Anaplastic Thyroid Carcinoma: Cytomorphologic Features on Fine-needle Aspiration and Associated Diagnostic Challenges

Peter Podany, MD; Rita Abi-Raad, MD; Andrea Barbieri, MD; James Garritano; Manju L. Prasad, MD; Guoping Cai, MD; Adebowale J. Adeniran, MD; Syed M. Gilani, MD

Disclosures

Am J Clin Pathol. 2022;157(4):608-619.

Abstract and Introduction

Abstract

Objectives: Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy, and early diagnosis, often aided by fine-needle aspiration (FNA), is key to improving patient prognosis. While the current literature describes some of the cytologic features (CFs) of this entity, a comprehensive examination of the CFs has not yet been performed.

Methods: We retrospectively searched our electronic database for ATC cases with available slides between January 2008 and December 2019. Cases were examined for 22 CFs and compared with a control group of differentiated thyroid carcinoma.

Results: A total of 18 ATC cases meeting our inclusion criteria were identified. Most cases showed moderate to high cellularity (83%) and epithelioid cytomorphology (83%). Architecture included either predominantly groups/clusters of tumor cells (56%) or single tumor cells (44%). The other CFs were as follows: nuclear enlargement (100%), nuclear crowding (89%), nuclear membrane irregularities (100%), multinucleated tumor cells (33%), and background acute inflammatory cells (50%). Of the CFs examined, statistically significant differences between ATC and the control groups were found in the following: nuclear pleomorphism, coarse/clumped chromatin, macronucleoli, apoptosis, and necrosis.

Conclusions: Identification of key CFs in FNA coupled with the clinical history aids in the diagnosis of ATC and helps distinguish it from other mimickers.

Introduction

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive thyroid malignancies and is associated with low overall survival rates.^[1] It typically presents as a rapidly enlarging thyroid mass most often affecting patients during the sixth and seventh decades of life.^[2] ATC can either arise de novo or in a background of differentiated thyroid carcinoma (DTC), typically papillary thyroid carcinoma (PTC). It is essential to appropriately evaluate and diagnose these cases in a timely manner, as patients with ATC with smaller tumor size (<5 cm) and without any nodal disease have better median survival rates compared with patients with larger tumor size (>5 cm) or disease metastatic to the lymph nodes.^[3] Fine-needle aspiration (FNA) cytology plays an important role in the assessment and diagnosis of thyroid lesions, including ATC.^[4] Some of the cytologic features of ATC have been described in previously published studies, but a comprehensive evaluation of cytologic features has yet to be performed.^[5,6] The cytologic features evaluated in this study are more comprehensive than those reported in previous studies.

1 2 3 4

Next Section

Table 1. Clinicopathologic Characteristics of Anaplastic Thyroid Carcinoma Cases
Characteristic	Value
Age, mean (range), y	67.38 (53–93)
Sex, No.
Male	10
Female	8
Clinical presentation, No.
Enlarging thyroid or neck mass	13
Others^a	5
Tumor site (based on histology follow-up: n = 16), No.
Thyroid gland	13
Left	4
Right	2
Bilateral	7
Neck mass/lymph node	3
Tumor size, mean (SD), cm	6.6 (2.7)
Cytology diagnostic category, No.
Malignant	15
Suspicious for malignancy	2
Neoplasm	1
Cell blocks available, No.	7
Histologic follow-up available, No.	16
Procedure, No.
Biopsy	3
Resection	13
Cytology-histology follow-up, mean, d	33

^aOther: Compressive symptoms (n = 5) including one case with longstanding thyroid nodule/goiter and shortness of breath.

Table 2. Cytology-Histology Details
		Cytology		Histology
Case No.	Tumor Size, cm	Cytology FNA Site	Cytology Diagnosis	Procedure	Predominant Histologic Pattern	Differentiated Thyroid Carcinoma
1	3.4	T	AC	—	1^a	—
2	7	T	AC	—	2^b	—
3	12	T	PFMC^c	Resection	Spindle cell	Not seen
4	2.5	NLN	MC	Resection	Epithelioid	Present
5	6	T	FN/HCN	Biopsy	Mixed spindle and epithelioid	Not seen
6	3.6	T	Suspicious for carcinoma	Resection	Pleomorphic/giant cell	Present
7	10	N	AC	Biopsy	Epithelioid	—
8	7	N	PFMC^c	Resection	Epithelioid	Not seen
9	11	T	HGC with AF	Resection	Pleomorphic/giant cell	Present
10	2	NLN	PDC		Epithelioid	Not seen
11	5.7	NLN	PDMN	Biopsy	Epithelioid	—
12	7.9	T	Suspicious for SCC^c	Resection	Epithelioid with SD	Present
13	7.5	T	HGMN with AF	Resection	Pleomorphic/giant cell	Present
14	4.5	T	PTC	Resection	Epithelioid	Present
15	5.8	T	PDMN with AF	Resection	Epithelioid	Not seen
16	8	T	Consistent with AC	Resection	Epithelioid with giant cells	Present
17	8	T	PDC^c	Resection	Pleomorphic/giant cell	Not seen
18	6.5	NLN	HGC	Resection	Epithelioid with SD	Not seen

AC, anaplastic carcinoma; AF, anaplastic feature; FN/HCN, Hurthle cell neoplasm; HGC, high-grade carcinoma; HGMN, high-grade malignant neoplasm; MC, metastatic carcinoma; N, neck; NLN, neck lymph node; PDC, poorly differentiated carcinoma; PDMN, poorly differentiated neoplasm; PFMC, positive for malignant cells; PTC, papillary thyroid carcinoma; SCC, squamous cell carcinoma; SD, squamous differentiation; T, Thyroid; —, not applicable.
^aOn cytology: spindle cell pattern.
^bOn cytology: epithelioid pattern.
^cWith differential diagnosis.

Table 3. Comparison of Cytologic Features Between Anaplastic Thyroid Carcinoma (ATC) and Differentiated Thyroid Carcinoma (DTC)
Cytologic Features	ATC (n = 18), No.	DTC (n = 18), No.	P Value	Odds Ratio (95% CI)
Cellularity
Low	3	2	1^a	1.58 (0.157–21.4)
Moderate	11	10
High	4	6
Architecture (predominant)
SC	8	0	.064^b	∞^b (2.36-∞)
LCG	3	5
CG	7	9
PG	0	4
Cell type (predominant)
Spindle cells	3	0	1	∞ (0.428-∞)
Giant cells	2	0
Epithelioid cells	15	18
Giant cells	5	4
Squamous cells	2	0
Pleomorphism
None or mild to moderate	3	18	<.0001	0 (0.000–0.086)
Moderate to severe	15	0	<.0001	0 (0.000–0.086)
Nuclear changes
Nuclear enlargement
Present	18	15	1	∞ (0.428-∞)
Absent	0	3	1	∞ (0.428-∞)
Nuclear crowding
Present	16	13	1	2.99 (0.405–36.261317)
Absent	2	5	1	2.99 (0.405–36.261317)
Nuclear shape
Round or round to oval	13	18	1	0 (0.000–0.962)
Spindle/plumped spindle	5	0	1	0 (0.000–0.962)
Irregular nuclear membrane
Present	18	13	1	∞ (1.04-∞)
Absent	0	5	1	∞ (1.04-∞)
Nuclear grooves
Present	4	11	.900	0.192 (0.032–0.946)
Absent	14	7	.900	0.192 (0.032–0.946)
Prominent or macronucleoli
Present	13	0	<.0001	∞(7.05-∞)
Absent	5	18	<.0001	∞(7.05-∞)
Small nucleoli
Present	11	13	1	0.613 (0.116–3.01)
Absent	7	5	1	0.613 (0.116–3.01)
Intranuclear pseudoinclusions
Present	5	7	1	0.613 (0.116–3.01)
Absent	13	11	1	0.613 (0.116–3.01)
Multinucleated tumor cells
Present	6	1	1	8 (0.814–412)
Absent	12	17	1	8 (0.814–412)
Chromatin
Coarse, clumped, irregular	14	0	<.0001	∞(8.937137-∞)
Other (powdery or coarse granular)	4	18	<.0001	∞(8.937137-∞)
Cytoplasm
Moderate to abundant	15	8	.780	5.91 (1.10–43.3)
Scant	3	10	.780	5.91 (1.10–43.3)
Mitosis
Present	8	0	.064	∞(2.356525-∞)
Absent	10	18	.064	∞(2.356525-∞)
Apoptosis
Present	13	0	<.001	∞(7.051877-∞)
Absent	5	18	<.001	∞(7.051877-∞)
Necrosis
Present	12	0	<.001	∞(5.644604-∞)
Absent	6	18	<.001	∞(5.644604-∞)
Inflammation
Acute	9	1	.160	15.7 (1.72–784)
Other (no or mixed)	9	17	.160	15.7 (1.72–784)
Neutrophils within tumor cell cytoplasm
Present	3	1	1	3.29 (0.235–189)
Absent	15	17	1	3.29 (0.235–189)
Colloid
Present	6	13	.960	0.202 (0.036–0.964)
Absent	12	5	.960	0.202 (0.036–0.964)
Papillary thyroid carcinoma
Present	3	8	1	0.260 (0.036–1.43)
Absent	15	10	1	0.260 (0.036–1.43)

CG, cohesive group; CI, confidence interval; LCG, loosely cohesive group; PG, papillary group; SC, single cell.
^a P value is calculated between 2 groups as follows: group 1 (low) vs group 2 (moderate and high).
^b P value is calculated between 2 groups as follows: group 1 (single cells) vs group 2 (LCG, CG, and PG).

Table 4. Cases With "Malignant" Diagnosis on Cytology
Cytologic Features	Definitive Diagnosis (n = 7)	Indeterminate Diagnosis (n = 8)	P Value	Odds Ratio (95% CI)
Predominant architecture
Single cells	5	2	1	6.4 (0.520–128)
Other (LCG, CG, PG)	2	6	1	6.4 (0.520–128)
Cell type
Spindle	1	2	1	0.52 (0.007–12.7)
Epithelioid	6	6	1	0.52 (0.007–12.7)
Pleomorphism
Mild	0	2	1	0 (0.000–6.00)
Moderate to severe	7	6	1	0 (0.000–6.00)
Nuclear grooves
Present	2	2	1	1.19 (0.063–22.2)
Absent	5	6	1	1.19 (0.063–22.2)
Macronucleoli
Present	4	6	1	0.47 (0.027–6.24)
Absent	3	2	1	0.47 (0.027–6.24)
Multinucleated tumor cells
Present	4	2	1	3.62 (0.302–64.1)
Absent	3	6	1	3.62 (0.302–64.1)
Mitosis
Present	5	3	1	3.76 (0.325–65.7)
Absent	2	5	1	3.76 (0.325–65.7)
Apoptosis
Present	6	5	1	3.31 (0.191–220)
Absent	1	3	1	3.31 (0.191–220)
Necrosis
Present	6	4	1	5.3 (0.346–343)
Absent	1	4	1	5.3 (0.346–343)
Acute inflammation
Present	3	3	1	1.23 (0.101–15.4)
Absent	4	5	1	1.23 (0.101–15.4)
Cell block
Present	5	2	1	6.4 (0.520–128)
Absent	2	6	1	6.4 (0.520–128)
Immunostain
Performed	5	2	1	6.4 (0.520–128)
Not performed	2	6	1	6.4 (0.520–128)

CG, cohesive group; CI, confidence interval; LCG, loosely cohesive group; PG, papillary group.

Table 5. Cytologic Diagnosis of Anaplastic Thyroid Carcinoma: Helpful Features and Diagnostic Considerations
Feature	Differential Diagnosis
Presence of clinical or imaging concern	Riedel thyroiditis, any other malignancy (primary vs secondary)
Cytology features
Reasonably cellular specimen (may aid in diagnosis)	Riedel thyroiditis (in cases with low cellularity and spindle cytomorphology)
Presence of the following features:
Moderate to severe pleomorphism	Reactive/inflammatory conditions, PDTC, metastatic malignancy
Macronucleoli	Hurthle cell lesions
Coarse clumped chromatin	PDTC, metastatic malignancy
Apoptosis	Lymphoid malignancy
Necrosis	PDTC, metastatic malignancy
Immunostains on cell block (cases with clinical/imaging concern for ATC)	To confirm ATC and to rule out other differential diagnosis