Cystic Thyroid Nodules (CTN) – Summary Points

Felix Martinez, Jr., M.D.

Cystic thyroid nodules (CTN) are very common and are frequently aspirated for cytology examination.  In what follows, I attempt to summarize notes, key points, and my experience with cystic lesions.

CTN

• Common
• 15-20% of solitary thyroid nodules are purely cystic
• 40% of all thyroid nodules have at least a small cystic component
• CTNs often recur after needle drainage

Etiology

• Most often caused by hemorrhagic degeneration of hyperplastic regions of the thyroid parenchyma.
• Rarely result from hemorrhagic necrosis/cystic change of malignant thyroid neoplasm

Management of CTNs

• Controversial
• In the past, all CTNs considered benign and managed conservatively
• Reporting terminology using the terms “non-diagnostic/unsatisfactory” creates confusion (see pg. 3)
• Unfortunately, no clinical or pathologic criteria reliably distinguish between benign and malignant CTN.
• Currently, we still struggle with the possibility (admittedly low probability) of malignant cyst in the evaluation of many CTNs.

General Diagnostic Approach

• Fine Needle Aspiration (FNA)
• Ultrasound-guided FNA is especially useful for obtaining a sample of the solid portion of a thyroid cyst.

FNA Findings in a Pure Cyst

“Cyst contents” in Figure 1 below are comprised of (in decreasing order of occurrence):

• proteinaceous debris
• foamy histiocytes
• blood
• hemosiderin-laden macrophages
• multinucleated giant cells
• cholesterol crystals

Figure 1. Cytology of Cyst Contents

Risk of Malignancy of CTN

• Low (4%) in purely cystic nodules
• Increases to 14% in:

• mixed solid cystic lesions
• cysts larger than 4 cm
• recurring cysts

Risk Factors for Malignancy in CTN

• Large ( >3.5 cm) cyst size
• Bloody cystic fluid on first pass of FNA
• Recurrent cyst (incomplete cyst resolution)
• History of neck irradiation

Limitations of FNA of CTN

• FNA has a poor track record in diagnoses of any cystic lesion at any anatomic site.  Thus, cysts can be a common cause of false-negative diagnosis, especially in the thyroid.
• Greater risk of sampling error exists in CTN.
• Cyst may collapse, thereby becoming less echogenic on ultrasound, thereby possibly being undersampled in later passes due to loss of visualization of the lesion.
• Cystic papillary thyroid carcinoma (PTC) may yield few to no malignant cells on any given FNA pass. (See Figure 2)

Figure 2. Cystic Papillary Thyroid Carcinoma Nodule

Malignancy in a CTN

• Of all the thyroid neoplasms, papillary thyroid carcinoma (PTC) is most commonly cystic.
• When an FNA diagnosis of “cyst” occurs in a clinical setting where there is suspicion for malignancy, false negative FNA results are possible, and the patient should be followed closely.

False Negative (FN) Diagnosis in CTN

• FN = Missed Diagnosis
• FN in CTN varies in different studies, ranging from 1.5% to 11.5% (average 2-5%)
• Defined by thyroidectomy specimens having malignancy and occurring in patients with “benign” preceding cytology.

False Positive (FP) Diagnosis in CTN

• Reparative changes can display marked cytologic atypia
• Repair: Fibroblasts, new blood vessels, damaged/regenerating thyroid follicles
• Reactive/reparative changes are a cause of FP results
• Cellular lining of a cyst often has repair
• Major differential diagnostic considerations are usually between cyst-lining cells with repair versus cystic papillary thyroid carcinoma.

Common Error in Technique During FNA

• False negative FNA of a cystic lesion can occur when a needle penetrates a cyst and cyst contents rapidly fill the aspirating needle (and/or the attached syringe), leaving little time to perform the important reciprocating, in-and-out motion, maneuvers of FNA sample collection.
• Sampling error, therefore, can occur when an aspirating needle remains stationary, thereby merely evacuating the cyst rather than sampling the tissue within or around a cystic nodule.
• In order to sample adequately and thoroughly, the aspirating needle needs to continually move in and out while the cyst is draining.  This “sewing machine” motion is paramount to adequate collection, whether the target lesion is solid or cystic.  Sampling a thyroid cyst is not like drawing blood, where the needle remains stationary in a vein during the collection.

Figure 3. Cystic Papillary Thyroid Carcinoma

Determination of “Adequacy” in FNA of CTN: Subjective and Controversial

• Most FNAs of CTNs are comprised of only cyst fluid with little, if any, associated epithelium to identify the type of cyst.
• No clinical study unequivocally supports any specific cellularity or number of follicles as being assurance of adequate sampling in all cases.
• No consensus regarding minimum number of FNA passes required to obtain “adequate” sample.
• InCyte’s Approach to Cystic Lesions:  Proficient collection combined with excellent slide preparation, slide processing, slide staining, and cytopathologic interpretation.

Bethesda System for Reporting Thyroid Cytopathology (BSRTC)

• Recommends that all thyroid FNA reports have a “general diagnostic category” in the first diagnostic line (Benign, Indeterminant, Atypical, Suspicious, Malignant) followed by a description of findings
• BSRTC FNA Criteria for Adequacy: “minimum of six groups of well visualized follicular cells, with at least 10 cells per group.”

FNA CTN Lacking an Epithelial Component “(Cyst Contents, No Follicles)”

• Hard to interpret “adequacy”
• Low risk for cystic malignancy exists in all cysts
• Formerly deemed “less than optimal” by BSRTC, this diagnostic terminology was unsatisfying for all (clinician, pathologist, patient).
• According to BSRTC, cyst fluid having fewer than six groups of ten, well-preserved, benign follicular cells is considered “non-diagnostic/unsatisfactory”

Problems with the Terms “Non-Diagnostic” and “Inadequate/Unsatisfactory”

• Historically, these terms were used interchangeably by some interpreting pathologists.
• National Cancer Institute (NCI) reporting criteria: The terms “non-diagnostic” and “unsatisfactory” are recommended only to describe an inadequate or insufficient sample.
• The newest Bethesda terminology uses “non-diagnostic/unsatisfactory” in CTN cytology to imply “repeat collection needed.”

FNA of Thyroid Nodules: Sensitivity and Specificity

AACE Clinical Practice Guidelines, Endocrine Practice, Vol. 2, No. 1, January/February 1996

• Cystic lesions are as likely as solid lesions to harbor malignancy.
• Likelihood of malignancy within a cyst cannot be predicted from the cyst’s clinical or imaging characteristics, or by the patient’s demography.
• Although FNA is the best predictor of malignancy in either cystic or solid lesions, it is less reliable when a thyroid target lesion is fluid-filled rather than solid.

Predictive Value of a Negative Result (PVNR) in FNA of CTN

Fortunately, given all of the limitations discussed above, the PVNR is high because:

1. Nearly all cystic thyroid nodules are benign.
2. The prevalence of malignant thyroid nodules is low.
3. The prevalence of cystic papillary thyroid carcinoma is low.
4. Malignant cysts, when present, are almost all papillary carcinoma.

InCyte Pathology’s Approach to CTN

1. Acknowledge the difficulties (many)
2. Understand the risk (low)
3. Promote clinician education regarding #1 and #2 above
4. Encourage good FNA technique and effective sampling of CTNs.
5. Pathology report: Describe what is present in the sample, using reporting terminology understood by our providers.
6. Minimize repeat procedures for patients having low probability of malignancy.
7. Encourage repeat sampling in patients having paucicellular samples, large (>3.5 cm) cystic lesions, a history of irradiation, clinical/imaging findings suspicious for malignancy and/or negative cytology findings discordant with clinical imaging findings.