Insular carcinoma of the thyroid. (Original Article).

Abstract

Thyroid surgeons are becoming increasingly more aware of a histologically distinct subset of thyroid carcinoma whose classification falls between well-differentiated and anaplastic carcinomas with respect to both cell differentiation and clinical behavior. This subtype of tumors has been categorized as poorly differentiated or insular carcinoma, based on its characteristic cell groupings. Although the differentiation of insular carcinoma from other thyroid carcinomas has important prognostic and therapeutic significance, relatively little about insular carcinoma has been published in the otolaryngology literature. In this article, we describe a new case of insular carcinoma and we discuss the findings of our review of the literature. We conclude that insular thyroid carcinoma warrants aggressive management with total thyroidectomy followed by radioactive iodine ablation of any remaining thyroid tissue.

Introduction

In 1984, Carcangiu et al described a thyroid neoplasm whose characteristics placed it between well-differentiated thyroid carcinoma and anaplastic thyroid carcinoma with respect to its morphologic, biologic, and clinical behavior. (1) They called this malignancy insular carcinoma based on its distinct microscopic features. These features include characteristic islands of neoplastic cells (insulae) that have indistinct nucleoli and that are surrounded by hypocellular fibrous tissue. Another characteristic commonly seen in insular carcinoma is necrosis that creates islands of viable cells that surround small vessels and form a peritheliomatous pattern. (1-3) Insular carcinoma has been shown to be thyroglobulin-positive and calcitonin-and carcinoembryonic-antigen-negative. Insular carcinoma also is considered to be identical to the "wuchernde Struma" tumor described by Langhans in 1907. (1,6) This neoplasm has not been found to be rapidly or uniformly fatal, but it has a greater propensity for local and regional recurrence and distant metastatic behavior than do the well-differentiated papillary and follicular carcinomas. (1,4,7,8)

Insular carcinoma has been consistently misdiagnosed. It has often been grouped with either solid or moderately differentiated tumors, and it has been mistaken for anaplastic carcinoma. (1,7) Some authors have recommended that insular carcinoma be classified as a poorly differentiated thyroid tumor that is less aggressive than undifferentiated or anaplastic thyroid carcinoma, while others have suggested that insular carcinoma is an aggressive variant of a well-differentiated thyroid cancer that manifests insular features." (1,2,4,9,10) In several series, (2,8,11,12) authors reviewed archived pathologic specimens that fell into these categories and reclassified them as insular carcinomas based on the histologic criteria established by Carcangiu et al. (1)

Yet even with this reclassification, we found only 260 cases that were previously reported in the literature. (1-29) Because of insular carcinoma's aggressive nature, proper identification has important prognostic and therapeutic significance. In this article, we report a new case of insular carcinoma of the thyroid. We also discuss its behavior, diagnosis, and management, and we report the results of our review of the literature.

Case report

A 56-year-old black woman came to our center with a gradually enlarging neck mass, dysphagia, and dyspnea while lying flat. She reported no history of hoarseness, radiation exposure, thyroid disease, or rapid growth of the mass. Physical examination revealed a markedly enlarged, nodular thyroid gland. Axial computed tomography (CT) with intravenous contrast demonstrated a heterogenously enhancing thyroid that measured 8 cm in its largest dimension as well as areas of central necrosis in the right lobe (figure 1). No enlarged lymph nodes were present.

Surgical exploration revealed an enlarged right thyroid lobe, and a total thyroidectomy was performed (figure 2). No local invasion, adherence, or pathologic adenopathy was apparent. Microscopic examination of the thyroid mass identified areas of poorly differentiated insular carcinoma and characteristic areas of necrosis and peritheliomatous formations (figure 3). Additionally, a well-differentiated component was noted with features that fell into the classification spectrum between follicular carcinoma and the follicular variant of papillary carcinoma.

On immunohistochemical evaluation, the specimen was positive for thyroglobulin and negative for calcitonin, p53, and K167. Electron microscopy detected features that were consistent with poorly differentiated carcinoma: epithelial cells with round nuclei, scattered chromatin, some secondary lysosomes, a dilated rough endoplasmic reticulum, and swollen mitochondria.

A thyroid scan and whole-body survey performed 6 weeks postoperatively detected an increased uptake in the right anterior neck. The patient was treated with 100 mCi of radioactive iodine 131I. A follow-up scan 1 week later showed that a small focus of tissue remained functional in the right anterior neck. The patient was maintained on thyroid hormone replacement therapy and external-beam radiation. Six years later, she exhibited no evidence of disease. However, she was later diagnosed with metastatic disease and was subsequently lost to follow-up.

Results of previous studies

In our review of the literature, we identified 260 cases of insular carcinoma that were described with various degrees of detail in 29 reports. (1-29) The findings discussed here are taken from one or more of these 29 reports.

Patients with insular carcinoma ranged in age from 11 to 86 years, and approximately two-thirds were female (ratio: 2.2 to 1). The most common initial signs were an enlarging neck mass or goiter; dysphagia and dyspnea were common in patients with large lesions. One patient had cervical spinal cord compression and biphasic stridor. (13) Hoarseness was notably absent, although preoperative direct evaluation of vocal fold mobility was reported in only one case. (14) Most patients were euthyroid, and only 7 of 60 (11.7%) had a history of radiation exposure to the neck. (1,4,14,18,28,29)

A small number of patients underwent scintigraphic examination to evaluate thyroid nodules. Radioactive thyroid scans detected a cold nodule in 18 of 23 patients (78.3%) and a hot nodule in 2 of 21 (9.5%). (1,2,4,14,28) Reported rates of regional and distant metastasis present at the initial evaluation ranged from 5 to 52%; overall, metastatic disease was present in 94 of 248 patients (37.9%) (1-14,8, 11-14,16-18,21,22,24,28,29)

When the method of treatment was definitively reported, the most common treatment was total thyroidectomy, which was performed on 81 of 104 patients (77.9%) (1,2,4,8,13,14,17,22,28,29) 131I ablation was performed on 72 of 110 patients (65.5%) who had undergone full or partial removal of their thyroid. (1,2,4,5,8,13,14,17,22,28,29) Only five reports included data on cervical lymph node dissection; in these reports, 13 of 42 patients (31.0%) were treated with this procedure. (1,2,4,24,29) Justin et al found that four of five patients had postoperative 131I localization and that three of the four cases demonstrated extrathyroid localization. (2) Although the percentage of insular carcinomas that localize (131) I sufficiently enough to allow for treatment is not known, 110 of 166 lesions (66.3%) we reviewed were treated with (131) I. (1,2,4,5,8,12,14,18,22,24,28,29)

External-beam radiation was used to treat patients who had invasive, persistent local disease or bony metastases. Recurrences were often local (12/30; 40.0%), but metastases were often found in cervical and mediastinal lymph nodes (25/43; 58.1%), in the lung (21/64; 32.8%), and in bone (13/62; 21.0%). (1,2,4,5,12,24,29)

The degree of follow-up was variable, and 10 of 136 patients (7.4%) were lost to follow-up. At 1 year, 59 of 140 patients (42.1%) were alive and free of disease. (1,2,4,5,8,11,14,17,18,24,29) There were many reports of long-term survivors. Papotti et al reported recurrences in 26 of 63 patients (41.3 %). (8) Thus, insular carcinoma carries a better prognosis than does anaplastic carcinoma, which has a 2-year mortality rate of 100%. (1,15) On the other hand, insular carcinoma is more aggressive than well-differentiated thyroid carcinoma. Across all series and with various lengths of follow-up, 32 of 138 patients (23.2%) with insular carcinoma were reported dead of disease, and 39 of 139 (28.1%) were alive with persistent disease. Lam et al reported that 10-year survival rates were 42% for patients with insular carcinoma, 92% for those with papillary carcinoma, and 80% for those with follicular neoplasms. (12) Rosai et al found that the cause of death from insular carcinoma was usually a distant metastasis. (7 )

Discussion

Insular carcinoma represents a distinct form of thyroid cancer whose clinical behavior falls in the spectrum between that of well-differentiated and anaplastic thyroid carcinoma. (1,8,11,12) In our study, we noted a female preponderance, although Machens et al reported no significant difference between the sexes on univariate analysis when insular carcinoma was compared with noninsular carcinoma. (16) The reported incidence of insular carcinoma in the literature ranges widely, from 0.4 to 10% of all thyroid cancers. (3,8,11,12,17,18)

Histology. Insular carcinoma is characterized histologically by the presence of islands of neoplastic cells surrounded by hypocellular fibrous tissue. (1) Microscopic features common to both follicular and papillary carcinomas are found in insular carcinoma, which explains at least some of the confusion that attends to the diagnosis of these comparatively rare tumors. (11) Justin et al wrote that all insular carcinomas arise from follicular epithelium, and, indeed, most cases manifest a concomitant follicular pattern that can predominate the insular pattern. (2) Even so, the presence of ground-glass nuclei and findings on keratin, staining that are characteristic of papillary carcinoma are not uncommon. (7) Necrosis is also a prominent finding, and both capsular and vascular invasion can be found within these tumors. (1,2)

The diagnosis of insular carcinoma is often elusive because these tumors have been classified as poorly differentiated papillary carcinomas when papillary features are present and as undifferentiated thyroid carcinomas of the small-cell category when papillary features are absent.' Insular carcinoma has also been confused with follicular carcinoma. (1,11) Pilotti et al demonstrated that insular carcinoma is a separate entity from widely invasive follicular carcinoma and is associated with significantly more advanced T and N stages. (11) A multivariate analysis by Machens et al found no significant correlation with extrathyroidal tumor extension or nodal metastasis. (16) Tumors diagnosed as small-cell undifferentiated carcinomas with "compact" architecture were probably insular' carcinomas. (19) Many cases that were classified as undifferentiated have been shown to be lymphomas and medullary carcinomas. (7,15) Electron microscopy has been useful in distinguishing lymphomas from insular carcinomas because lymp homas do not have tight junctions or hemidesmosomal connections. (20)

Diagnosis of insular carcinoma by fine-needle aspiration biopsy has been reported. (3,5,21) A definitive diagnosis might not be feasible with cytologic smears, but fragments of tissue might reveal a characteristic trabecular pattern. (3,5) Smears demonstrate high cellularity, micro-follicle-like structures, low grades of atypia, irregular cohesive cell clusters, trabeculae with poorly outlined cytoplasm, nuclear inclusions and grooving, and cytoplasmic vacuoles that contain thyroglobulin. (14,22,23) The prominent single-cell pattern and atypia found on fineneedle aspiration biopsy suggests a lesion other than a papillary carcinoma; such a pattern and atypia can be differentiated from those seen in anaplastic lesions by the lack of spindle cells and a fewer number of atypical cells. (5,21-23) However, Nguyen and Akin suggested that (1) because insular carcinomas coexist with other thyroid carcinomas (e.g., papillary, follicular, and anaplastic), (2) because they share common cytologic features with microfolli cular neoplasms, and (3) because they have no distinctive cytologic characteristics, cytodiagnosis of insular carcinomas by fine-needle aspiration biopsy can be complicated if a cell sample is obtained from a tumor component other than insular carcinoma. (3) They concluded that the only definitive way to diagnose thyroid insular carcinoma is by histologic examination of the excised tumor.

Immunohistochemical staining of insular carcinomas for thyroglobulin has been uniformly positive. (1,8,17,18,24) The absence of staining for calcitonin, surface and cytoplasm immunoglobulin, and leukocyte common antigen helps differentiate insular carcinomas from medullary carcinomas and malignant lymphomas (table). (4,5)

Genetic factors. It has been reported that a mutation or deletion of the p53 gene is one of the most frequently detected genetic changes seen in human cancers in general, and this genetic alteration is important in thyroid carcinomas. (25) The p53 gene is frequently over-expressed in anaplastic carcinoma and uniformly absent in insular carcinoma. (12) Additionally, mutations in the family of ras genes are found in a high percentage of insular carcinomas and widely invasive follicular carcinomas.

Prognosis. The prognostic significance of insular carcinoma is controversial, and some reports have been conflicting. (8,17) Papotti et al noted that patients whose tumors were 65 to 100% insular carcinoma experienced the same survival rates as did patients whose tumors were 24 to 45% insular carcinoma, even though the former group had a significantly higher percentage of recurrences and distant metastases. (8) Likewise, Ashfaq et al found that patients with predominantly insular carcinoma were as likely to be alive without evidence of disease as were patients whose tumors contained only a minor component of insular carcinoma. (8,17) They added that tumors that had only a minor component of insular carcinoma were just as likely to exhibit regional and distant spread as were tumors that were predominantly insular carcinoma. In their review of 63 cases, Ashfaq et al concluded that insular carcinoma within papillary or follicular carcinoma did not adversely affect the patient's prognosis and that the only signif icant factors that affect the behavior of insular thyroid carcinomas were advanced patient age and the tumor stage at diagnosis. Tumor stage at diagnosis has long been known to affect the prognosis of patients with well-differentiated thyroid carcinomas. (26)

Conversely, other authors have found that insular carcinoma was associated with a worse prognosis than was well-differentiated carcinoma. (12,18) One study found that even small amounts of anaplastic dedifferentiation in a primary tumor or in lymph nodes predicted a fatal outcome. (18) Lam et al made the interesting suggestion that because concomitant well-differentiated thyroid carcinoma is seen in both anaplastic and insular carcinomas and foci of insular carcinoma are seen in anaplastic carcinoma, perhaps there is a progression of dedifferentiation of well-differentiated carcinoma to insular carcinoma to anaplastic carcinoma. (12)

Treatment. As mentioned, our review of the literature determined that the most common treatment for insular thyroid carcinoma was total thyroidectomy with [I.sup.131] ablation of remaining functioning tissue. Justin et al recommended postoperative [I.sup.131] imaging for the early detection of persistent disease or metastasis in order to enhance survival or palliation. (2) However, in their retrospective review of 25 cases, Carcangiu et al reported that neither the extent of the surgical operation nor the prophylactic use of [I.sup.131] altered the course of disease or the rate of cervical or distant metastasis. (1)

External-beam radiation was used in patients with invasive tumors, persistent local disease, or bony metastases. Recurrences were often local, but lung and bony metastases were also common. Typically, the tumor's insular pattern is conserved in recurrences or metastases. (1,3) Occasionally, recurrences of thyroid carcinoma originally typed as papillary carcinoma have displayed an insular pattern. However, it is possible that small foci of insular carcinoma were overlooked in the primary lesion.

Table 1

Immunohistochemical profile of thyroid tumors

                                      Tumor type

                      Insular             Papillary  Follicular
Antibody             carcinoma  Lymphoma  carcinoma  carcinoma

Keratin                  +         -          +          +

Thyroglobulin            +         -          +          +

Calcitonin               -         -          -          -

Carcinoembryonic
 antigen                 +         -         +/-         +

Surface/cytoplasmic
 antigen                 -         +          -          -

Leukocyte common
 antigen                 -         +          -          -

Neuron-specific
 enolase                 -         -          -          -

Chromogranin             -         -          -          -

Synaptophysin            -         -          -          -

                           Tumor type

                     Medullary  Anaplastic
Antibody             carcinoma  carcinoma

Keratin                  +          +

Thyroglobulin           +/-        +/-

Calcitonin               +          -

Carcinoembryonic
 antigen                 +         +/-

Surface/cytoplasmic
 antigen                 -          -

Leukocyte common
 antigen                 -          -

Neuron-specific
 enolase                 +          -

Chromogranin             +          -

Synaptophysin            +          -

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From the Department of Otolaryngology--Head and Neck Surgery (Dr. Cornetta, Mr. Burchard, Dr. Pribitkin, Dr. O'Reilly, and Dr. Keane) and the Department of Pathology (Dr. Palazzo), Jefferson Medical College, Philadelphia.

Reprint requests: Edmund A. Pribitkin, MD, Department of Otolaryngology--Head and Neck Surgery, 925 Chestnut St., 6th Floor, Philadelphia, PA 19107. Phone: [phone]; fax: [phone]; e-mail: [e-mail]