Post Fine-Needle Aspiration Histologic Alterations of Thyroid Revisited

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1 A J C P / REVIEW ARTICLE Post Fine-Needle Aspiration Histologic Alterations of Thyroid Revisited Zubair W. Baloch, MD, PhD, and Virginia A. LiVolsi, MD Key Words: Endothelial hyperplasia; Fine-needle aspiration; Post-FNA alterations; Thyroid; Tumor infarction Fine-needle aspiration biopsy (FNA) is widely performed in the initial management of both palpable and nonpalpable thyroid nodules. The procedure is well tolerated, with low morbidity.1-7 Since its introduction as a routine diagnostic tool, the number of patients with thyroid nodules being referred for surgical intervention has decreased dramatically.4-7 However, despite its effectiveness as a diagnostic tool, the trauma induced by the aspiration needle can lead to tissue alterations of varying severity and occasionally causes problems in histologic assessment of thyroid nodules Several reports have described such tissue changes, including hemorrhage, infarction, granulation tissue formation, vascular changes, spindle cell proliferation, and capsular and vascular pseudoinvasion.8-19 LiVolsi and Merino8 separated post-fna alterations into acute and chronic types. Major acute changes include hemorrhage and granulation tissue formation, and associated nuclear atypia; and chronic changes include capsular distortion, vascular pseudoinvasion, and papillary endothelial hyperplasia.8 Since their description, a few reports of similar changes have appeared,1319 which have led to awareness of post-fna alterations in the thyroid gland. Nevertheless, some changes still can generate problems in classification of thyroid lesions. In our experience, the 3 most common post-fna changes that lead to requests for pathology consultation are infarction, vascular changes, and nuclear atypia. We review these histologic alterations in light of past and present experience, point out possible pitfalls, provide helpful hints for differentiating FNA-induced changes from more ominous thyroid lesions, and discuss use of immunohistochemical stains to confirm the histologic observations. Materials We reviewed more than 5,000 case reports of various thyroid lesions from the personal consultation files of one of us (V.A.L.). These cases were referred for expert opinion from both community-based practices and academic centers, from 1993 through mid Approximately 250 cases (about 5%) had been referred because of post-fna tissue alterations. The major reasons for consultation requests were difficulty in classification of a partly or totally infarcted nodule, distinguishing true capsular and vascular invasion from pseudoinvasion, and abnormal vascular proliferations. Less frequently consultations were requested because of spindle cell proliferations, papillary changes, nuclear clearing, and calcification. Although clinical information was limited, in almost all cases the lesion in question was a dominant or solitary nodule in a patient with normal thyroid function. The majority of cases were aspirated by an endocrinologist and pathologist as an office procedure without radiologic guidance; only a limited number (fewer than 2%) were aspirated with ultrasound guidance. The lesions ranged in size from 1.0 to 10 cm; most measured 2 to 4 cm. Knowledge of the time interval between the performance of FNA and surgery was limited; however, when this was known, the interval ranged from 7 days to 2 months. In most cases, FNA diagnosis was "consistent with" or "cannot rule out" follicular or Hiirthle cell neoplasm; a few cases (fewer than 1%) were diagnosed as "suspicious for papillary carcinoma." The histologic examination usually showed a benign hyperplastic or adenomatous nodule or an adenoma. Fewer than 20% of cases demonstrated papillary carcinoma, or follicular or Hiirthle cell carcinoma. Histology Infarction Total or near total infarction of a thyroid nodule after FNA has been described most commonly in Hiirthle cell lesions Infarction is usually manifested as replacement of viable tissue with necrotic debris surrounded by a rim of 311

2 Baloch and LiVolsi / POST FINE-NEEDLE ASPIRATION HISTOLOGIC ALTERATIONS OF THYROID granulation tissue and a few viable cells In some cases, the entire lesion is replaced by a fibroinflammatory process, similar to that seen in postoperative spindle cell nodules of the genitourinary tract described by Baloch et al15 and Proppe et al.20 LiVolsi and Merino8 described 3 patterns of post-fna necrosis in thyroid nodules: central necrosis with viable periphery, wedge-shaped or triangular necrosis, and total necrosis of the entire lesion. In the first 2 patterns, it is usually possible to correctly classify the lesion by evaluating the residual viable portion.8 When the entire nodule undergoes infarction, one is left with only FNA diagnosis. Since most totally infarcted lesions are reported as follicular or Hurthle cell neoplasm on FNA, and since invasive growth characteristics cannot be predicted with this technique, the patient and the clinician are faced with an inadequate diagnosis, which may affect follow-up management in some cases. Judkins et al21 performed immunohistochemical analysis of infarcted thyroid nodules, and reported that most of their cases retained immunoreactivity for cytokeratins AE1/AE3 and thyroglobulin in necrotic areas of the tumor, whereas all cases were negative for pancytokeratin. What is interesting in this series is that the Hurthle cell lesions also showed positive staining with SI00 protein in necrotic areas. This study is useful because it enables confirmation of the cell of origin and extent of infarcted tumor, and thus can correlate with FNA findings. However, assessment of malignancy is often impossible. We have observed a few cases in which the tumor nodule is partly or entirely replaced by an exuberant spindle cell proliferation after FNA llmage II. The myofibroblastic nature of such lesions can be determined with appropriate immunostains. It is interesting that such lesions are rare, because in most of these cases the time from FNA to surgery was not much different from that in cases that demonstrated partly or totally infarcted nodules without any evidence of repair.15 We believe this may be a reflection of the size of needle used for FNA, host factors, and the inherent biology of the lesion. Hurthle cell tumors infarct more commonly than other follicular lesions and papillary carcinoma.s It has been postulated that there is a difference between the vasculature of neoplastic and nonneoplastic thyroid lesions, which may be 1 reason for posttraumatic thrombosis and micovasculature disruption. 814 Differentiated thyroid tumors express higher levels of vascular endothelial growth factor than does normal or benign thyroid tissue This vascular endothelial growth factor expression may be 1 factor responsible for angiogenesis and thus the difference between the microvasculature of tumorous and nontumorous thyroid tissue. Another potential diagnostic problem can arise when the nodules undergoing infarction are reaspirated because of unsatisfactory results of thefirstfna procedure. Some tumors of the thyroid can undergo spontaneous necrosis (eg, papillary carcinoma, Hurthle cell tumors, anaplastic carcinoma).5'2425 Thus on repeat aspiration the necrotic background may be mistaken for evidence of potentially malignant tumor. However, this problem can be averted by awareness of the previous FNA procedure and greater diagnostic reliance on nuclear morphology rather than the background necrotic material. Capsular and Vascular Invasion Is it true or pseudo capsular or vascular invasion? This is the most frequent question asked of the consultant, and the '--v " 7 «j-iq>> - ;, w. ' * '. ' ', O ' C A V <» < V " *?A % i, "» in ' i b «'1» ' %si. x' llmage I I A, Replacement of a major portion of tumor nodule by fibroinflammatory tissue, with residual tumor at the edge (H&E, x100). B, High-power photomicrograph shows residual Hurthle cells at the edge (H&E, x200). 312

3 AJCP / REVIEW ARTICLE most difficult to resolve. Capsular or vascular invasion defines the benign or malignant nature of a follicular or Hiirthle cell neoplasm.5-25 Areas of possible capsular invasion due to capsular distortion or carryover can be worrisome.8 However, there are some clues that can be helpful in distinguishing between true and pseudo capsular invasion. Post-FNA alterations in the capsule are always linear, and are surrounded by an inflammatory response and hemorrhage, depending on the interval between FNA and surgery.8 In true capsular invasion, the lesion cells usually mushroom into the capsule with a broad front and traverse the capsule horizontally.5-25 We have also noted that in areas of true invasion the capsule becomes thickened and hyalinized, and exhibits focal areas of myxoid degeneration of the fibrous tissue similar to invasive tumors found elsewhere in the body such as breast and cervix. This is in contrast to the tissue pushed or pulled into the capsule by the aspiration needle, which is usually devoid of any surrounding degenerative changes llmage 21. Vascular invasion is usually considered the deciding factor in differentiating benign and malignant follicular lesions.5-25 FNA can either induce exuberant vascular proliferation in the capsule and within the substance of the nodule, or lead to mechanical displacement of lesion cells into capsular vessels, which can cause difficulty in determining the true vascular invasion.8 This problem can be overcome by applying rigid criteria for defining true vascular invasion, such as lesion cells within a well-defined lumen of a vessel, covered on all sides by endothelium with attachment to the vessel wall5-25 llmage 31. We also have found that immunostains B -r-r Z 1 ^r-.. _.. -' r-ro Image 21 A, True capsular invasion. Note broader edge of tu changes (H&E, x200). B, Displacement of lesion cells into tu and surrounding hemorrhage (H&E, x200). llmage 31 True vascular invasion into capsular vessels. Lesion cells are present within the vascular lumen and are surrounded by endothelium (H&E, x200). for endothelial markers factor VIII and CD31 are often helpful in this regard. Vascular Changes FNA can also induce an exuberant endothelial hyperplasia, which in some cases may resemble that originally described by Masson26 in thrombosed hemorrhoids. The mechanism for such response is believed to be due to FNAinduced trauma, bleeding, hematoma formation, organization, and recanalization Some of these lesions have B invasion, surrounded by hyalinization and degenerative capsule due to FNA. Note linear arrangement of tumor cells 3 1 3

4 B a l o c h and LiVoIsi / POST FINE-NEEDLE ASPIRATION HISTOLOGIC ALTERATIONS OF THYROID I U*. I4E Ir^cSfe*; %-^s^. ^jp&p', Image 41 A, Post-FNA vascular proliferation involving center of tumor nodule (H&E, x200). B, High-power photomicrograph shows cellular atypia, which can be mistaken for angiosarcoma (H&E, x400). * *' j ' $ V- v % I ' &9B ^BpHH^fc % -#8" " * > "* ; * 0 p. SW* or ^jr*- " * * 1,4i '<n^m tv %" J # i ; ';> * 1 T # Image 51 A, Post-FNA intravascular endothelial hyperplasia involving capsular vessels of tumor (H&E, x400). B, Immunoperoxidase stain shows factor VIII positivity in endothelial cells (immunoperoxidase, x400). been reported to show noticeable cytologic atypia, and may mimic angiosarcoma.27'28 In the thyroid, similar lesions are usually observed in nodules that have undergone repeated FNA or FNA with multiple passes (Image 41. The helpful features in favor of benign or reactive change include lack of extreme cellular pleomorphism, true vascular differentiation, paucity of mitoses, and presence of thrombosed vascular structures.817,18 Sometimes the vascular proliferations are limited to capsular vessels, where the endothelial cells may focally proliferate and project in vascular lumina, mimicking tumor thrombi. In such cases, this dilemma can be solved by performing immunostains for factor VIII 314 antigen, keratins, and thyroglobulin to distinguish between endothelial and epithelial lesion cells (Image 51. Cellular or Nuclear Atypia "Reactive cellular or nuclear atypia" is a term often applied in pathology reports, and such atypia usually is seen in inflammatory and reparative processes. It is characterized by nuclear enlargement, chromatin clearing, and prominent nucleoli; these changes can be difficult to distinguish from a neoplastic process. Nuclear changes are well documented in various organs and can be seen in cells along the edges of gastric ulcer and inflammatory colonic polyps.29 Similar

5 AJCP / REVIEW ARTICLE a. \ <* irfa \ IL J KStm** ^ *TL^ ' jmksci. ).. am.«, i ^ ^ ^ H Hmage6IA, low-power photomicrograph shows post-fna fibrosis and psammomatous calcification (H&E, x100). B, highpower photomicrograph shows nuclear clearing and atypia in cells surrounding post-fna fibrosis and hemorrhage. These changes were only limited to the cells in the needle tract, and the main tumor nodule was devoid of nuclear features of papillary carcinoma (H&E, x400). cellular or nuclear changes can also be seen in chronic lymphocytic thyroiditis; these nuclear alterations are more prominent in follicles heavily infiltrated by chronic inflammatory cells.5,25 In some cases, these nuclei can suggest papillary carcinoma.5-25 Follicular cells along the needle tracts often display analogous cellular change in that they show nuclear enlargement and chromatin clearing.8 This finding can be further complicated when the FNA tract has had time to heal and become hyalinized. The combination of clear and enlarged nuclei and hyalinized stroma is suspicious for papillary carcinoma; however, these nuclei fail to show any nuclear elongation, grooves, or inclusions llmage 61. We propose that the physician refrain from making a diagnosis of papillary carcinoma if the nuclear changes are found only in the vicinity of a needle tract, without similar nuclear changes in the main tumor nodule or surrounding thyroid. In our experience, similar diagnostic difficulties can also be encountered in repeat FNA specimens, in which the nuclei may show enlargement and chromatin clearing. However, knowledge of a history of FNA and adherence to strict nuclear criteria for the diagnosis of papillary carcinoma should prevent a false-positive diagnosis. Discussion We have reviewed our experience, and that reported in the literature, with worrisome post-fna changes in the thyroid gland. Fine-needle aspiration biopsy of the thyroid gland is being performed more commonly as the initial management tool in assessing thyroid nodules. Thus both community-based and academic pathologists will see at least a few FNA-induced tissue alterations in the thyroid. As experience with these alterations has increased and a number of published reports have addressed this diagnostic problem,8-15 pathologists have become more comfortable in attributing these changes to FNA. The number of such cases referred for consultation has decreased, from 10% in to 5% in In conclusion, these changes should be recognized, and strict morphologic criteria should be followed before a diagnosis of thyroid malignancy is made. Address reprints requests to Dr Baloch: Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, 3400 Spruce St, 6 Founders Pavilion, Philadelphia, PA References 1. Ashcraft MW, Van Herle AJ. Management of the thyroid nodule: scanning techniques, thyroid suppressive therapy and fine-needle aspiration. Head Neck Surg. 1981;3: Silverman JF, West RL, Larkin EW, et al. The role of fineneedle aspiration biopsy in the rapid diagnosis and management of thyroid neoplasm. Cancer. 1986;57: Nunez C, Mendelsohn G. Fine-needle aspiration and needle biopsy of the thyroid gland. Pathol Annu. 1989;24:

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