EDITORIAL

Cytologic Diagnoses of Follicular Tumors of the Thyroid Barbara Atkinson, M.D., Carolyn S. Ernst, M.D.. and Virginia A. LiVolsi, M.D.

Fine-needle aspiration cytology for the diagnosis of thy- roid nodules has become standard practice in many institutions. Ease of performance and virtual absence of complications have made fine-needle aspiration a widely acceptable technique.’-’

A thyroid nodule that is solitary and hypo- or nonfunc- tional may represent a benign lesion or a thyroid cancer. Although in the general population the percentage of malignancy in thyroid nodules ranges from 1 % to 4%, in surgical series it has been found to be about 10’%-20%.6 Studies tabulated by Kline’ indicate a slightly higher percentage of malignancy in nodules, ranging from 5% to 8% in the general population to 15%-28% in the surgical series. In our cancerophobic society, this percentage is high enough to necessitate either the removal of the nodule (surgery) or the finding of a technique for the precise diagnosis of that nodule to screen specific cases in which surgery should be undertaken. Use of fine-needle aspiration has decreased the need for thyroid surgery with its attendant surgical complications. In fact, the percent- age of malignancies found in nodules removed surgically has increased from approximately 10% to over 50% in recent years following the advent of fine-needle aspiration cytology.’ The increase in proportion of malignant nod- ules at resection implies that fewer nonmalignant nodules are being operated on; fine-needle aspiration, therefore, is an excellent screening procedure for defining the need for surgery.

For papillary, medullary and anaplastic carcinomas, this method proves diagnostically accurate in a very high percentage of cases, It has become apparent that increas- ing experience has also increased diagnostic accuracy.’

Received August 8, 1984. Accepted June 27, 1985. From the Departments of Pathology and Laboratory Medicine,

University of Pennsylvania School of Medicine, and the Departments of Cytopathology and Surgical Pathology, Hospital of the University of Pennsylvania, Philadelphia.

Address reprint requests to Barbara Atkinson, M.D., Division of Cytopathology, Grand Gibson Hospital of the University of Pennsylva- nia, 3400 Spruce, Philadelphia, PA 19104.

However, most cold nodules in the thyroid represent follicular lesions. For such lesions, the problem of relying upon cytologic details including nuclear features and cell groupings has not been easily overcome. Some patholo- gists and cytologists believe they can distinguish among adenomatous nodules of nontoxic nodular goiter, follicu- lar adenoma, or follicular carcinoma readily and accu- rately on the basis of cytologic pattern and nuclear a~pearance‘*~*~; others find this distinction d i f f i ~ u l t . ~ ~ ~ ~ ~ ~ ’ ’

See article on page 25.

The cytologic features of well-differentiated follicular carcinomas may closely resemble those of adenomas and adenomatous nodules. Recent studies attempting to define cytologic differences between benign and malig- nant follicular thyroid lesions using refined techniques (scanning electron microscopy, image analysis, flow cytometry) have disclosed that even with such methods a diagnostic differentiation among follicular tumors cannot be easily Indeed, the diagnosis of well- differentiated follicular carcinoma of the thyroid depends upon the demonstration of invasion (capsule, adjacent thyroid, extrathyroidal tissues, or, most frequently, vein^).'^ Such invasion can only be identified in well-fixed histologic sections of a follicular neoplasm. Sometimes it is necessary to examine multiple sections of the tumor- capsule interface to identify this invasion. Rosai and CarcanguiI5 have recently stated that in their opinion vascular invasion has been overrated as a factor in determining whether an otherwise encapsulated follicular lesion, without other microscopic features of malignancy (invasiveness, mitoses, and atypia), is malignant.

Review of the experience at the Hospital of the Univer- sity of Pennsylvania with fine-needle aspiration cytology of the thyroid indicates that since 1978 we have evaluated over 1,400 fine-needle aspiration biopsies. In the first 5 yr of our experience we generally separated cases into “no evidence of malignancy,” “atypical follicular epithe- lium,” “suspicious papillary epithelium,” and “unequivo-

o 1986 IGAKU-SHOIN MEDICAL PUBLISHERS, INC Diagnostic Cytopathology. Vol2, No 1, January-March 1986 1

AXKINSON ET AL.

cal evidence of malignancy.” More specific diagnoses were made as to cell type or possible abnormality when- ever possible.

There were a number of problem areas when the diagnoses of the surgical excisions were tabulated. The diagnosis of atypical follicular epithelium was found to correlate in the majority of cases with nodules that turned out to be nontoxic goiter; another problem area was the atypia found in the epithelium associated with thyroiditis. On the other hand, in the instances where an unequivocal diagnosis of malignancy was made on the fine-needle aspiration cytology material, two cases represented folli- cular adenomas.

Our data indicated to us that the biggest problem with using the criteria of cell size and nuclear size to make the diagnosis of follicular lesions of the thyroid is that there is a large overlap wilh nontoxic nodular goiter and thyroidi- tis, allowing a large and unacceptable number of atypical and suspicious diagnoses. Hence, too many patients were still subjected to open biopsy procedures.

In our current diagnostic process, which has been modified by our experience, we have applied new criteria to the diagnosis of thyroid fine-needle aspiration cytology specimens. Thus, we currently look for increased cell and nuclear size and nuclear abnormalities, but we do not make a diagnosis of atypical or suspicious epithelium based solely on these features unless these changes are quite severe. We now look more specifically for the growth pattern and make a diagnosis of suspicious follicu- lar lesion for microfollicular, fetal pattern, or Hiirthle cell change. We look carefully for papillary groups and have found them in most papillary carcinomas; the nuclear features of papillary carcinoma, even with a predomi- nantly follicular growth pattern, are also very helpful. Thcrefore, making a cytologic diagnosis based on growth pattcrns is a much morc specific way of distinguishing among the various follicular lesions.

Wc recognize that the overwhelming majority of follic- ular nodules (80%-90%) represent adenomatous nodules (“adenomas”). Therefore, intcrprctation of a fine-needle aspiration cytology specimen of a follicular lesion as “adenomatous nodule” or “adenoma” will be correct in about 90% of cases or more. The false-negative rate is low enough to be acceptable. In fact, any diagnostic test with a 90% or more accuracy rate is considered excellent. Howcvcr, well-differentiated follicular carcinomas have an indolent biologic behavior, and follow-up in many cases diagnosed by fine-needle aspiration as benign folli- cular nodule is too short to be sure that there is not a malignant lesion. It is also important to recognize that sampling error may limit fine-needle aspiratc diagnosis; any lesion that continues to grow, particularly during

hormonal suppression, should be biopsied. The biologic answers are not in. For this reason, we believe caution must be exercised and more evaluation obtained until a larger experience and more prolonged follow-up become available.

We are encouraged by our experience, supported by that of others,* that, in practice, follicular lesions that on cytologic examination appear cellular or show a microfol- licular pattern, nuclear irrcgularity, or pleomorphism are diagnosed as “atypical.” Now, when the pathologist rec- ognizes abnormality and makes a diagnosis of “atypical follicular epithelium,” but cannot be convinced that malignancy is present, the problem has been returned to the clinician, and most patients with such a cytologic diagnosis will undergo surgery. Still, in this subgroup, many follicular lesions will be benign after extensive histologic examination. Conversely, lesions with a macro- follicular pattern are usually benign; however, this is not always the case. Some follicular cancers show a macrofol- licular pattern.

In conclusion, fine-needle aspiration cytology of thy- roid nodules can serve as a screening procedure for separating patients requiring surgery from those who do not.*”’ A correct diagnosis of papillary, medullary, and even anaplastic carcinoma may be rcndered. Such defini- tivc diagnoses can then be acted upon by surgery or radiation. If the nodule is follicular and without atypical featurcs, the clinician can assume a high probability of a benign lesion; hence, such patients can be screened out from the surgical group. Nonsurgical therapy or watchful waiting will usually suffice.

References 1 . Walfish PG, Hazani E, Strawbridge HTG, Mishkin M, Rosen 1B. A prospective study of combined ultrasonography and needle aspiration biopsy in assessment of the hypofunctioning thyroid nodule. Surgery 1971;82:474. 2. Lowhagen T, Granberg PO, Lundell G, Skinnari P, Sundblad R, Wilklerns JS. Aspiration biopsy cytology (ABC) in nodules of the thyroid gland suspected to be malignant. Surg Clin North Am

3. Fiedman M, Shimaoka K, Celaz P Needle aspiration of 310 thyroid lesions. Acla Cytol 1979;23: 194-203. 4. Gershengorn MC, McClung MR, Chu EW, Hanson TAS, Wcin- traub BD, Robbins J. Fine needle aspiration cytology in the preoperative diagnosis of thyroid nodules. Ann Intern Med 1977;87:265-9. 5. Hamburger J, Miller JM, Kini SR. Clinical pathological evaluation of thyroid nodules. Southfield, MI: Associated Endocrinologists, 1979. 6. Katz AD, Zager WJ. The malignant “cold” nodule of the thyroid. Am J Surg 1976;132:459-62. 7 . Kline TS. Aspiration biopsy cytology. St. Louis: C. V. Mosby, I98 I . 8. Suen KC, Quenville NF. Fine needle aspiration biopsy of the thyroid gland: A study of 304 cases. J Clin Pathol 1983;36:1-36. 9. Luck JB, Murnaw VC, Frable WJ. Video planc image analysis on fine needle aspiration biopsies of the thyroid gland. Acta Cytol

I979;59:3-18.

1981 ;25:728-3.

2 Diagnostir CytopatholoKy, Vol2 , No I , January.-.March 1986

DIAGNOSIS OF THYROID TUMORS

10. Prinz RA, OMorochoe PJ, Barbato AL, et al. Fine needle aspira- tion biopsy of thyroid nodules. Ann Surg 1983;198:70-3. 11. Johannessen JV, Sobrinho-Simoes M, Finseth I, Pilstrom L. Ultra-

13. Johannessen JV, Sobrinho-Simoes M, Lindmo T, Tangen KO. The diagnostic value of flow cytoometric DNA measurements in selected disorders of the human thyroid. Am J Clin Pathol 1982;77:20-5.

structural morphometry of thyroid neoplasms. Am J Clin Pathol

12. Johannessen JV. Sobrinho-Simoes N. Follicular carcinoma of the

14. Katz NF, Perzin KH. Follicular carcinoma of the thyroid. Pathol Ann 1983;18:221-53. 1983;79:162-7.

human thyroid gland: An ultrastructural study with emphasis on scanning electron microscopy. Diagn Histopathol 198 1 ;5: 1 13-127.

15. Rosai J, Carcangui ML. Pathology of thyroid tumors: Some recent and old questions. Hum Pathol 1984;15:1008-12.

Diagnostic Cytopathology, Vol2, No I , January-March 1986 3