo‐
logically, it consists of an intimate admixture of follicu‐
lar and cribriform growth patterns without intraluminal
colloid. Papillary and trabecular growth patterns areusually observed. The tumor cells are columnar to cuboi‐
dal in shape. Their nuclei are slightly large with grooves
and frequently show a clear chromatin pattern (nuclear
clearing). They occasionally appear spindle shaped.
Squamous metaplasia with a morula is detected. Immuno‐
histochemistry reveals aberrant expression of β-catenin intumor cell nuclei.
8) Papillary carcinoma, hobnail variant
This variant consists of papillary structures with api‐
cally placed nuclei and bulging of the apical surface(hobnail features). It is defined by the presence of morethan 30% of the tumor cells with hobnail features. Recur‐
rence and metastasis are frequent, and the prognosis ispoorer than that of conventional PTC.
9) Other variants
PTC, clear cell variant, Warthin tumor-like PTC, PTC
with fibromatosis-like stroma, and PTC with squamouscell or mucoepidermoid carcinoma are described as othervariants of PTC.
Appendix*1 Microcarcinoma
It is defined as a carcinoma measuring 1 cm or less indiameter. Most microcarcinoma cases are PTC, but otherhistological types also occur as microcarcinomas.
*2 Encapsulated papillary carcinoma
This variant is surrounded by a fibrous capsule.
Regional lymph nodes and distant metastases are rare.
Follicular carcinoma
Follicular carcinoma (FTC) is a malignant tumor withfollicular growth patterns derived from the thyroid
follicular epithelium. FTC lacks the nuclear featurescharacteristic of papillary carcinoma. The diagnosis ofmalignancy requires a demonstration of invasion to thecapsules, vessels, and/or extrathyroidal tissues. The cyto‐
logical atypia of neoplastic cells cannot distinguish FTCfrom benign follicular neoplasms.
FTC shows a predominant follicular architecture withscant interstitial components. FTC is well differentiated,
and the cytoarchitectural features of FTCs are sometimes
indistinguishable from those of normal thyroid tissue.
Capsular invasion refers to the complete penetration oftumor cells through the capsule, and the tumor cells
should be bulging out from the capsular margins,
invading thyroid and/or extrathyroidal tissues. Capsular

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Fig. 3

Kamma et al.

Schematic diagram of the capsular invasion
Capsular invasion is defined as complete penetration of tumor cells through the entire thickness of the capsule. When the tumor
cells stay within the capsule, they are evaluated as negative for invasion regardless of the irregular tumor margins.

Fig. 4

Schematic diagram of the vascular invasion
Vascular invasion is defined as presence of tumor cells in
the lumens of vessels located within or near the capsules.
Endothelial cells can be found on the surface of thetumors in the vascular lumens. Degenerated inviable
tumor cells floating in the vascular lumens are not definedas vascular invasion.

invasion is defined as shown in Fig. 3. Pseudoinvasioncan be observed around the scar of the fine needle
aspiration.
Vascular invasion should be carefully evaluated byobserving the vessels within or near the capsule (Fig. 4).
The vascular cavity is defined as a true cavity lined withendothelial cells. Vascular invasion requires intravasculartumor cells that are covered by the endothelium or
thrombus. Degenerated inviable tumor cells floating in
the vascular lumen or aggregation of tumor cells, capil‐
laries, and lymphocytes within the capsules are notdefined as vascular invasion.
The diagnosis of primary thyroid FTC can also be
achieved by existence of the metastatic lesion, eventhough the intrathyroidal lesion does not meet the abovementioned malignancy criteria, which was formerlyreferred to as metastasizing goiter or malignant adenoma.
Atypical adenomas often show more severe cytologi‐
cal atypia than conventional FTC. The differential diag‐nosis of FTC and atypical adenoma should be madebased on capsular/vascular invasion and metastasis, but
not on cytological atypia. Consequently, the diagnosis of
FTC requires careful examination of the tumor margins
containing both tumor capsules and adjacent normal thy‐roid tissues by making a sufficient number of tissue
blocks.
FTC is subclassiﬁed into three groups based on thepatterns of invasion
1) Follicular carcinoma, minimally invasive
FTC, minimally invasive, is macroscopically welldemarcated with a thick fibrous capsule characteristic offollicular neoplasms. Minimally-invasive FTC can be
distinguished from follicular adenoma by the identifica‐tion of microscopic capsular invasion.
2) Follicular carcinoma, encapsulated angioinvasive
FTC, encapsulated angioinvasive, is defined as an
encapsulated follicular neoplasm with vascular invasion,
regardless of capsular invasion. FTC with extensive vas‐
cular invasion (≥4 vessels) has a poorer prognosis thanthose with limited vascular invasion (<4 vessels).
Encapsulated-angioinvasive FTC with extensive vascularinvasion and with limited vascular invasion were classi‐
fied as widely-invasive FTC and minimally-invasive
FTC, respectively, in the previous GRDTC (7th edition).
3) Follicular carcinoma, widely invasive
FTC, widely invasive, shows extensive invasion of
the thyroid and extrathyroidal tissues with ill-defined
margins. Fibrous capsules are often indistinct in widelyinvasive FTC.
Variants
1) Follicular carcinoma, oxyphilic cell (oncocytic)
variant
FTC, an oxyphilic cell variant, consists mainly of>75% tumor cells with eosinophilic granular cytoplasm.
Macroscopically, it is typically reddish brown and occa‐
sionally has hemorrhage, cyst formation, fibrosis, andinfarction. Microscopically, the tumor has solid, trabecu‐
lar, and papillary growth patterns without nuclear fea‐tures characteristic of papillary carcinoma. In thisclassification, the diagnosis of FTC, an oxyphilic cell

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Pathological diagnosis of GRDTC

variant, requires evidence of capsular/vascular invasion
or metastasis, although some pathologists believe that all
tumors with eosinophilic granular cytoplasm have malig‐nant potential.
2) Follicular carcinoma, clear cell variant
FTC, a clear cell variant, mostly consists of tumor
cells with clear cytoplasm. Cytoplasmic clearing of thetumor cells is due to the ballooning of the mitochondria
and accumulation of lipids, glycogen, and/or thyroglobu‐
lin. The diagnosis of FTC requires the exclusion ofmetastatic clear cell renal cell carcinoma. Evidence of
thyroglobulin production confirmed by immunostaining
strongly supports the diagnosis of FTC, a clear cellvariant.
Poorly differentiated carcinoma
Poorly differentiated carcinoma (PDTC) is defined asa malignant follicular cell-derived tumor showing inter‐mediate morphological features and biological behavior
between well-differentiated thyroid carcinoma (WDTC;
PTC and FTC) and anaplastic carcinoma. It has a higher
incidence of distant metastasis and poorer prognosis
than WDTC.
Macroscopically, PDTC exhibits invasive growth andoccasionally a fibrous capsule. Diagnosis requires histo‐
logical confirmation of the presence of capsular invasion,
vessel invasion, or distant metastasis, and poorly differ‐entiated components with solid/trabecular/insular growth
patterns occupying more than 50% of the tumor. Diag‐nostic criteria also exclude tumors with nuclear featuresthat are characteristic of papillary carcinoma. Mitotic
figures and coagulation necrosis are frequently observed.
Both cellular atypia and mitosis are more significant
than WDTC, but less significant than that of anaplastic
carcinoma.
The PDTC may be accompanied by a component of
the WDTC. If a case predominantly shows a componentof WDTC, it is diagnosed as WDC with a poorly differ‐entiated component instead of PDTC. A PDTC case witha minor component of anaplastic carcinoma is diagnosed
as anaplastic carcinoma.
Anaplastic carcinoma
Anaplastic carcinoma (ATC) is a malignant epithelial
tumor with high-grade structural and cellular atypia.
ATC rapidly enlarges and is frequently accompaniedby necrosis and hemorrhage. Cell atypia is highly signifi‐
cant compared to WDTC and PDTC. ATC shows highly
pleomorphic and mixed histology, consisting of spindleshaped cells resembling high-grade pleomorphic sar‐coma, squamoid cells, and giant cells.
ATC may include a component of WDTC and PDTC,
suggesting anaplastic transformation of preexistinglesions. A rare subset of ATC may include heterologous
components such as bone and cartilage. ATC is usually7

immunopositive for cytokeratins, which is useful fordifferentiating from non-epithelial tumors resembling
ATC. Carcinosarcoma should be classified as ATC in
the thyroid.
(also see the “Saracomas” section).
Medullary carcinoma
Medullary carcinoma (MTC) is a malignant epithelial
tumor derived from C-cells that characteristically secrete
calcitonin. Stroma has amyloid deposits that express
positivity with Congo Red or direct fast scarlet (DFS)
staining and are frequently accompanied by coarse calci‐
fications.
MTC exhibits a wide variety of morphologies withboth histological and cytological features. Histologicalfeatures typically show solid growth. MTC cases consist‐ing of follicular, papillary, and trabecular structures
resemble follicular cell-derived tumors. MTC shows var‐ious cytological features, such as polygonal, round, andspindle-shaped, and may comprise small and giant cells.
C-cell differentiation is confirmed using immunohisto‐
chemistry for calcitonin. It is also immunopositive for
CEA, synaptophysin, and chromogranin A.
Genetic background is well known in a subset of
MTC, which possesses a functional gain-type point
mutation in the RET protooncogene in germ cells. Most
patients with an autosomal dominant family history arecases of multiple endocrine neoplasia (MEN) type 2A
and 2B complicating neoplasia in the adrenal medulla
and parathyroid, or cases of familial MTC without any
complicated neoplasia. In hereditary cases, C-cell hyper‐
plasia is frequently observed in non-neoplastic thyroid
tissues.
Mixed medullary and follicular cell carcinoma
This tumor is defined as a malignant epithelial tumor
that shows differentiation of both C -and follicular cells
in the same lesion. The histological type of follicularcell-derived neoplasia includes both PTC and FTC.
Components of FTC in this tumor should be carefully
differentiated from incorporated normal follicles.
Lymphoma
Primary lymphoma accounts for 1%–5% of thyroid
malignancies, frequently affects elderly women, andusually arises in a background of chronic thyroiditis.
Grossly, it is a gray-whitish rubbery mass on the cut sur‐face that involves single or both lobules.
Almost all are B-cell type lymphomas with immuno‐
reactivity for CD20 expression, such as extranodal mar‐
ginal zone lymphoma of mucosa-associated lymphoidtissue (MALT lymphoma) and diffuse large B-cell lym‐
phoma (DLBCL). Furthermore, several cases can trans‐
form to DLBCL from MALT lymphoma, which may
have a phenotype distinct from that of de novo DLBCLand must be subclassified from a prognostic point ofEndocrine Journal Advance Publication

8

Kamma et al.

view. Other rare types include follicular lymphoma,
mantle cell lymphoma, Burkitt-like lymphoma, and Tcell lymphoma. Most cases formerly designated as plas‐macytoma are currently considered MALT lymphomasthat show extreme differentiation to plasma cells.
MALT lymphoma comprises a variety of B-celllineage lymphocytes, including mainly centrocyte-likecells and monocytoid B cells, as well as small lympho‐
cytes, plasmacytes, and rarely immunoblasts, andexhibits a diffuse or unclear nodular growth pattern.
Neoplastic lymphocytes mainly proliferate in the outerzone of reactive lymphoid follicles and infiltrate into theinternal part, which resembles follicular lymphoma andis called follicular colonization. Lymphoma cells charac‐
teristically infiltrate into the thyroid follicles, forming
lymphoepithelial lesions (LELs) or MALT balls, which
are packed cells in their lumen. MALT lymphoma is a
low-grade malignancy. Genetically, it has a rearrange‐
ment of the immunoglobulin heavy-chain variable region(IgH) gene, which is useful in differentiating from reac‐
tive lymphoid lesions such as Hashimoto thyroiditis.
DLBCL is a biologically high-grade malignancy thatconsists of diffuse proliferation of large lymphoma cells,such as centroblasts and immunoblasts, and frequently
shows destructive growth with infiltration to surrounding
tissue and/or strap muscles. The immunophenotype ofeach subtype follows the WHO classification.

Other tumors
Hyalinizing trabecular tumor
Hyalinizing trabecular tumor (HTT) is a follicularcell-derived tumor characterized by a trabecular growth
pattern and hyalinized stroma containing abundant base‐ment membrane material. HTT is a solid and welldemarcated tumor with or without a thin fibrous capsule.
Tumor cells are generally polygonal or elongated spin‐
dles, and occasionally have a rich clear cytoplasm.
Tumor cells frequently show nuclear grooves and intra‐
nuclear cytoplasmic inclusions and may show yellow
bodies, which are pale yellowish cytoplasmic inclusions
with a peripheral halo. Stromal hyalinization, which is
positive for periodic acid-Schiff (PAS) reaction, is due toabnormal thickening of the basement membrane, demon‐
strating intercellular irregular deposits or dendrite-likestructures.
Immunohistochemistry showed that cytokeratin 19(CK19) is negative in HTT and consistently positive in
papillary carcinoma. The membranous and cytoplasmic
positivity of Ki-67 (MIB-1) is a unique immunoreacti‐
vity for HTT. Hyalinized stroma is immunopositive forlaminin and type IV collagen. Medullary carcinoma is adifferential diagnosis because amorphous hyalinization
mimics amyloid material.

Columnar cell carcinoma
Columnar cell carcinoma is composed of pseudostrati‐
fied high columnar cells arranged in papillary, trabecular,
follicular, acinar, and solid growth patterns. Colloid
materials are usually lacking in follicles or acinar lumen.
The nuclei are round to oval-shaped, with dark chroma‐tin. Tumor cells may show sub- or supra-nuclear
vacuoles that mimic the endometrium during the secre‐
tory phase. Columnar cell carcinoma shows aggressive
behavior than that of conventional papillary carcinoma.
Mucinous carcinoma
Mucinous carcinoma is an epithelial malignancy
which produces extensive extracellular mucin and showsdifferentiation to thyroid follicular cells. Other thyroid
tumors with intracytoplasmic mucin, including follicularadenoma, papillary carcinoma, follicular carcinoma,
medullary carcinoma, and mucoepidermoid carcinoma,
are excluded from the definition of mucinous carcinoma.
Immunohistochemically the tumor cells are positive forcytokeratin.
Mucoepidermoid carcinoma
Mucoepidermoid carcinoma of the thyroid shows his‐
tological features similar to those of mucoepidermoid
carcinoma of the salivary gland. The tumor is composedof a mixture of squamous cells, mucous cells, andintermediate cells. Cyst formation, containing mucin or
keratin material, is occasionally observed in tumors.
Papillary carcinoma may coexist with mucoepidermoid
carcinoma.
Sclerosing mucoepidermoid carcinoma with eosino‐philia showed prominent fibrosis and infiltration of eosi‐
nophils, lymphocytes, and plasmacytes in the tumor.
Tumor cells with distinct nucleoli arranged in a trabecu‐
lar pattern show invasive growth. In almost all patients,
histological findings of Hashimoto thyroiditis (chronic
lymphocytic thyroiditis) are observed in non-neoplastic
thyroid tissues.
Intrathyroid thymic carcinoma
Intrathyroid thymic carcinoma (ITTC) is a malignant
thyroid tumor that histologically resembles a thymic epi‐
thelial tumor. Synonyms of ITTC include carcinoma
showing thymus-like differentiation (CASTLE) andintrathyroidal epithelial thymoma (ITET). ITTC mainly
occurs in the lower lobes of the thyroid gland. Tumor
cells are arranged in variable-sized islands with dense
fibrous stroma. Lymphocyte and plasmacyte infiltration
is observed in the entire tumor. Tumor cells are polygo‐
nal or spindle-shaped, with large nuclei, prominent
nucleoli, and indistinct cell borders. Immunohistochem‐
istry revealed that the tumor cells are positive for CD5.
Spindle cell tumor with thymus-like differentiation
Spindle cell tumors with thymus-like differentiation(SETTLE) commonly affect children and young adults.

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Pathological diagnosis of GRDTCThe tumor is grossly lobulated. Microscopically,
SETTLE shows a biphasic pattern, including afascicular-arranged spindle cell component and a glandu‐
lar component composed of cuboidal/columnar cells.
Immunohistochemically, both histological components
are positive for cytokeratin and negative for thyroglobu‐
lin. Squamous differentiation is a rare histological find‐ing of SETTLE.
Squamous cell carcinoma
Primary thyroid squamous cell carcinoma is a thyroid
epithelial malignancy composed of tumor cells with
distinct squamous differentiation. The prognosis of SCC
is poor as same as anaplastic carcinomas. The tumor
commonly shows invasive growth and extension to theextrathyroidal tissues. Differential diagnoses include
squamous metaplasia of papillary carcinoma, metastasis
or direct invasion of non-thyroidal squamous cell carci‐noma, and carcinoma with thymic differentiation. Whensquamous cell carcinoma and papillary carcinoma coex‐
ist in the tumor, both components should be recorded inpathology reports.
Sarcomas
Primary thyroid sarcomas include leiomyosarcoma,angiosarcoma, fibrosarcoma, and osteosarcoma. The
most frequent differential diagnosis is spindle cell type
anaplastic carcinoma, mimicking true sarcoma. In the
thyroid, the so-called carcinosarcoma is classified as ana‐
plastic carcinoma.
OthersRare primary thyroid tumors include teratomas,
ectopic thymomas, smooth muscle cell tumors, periph‐eral nerve sheath tumors, paragangliomas, solitary
fibrous tumors, follicular dendritic cell tumors, andLangerhans cell histiocytosis.
Secondary (metastatic) tumors
Secondary tumors are excluded from GRDTC. How‐ever, these are critical for the differential diagnosis ofprimary thyroid tumors. Secondary tumors include direct
invasion of non-thyroidal neck malignancies and meta‐
static carcinomas from other organs, such as the kidney,lung, and breast. Immunohistochemistry for thyroglobu‐
lin is useful for differentiating primary thyroid tumors
from secondary tumors.

Unclassified tumors
These are rare thyroid tumors which are unclassifiablein the above categories.
Tumor-like lesions
Adenomatous goiter
Adenomatous goiter is a nodular enlargement of the
thyroid due to non-neoplastic multiple nodules. Nodules
are characterized by morphological and gross heteroge‐

9

neity. The number, distribution, size, and histology of thenodules vary among patients. Secondary degeneration,
including hemorrhage, necrosis, cystic formation,
fibrosis, hyalinization, and calcification, are variably
observed in each nodule.
The fibrous capsule is either incomplete or absent. The
size of follicles and morphology of epithelial cells are
significantly variable in each nodule. Large follicles withrich colloid and small follicles with less colloid are vari‐
ably mixed in the nodules. Epithelial cells are columnar,
cuboidal, or flat. Nodules are predominantly composedof oxyphilic cells. Sanderson polster, a cluster of smallfollicles projecting into large follicles, is a histologicalcharacteristic of adenomatous goiter. Adenomatousgoiter may show papillary structure and nuclear overlap‐
ping but lacks typical nuclear features of papillary carci‐
noma. The stromal component is commonly rich andmay show fibrosis, granulation tissue, inflammatory
cells, hemosiderin deposits, and calcification. Cyst withfoamy macrophages and lymph-follicle formation arecommon findings in adenomatous goiter.
Nodules show no compression of the surrounding thy‐roid tissues, which is distinct from follicular adenomas.
For instance, the histological findings of nodules, follicu‐
lar cells, and lymphoid follicles are similar to those of
non-nodular areas. A single nodule is called an adenoma‐
tous nodule. Adenomatous nodules generally show nomarked enlargement of the thyroid gland. Hyperthyroid‐
ism may be complicated by adenomatous goiter or ade‐
nomatous nodules. Congenital defects in the synthesis of
thyroid hormones may cause multi-nodular enlargementof the thyroid (dyshormonogenetic goiter).
Amyloid goiter
Amyloid goiter is a hard enlargement of the thyroid
due to amyloid deposits. Primary and secondary amyloi‐
dosis, including Hashimoto’s thyroiditis, may cause
amyloid goiter. The differential diagnosis is amyloid
deposition in medullary carcinoma.
Cyst
True thyroidal cysts are relatively rare. Hypoglossal
duct cysts, originating from the remnant of the thyroglos‐
sal tract, are located in the middle of the neck. Hypoglos‐
sal duct cysts are lined by columnar, ciliated columnar,
and/or squamous cells.
Lymphoepithelial cysts are lined by squamous cellswith a subepithelial lymphocytic infiltrate. Hashimoto
thyroiditis is commonly found in the non-cystic area ofthe thyroid.
Secondary cysts are pseudocysts that develop due todegeneration, necrosis, and hemorrhage in various thy‐roid nodules. Adenomatous goiters and follicular adeno‐mas may present as secondary cysts.

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Kamma et al.

Commentary on Major Differences from
WHO Classification, 4th Edition (2017)1) Borderline lesions
In the WHO classification, a new category of border‐line lesions is proposed for “encapsulated follicularpatterned follicular cell tumor” with uncertain malignant
potential or extremely indolent behavior (Fig. 5). In this
propose, terms of “malignant tumors” or “carcinomas”
are not used when invasive growth (capsular and vascu‐
lar invasion) is absent or questionable. The borderline
lesions consist of 1) Follicular tumor of uncertain malig‐nant potential (FT-UMP), 2) Well-differentiated tumorsof uncertain malignant potential (WDT-UMP) and 3)
Noninvasive follicular thyroid neoplasm with papillarylike nuclear features (NIFTP). FT-UMP is defined as aborderline lesion between follicular carcinoma andfollicular adenoma. Some follicular variant papillarycarcinomas, defined in the current GRDTC, may be reclassified into NIFTP and WDT-UMP.
1) FT-UMP is an encapsulated follicular-patterned
tumor with questionable invasion and without nuclear
features of papillary carcinoma. FT-UMP may be classi‐
fied as follicular adenoma in GRDTC.
2) WDT-UMP is an encapsulated follicular-patterned
tumor with questionable invasion. The nuclear featuresof papillary carcinoma are present or questionable.
WDT-UMP may be classified as follicular adenoma or
encapsulated follicular variant papillary carcinoma in
GRDTC.
3) NIFTP is an encapsulated follicular-patterned tumor
without invasion. The nuclear features of papillary carci‐
noma are present or questionable. NIFTP may be classi‐
fied as follicular adenoma or encapsulated follicularvariant papillary carcinoma in GRDTC.

Fig. 5

Diagnosis of encapsulated follicular-patterned follicularcell tumors (WHO classification, 4th edition)2) Poorly differentiated carcinoma
In the current GRDTC, conventional Japanese diag‐nostic criteria are applied to poorly differentiated carci‐
nomas. In the 4th edition of the WHO classification, theTurin proposal (2007) was adopted for the histologicaldiagnosis of poorly differentiated carcinoma in addition
to conventional criteria. The Turin proposal includes thefollowing: (1) the presence of a solid/trabecular/insularpattern of growth, (2) absence of the conventional
nuclear features of papillary carcinoma, and (3) presenceof at least one of the following features: convoluted
nuclei, mitotic activity ≥3 × 10 HPF, and tumor necrosis.

Checklists for Pathological Diagnosis
Report (Table 2)
Cytology
Fine needle aspiration cytology is the most usedmorphological method for diagnosing thyroid lesions
because it is simple, less painful, repeatable, and qualita‐
tively as accurate as needle biopsy. In addition, cytology
with an imprint smear is useful in intraoperative rapid
consultation because frozen sections often show intranu‐
clear cytoplasmic inclusion-like structures as artifacts
causing a misdiagnosis.

Informed consent
Prior to an aspiration, it is necessary to explain theprocedure to the patient and obtain his/her consent tominimize his/her fear and obtain full cooperation during
the examination.
a. Explain detected lesions of the patient.
b. Explain several methods of diagnosis and theiradvantages, disadvantages, and complications.
c. Explain the technique of aspiration cytology to get
the patient’s cooperation.
d. Explain that aspirated specimens are inspected bycytotechnologists and by cytopathologists.
e. Assure the patient that the obtained specimens areused only for diagnostic purposes. Alternatively, we
obtain his/her consent to use the specimen for otherpurposes.
Aspiration technique
The details of the equipment required for sampling andprocessing are available in the literature. Following is abrief list of precautions and procedures for the puncture.
a. To safely obtain cells from the appropriate site fordiagnosis, ensure that the needle tip reaches the tar‐
get site under ultrasound guidance.
b. To obtain cells in a clipping motion under negative

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Pathological diagnosis of GRDTCTable 2

11

Checklists for pathological diagnosis report

1. Macroscopic findings
Tumor site: □ right lobe □ left lobe □ isthmus and pyramidal lobe
□ upper □ middle □ lower
Tumor size (maximum diameter): □cm
Cut surface: □ Localized, solid □ Localized, cystic □ Diffuse
Tumor focality: □ Multifocal □ Unifocal □ Cannot be determined
2. Histological findings
Primary tumor (pT)
□ pTx □ pT0 □ pT1a □ pT1b □ pT2 □ pT3a □ pT3b □ pT4b
Regional lymph node (pN)
□ pNX □ pN0 □ pN1a □ pN1b
Vascular invasion (for follicular carcinoma)□ Not identified□ Present□ <4 vessels□ ≥4 vessels□ Cannot be determined
Extrathyroidal extension□ Not identified□ Present□ Perithyroidal adipose tissue □ Strap muscles □ subcutaneous soft tissue□ Larynx □ Trachea □ Esophagus □ Recurrent laryngeal nerve□ Prevertebral fascia □ Carotid artery □ Mediastinal vessels.
□ Cannot be determined
3. Pathological diagnosis
Histological type □pressure, move the needle tip quickly back and forth
within the mass or rotate within it. It is important tounderstand that cells are not simply placed in theneedle under negative pressure.
c. The amount of specimen within the injection needle
should be sufficient for diagnosis. If punctureaspiration materials are aspirated into the syringe,
the operation is stopped immediately. An exception
is made when liquid materials are aspirated.
d. Remove the needle after the release of the negative
pressure. If the needle is removed under negative
pressure, the specimens move into the syringe andbecome dry, causing cellular degeneration. It is
impossible to remove the collected cells from thesyringe.
e. Remove the needle once, fill the syringe with air,reattach the needle, and then blow out the speci‐
mens within the needle onto glass slides.
f. In cystic lesions with a solid area, puncture the solidarea.
g. No-aspiration method: This is a sampling method inwhich the needle is held directly with the finger. In
cases of cell-rich lesions, a sufficient number ofcells can be obtained without aspiration. It is recom‐
mended for vascular-rich lesions (follicular ade‐noma and follicular carcinoma) and lesions prone tocellular degeneration (lymphoma). However, hypo‐cellular lesions or fibrous lesions tend to cause poor
sampling.

Specimen preparation
Smearing methods
Select the most appropriate smearing method depend‐ing on the nature and volume of the obtained specimen.
Semi-solid specimens, viscous liquid specimens, andsmall amount of liquid specimens
The specimen is placed between two glass slides thenpressed and release by separating slides vertically (press
and release method). This method is suitable for observa‐
tion of both cytological characteristics and tissue archi‐
tecture because it minimizes cell destruction andmaintains tissue architecture.
Large amount of specimens
Place the specimen between the two glass slides andstretch the specimen by shifting the glasses horizontally(press and rubbing method). Alternatively, repeat thepress and release method.
Specimen containing tissue fragments
The specimen is placed between two glass slides, andpressure is applied with the fingers to compress the
specimen (compression method).
Very small amount of specimens
To prevent drying artifacts, the specimen is blown
onto a glass slide and fixed immediately without any

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Kamma et al.

treatment (blowing method). Subsequently, the remain‐
ing samples is prepared for liquid-based cytology (LBC)
using a needle washout fluid.
Cyst fluid
Smear the sediment after centrifugation. Alternatively,
perform LBC preparation.
Specimens contaminated with blood
Immediately after smearing, the slide glasses areturned diagonally or vertically, and the blood componentis allowed to flow downward. If the blood does not flow,
gently tap the glasses. Most of the cellular components
remain as granular materials in the first smeared area.
After removing the blood, the press and release method
is performed.
Fixation method
Wet fixation is typically performed. There are several
methods for wet fixation, including the dipping method(95% ethanol), spraying method, and dropping method.
Fixation should be performed after smearing, but only
for liquid specimens. It is recommended to wait 5–10
seconds after smearing to prevent cell detachment. Dry
fixation should be used for Giemsa staining.
Liquid-based cytology (LBC)
In the LBC method, specimens are transferred to a
special preservation solution and smeared onto glass
slides. There are two methods: filter transfer and centri‐
fugal sedimentation. The washout fluid of the needle
after smearing or all aspirated materials are used for
LBC preparation. LBC-specific fixative solutions withhemolytic and proteolytic effects are recommended. The
advantage of LBC is that the aspirated cells can be col‐lected efficiently, which contributes to a reduction in theunsatisfactory rate. The LBC method is useful in cases
where the aspirated cells are considered to be few,
peripheral blood is contaminated, and fluid sample isaspirated. The cellular morphology of the LBC speci‐
mens is similar to that of conventional smears. There‐
fore, knowledge and experience are required to observe
the LBC specimens.

Reporting system of GRDTCThe GRDTC reporting system specifies categories anddescriptions for reporting thyroid aspiration cytology.
Accordingly, there are seven categories: unsatisfactory,
cystic fluid, benign, undetermined significance, follicularneoplasm, suspicion for malignancy, and malignancy.
Describe the presumed histological type as much as pos‐sible based on the histological classification of GRDTC(Table 1).
Categories for thyroid aspiration cytology
Unsatisfactory
Cyst Fluid
BenignUndetermined Significance
Follicular Neoplasm
Suspicious for malignancy
MalignantDiagnostic criteria for category (Table 3)
UnsatisfactoryThis refers to specimens that cannot be cytologicallydiagnosed because they are poorly prepared or do notcontain enough cells or components to infer a lesion(Table 4). For specimens that are considered unsatisfac‐
tory, the reason should be clearly stated (e.g., small num‐
ber of follicular cells, desiccation or degeneration ofcells, peripheral blood contamination, poor smearing,etc.). Histiocytes suggestive of cysts, bloody compo‐
nents, muscle, and hair cells are not included in the crite‐
ria. A clinical recommendation for this category isrepeated aspiration.
Cyst fluidSpecimens that are cyst fluid and do not contain col‐loid or follicular cells fall into this category. Most cysts
in this category are benign. Since cystic papillary carci‐
noma may be included in rare cases, a regular follow-up
is recommended. If there is a solid area within the cyst
on imaging, re-aspiration from the solid area is also rec‐ommended.
BenignThis refers to specimens that do not show malignant
cells. This category includes normal thyroid gland, ade‐
nomatous goiter, thyroiditis (acute, subacute, chronic,
and Riedel), and Graves’ disease.
Undetermined significanceThis refers to specimens that are difficult to differenti‐
ate cytologically as benign or malignant. It includes
specimens that do not fall into any of the other categories
and specimens that are difficult to diagnose. Specimens
presumed to be follicular neoplasms and their oxyphilicvariants are excluded. This category includes the possi‐
bility of papillary carcinoma (a small number of cells
suggestive of papillary carcinoma, difficulty differentiat‐
ing adenomatous goiter from papillary carcinoma, diffi‐
culty differentiating follicular tumor from papillarycarcinoma, and difficulty differentiating Hashimoto thy‐roiditis from papillary carcinoma), a small number ofatypical cells that are difficult to identify, difficulty
differentiating adenomatous goiter from follicularneoplasm, and difficulty differentiating Hashimoto thy‐roiditis from lymphoma. Re-aspiration is desirable forthis category.
Follicular neoplasm
Specimens with presumed or suspected follicular ade‐nomas or carcinomas are included in this category.
Specimens presumptive of oxyphilic cell variants of fol‐licular neoplasm and follicular adenoma with bizarre

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Pathological diagnosis of GRDTCTable 3

Diagnostic categories for thyroid aspiration cytology and explanation

Categories

Statement

Explanation

Unsatisfactory

Cannot be diagnosed

Poorly preserved specimen
No cells or components to infer with the lesion (Table 4)

Cyst fluid

Cyst fluid without colloid orfollicular cells

Almost all benign cysts, rarely cystic papillary carcinoma

BenignNo malignant cells

Normal thyroid gland, adenomatous goiter, thyroiditis (acute, subacute,chronic, and Riedel), and Graves’ disease

Undetermined
SignificanceDifficulty in differentiating
between benign and malignant,Not included in any of the othercategories, Difficulty making adiagnosis

Possibility of papillary carcinoma (a small number of cells suggestive ofpapillary carcinoma, difficulty differentiating adenomatous goiter frompapillary carcinoma, difficulty differentiating follicular tumor from papillarycarcinoma, and difficulty differentiating Hashimoto thyroiditis frompapillary carcinoma); a small number of atypical cells that are difficult to
identify; difficulty differentiating adenomatous goiter from follicularneoplasm; and difficulty differentiating Hashimoto thyroiditis fromlymphoma

Follicular
Neoplasm

Presumed or suspected follicularadenoma or follicular carcinoma

Mostly follicular adenoma and follicular carcinoma, oxyphilic cell variantsof follicular neoplasm, follicular adenoma with bizarre nuclei, adenomatousgoiter, papillary carcinoma, and parathyroid adenoma may be included

Suspicious formalignancy

Only a few cells that appear to be
malignant, insufficient findings todetermine malignancy

A variety of malignant tumors and hyalinizing trabecular tumor are
included, mostly papillary carcinoma, papillary carcinoma is suspected but
follicular tumor cannot be ruled out, follicular adenoma with bizarre nuclei,
adenomatous goiter, and Hashimoto thyroiditis may be included

Malignantspecimens with malignant tumors

Papillary carcinoma, poorly differentiated carcinoma, undifferentiatedcarcinoma, medullary carcinoma, lymphoma, metastatic carcinoma, etc.

Table 4

Criteria for satisfactory and unsatisfactory specimens

Satisfactory: Any of the following four scenarios shall be considered satisfactory.
1) A minimum of six groups of well-visualized follicular cells, with ≥10 cells per group2) Abundant colloid
3) Cells with significant cytological atypia4) Inflammatory cells, including lymphocytes, plasma cells, or histiocytes
Unsatisfactory: Any of the following two scenarios should be considered unsatisfactory.
1) Poorly preserved specimens, including degeneration due to desiccation, poor fixation, obscuring blood, clotting artifacts, andsmearing failures
2) None of the above satisfactory four scenarios.

nuclei are also included. The majority of cases in thiscategory are follicular adenomas and follicular carcino‐mas, but adenomatous goiter, papillary carcinoma, andparathyroid adenoma may also be present. It is unlikelythat the results of re-aspiration are classified into any
other category.
Suspicious for malignancy
This refers to specimens that could not be confirmed
as malignant because there are only a few cells thatappear to be malignant or have insufficient findings todetermine malignancy. This category includes a variety
of malignancies, most of which are papillary carcinomas.
A diagnosis of “suspected follicular carcinoma” does notexist in this category. Specimens in which papillary car‐cinoma is suspected but follicular tumors that cannot be

ruled out are also included. HTTs, follicular adenoma
with bizarre nuclei, adenomatous goiter, and Hashimoto
thyroiditis may be included in this category.
MalignantThis refers to specimens with malignant tumors. This
category includes papillary carcinoma, poorly differenti‐
ated carcinoma, anaplastic carcinoma, medullary carci‐noma, lymphoma, and metastatic carcinoma.
Supplementary1) The frequency of aspirated nodules categorized as“Unsatisfactory” is recommended to be ≤10%; if it
exceeds 10%, the aspiration and smearing methods
should be checked.
2) The recommended frequency of nodules with
“Undetermined significance” is ≤10% of adequate

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Kamma et al.

samples.
3) The recommended frequency of nodules with “Fol‐licular neoplasm” is ≤10% of adequate samples.
4) It is recommended that more than 80% of nodules
with “suspicious for malignancy” should be histo‐
logically confirmed to be malignant.
5) Clear deviation from 10% for tumors of undeter‐
mined significance or follicular neoplasm, and 80%
for suspected malignancy, requires cytodiagnostic
studies. Cytodiagnostic considerations are warranted
when the frequency of “undetermined significance”
or “follicular neoplasm” clearly deviates from 10%,and when the frequency of malignancy in “suspi‐
cious for malignancy” clearly deviates from 80%.
6) The cytological report should be made in accord‐
ance with the clinical imaging findings.
Comparison of the GRDTC system and the Bethesda
System1) Terminology
The terms used in the GRDTC system are reduced
compared to those in the Bethesda system. In the
Bethesda system, “atypia of undetermined significance;
AUS or follicular lesion of undetermined significance;
FLUS,” “follicular neoplasm; FN or suspicious for folli‐
cular neoplasm; SFN” are referred to as “undeterminedsignificance” and “follicular neoplasm,” respectively, in
the GRDTC system. They are simple and widely ac‐
cepted by Japanese cytopathologists and cytotechnologists.
2) Cyst fluid lesions
In the Bethesda system, cyst fluid with only foam cells
is classified as “Nondiagnostic/Unsatisfactory; ND/
UNS,” because the possibility of cystic papillary carci‐
noma cannot be ruled out. In this rule, the risk of malig‐
nancy in such cases is lower than that of “unsatisfactory
specimen” and is almost the same as that of “benign
specimen,” so it is judged adequate and reported as “cystfluid” in a separate category.
3) Classification of follicular lesions with nuclear
findings of papillary carcinoma
Specimens showing a follicular arrangement with mild
nuclear findings suspicious of papillary carcinoma, suchas enlarged nuclei, irregular-shaped nuclei, and clear
chromatin pattern, are classified as “follicular neoplasm”
in the Bethesda system but are classified as “undeter‐
mined significance” or “suspicious for malignancy” in
the GRDTC system.
4) Risk of malignancy and recommended clinicalmanagement
The Bethesda system describes the risk of malignancy
and recommends clinical management. However,
because the frequency of each tumor, indications forresection, and social conditions differ between Japan andthe West, it is difficult to introduce Western standards

directly to Japan. Therefore, we decided not to mention
the risk of malignancy and recommended clinical man‐agement in the GRDTC system.

Cytological findings
In fine needle aspiration cytology, the tissue itself,
including not only the tumor cells but also the stromalcells, can be collected. Therefore, when observing speci‐
mens, it is important to pay attention to the structure ofcell clusters and stromal components, in addition toindividual cell findings, and to recognize the threedimensional structure of clusters.
Adenomatous goiter
The cell findings of adenomatous goiter are also
diverse, reflecting the diversity of tissue findings. Folli‐
cular cells are generally small, round to cuboidal, andappear sheet-like, follicular, and sometimes papillary.
The size of the follicles varies from small to large. Cyto‐
plasmic staining also varies, and eosinophilic cells may
be the main component. In May-Giemsa staining, lipo‐
fuscin granules (paravacuolar granules) with vacuoles
are often found in the cytoplasm of follicular cells.
Colloid, foamy cells, hemosiderin-laden macrophages,
multinuclear cells, fibroblasts, and degenerated RBCs areobserved in the background, but their frequency and pro‐portion vary depending on the case.
In the case of cystic lesions, a large amount of liquidsample is collected, and most of the cell components arefoamy cells. If there are few or no follicular cells, they
are placed in the “cystic fluid” category. In this case, careshould be taken because cystic papillary carcinomas may
show similar findings.
Subacute thyroiditis
The appearance of multinucleated giant cells and epi‐
thelioid cells is characteristic of subacute thyroiditis,
accompanied by lymphocytes, neutrophils, and karyo‐
clastic cells. Follicular cells are swollen or degenerated
and difficult to recognize because of the unclear cyto‐
plasm.
Hashimoto thyroiditis
In Hashimoto thyroiditis, eosinophilic follicular cells
are found in the background of many lymphocytes. Eosi‐
nophilic cells appear in the form of sheets and follicles.
If the size of the nucleus is different or the nucleolus
is swollen, care must be taken not to mistake it for amalignant tumor. Small lymphocytes predominate, andmedium-to-large lymphocytes coexist.
Follicular neoplasms
Diagnosis of follicular carcinoma is made whencapsular invasion, vascular invasion, or metastasis ishistologically confirmed. Therefore, because cytologicalfindings are not the main criterion, it is difficult to distin‐
guish follicular adenoma from follicular carcinoma based

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Pathological diagnosis of GRDTC

on cytological findings alone, and it is currently appro‐
priate to diagnose FN.
FNA specimens from FN are often bloody with nocolloids, lymphocytes, or foamy cells in the background.
The number of tumor cells collected is usually high.
Tumor cells are uniform in size and morphology andappear in the form of small follicles or cords. A smallfollicular aggregate is a cell clump of 15 or less, andthe cells are arranged in a circumferential shape. Con‐
centrated round colloids may be observed in follicles.
Cytoplasmic stainability is lighter than that of papillarycarcinoma, and the cell boundaries are unclear. In somecases, capillaries are found between follicles.
In cases of the oxyphilic cell variant, the cytoplasm oftumor cells favorably stains light green, is granular, andhas clear cell boundaries. The nucleolus is large and con‐spicuous. It should be noted that in follicular adenomas
with bizarre nuclei, large atypical cells are scattered andeasily confused with malignant tumors.
Hyalinizing trabecular tumor
Hyalinizing trabecular tumors are characterized by theappearance of tumor cells that surround the hyalinizedmaterial with unclear boundaries. Poor binding, no papil‐
lary, follicular, or sheet-like arrangements exist. Tumor
cells are round to spindle-shaped, cell boundaries are
extremely obscure, and the cytoplasm is lightly stained.
A light-stained yellow body with a halo around it isobserved in the cytoplasm. Intranuclear cytoplasmic
inclusions and nuclear grooves are observed, however,ground glass-like nuclei and nuclear overlapping are notobserved.
Papillary carcinoma
In papillary carcinoma (PTC), the amount of collected
cells is abundant, and tumor cells appear as papillary,follicular, sheet-like, isolated, and scattered. The papil‐
lary cluster is a fibrovascular stromal component sur‐rounded by tumor cells. When only tumor cells are
smeared without stromal components, they appear as
monolayer sheets, with bends at the edges of the sheets
and linear palisade arrangements in the nucleus.
The nuclei are densely crowded and present in a roundor slightly oval shape. The nuclear findings are charac‐terized by fine granular (ground glass-like) chromatin,
intranuclear cytoplasmic inclusion bodies, nuclear
grooves, and lobulated nuclei. Although intranuclear
cytoplasmic inclusions and nuclear grooves are observed
more frequently than tissue specimens, it is dangerous todiagnose PTC based on their presence alone. The cyto‐
plasm is light green favorable, and the cell boundaries
are often clear. In cases of cyst-forming tumors, many
septate intracytoplasmic vacuoles may be found in thecytoplasm of tumor cells.
The psammoma body in the background, the ropy col‐15

loid in the shape of a stretched chewing gum, and thebizarrely shaped polynuclear giant cells are also findings
suggestive of PTC. Lymphocytes sometimes stand out
from the background.
Poorly differentiated carcinoma
The number of collected cells is high in poorly differ‐entiated carcinomas. It is characterized by a cell cluster
and appears as a large solid (island-like), cord-like, orscattered. Vascular endothelial cells adhering to themargins of island-shaped or cord-shaped clusters areobserved. Tumor cells are round, show a relatively uni‐
form morphology, and are less atypical than anaplastic
carcinomas. The cytoplasm is pale, and cell boundaries
are unclear. Mitosis is often observed.
Anaplastic carcinoma
Anaplastic carcinoma (ATC) is not mistaken for abenign tumor because large tumor cells showing a highdegree of atypia are collected in this case. When there
are abundant connective tissue components or inflamma‐
tory cells, it is difficult to collect tumor cells, making
diagnosis difficult. Tumor cells are poorly bound, exhibit
various morphologies such as polygonal, spindle-shaped,
and rounded, and have many findings suggestive ofmalignancy such as anisocytosis, hyperchromatic nuclei,
large nucleoli, and mitotic figures. Inflammatory cells,
mainly neutrophils, are often found in the background,and necrotic substances are common. ATC requires dis‐tinction from metastatic tumors and sarcomas. The com‐ponent of papillary or follicular carcinoma may present
as preceding lesions.
Medullary carcinoma
Tumor cells of medullary carcinoma are poorly boundand do not show a clear arrangement pattern. The cell
shape is round, sometimes spindle-shaped, and plasmacell-like when round cells appear scattered. The nucleus
is eccentric and protruded from the cytoplasm. Nuclear
chromatin is in the form of coarse granules, and nuclear
atypia and anisocytosis are often stronger than papillarycarcinoma, double nuclear cells, hyperchromatic giant
nuclei, and intranuclear cytoplasmic inclusions may befound. The cytoplasm is lightly stained and shows finegranules, and the cell boundaries are unclear. MayGiemsa staining reveals metachromatic granules in somecells. The presence of amyloid substances in the back‐ground is one of the characteristics of this tumor, but it
does not appear in all cases. Congo red staining is usefulfor distinguishing amyloids from connective tissues andconcentrated colloids. The tumor cells are positive for
calcitonin and CEA by immunostaining.
Malignant lymphoma
In diffuse large B-cell lymphoma, tumor cells areround cells of the size corresponding to large lympho‐
cytes and appear scattered. The cytoplasm is relatively

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Kamma et al.

abundant and stained with light. Nuclear membrane
depressions and deformed nuclei are often observed.
Lymphoglandular bodies and non-neoplastic small
lymphocytes are observed in the background. In MALT
lymphoma, tumor cells are small to medium-sized
lymphocytes, with mild atypia, and are often difficult todistinguish from Hashimoto thyroiditis. In Hashimoto
thyroiditis, the types of cells appearing are diverse,
whereas in MALT lymphoma, they are monotonous andthe chromatin pattern is uniform regardless of the size ofthe nucleus. When a definitive cytological diagnosis isdifficult, it is necessary to apply a surface marker using
flow cytometry.

eighth edition GRDTC included the following commit‐
tees and members:
Eighth edition GRDTC committee of the JapaneseSociety of Thyroid Pathology,
Seventh edition GRDTC committee of the JapaneseSociety of Thyroid Pathology:
Ryohei Katoh, Suguru Koshikawa, Hiroshi Naganuma,
Atsuhiko Sakamoto
Eighth Edition GRDTC Committee of the Japan
Association of Endocrine Surgery: Iwao Sugitani,
Yasuhiro Ito, Morimasa Kitamura, Seigo Kinuya,
Nobuyasu Suganuma, Shinichi Suzuki, Yatsuka Hibi,
Kiyomi Horiuchi, Hisato Hara.

Acknowledgment
The task force for the revision and translation of theReferences
1. Japan Association of Endocrine Surgery and The JapaneseSociety of Thyroid Pathology (ed) (2019) General Rules
for the Description of Thyroid Cancer (8th), Kanehara
Publishers, Tokyo (In Japanese).
2. Lloyd RV, Osamura RY, Kloeppel G, Rosai J (ed) (2017)
WHO Classification of Tumours of Endocrine Organs(4th), International Agency for Research on Cancer, Lyon.
3. Pusztaszeri M, Rossi ED, Auger M, Baloch ZW, Bishop J,
et al. (2016) The Bethesda System for reporting thyroid
cytopathology: proposed modification and updates for thesecond-edition from an international panel. Acta Cytol 60:
399–405.

Endocrine Journal Advance Publication