Fine Needle Aspiration Cytology of Selected Thyroid lesions

Transcription

1 Fine Needle Aspiration Cytology of Selected Thyroid lesions With Discussion of Participant performance in The Interlaboratory Comparison Program in Non Gynecologic Cytopathology Of The College of American Pathologists Theodore R. Miller, MD Director of Cytology University of California at San Francisco

2 Page 2 of 20 Introduction 2 The Interlaboratory Comparison Program in Non-Gynecologic Cytology (ICP in N-G) for thyroid FNA material confirms the excellent triage nature of this procedure. For benign conditions, non-neoplastic goiter and Hashimoto s, the lab response was negative in 80% and 84% of the challenges respectively. The lab response rate for nodular goiter and Hashimoto s has remained stable for the past several years. Papillary carcinoma cases performed well in the triage mode with lab responses of positive for Papillary carcinoma 78%, positive for a neoplastic condition 84%, and 12% suspicious. The following material should be useful in arriving at a more specific diagnosis. Fine needle aspiration biopsy (FNAB) has become an accepted tool in the initial evaluation of palpable and nonpalpable thyroid masses. In the hands of experienced individuals, FNAB is extremely sensitive and specific. It can be performed as an outpatient procedure and is minimally discomforting to the patient both in terms of physical pain and in cost. For the clinician, the procedure allows for rapid turnaround time from biopsy to diagnosis and features high positive and negative predicative values. In the era of managed care, the low cost of fine needle aspiration will likely drive up the demand for this technique and thus, pathologists will be asked to perform and interpret more and more of them. Optimal performance and interpretation of FNABs of the thyroid requires both good technical and interpretive skills. The technical component of FNAB includes not only the performance of the biopsy, but also the processing and staining of the slides; this aspect cannot be overemphasized. If adequate material is not harvested from a lesion, or if the smears are technically deficient, the ability to make an informative diagnosis is markedly diminished. Smears should be prepared on clean, partially frosted slides and both air-dried and alcohol-fixed material should be available for May-Grünwald-Giemsa and Papanicolaou stains, respectively. When FNAB of the thyroid is carried out under optimal conditions, accuracy exceeds 95% and inadequacy rates are usually less than 10% [2,9,14].

3 Page 3 of 20 3 Overview Although fine needle aspiration is widely viewed as a screening tool for malignant neoplasms, it is important to bear in mind that the majority of lesions evaluated by this technique are benign. It is equally important to remember that for most malignant cases, this is not merely a screening test, but it can provide a definitive and accurate diagnosis. Although it is difficult to give accurate numbers because of differences in both geography and medical practices, approximately 80 to 85% of all thyroid aspirates are for benign conditions [2,11,21], including, most frequently, colloid and degenerative cysts, benign thyroid nodules (goitrous nodules), and chronic thyroiditis. Follicular lesions, which comprise both follicular adenoma and well-differentiated follicular carcinoma, represent approximately 5% of all thyroid aspirates. Papillary carcinoma, the most frequently encountered malignancy, accounts for 2 to 3% of cases. Hürthle cell lesions make up between 1 and 3% of cases. The "grey zone" or "suspicious for malignancy" category accounts for approximately 1 to 10% of cases and nondiagnostic aspirates account for 2 to 21%. Less common entities, such as lymphoma, medullary carcinoma, anaplastic carcinoma, and metastatic malignancies, account for less than 1% of all thyroid aspirates [9]. Diffuse, Multinodular, and Uninodular Goiter (FIG. 1) Diffuse and nodular goiters have similar cytologic pictures. In most cases, aspirates of these lesions contain abundant colloid and benign thyroid epithelium. Grossly, colloid is typically shinny and may be light tan to dark brown. Microscopically, it is watery blue with MGG and blue-green to eosinophilic with the Papanicolaou stain. When aspirates are overly bloody, serum may be mistaken for colloid, especially on Pap stains. Features that can help to identify the colloid component include the presence of cracking artifact, rouleaux formation, and "colloid tide" at the edge of the smear. "Colloid tide" refers to the sharp, irregular border of colloid at the edge of the slide. Serum, in contrast, blends imperceptibly with the edge of the smear. The thyroid epithelium has uniform round

4 Page 4 of 20 nuclei that are approximately the size of a red blood cell with scanty delicate cytoplasm. The epithelial cells are arranged in small groups or flat sheets with evenly spaced nuclei, which impart a honeycomb appearance. Hürthle cell change may also be present; however, in contrast to Hürthle cell neoplasms, aspirates of these lesions lack cellular homogeneity and demonstrate groups of Hürthle cells admixed with otherwise typical thyroid epithelium. Involutional changes are common and may include old blood, foamy macrophages, and iron-laden macrophages. Goitrous thyroids may occasionally contain nodules that demonstrate a predominantly microfollicular structure. Aspirates of these cellular nodules may be very difficult to differentiate from follicular neoplasms. In many cases, groups or sheets of normal thyroid epithelium with uniform cellular polarity and a honeycomb pattern may be identified, which helps identify the lesion as benign. However, 10-15% of aspirates from goitrous thyroids may demonstrate a microfollicular pattern similar to that seen in both follicular adenoma and follicular carcinoma [3,14]. 4 Table I 2003 Interlaboratory Comparison Program in Non-Gynecologic Cytopathology Site, General and Reference Diagnosis Specific Evaluation of Participant Responses Dx Groups w/>100 lab responses only Table I FNA Thyroid/Parathyroid General Diagnosis: Negative Reference Diagnosis: Nodular/nonneoplastic goiter (adenomatous nodule) Pathologist Cytotechnologist Laboratory Participant responses N % N % N % General Diagnosis Negative % % % Uspicious % % % Positive % % 23 4% Unsatisfactory % % % Specific Diagnosis Nodular/non-neoplastic goiter (adenomatous nodule) % % % Follicular neoplasm % % % Correct general and specific diagnosis are highlighted Only most frequent specific diagnosis are included in table FIG. I: MNG with large follicular structures and watery colloid.

5 Page 5 of 20 5 Chronic Thyroiditis (Fig. 2) Chronic thyroiditis or Hashimoto's thyroiditis is usually a disease of middle aged women who present with a history of hypothyroidism. The thyroid in these patients is diffusely enlarged in most cases but may present as a uninodular goiter. Aspiration of these thyroids demonstrates a heterogeneous population of lymphocytes and Hurthle cells. The lymphoid component is composed predominantly of small round lymphocytes but may also include plasma cells, immunoblasts, large lymphocytes, and macrophages. Often these are seen as "lymphoid tangles", an amorphous stretched out conglomerated of fragile lymphocytes. In some cases the lymphoid component is scant or mixed with peripheral blood. Finding lymphoid tangles, macrophages, or plasma cells may help identify the inflammatory nature of this lesion. In other cases, the lymphoid component may predominate

6 Page 6 of 20 prompting the differential of lymphoma or lymph node. The Hurthle cell change may be a minor component admixed with unremarkable thyroid epithelium or may be the predominant component. In the latter case, the differential includes a Hurthle cell neoplasm [12,14]. TABLE II 2003 Interlaboratory Comparison Program in Non-Gynecologic Cytopathology Site, General and Reference Diagnosis Specific Evaluation of Participant Responses Dx Groups w/>100 lab responses only Table II FNA Thyroid/Parathyroid General Diagnosis: Negative Reference Diagnosis: Lymphocytic thyroiditis (Hashimoto's) Pathologist Cytotechnologist 6 Laboratory Participant Responses N % N % N % General Diagnosis Negative % % % Suspicious % % % Positive % % % Unsatisfactory 5 0.8% 1 0.2% 2 0.6% Specific Diagnosis Lymphocytic thyroiditis (Hashimoto's) % % % Hurthle cell neoplasm % % 7 2.1% Follicular neoplasm, suspicious for malignancy % % % Lymphoma % % 7 2.1% Correct general and specific diagnosis are highlighted Only most frequent specific diagnosis are included in table Fig. 2: Chronic thyroiditis with Hurthle cells and lymphocytes

7 Page 7 of 20 Follicular Neoplasms (fig. 3) 7 The spectrum of follicular lesions consists of cellular adenomatoid nodules, follicular adenomas, follicular carcinoma, and the follicular variant of papillary carcinoma. The classification of follicular adenomas includes the trabecular (embryonal), microfollicular, normofollicular (simple), and macrofollicular subtypes. In general terms, the cytologic pattern of cellular adenomatoid nodules, trabecular adenomas, microfollicular adenomas, parathyroid adenomas, and well-differentiated follicular carcinoma is very similar. Given that the diagnosis of follicular carcinoma depends largely on the presence of vascular or capsular invasion, it is generally not possible to discriminate between follicular adenoma and well-differentiated follicular carcinoma [3,17]. At the other end of the spectrum, cellular adenomatoid nodules are often indistinguishable from follicular neoplasms. Thus, all follicular lesions are lumped into one diagnostic and surgical management group. Normofollicular and macrofollicular adenomas are cytologically indistinguishable from goitrous nodules. Follicular lesions are cellular and contain groups of thyroid epithelial cells arranged in small microfollicles, which have a uniform appearance throughout the smear. These microfollicles may be monolayered and have a central lumen or they may be three-dimensional. Inspissated, thick colloid, which stains dark green or red with the Pap stain and dark blue with MGG, may sometimes be seen within the microfollicles. However, the abundant watery colloid seen in colloid and goitrous nodules is not present. In lesions containing trabecular and/or microfollicular components, serpiginous tissue fragments composed of thyroid epithelial cells are also seen [19]. In contrast to the monolayered pattern of goitrous nodules, these tissue fragments demonstrate crowded and overlapping cells (i.e., a "syncytia" of cells). Within this syncytia of cells occasional microfollicles can sometimes be identified. As a rule it is not possible to distinguish benign from malignant follicular tumors; however, carcinoma should be suspected in cases that demonstrate marked nuclear enlargement, pleomorphism, and necrosis. The relationship of neoplasia with the amount of microfollicular or solid growth has been described [3,15,18].

8 Page 8 of 20 8 TABLE III 1999,2000, & 2001 Interlaboratory Comparison Program in Non-Gynecologic Cytopathology Site, General and Reference Diagnosis Specific Evaluation of Participant Responses Total lab responses >100 Table III - FNA Thyroid/Parathyroid General Diagnosis: Suspicious Reference Diagnosis: Follicular Pathologist Cytotechnologist Laboratory neoplasm Participant Responses N % N % N % General Diagnosis Negative Suspicious Positive Specific Diagnosis Follicular neoplasm Papillary carcinoma Correct general and specific diagnosis are highlighted Only most frequent specific diagnosis is included in table Fig. 3: Follicular neoplasm with microfollicular pattern. Papillary Carcinoma (Figs. 4&5) Papillary carcinoma is the most common malignant thyroid tumor. Of the many welldescribed cytologic features of papillary carcinoma, the three most important for making the diagnosis are intranuclear inclusions, metaplastic cytoplasm, and avascular papillary structures [16].

9 Page 9 of 20 Intranuclear inclusions are evident, as a protrusion of the cytoplasmic contents into, but not through, the cytoplasmic membrane. These protrusions deform the nuclear membrane in such a way that they appear to enter the nucleus; thus, they are actually pseudoinclusions. The inclusions have a sharp, well-circumscribed border whose edge is darker than the surrounding chromatin. The contents of the inclusions are the same as in the cell's cytoplasm. Occasionally, cytoplasmic vacuoles may overlay the nucleus and give the appearance of an inclusion. These vacuoles are usually clear and irregular, lacking both the sharp circumscription and dense border of an inclusion. Metaplastic cytoplasm is dense and "waxy" and is a near facsimile of the metaplastic cells of the endocervix. This is in contrast to the well-defined cytoplasm that can be seen not only in papillary carcinoma but in several other thyroid conditions as well. Well-defined cytoplasm is more dense than normal thyroid epithelium but not as dense as metaplastic cytoplasm. It also has a granular texture, which contrasts with the "waxy" cytoplasm of metaplastic cells. Well-defined cytoplasm is found in Hürthle cell lesions, chronic thyroiditis, follicular lesions, medullary carcinoma, and goitrous nodules. It can be misinterpreted as metaplastic cytoplasm, especially if slides are overstained. The avascular papillae in papillary carcinoma consist of bluntly rounded fragments of tissue. Occasionally, these fragments have a filiform configuration with multiple papillae. In other cases, the papillae are small and singular. These fragments are multilayered and overall, the cells are arranged in a disorderly fashion; however, they often demonstrate polarity towards the edge of the papilla. Focusing in and out of multiple planes will demonstrate the multilayered avascular nature of the papilla. In contrast, fragments of tissue from a goitrous nodule demonstrate flat sheets of cells, many of which have a follicular configuration. The finding of any two of these three features is highly suggestive of papillary carcinoma. However, intranuclear inclusions, although a sensitive indicator of papillary carcinoma and present in approximately 90% of cases, are not specific for papillary carcinoma since they can also be seen in follicular lesions, medullary carcinoma, parathyroid adenomas, Hürthle cell tumors, and chronic 9

10 Page 10 of 20 thyroiditis. The inspissated thick colloid commonly seen in papillary carcinoma ( sticky colloid ), while a specific cytologic feature, is usually only found in less than 20% of cases. Other features that may be seen in papillary carcinoma include psammoma bodies, vascular papillae, septate vacuoles, and epithelial giant cells. These minor features may be seen in up to 60% of papillary carcinomas but may also be identified in other thyroid lesions, including multinodular goiter, follicular adenoma, chronic thyroiditis, and follicular carcinoma. Nuclear grooves, a common histological feature of papillary carcinoma, can also be found in up to 100% of papillary carcinoma FNABs [1,7]. Unfortunately, nuclear grooves are not a specific finding as they are also seen in a number of thyroid conditions, including follicular neoplasms, Hürthle cell tumors, medullary carcinoma, Hashimoto's thyroiditis, subacute thyroiditis, and multinodular goiters. Some investigators have claimed that nuclear grooves are present in greater numbers in papillary carcinoma and that a nuclear groove index of >20% can reliably distinguish papillary carcinoma from other thyroid lesions [7]. However, nuclear grooves can be subtle and their identification depends greatly on staining types and methods. Thus, while nuclear grooves may help raise the suspicion of papillary carcinoma, the diagnosis should rest on the finding of at least two of the three major features: intranuclear inclusions, metaplastic cytoplasm, and avascular papillae. A stepwise logistic regression analysis of the three major cytologic features of papillary carcinoma demonstrated that 87% of lesions have at least two of the three major cytologic features and 53% of papillary carcinomas have all three [16]. Using these criteria, the sensitivity for papillary carcinoma is 95% with a positive predictive value approaching 100%. An occasional papillary carcinoma will be missed due to inadequate sampling or the presence of atypical features (discussed below). There are several atypical variants of papillary carcinoma that may be encountered in fine needle aspiration material. These include the follicular, sclerosing [5], and tall cell variants [13]. These variants of papillary carcinoma usually demonstrate at least some of the typical cytological features of papillary carcinoma. In the case of follicular papillary carcinoma, lesions lack the 10

11 Page 11 of 20 avascular papillae but they may have intranuclear inclusions and metaplastic cytoplasm. In tall cell papillary carcinomas, intranuclear inclusions, metaplastic cytoplasm, and avascular papillae can all be identified. In most instances, these unusual variants of papillary carcinoma are recognizable cytologically because they retain the typical features of papillary carcinoma, but their "variant" nature is not often detected on the cytologic material. Given the cytologic criteria for papillary carcinoma, the diagnosis is often apparent with adequate sampling. However, several diagnostic pitfalls may be encountered by both inexperienced and experienced cytologists [4,12]. These pitfalls include interpretive and diagnostic errors. The former category includes such errors as the misinterpretation of various cytologic changes as nuclear inclusions, metaplastic cytoplasm, or avascular papillae. In the latter category are the rare and atypical variants of thyroid neoplasia, which may be misinterpreted as papillary carcinoma. Occasionally, thyroid cysts will possess an epithelial lining with metaplastic cytoplasm. Aspiration of these cysts will yield small groups of cells with metaplastic-like cytoplasm and ovoid nuclei. For the uninitiated, these cells may present a diagnostic dilemma. However, these cells are few in number and the nuclei tend to be arranged in one direction in a "flowing" pattern similar to that described for reparative changes in cervical smears. Moreover, the cytoplasm of these cells is much less dense than that of a papillary carcinoma and other features of papillary carcinoma, such as intranuclear inclusions and avascular papillae, are absent. False positive diagnoses of papillary carcinoma can occur in follicular adenomas, goitrous nodules [6], and hyalinizing trabecular adenomas [18]. Misinterpretation of these lesions as papillary carcinoma usually occurs because of an overreliance on one or two major, or multiple minor cytologic features to establish a diagnosis of papillary carcinoma. Identifying all three major cytologic features before calling a lesion papillary carcinoma will avoid overdiagnosis. Rare and unusual thyroid neoplasms may also be a potential source of confusion because they are poorly defined cytologically and yet may possess one or more cytologic features of papillary carcinoma. Hyalinizing trabecular adenoma is a rare thyroid neoplasm, which, if encountered in fine needle 11

12 Page 12 of 20 aspirates, can be easily confused with papillary carcinoma. These lesions may demonstrate intranuclear inclusions, metaplastic type cytoplasm, and psammoma bodies [20]. 12 TABLE IV 2003 Interlaboratory Comparison Program in Non-Gynecologic Cytopathology Site, General and Reference Diagnosis Specific Evaluation of Participant Responses Dx Groups w/>100 lab responses only Table IV - FNA Thyroid/Parathyroid General Diagnosis: Positive Reference Diagnosis: Papillary carcinoma Pathologist Cytotechnologist Laboratory Participant responses N % N % N % General diagnosis Positive % % % Suspicious % % % Negative % % % Unsatisfactory 2 0.3% 2 0.4% 0 0.0% Specific Diagnosis Follicular Neoplasm % % % Papillary carcinoma % % % Correct general and specific diagnosis are highlighted Only most frequent specific diagnosis is included in table Fig. 4: Papillary structure without a visible vessel.

13 Page 13 of Fig. 5: Papillary carcinoma showing metaplastic cells and a nuclear inclusion. Hurthle cell tumors (Fig. 6) Hurthle cell neoplasms include both benign Hurthle cell adenomas and Hurthle cell carcinomas. Although Hurthle cell carcinomas may demonstrate significant nuclear pleomorphism, there are no cytologic features, which reliably distinguish, benign from malignant tumors. Hurthle cell tumors are therefore regarded as one surgical management group. Hurthle cell tumors are usually cellular and composed of a monomorphic population of oval to polygonal shaped Hurthle cells. The Hurthle cells characteristically have abundant granular cytoplasm which stains either cyanophilic or eosinophilic on the pap stain and light to dark blue on the MGG stain. The nuclei tend to be round, eccentrically placed and contain a large macronucleolus. Cells may be arranged in small clusters, but have a tendency to be dispersed singly throughout the smear. The differential diagnosis of Hurthle cell tumors includes chronic thyroiditis and Hurthle cell metaplasia in goitrous nodules. It is important to distinguish both goitrous lesions and chronic thyroiditis from Hurthle cell tumors because the former group of lesions may be managed medically. In contrast to Hurthle cell neoplasms, both chronic thyroiditis and goitrous nodules demonstrate a heterogeneous population of cells and the Hurthle cells are almost always in cohesive groups.

14 Page 14 of 20 Moreover, the Hurthle cell change in chronic thyroiditis and goitrous nodules if often less well developed compared to Hurthle cell tumors. Chronic thyroiditis is characterized by the presence of chronic inflammation and Hurthle cells. The inflammatory component may consist of lymphocytes and/or plasma cells. Lymphocytes are often crushed in smear preparations and appear as "tangles" of cells on the smear. The Hurthle cell component may consist of only a few groups of cells admixed with otherwise benign appearing thyroid epithelium or may be quite cellular. Goitrous nodules may also contain significant numbers of Hurthle cells, however these cells are cohesive and are usually admixed with otherwise benign appearing thyroid epithelium [10]. 14 Table V 1999 Interlaboratory Comparison Program in Non-Gynecologic Cytopathology Site, General and Reference Diagnosis Specific Evaluation of Participant Responses Dx Groups w/>100 lab responses only Table V - FNA Thyroid/Parathyroid General Diagnosis: Suspicious Reference Diagnosis: Hurthle cell Pathologist Cytotechnologist Laboratory neoplasm Participant Responses N % N % N % General diagnosis Negative Suspicious Positive Specific* Diagnosis Negative - Hurthle cell neoplasm Negative - Lymphocytic thyroiditis (Hashimoto's) Suspicious - Follicular neoplasm Suspicious - Hurthle cell neoplasm % Positive - Hurthle cell neoplasm *Includes combination of general and reference diagnosis Correct general and specific diagnosis are highlighted Only most frequent specific diagnosis is included in table

15 Page 15 of Fig. 6: Hurthle cell tumor with numerous single oncocytic cells. Medullary Carcinoma (Fig. 7) Medullary carcinoma is among the rarer lesions encountered in both surgical and cytology specimens representing approximately 5% of all thyroid carcinomas and comprising no more than.2% to.4% of all thyroid aspirates [14,22]. In other words, medullary carcinoma is diagnosed on average in one out of every 250 fine needle biopsies of the thyroid. Despite these reassuring numbers, medullary carcinoma is frequently considered in thyroid fine needle biopsies and may be over diagnosed. The most characteristic feature of medullary carcinoma is a variable cytologic pattern. The aspirates are often cellular and composed of spindle cells and polygonal cells, which are usually dispersed singly throughout the smear, but also may appear in irregular disorganized groups. Frequently the polygonal cells are multinucleated with eccentrically placed nuclei. Amyloid may be observed in approximately 50%-60% of cases and appears as faint eosinophilic hyaline material on Papanicolaou stain and light blue hyaline material on May-Grunwald Giemsa stain [8,22]. Amyloid may be readily mistaken for inspissated colloid, however it characteristically occurs as irregular

16 Page 16 of 20 amorphous material in the background of the slide and may be identified definitively with Congo red stains. Cytoplasmic granules which characteristically stain red with the MGG stain and blue with the Papanicolaou stain are another feature which may be seen in up to 30% of cases. The differential diagnosis includes papillary carcinoma, Hurthle cell tumors, and anaplastic carcinoma. Papillary carcinoma is occasionally a consideration when intranuclear inclusions are identified in addition to the other features listed above. However, papillary fragments and metaplastic type cytoplasm are not characteristic features of medullary carcinoma. Moreover, a variable cell pattern with both spindle and polygonal cells, which are predominantly dispersed singly throughout and aspirate, are uncommon features in a papillary carcinoma. Hurthle cell tumors are a primary consideration in lesions composed predominantly of polygonal cells, which are dispersed singly throughout the smear. However, Hurthle cells typically have fine densely granular cytoplasm with uniform nuclei and prominent round nucleoli. In contrast, medullary carcinoma cells usually have very course, evenly distributed nuclear chromatin with or without nucleoli and variable cytoplasmic granularity. Anaplastic carcinoma is a consideration in any lesion with large pleomorphic multinucleated giant cells. However, anaplastic carcinomas demonstrate greater degrees of anaplasia that are more uniformly expressed in all the tumor cells. In difficult cases, calcitonin immunoperoxidase stains may be invaluable. These may be performed on alcohol fixed Papanicolaou stained slides or cellblocks. 16

17 Page 17 of 20 TABLE VI 2003 Interlaboratory Comparison Program in Non-Gynecologic Cytopathology Site, General and Reference Diagnosis Specific Evaluation of Participant Responses Dx Groups w/>100 lab responses only Table VI - FNA Thyroid General Diagnosis: Positive Reference Diagnosis: Medullary carcinoma Pathologist Cytotechnologist 17 Laboratory Participant responses N % N % N % General diagnosis Positive % % % Suspicious % % % Negative % % % Unsatisfactory Specific Diagnosis Follicular neoplasm % % 6 4.9% Medullary carcinoma % % % Lymphoma % % Correct general /specific diagnosis are highlighted, Only most frequent specific diagnosis is included in table Fig. 7: Medullary carcinoma with spindle and epitheloid cells.

18 Page 18 of 20 References Bhambani S, Kashyap V, Das DK: Nuclear grooves: Valuable diagnostic features in May- Grünwald-Giemsa stained fine needle aspirates of papillary carcinoma of the thyroid. Acta Cytol 34: , Bisi H, Asato de Camargo RY, Filho AL: Role of fine needle aspiration cytology in the management of thyroid nodules: Review of experience with 1925 cases. Diagn Cytopathol 8: , Busseniers AE, Ortel YC: Cellular adenomatoid nodules of the thyroid: Review of 219 fine needle aspirates. Diagn Cytopathol 9: , Caraway NP, Sneige N, Samaan NA: Diagnostic pitfalls in thyroid fine needle aspiration:, Review of 394 cases. Diagn Cytopathol 9: , Caruso G, Tabarri B, Lucchi I, Tison V: Fine needle aspiration cytology in a case of diffuse sclerosing carcinoma of the thyroid. Acta Cytol 34: , Fiorella RM, Isley W, Miller LK, Kragel PJ: Multinodular goiter of the thyroid mimicking malignancy: Diagnostic pitfalls in fine needle aspiration biopsy. Acta Cytol 9: , Francis IM, Das DK, Sheikh ZA, et al: Role of nuclear grooves in the diagnosis of papillary thyroid carcinoma. Acta Cytol 39: , Geddie WR, Bedard YC, Strawbridge HT. Medullary carcinoma of the thyroid in fine needle aspiration biopsies. Am J Clin Pathol 1984; 82: Gharib H,Goellner JR: Fine-needle aspiration biopsy of the thyroid: An appraisal. Ann Int Med 118: , Gonzalez JL, Wang HH, Ducatman BS. Fine-needle aspiration of Hurthle cell lesions. A cytomorphologic approach to diagnosis. Amer J Clin Pathol 1993; 100: Hawkins F, Bellido D, Bernal C, et al: Fine needle aspiration biopsy in the diagnosis of thyroid cancer and thyroid disease. Cancer 59: , 1987.

19 Page 19 of Jeffrey PB, Miller TR: Fine-needle aspiration cytology of the thyroid. In: Ljung BM (ed), Fine Needle Aspiration Biopsy. Pathology: State of the Art Reviews Vol 4, Philadelphia, Hanley & Belfus, Inc., pp Kaw YT: Fine needle aspiration cytology of the tall cell variant of papillary carcinoma of the thyroid (letter). Acta Cytol 38: , Kini SR (ed): Guides to Clinical Aspiration Biopsy: Thyroid. New York: Igaku-Shoin, Miller JM, Hamburger JI: The diagnosis of malignant follicular neoplasms of the thyroid by needle biopsy. Cancer 55: , Miller TR, Bottles K, Holly EA, et al: A step-wise regression analysis of papillary carcinoma of the thyroid. Acta Cytol 30: , Ravinsky E, Safneck JR: Fine needle aspirates of follicular lesions of the thyroid gland: The intermediate smear. Acta Cytol 34: , Schmidt KW, Hofstadter F, Propst A Jr, et al: A fourteen year practice with the fine needle aspiration biopsy of the thyroid in an endemic area. Pathol Res Pract 181: , Sironi M, Collini P, Cantaboni A: Fine needle aspiration cytology of insular thyroid carcinoma. Acta Cytol 36: , Strong CJ, Garcia BM: Fine needle aspiration cytologic characteristics of hyalinizing trabecular adenoma of the thyroid. Acta Cytol 34: , Vojvodich SM, Ballagh RH, Cramer H, Lampe HB: Accuracy of fine needle aspiration in the preoperative diagnosis of thyroid neoplasia. J Otolaryngol 23: , Zeppa P, Vetrani A, Marino M, Fulciniti F, Boschi R et al. Fine needle aspiration cytology of medullary thyroid carcinoma: a review of 18 cases. Cytopathology 1990; 1: A flow chart is provided to indicate helpful diagnostic points and considerations as well as areas of overlap.

20 DIAGNOSTIC FLOW CHART Fine Needle Aspiration of the Thyroid Colloid (protein) 1. Abundant watery colloid + phagocytic cells, normal follicular cells in sheets or 3D spheres 2. Inspissated colloid in small microfollicles 3. Bubblegum colloid Benign Thyroid Nodule (BTN) Follicular Neoplasm Papillary Carcinoma Macrophage Dominance 1. BTN, involutional type, lesser degrees of cellular and colloid components can be seen 2. Papillary carcinoma, involutional pattern 3. Thyroglossal duct cyst (+ squamous or metaplastic cells & debris) Follicular Cells (few) Lymphocyte-sized nuclei with scanty to absent cytoplasm. Small clusters may be seen Often seen in BTN or T4-treated patient Follicular Cells (numerous) Nuclear enlargement & variable oxyphilic change of cytoplasm 1. Trabecular or microfollicular pattern a. Follicular adenoma b. Follicular carcinoma c. Follicular variant of papillary carcinoma d. Chronic thyroiditis e. Parathyroid adenoma a. MNT b. Benign macrofollicular adenoma a. MNT b. Follicular adenoma Papillary Groups 1. Hyperplastic papillations as in Graves' disease, chronic thyroiditis, or MNT 2. Papillary carcinoma 2. Macrofollicles (BTN) 3. Mixed follicular pattern (BTN) Intranuclear Inclusions (INC) 1. Papillary carcinoma 2. Radiation to thyroid 3. Neoplasm reported to have INC 4. MNT (rare) a. Hurthle cell tumor b. Follicular adenoma c. Medullary carcinoma d. Parathyroid adenoma e. Metastatic disease Calcified Bodies 1. Calcium oxylate (geometric) 2. Dystrophic calcifications (aggregates of micropheroids) 3. Psammoma bodies (concentrically laminated) a. Papillary carcinoma b. Intrafollicular psammoma bodies as seen in toxic goiter Hurthle Cells (distinct cell borders, granular cytoplasm, prominent single nucleoli) 1. Pure Hurthle cell tumor 2. Hurthle cell change in a. Papillary carcinoma b. Chronic thyroiditis c. MNT Inflammatory Dominance 1. Lymphocytes 2. Granulomatous a. Chronic thyroiditis b. Lymph node c. R/O lymphoma, subacute thyoiditis Cells with "Malignant" Nuclear Features, not just Variations in Size 1. Small cell anaplastic (R/O lymphoma) 2. Large cell anaplastic carcinoma, often few cells per case with large amounts of necrosis and blood 3. Less than well-differentiated thyroid carcinoma 4. Metastatic carcinoma 5. Medullary carcinoma (red granules in cytoplasm on Wright's stain) 6. Ablative 131 I or other radiotherapy