CANCER 196 CYTOPATHOLOGY Cytopathology of Insular Carcinoma of the Thyroid Gerardo E. Guiter, M.D.1 Manon Auger, M.D.2 Syed Z. Ali, M.D.3 Elizabeth A. Allen, M.D.3 Maureen F. Zakowski, M.D.1 1 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York. 2 Department of Pathology, McGill University, Montreal, Province of Quebec, Canada. 3 Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland. BACKGROUND. Insular carcinoma of the thyroid (ICT) first was reported in 1984. To the authors’ knowledge, few cytology reports have been published since that time. The authors describe the cytologic features of six tissue-proven ICTs and propose criteria that suggest its diagnosis. METHODS. Four cases were thyroid fine-needle aspiration (FNA) samples. Two cases were FNAs of metastases. All cases were found to be classic ICT on examination of primary or metastatic surgical specimens. RESULTS. Three cases originally were diagnosed as carcinoma, including two FNAs of metastatic sites and one thyroid FNA. Two additional thyroid FNAs were diagnosed as suspicious for malignancy, favor follicular neoplasm. One case was termed a neoplasm, favor follicular type. Smears showed high cellularity and scanty colloid. Three cases were found to contain some microfollicles. One case showed a few papillae. Necrosis and mitosis were rare. Cells were round with pale, poorly defined cytoplasm. Nuclei were round and monomorphic with finely granular chromatin, mild hyperchromasia, smooth nuclear membranes, and small nucleoli. Nuclear grooves and inclusions were rare. CONCLUSIONS. Three cases were diagnosed as suspicious for follicular neoplasm, the main differential diagnosis of ICT. Both tumors exhibited high cellularity and scanty colloid. However, ICT showed a predominance of single cells whereas follicular neoplasms reveal microfollicles with more nuclear atypia. There is cytologic overlap between these two neoplasms. Papillary thyroid carcinoma should be distinguished from ICT easily because the latter usually does not reveal the classic cytologic features associated with the former. ICT should be considered in the differential diagnosis of follicular neoplasms. Features favoring ICT are predominance of single cells, small loose nests of cells with few microfollicles, and little nuclear atypia. Cancer (Cancer Cytopathol) 1999;87:196 –202. © 1999 American Cancer Society. KEYWORDS: cytology, fine-needle aspiration, insular carcinoma, thyroid. P Abstract presented at the United States and Canadian Academy of Pathology Annual Meeting, San Francisco, California, March 21–26, 1999. Address for reprints: Maureen F. Zakowski, M.D., Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Received September 4, 1998; revision received January 11, 1999; accepted January 20, 1999. © 1999 American Cancer Society oorly differentiated “insular” carcinoma of the thyroid originally was reported in 1984 by Carcangiu et al.,1 who defined its histopathologic diagnostic criteria. The tumor was so named because of its growth pattern of solid clusters or nests of cells reminiscent of what is observed in the majority of examples of carcinoid tumor, occasionally referred to as insular. Intermediate in aggressiveness between well differentiated (follicular and papillary) and anaplastic thyroid carcinomas, insular carcinoma of the thyroid (ICT) subsequently has been well documented both as a discrete tumor entity and as a component of other, better differentiated thyroid neoplasms.2– 4 To our knowledge, few cytology reports have been published.2,5– 8 This neoplasm appears to be less common in the Americas than in Europe.1 The ability to recognize ICT in cytologic material may be important in devising an appropriate therapy, which would be more aggressive than that for the more Cytology of Insular Carcinoma of Thyroid/Guiter et al. 197 TABLE 1 Clinicopathologic Data Patient Age (yrs) Gender Clinical Hx FNA site Original cytologic diagnosis 1 60 F Goiter 1 ICT Liver 2 77 F Goiter Thyroid 3 18 M Thyroid 4 37 F Thyroid Suspect follicular neoplasm 5 58 M Mass on physical examination Hashimoto’s thyroiditis 3 3 yrs Thyroid tumor Poorly differentiated carcinoma c/w thyroid origin Poorly differentiated thyroid carcinoma Suspect follicular neoplasm 6 62 M Goiter Cervical lymph nodes Thyroid Poorly differentiated carcinoma Suspect follicular neoplasm Hx: history; FNA: fine-needle aspiration; F: female; ICT: insular carcinoma of the thyroid; c/w: consistent with; M: male. TABLE 2 Cytopathologic Features of ICT Background Cell pattern Cell shape Nuclear features Cytoplasm Bloody but clean, no necrosis, no debris, no psammoma bodies, scant colloid Well formed nests, loose clusters, acinar structures, many single cells Mostly round to oval, pleomorphism, occasional syncytial arrangements High N:C, fine to coarse chromatin, hyperchromasia, prominent overlapping, some nuclear grooves and inclusions, rare mitosis, occasional atypia Scant to moderate, usually eosinophilic on Pap stain, occasional small vacuoles, no Hürthle change ICT: insular carcinoma of the thyroid; N:C: nuclear-cytoplasmic ratio; Pap: Papanicolaou. common well differentiated carcinomas and may include total thyroidectomy and radioiodine, external beam radiotherapy, and chemotherapy.2,4 In the current study we describe the cytologic features in fine-needle aspiration (FNA) material from six cases of histologically proven ICT and expand the cytologic criteria that may suggest a preoperative diagnosis of this unusual tumor type. MATERIALS AND METHODS Surgically resected cases of ICT in which there was a previous or concomitant FNA were collected from several institutions. Six specimens from six patients were identified and constituted the basis of our study. One case previously was published as a case report.7 The patient profiles, along with the original cytologic diagnoses, are presented in Table 1. At least two patients (Patients 2 and 3) were found to have lymph node involvement at the time of initial surgery. In five cases, alcohol-fixed, Papanicolaou-stained smears were available for review. In one case air-dried Giemsa- FIGURE 1. Cellular smear of insular carcinoma of the thyroid showing cells with round, regular nuclei with marked overlap. stained smears were available for review. All cases were determined to be classic examples of ICT on examination of the primary thyroid surgical pathology 198 CANCER (CANCER CYTOPATHOLOGY) August 25, 1999 / Volume 87 / Number 4 FIGURE 2. Low power magnification of cellular aspirate demonstrating large clusters and single cells. Insert: finely vacuolated cytoplasm stained with DiffQuik (Scientific Products, McGaw Park, IL). specimen. All cases were reviewed by at least two of the authors. RESULTS All cases originally were diagnosed on cytologic material as favoring a neoplasm or suspicious or positive for malignancy. There were no false-negative or falsepositive results. In only one case (Patient 2) was the diagnosis of poorly differentiated ICT considered based on review of the cytologic material alone. In the remaining three cases of primary thyroid masses, follicular neoplasm was suspected and surgery recommended. FNA confirmed the suspected thyroid metastases to the cervical lymph nodes and liver in the remaining two patients (Patients 1 and 5). Examination of the smears revealed high cellularity in all six cases with very scanty colloid. Cells were arranged in well formed nests and single cells. The FIGURE 3. Papanicolaou staining demonstrating cellular nest of loosely cohesive tumor cells. single cell pattern predominated. In three cases a focally well developed microfollicular pattern was evident. In one case papillary structures were identified as a minor component. Blood was present significantly in the background of all cases. Necrosis was minimal. Mitoses were present in low numbers. No psammoma bodies were observed in any of the cases. The cells were round with scant to moderate amounts of pale cytoplasm that was eosinophilic on Papanicolaou stain and poorly defined. Slight vacuolization could be observed. Overlapping of the cells was a common feature. Nuclei were round and monomorphic with finely granular chromatin, mild to moderate hyperchromasia, and smooth nuclear membranes. Nucleoli were small. In two cases (Patients 2 and 3) focal nuclear atypia, both mild and extreme (represented by enlarged pleomorphic hyperchromatic nuclei), was evident. Nuclear grooves and intranuclear inclusions, features usually associated with papillary thyroid carci- Cytology of Insular Carcinoma of Thyroid/Guiter et al. FIGURE 4. Small microfollicle-like cluster of cells in insular carcinoma of the 199 FIGURE 5. Larger cluster of insular carcinoma of the thyroid showing that the nesting of the insular pattern is easily observed in the cell block. thyroid. noma, were observed focally in two cases. Cell blocks were prepared in one case and revealed classic features of insular carcinoma with a very well formed nesting pattern. In the two cases in which lymph node involvement by ICT was found at the time of surgery, the tumors demonstrated ICT identical to that in the primary tumor in one case and only papillary carcinoma without an insular component in the other case. The cytopathologic features of ICT are presented in Table 2. The morphologic features are presented in Figures 1–7. DISCUSSION ICT is an unusual primary thyroid neoplasm that to our knowledge only was described in the modern pathology literature in 1984.1 Since that time there have been various studies confirming the initial findings and expanding the description and experience with this tumor, with the majority of the reported work performed on resected surgical material.3,4 Histologically, these tumors have a characteristic pattern with small malignant cells, some in microfollicles, arranged in nests surrounded by stroma.9 Patients with this “poorly differentiated” malignancy usually are older10 and do clinically worse than their counterparts with papillary and follicular carcinomas but better than those with anaplastic carcinoma.9 The follicular cell of origin in ICT is supported by immunohistochemical staining for thyroglobulin8 and its association with goiter.1,4,5,8 Because this tumor represents only approximately 4 –7%9 of all primary thyroid neoplasms and appears to be more common in some parts of Europe and South America than in the U.S.,10 to our knowledge the total number of cases described remains few. Fewer still are the reports in the cytology literature.2,4,5,6 – 8 Generally, the cytologic findings 200 CANCER (CANCER CYTOPATHOLOGY) August 25, 1999 / Volume 87 / Number 4 FIGURE 6. High power Papanicolaou stain of mostly regular-shaped cells with finely vacuolated cytoplasm and round to oval, regular nuclear contours. have been similar, including cellular smears, single cells, and a common overlapping cell pattern,5 although the cytologic features are not uniform.11 The specimens in the current series were characterized by similar high cellularity with scanty colloid present. Overall, our cytologic findings correlated well with those described in the literature.5– 8 Three of our six patients had histories of goiter, for which an association with ICT already has been noted. Although nuclear atypia was not striking, it was observed in two of the cases, similar to a reported case12 in which considerable pleomorphism was found in the cytology smear. Although the presence of necrosis is believed to be useful in making the diagnosis of ICT11 because it is not often absent in other, better differentiated neoplasms, it is interesting to note that it was nearly completely absent in our series. Three of our cases were diagnosed as suspicious for follicular neoplasm, which is the main cytologic FIGURE 7. Cellular smear showing overlapping, scant cytoplasm, and, in this case, slight nuclear atypia. differential consideration of ICT. Both neoplasms are characterized in general by high cellularity and scanty colloid. However, ICT shows a predominance of single cells whereas follicular neoplasms reveal a predominance of syncytial-type tissue fragments as well as microfollicles that may be bland or can show nuclear atypia.13 Nevertheless, there is a considerable cytologic overlap between these two tumors and making a distinction based on cytologic material may be difficult. The arrangement of small cells in nests with cellular overlap of ICT and not the predominately microfollicular pattern of follicular carcinoma was a helpful feature in our series. The differential diagnosis of ICT also includes papillary carcinoma. Nuclear grooves and intranuclear inclusions as well as papillary formations in ICT have been described,7,8 although in only a minority of the cases reported. Nuclear pleomorphism and multinucleation also are unusual in this tumor.1,12 ICT also lacks the characteristic fine powdery nuclear Cytology of Insular Carcinoma of Thyroid/Guiter et al. 201 TABLE 3 Comparative Cytologic Features of Thyroid Tumors Insular carcinoma Follicular neoplasm Papillary carcinoma Medullary carcinoma Cellularity Single cells High Many Moderate to high Few Moderate to high Few Microfollicles Papillae Cytoplasm Many None Scant to moderate and poorly defined Mild to moderate Few to many Present Moderate and poorly or well defined Nuclear atypia Few Rare Moderate and poorly defined Mild High Many with small clusters and variable shape None None Variable Chromatin Finely granular Coarsely granular Nucleoli Grooves and inclusions Necrosis Small Few Reported5,11 Small to medium Very rare Rare chromatin of papillary carcinoma. However, papillary carcinoma may coexist with insular carcinoma.1 In those cases, FNA smears may reveal features of papillary carcinoma, at least focally. We have not examined cases in which ICT formed a minor component of an otherwise better differentiated tumor. However, because these cases have been described histologically,3 it may be interesting to study their cytologic features. Cellular thyroid aspirates with scanty colloid, predominance of single cells, and little nuclear atypia but without the classic features of papillary carcinoma should raise the possibility of a diagnosis of ICT. Medullary carcinoma of the thyroid may be included in the differential diagnosis of ICT. It can have a prominent single cell pattern with high cellularity. The background usually is clean without necrosis but amyloid deposition may be observed. Binucleation and multinucleation and spindled cells can be present. Although ICT generally lacks the multinucleation that can be present in medullary carcinoma, the single small cell pattern could be misleading. The presence of cytoplasmic granules and calcitonin positivity help to distinguish it from ICT.14 Anaplastic carcinoma can be distinguished from ICT based on the presence of a necrotic background and widespread marked nuclear atypia, including spindle and giant cells. The specific features of ICT compared with papillary and follicular carcinoma are presented in Table 3. Fine powdery chromatin Small Common Rare Small round to binucleate Coarsely granular Prominent Present Rare ever, a definitive FNA diagnosis of ICT may be difficult due to overlapping of cytologic features with follicular neoplasms. Careful attention to the cytologic criteria should allow for better categorization. Features that favor ICT are many single cells and nests with little nuclear atypia and finely granular nuclear chromatin. 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