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UNUSUAL TYPES OF THYROID NEOPLASMS
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UNUSUAL TYPES OF THYROID NEOPLASMS Kenneth D. Burman, MD, Matthew D. Ringel, MD, and Leonard Wartofsky, MD
This review describes the clinical diagnosis, presentation, and treatment of several unusual types of thyroid neoplasms. The discussion focuses on the tall cell variant (TCV) of thyroid cancer, insular thyroid cancer, anaplastic thyroid cancer, and lymphoma of the thyroid gland. The clinical entities of Cowden’s syndrome and familial adenomatous polyposis (FAP) also are reviewed as they relate to thyroid neoplasms. We have chosen these disorders because of their importance clinically, and because the ability to recognize these thyroid cancer subtypes or variants may influence patient management and outcome. Unfortunately, long-term prospective controlled studies of these neoplasms do not exist, and, therefore, the clinician must frequently render management decisions without strong literature support. In addition, for several of the tumors discussed, such as the TCV and columnar thyroid cancer, there has been no critical evaluation of either intraobserver or interobserver variation in the ability to recognize these tumors. TALL CELL VARIANT OF PAPILLARY THYROID CANCER
Histologic characterization and identification of the TCV of papillary carcinoma were established by Hawk and Hazzard in 1976.14 Although relatively subjective, the following criteria apply: (1) there must From the Section of Endocrinology (KDB), Department of Medicine (LW), Washington Hospital Center, Washington, DC; the Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda (KDB);and the Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland (MDR) ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA VOLUME 25 * NUMBER 1 MARCH 1996
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be a papillary thyroid cancer (PTC) component in which the cell height is at least twice the width; (2) oxyphilic cells must be present; (3) microfollicles may be formed; and (4) tall cells must encompass at least 30% of the tumor (Fig. 1). It may be difficult to assess whether tall cells are found in more than 30% of the entire tumor, as this observation depends on many factors including the diligence of the pathologist and the number of sections fixed and analyzed. Hawk and H a ~ z a r d believed ’~ that 18 of 197 of their PTCs fulfilled these criteria, and these tumors were labeled as TCV. These patients tended to have large tumors, and the average age of the patients was 57 years. Four of the 18 subjects (22%) died within 7 years of diagnosis. TCV may be confused with Hurthle cell neoplasms, because an oxyphilic cell component may be observed in both tumors. Johnson and cow o r k e r ~compared ~~ patients with TCV with a control group of patients with PTC matched for tumor size, age, sex, and disease duration. Between 1972 and 1986,12 patients were identified with TCV out of more than 300 cases of differentiated thyroid cancer (DTC). The patients with TCV had a mean age of 49.4 years, were predominately female (10 females to 2 males), had an average tumor size of 2.8 cm, and were followed up for 68 months. In comparison, control patients with PTC had an average age of 48.3 years, the identical gender ratio, a tumor size of 2.3 cm, and were followed up for 80 months. Tumor in cervical nodes was found in 9 of 12 patients (75%) with TCV compared with 5 of 12 patients (42%) with PTC. Distant metastases were found in 2 of 12
Figure 1. Tall cell variant of papillary thyroid cancer. Tall cell variant of papillary thyroid cancer is characterized by papillae lined by columnar cells with at least twice the height as width, eosinophilic granular cytoplasm, and predominantly basally located nuclei. Although these criteria are relatively subjective, this tall cell variant does seem to have a poorer prognosis in patients more than age 50 years. In patients fewer than 50 years old, the stage at diagnosis and tumor behavior seems similar to well-differentiated cancer. (Hematoxylin and eosin [H and El,original magnification, x 50.)
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patients (17%) with TCV and in none of 12 patients with PTC, and recurrent disease was identified in 7 of 12 of the TCV group compared with 1 of 12 of the PTC group. Mortality due to the tumor was noted in 3 of 12 patients (25%) with TCV, whereas none of 12 patients with PTC died of thyroid disease during follow-up (mean, 68 months). In the same time period, 7 of 12 patients with TCV had no evidence of disease despite the fact that four of these seven patients had extrathyroidal disease at surgery. It is difficult to define the criteria necessary to identify a tumor variant as inherently possessing a greater tendency toward invasion, metastasis, recurrence, and death, but matching tumors for stage at the time of presentation may be an important variable. Statistical evaluation showed that the frequencies of soft-tissue involvement, tumor recurrence, and metastases were more common for TCV. Tumor size and age greater than 50 years correlated with a higher frequency of death in patients with TCV disease. No differences were found in patients younger than 50 years regarding mortality or returrence rates at the end of the follow-up period. Sobrinho-Simoes and co-~orkers"~ agreed that TCV is associated with a poor prognosis and suggested that mitotic rates were related to invasiveness. Flint and co-workers9compared 11 patients with TCV with eight patients with DTC, these patients were matched for age and sex. There were no significant differences in the two groups; 6 of 11 of the TCV tumors and four of eight of the DTC tumors were aneuploid. Terry and ~ o - w o r k e r sin~ ~a recently published article noted that TCV accounted for approximately 10% of all thyroid papillary cancers. In 19 such tumors, the average tumor size was about 4.2 cm compared with 2.8 cm for customary differentiated PTC. Patients with TCV who were aged more than 50 years had larger tumors (5.6 versus 2.7 cm) and also a higher likelihood of having stage 3 and 4 disease. They also noted increased recurrence rates with TCV when compared with DTC. Specifically, none of six patients aged less than 50 years with tumors less than 4 cm in size had recurrences in the TCV group compared with 1 of 63 patients in the PTC group. Similarly, if the tumor was less than 4 cm and the patients were aged more than 50 years, two of four and 1 of 33 patients had recurrences in the TCV and PTC groups, respectively. Of patients aged less than 50 years with tumors greater than 4 cm, none of two and none of 22 had recurrences in the groups with TCV and PTC, respectively. However, four of five patients aged more than 50 years with TCV had recurrences compared with 2 of 14 patients with PTC. When all of the patients were grouped together, the presence of adenopathy at surgery and multicentricity of tumors did not vary significantly between the TCV and PTC groups. Age was significantly greater in the TCV group, and there was a significantly greater ratio of males with TCV when compared with patients with PTC. Extrathyroidal invasion, vascular invasion, recurrences, and mortality were significantly more frequent in the TCV group. It was concluded that PTC in patients aged more than 50 years and with larger tumors had a significantly worse prognosis than more customary PTC, but these differences in
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clinical outcome seemed to be less important in patients with smaller tumors who were younger. Egea and co-workers8 studied five patients with TCV and noted vascular invasion in two, multicentricity in four, recurrences in four, and metastasis and mortality in one patient. Ain and Merino33 have retrospectively reviewed 25 patients with TCV seen at the National Institutes of Health (NIH) between 1976 and 1990. The reader is referred to Dr. Ain’s article on papillary carcinoma in the preceding issue of Endocrinology and Metabolism Clinics of North America for further detailed information. He reports that 23 patients had extensive disease at the time of initial diagnosis; 32% had local nodal metastasis at the time of surgery. Pulmonary metastasis developed in 36% and bone metastasis in three patients. There was a 16% mortality rate in this group, who were followed up for an average of 5 years with a maximum time interval of 14 years. In our opinion, these earlier studies seem difficult to interpret given the varying time of follow-up, the relatively small number of patients, and the seemingly discrepant outcomes. In an attempt to understand this disease entity better, and realizing that the evaluation period was variable in the patients with TCV, we have summarized the results found in the total number of patients with reported clinical follow-up in the literature thus far, including Dr. Ain’s analysis of 25 new patients with TCV. We found 76 patients with TCV for whom data could be analyzed. We compared the results with that in 1355 patients with DTC recently reported on by Mazzaferri and Jhiang,25with specific attention to stage at presentation and patient outcome by age. Although the mean age of the patients with TCV was greater (53 versus 36 years) and the size of the tumor was relatively larger (3.7 versus 2.5 cm), there were no apparent differences in the frequency of regional invasion (51% versus 50%); the frequency of metastasis was higher (19% versus 2%), and intrathyroidal tumors were less common (30% versus 38%) (Table 1). Clinical outcomes are summarized in Table 2. When all of the patients are combined, those with TCV had higher mortality and a higher rate of recurrent or persistent disease. However, in patients aged less than 50 years, the prognosis seems comparable with that for welldifferentiated thyroid cancer. Our review of the literature suggests that, in comparison with welldifferentiated thyroid cancer, TCV has a worse prognosis in patients Table 1. CLINICAL PRESENTATION OF TCV COMPARED WITH WELLDIFFERENTIATEDTHYROID CARCINOMA Tall Cell Variant ( n = 76) Age (years) Size (cm) lntrathyroidal Regional (neck) Metastases Female
53 3.7 30% 51% 19% 69%
Differential Thyroid Cancer ( n = 1355) 36 2.5 48% 50% 2% 67%
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Table 2. CLINICAL OUTCOMES OF TCV COMPARED WITH WELL-DIFFERENTIATED THYROID CARCINOMA All Patients
Outcomes
Dead Alive with disease Alive without disease
Over Age 50 Years
Differentiated (%) (fl = 1355)
TCV (%) (fl = 19)
42
0 29
26 42
29
63
32
TCV (%) (n = 76) 29
Under Age 50 Years TCV (%) (n = 14)
Differentiated (%) ( n = 1133)
23
0 21
2 21
58
79
77
Differentiated (fl
(“h) = 222) 19
older than 50 years. These patients often present with large, more advanced tumors. In patients aged less than 50 years, the stage at diagnosis and tumor behavior appear similar to that with well-differentiated cancer, with the caveat of a much shorter reported follow-up period and no standardized treatment regimen. These tumors tend to concentrate radioiodine and respond to thyrotropin as a growth factor, and, when possible, the use of radioiodine therapy and thyroid-stimulating hormone (TSH) suppression is encouraged. Further studies will help to clarify the clinical characteristics and outcomes of the TCV. INSULAR THYROID CANCER
Insular thyroid cancer, originally described as “Wuchernde struma” by LanghansZ0in 1907, represents approximately 5% of all thyroid cancers. This entity was renamed insular thyroid cancer in 1984 by Carcangiu and colleagues.5Histologically, the tumor has solid clusters of tumor cells with small follicles that resemble pancreatic islet cells; these cells stain positively with thyroglobulin antibodies but do not stain with calcitonin antibodies (Fig. 2). At the time of diagnosis, there usually is vascular and capsular invasion, frequently accompanied by necrotic foci; insular thyroid cancer also may be seen to a variable extent in typical papillary or follicular thyroid cancer. To date, there are 141 cases of insular thyroid carcinoma published in the world literature. In 1984, Carcangia and colleagues5 reported 25 cases of histopathologically defined insular thyroid cancer (8 men, 17 women). The average age was 55 years and the follow-up period 1 to 8 years (average, 3.5 years). Tumor size at surgery was about 4 cm. At presentation, 10 of 25 patients (40%) had intrathyroidal disease; 11 of 25 (44%) had regional spread, and 4 of 25 (16%) had metastatic disease. In terms of outcome, 11 of 25 patients (44%) died of disease; 7 of 25 (28%) were alive with disease, and 4 of 25 (16%) had no evidence of disease (when analyzed at follow-up; mean, 3.5 years). Three of 25 patients (12%) died of non-cancer-related causes with their disease. Three of four patients who presented with metastasis died of disease. It was appropriately concluded that insular thyroid cancer is a very aggressive variety of thyroid cancer.
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Figure 2. Insular thyroid cancer. Insular thyroid cancer is typically characterized by infiltrating sheets and nests of cohesive cells without evidence of either follicular or papillary differentiation. Insular thyroid cancer seems to have a poorer prognosis than differentiated thyroid cancer, including a higher recurrence rate and, in all likelihood, a higher mortality. A tumor that contains only a minor component of insular carcinoma in an otherwise welldifferentiated tumor is probably not associated with an adverse outcome. (Hand E, original magnification, x 50)
Ashfaq and co-workers' recently published a study of 41 patients with insular thyroid cancer with a male-to-female ratio of 1:1.6. Average age was 52 years; follow-up period was 1 to 12 years, with an average of 4 years. Interestingly, the prognosis seemed comparable regardless of the extent of the insular component in the histologic specimen. Increased age was predictive of tumor recurrence. At presentation, there were intrathyroidal metastases in 15 of 37 patients in whom clinical data were reported (41%). Regional invasion was found in 13 of 37 (%YO), and metastatic disease in 9 of 37 (24%). In terms of outcome, 5 of 28 patients (18%) were dead of disease, 6 of 28 (21%) alive with disease, and 14 of 28 (50%) had no evidence of disease. Three of 28 (11Y0) died of other causes with their disease. Follow-up data were not reported in nine patients. When insular cancer was located within follicular or PTC, the clinical outcome of the well-differentiated component did not seem to be adversely influenced. Papotti and co-workersz9studied 63 persons with thyroid cancer. Eighteen were male and 45 female. Average age was 55 years, and the follow-up evaluation period ranged from 3 months to 16 years, with an average of about 4.6 years. Average tumor size was 5.9 cm. A total of 31 subjects had insular thyroid cancer as the major component of the tumor, and the remaining 32 patients had DTC (follicular with minor insular component). The only difference between patients with a minor insular component ( n = 32) and those with a tumor that was mainly insular cancer was a higher tumor recurrence rate in the latter. At presentation, 46 of 62 patients (74%) were free of disease following thyroidectomy, and 16 of 62 (26%) had metastasis at the time of surgery.
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Ten patients with metastatic or recurrent disease were treated with 1-131 after surgery and followed up for 4 to 15 years (average, 8 years). Two of ten patients had no evidence of disease, four of ten were alive with disease, and the remaining four of ten died of disease at an average time of 7 years' follow-up. None of the tumors proved fatal within 6 months, and most seemed to respond to 1-131 therapy. Although there were no differences in survival, insular thyroid cancer was associated with a higher recurrence rate and an increased frequency of distant metastases. In an effort to compare the characteristics of insular thyroid cancer with those of DTC, we reviewed the literature and compiled Table 3. We again utilized the recently published work of Mazzaferri and JhiangZ5 to provide comparison data for DTC, again noting the shorter follow-up time and variable therapies in the insular carcinoma group. In analyzing stage 4 metastatic disease, 9 of 15 patients (60%) with insular thyroid cancer died with disease (at 0-15 years) compared with 65% with differentiated cancer (at 30 years). In the group with insular cancer, 3 of 15 patients (20%) were alive with disease, and 3 of 15 (20%) were alive without evidence of disease. A total of 39 of the 77 patients with insular cancer (51%) thought to be cured at surgery had a recurrence of tumor, whereas patients with DTC with stage 1 to 3 disease had a combined recurrence rate of 21% (stage 3 was associated with a rate of 26%). Justin and colleagues17reported on five cases and reviewed the ability of insular carcinomas to concentrate radioactive iodine. Each of these five patients had a large neck mass; one had local invasion, one had vascular invasion, and one had tracheal invasion. Radioiodine screening detected thyroid tissue in the neck bed and humerus area in the patient with vascular invasion; it showed cervical node uptake in the patient with tracheal invasion and neck bed concentration in a patient without known invasion. It is a complex issue to analyze and make clinically relevant comparisons regarding the behavior of insular thyroid cancer and more customary DTC, especially considering the difficulty in controlling for size of tumor and age of onset. Nevertheless, insular thyroid cancer appears to have a worse prognosis than DTC, including a higher recurrence rate and, in all likelihood, a higher mortality. Most tumors concentrate radioTable 3. COMPARISON OF CHARACTERISTICS OF INSULAR THYROID CANCER AND DIFFERENTIATED THYROID CANCER Presentation Insular Age (yr) Size (crn) lntrathyroid Regional (neck) Metastases
Differentiated 36 2.5 48%
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4.7 38% 36% 26%
DOD = dead of disease; AWD died with disease.
Outcome
50% 2% =
alive with disease; NED
Insular
Differentiated
DOD 25% AWD 29% NED 41% DWD 5%
8% 29% 63%
=
-
no evidence of disease; DWD
=
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iodine, supporting this modality of therapy as possibly effective, even for patients with metastatic disease. When analyzed at 5 years, there may be a 20% cure rate for adults with stage 4 insular thyroid cancer. Apparently, in an otherwise well-differentiated tumor, having a minor component showing insular carcinoma does not adversely influence outcome. SQUAMOUS CELL CARCINOMA
In endocrine textbooks, thyroid cancer is classically divided into papillary, follicular, medullary, and anaplastic, with thyroid lymphomas being prominently mentioned.24However, primary squamous cell carcinoma of the thyroid gland also is an important variant (Fig. 3). This disease accounts for approximately 1% of thyroid cancers, but it possesses unique clinical and biochemical characteristics that should be recognized. Once again, there are scant numbers of case reports of this entity and a lack of large-scale studies that have been reported and analyzed. This section discusses several of these case studies and emphasizes important or relevant aspects. Riddle and D i n ~ s o ydescribed ~~ a 66-year-old woman with primary squamous cell carcinoma of the thyroid. Frequently, this tumor occurs in elderly males with a long history of a goiter. This particular patient had a large goiter with dyspnea and chest pain; bilateral cervical adenopathy was present. The white blood cell count was 28,400/mm3 with 84%
Figure 3. Squamous cell thyroid cancer. This squamous cell thyroid cancer displays infiltrating nests of cohesive polygonal cells. Within the center of these nests are eosinophilic cells with keratinization. This tumor can be associated with a systemic syndrome characterized by leukocytosis, hypercalcemia, and fever, possibly mediated by colonystimulating factor or interleukin 1. (Original magnification, x 50)
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polymorphonuclear lymphocytes; serum calcium was elevated to 13 mg/dL; T3, T4, and TSH were normal. Chest radiography showed bilateral interstitial edema and nodular densities. At autopsy, the thyroid weighed 450 g, and histology showed a moderately differentiated squamous cell carcinoma with keratin pearl formation, necrotic areas, and giant and spindle cells. The larynx, trachea, hyoid, esophagus, and submandibular glands were normal on extensive sectioning. This case report illustrates the rapid clinical course of this disease-3 months in this patient. The precise cellular source of this tumor has been under considerable debate, as the presence of squamous cells within the thyroid gland is controversial. Squamous metaplasia of follicular epithelium of the thyroid does occur, especially in patients with chronic thyroid disease. Furthermore, squamous cell thyroid carcinoma has been described in remnant thyroid tissue, for example, a thyroglossal duct cyst.26It is likely that malignant transformation of benign metaplastic squamous cells arising from the thyroid is the histologic basis for squamous cell carcinoma of the thyroid. Patients with squamous cell carcinoma of the thyroid may present with systemic symptoms of hypercalcemia, fever, and leukocytosis as 21, 28, 32, 34, 35, 37 This exemplified in case reports described previ~usly.~, thyroid tumor has been successfully transplanted into athymic nude mice and resulted in leukocytosis and hypercalcemia. It was believed that colony-stimulating factor and interleukin 1-alpha had a role in mediating the leukocytosis and hypercalcemia, as the injection of interleukin 1 antibodies in these mice decreased thymocyte proliferation and bone resorption.28,34, 35 Furthermore, the tumor did not stain with parathyroid hormone antiserum, suggesting that nonparathyroid-mediated mechanisms are involved in the hypercalcemia. Harada and c o - ~ o r k e r s studied ’~ eight thyroid glands at autopsy obtained from patients with squamous cell carcinoma of the thyroid. Several of these patients were treated with bleomycin or external radiation or both to no avail. Histologically, all eight of these cases showed a major component in which squamous cell carcinoma of the thyroid was predominant, whereas, elsewhere in the tumor, there was primarily PTC. In addition, there was a third broad area of overlap and transition. Histologic examination of the metastases could demonstrate any of these patterns. Tumor metastases usually occurred in the lungs, nodes, liver, or mediastinums, in some cases, there was extensive local invasion. The mean age at diagnosis was 66 years. Half of the patients were male. Four of seven patients had soft-tissue calcification on radiography. Mucin staining in adenocarcinoma can help differentiate it from squamous cell carcinoma of the thyroid, although some believe that there are no squamous cells in the normal thyroid gland. Squamous metaplasia, if present, could represent a transition stage to squamous cell carcinoma of the thyroid. Klinck and Menkl* at the Armed Forces Institute of Pathology suggest that this mechanism is unlikely, because no other tissue or organ has been documented to show the transition of squamous metaplasia into squamous cell carcinoma, although they did
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identify thyroidal squamous cells in a wide variety of conditions, including DTC, thyroiditis, and Riedel’s struma. In a study of squamous cell carcinomas Harada and colleague^^^ did not find any areas of squamous metaplasia, whereas they identified 19 instances of squamous metaplasia in 480 cases of thyroid adenocarcinoma. The relationship between squamous cell carcinoma of the thyroid and therapy for other medical conditions has been evaluated. Bakri and co-workers2 described one patient who underwent x-ray therapy for Hodgkin’s disease and in whom 48 years later squamous cell carcinoma of the thyroid developed. Penn and First30observed patients after transplantation. A total of 2511 malignancies arose after transplantation in 2347 patients; 88 tumors developed after cyclosporine therapy. Although no pathophysiologic link between this agent and the development of squamous cell carcinoma of the thyroid has been established, this tumor developed in one patient. Diagnostic radioiodine scans of patients with squamous cell carcinoma of the thyroid show either a cold nodule or, surprisingly in some instances, a functional area. Gallium 67 does not concentrate well in differentiated adenocarcinoma but may do so in patients with squamous cell carcinoma of the thyroid and may be helpful in monitoring disease recurrence. Simpson and car rut her^^^ reported 17 cases of squamous cell carcinoma of the thyroid in 2214 patients with thyroid malignancy (0.8%). Between 1977 and 1984, they found eight cases of squamous cell carcinoma of the thyroid; only two patients were considered to have undergone a reasonably complete resection. X-ray therapy was given to six patients, and one received 5-fluorouracil and mitomycin C. The two patients who had surgical completions were alive 4 years after operation, whereas each of the other patients had died. Lee and co-workersZ1also reported on one patient who was alive several years after operations. These results suggest that complete surgical resection of tumor mass represents the best chance for cure. Radioiodine and thyroid hormone suppression are probably less helpful in patients with this neoplasm, but, in selected instances, it may be reasonable to perform a diagnostic radioiodine neck and chest scan and to determine the potential avidity of the tumor for radioiodine.* Squamous cell carcinoma of the thyroid is a rare disorder, that is most frequently observed in older patients with a history of thyroid gland enlargement. Metastasis to the thyroid from another site (e.g., lung, upper respiratory tract) must be excluded. It is usually a rapidly progressive malignancy with a predilection for local invasion and metastasis; early detection and extensive surgery represent the best chance for palliation and cure. It is speculated that squamous cell carcinoma of the thyroid may arise more frequently in a thyroid gland that has been exposed to radiation. The precise pathophysiologic mechanism by which squamous cell carcinoma of the thyroid arises has not been defined, but it is possible that it may arise from cellular transformation from squa“References2, 4, 13, 18, 21, 26, 28, 30, 32, 34, and 37.
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mous metaplasia. Squamous cell carcinoma of the thyroid usually is associated with a distinct clinical syndrome characterized by leukocytosis and hypercalcemia, probably mediated by the production and secretion of colony-stimulating factor and interleukin 1. Patients presenting with a thyroid nodule and these associated clinical parameters should be evaluated for squamous cell carcinoma of the thyroid gland. The finding of squamous cell carcinoma on biopsy or histology should prompt consideration of whether this tumor represents metastasis to the thyroid gland from another site or is primarily originating within the thyroid gland. COWDEN'S SYNDROME
Although not strictly considered an unusual cause of thyroid cancer, Cowden's syndrome deserves to be mentioned because of its coincidence with thyroid carcinoma, because of the recent developments in our understanding of the clinical manifestations of this syndrome, and because of the relevance to early clinical diagnosis. Cowden's syndrome is characterized by multiple mucocutaneous hamartomas, keratoses, and fibrocystic disease of the breast. In a study by Starink and co-workers,4" mucocutaneous hamartomas were found in each of 21 patients, most commonly on the face (Fig. 4).The keratoses are most prominent on the hands, feet, and mouth. Many of these lesions are actually trichilemmomas. Perhaps the most serious associated abnormalities are fibrocystic disease or cancer of the breast and gastrointestinal polyps. Skeletal and facial abnormalities and mucocutaneous neuromas and neurofibromas also may be present. Serum calcitonin and chromogranin A may be elevated, reflecting, perhaps, the Merkel cell origin of the tumors that are found throughout the body rather than the coexistence of medullary thyroid carcinoma. The most commonly associated thyroid cancer is well-differentiated thyroid cancer. Haibach and colleagues" reviewed the literature on Cowden's syndrome and found that 8 of 26 patients had thyroid carcinoma. Very little is known about the pathologic characteristics and the clinical aggressiveness of the thyroid carcinoma associated with Cowden's syndrome, but patients with this syndrome should be carefully evaluated for thyroid nodules. FAMILIAL ADENOMATOUS POLYPOSIS (GARDNER'S SYNDROME)
Familial adenomatous polyposis is a syndrome consisting of multiple adenomatous polyps frequently in conjunction with osteomas, epidermoid cysts, desmoid tumors, retinal pigmentation, and, more rarely, with adenomas in the upper gastrointestinal tract and pancreas and hepatobla~tomas.~ The disease is inherited as an autosomal dominant disorder, although there are isolated or sporadic cases as well. In their
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Figure 4. Facial lesions in a typical patient with Cowden’s disease. Multiple small papular lesions are observed in the temporal region and on the eyelids and nose (A), and gingivae (6).(From Carlson HE, et al: Cowden’s disease: Gene marker studies and measurements of epidermal growth factor. Am J Hum Genet 38:908-917, 1986; with permission.)
review, Bell and Mazzaferri3 documented the association of FAP with thyroid carcinoma. Plail and c o - w ~ r k e r sbelieved ~~ that the risk of thyroid cancer in young female patients may be enhanced about 160 times when compared with normal subjects. Bell and Mazzaferri3 found 37 reported cases of thyroid cancer in patients with FAP; 26 were PTC (88%), and the remaining 12% were follicular thyroid cancer. There were markedly more females than males with thyroid cancer (94% female, 6% male). Interestingly, the thyroid cancer appeared at a relatively young age, with patients averaging 23 years in age, and was diagnosed before the recognition of FAP in 30% of patients. Histologically, the thyroid tumors were frequently multicentric, and, in other patients with PTC, this represents a significant risk of tumor recurrence. The thyroid tumor
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seemed to have relatively low aggressiveness, as 4% of patients had distant metastases and local nodal disease was found in only 1 of the 37 patients. The average follow-up time was 7.2 years in 21 patients. More information relative to the nature and aggressiveness of the thyroid cancer that occurs in association with FAP needs to be obtained. Currently, however, it is important clinically to recognize this association and to perform appropriate studies, such as thyroid biopsies, sonograms, and scans, in patients with known FAP. If there is a dominant nodule that can be aspirated, this should be performed, but it is slightly more difficult to interpret a benign result because the thyroid cancer may be multicentric. Close clinical observation for neoplasia in the thyroid gland in patients who have a personal or family history of FAP is important. Conversely, clinical follow-up including questioning for a family or personal history of gastrointestinal polyps, bleeding, or cancer in patients who have had thyroid cancer, particularly if it presented at an early age, is appropriate. It is unknown whether patients with PTC should have earlier or more frequent examinations, sigmoidoscopy, or examinations for stooI blood than the general population or what the effect would be on clinical outcome or cost effectiveness. ANAPLASTIC THYROID CANCER
Anaplastic carcinoma is the most aggressive type of thyroid cancer. This disease occurs more frequently in older individuals and usually presents as a rapidly enlarging thyroid or neck mass in association with dysphagia, neck tenderness, and, occasionally, superior vena cava syndrome. Lampertico19has suggested that there has been a three- to four-fold decrease in reported cases of anaplastic cancer compared with several decades earlier, although the aggressive nature of the disease has not seemed to change. Virtually all patients with anaplastic cancer die from the progression of this tumor. Histologically, anaplastic cancer invades locally but may also metastasize distantly. Upon microscopic examination, there are giant cells, intranuclear cytoplasmic invaginations, and usually residual elements of more differentiated thyroid cancer (Fig. 5). It is suspected, but not proven, that anaplastic thyroid cancer arises or evolves from DTC, and it is hypothesized that prior radioiodine therapy may have a role in this process. Radioiodine therapy does not help in this tumor as the anaplastic cells do not concentrate radioiodine. Levendag and retrospectively reviewed 51 patients with anaplastic thyroid cancer who were treated with external beam radiation therapy in the presence or absence of adjunctive chemotherapy. Metastases without significant local invasion were associated with a median survival of 7.5 months, whereas patients with local disease had a mean survival of 1.6 months. External beam radiation in conjunction with Adriamycin did not seem to be effective, and the most appropriate therapy rests with early diagnosis and aggressive surgical management.
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Figure 5. Anaplastic thyroid cancer. This tumor consists of pleomorphic spindle cells containing hyperchromatic nuclei. The portion of the tumor shown contains numerous dispersed multinucleated giant cells. In contrast with the undifferentiated insular type, the cells show increased pleomorphism and a more haphazard pattern. Anaplastic thyroid cancer is associated with a very poor prognosis. (H and E, original magnification x 20.)
Nicolosi and co-workersZ7studied 19 patients, average age 66 years, with anaplastic thyroid carcinoma. Four patients had disease presenting as an intrathyroidal mass, 11 had local infiltration, and four had distant metastases. Seven subjects had a history of thyroid enlargement. All of the patients with anaplastic thyroid carcinoma received external radiation therapy, and the median survival was 6 months. Thyroidectomy or only diagnostic thyroid biopsy did not seem to alter prognosis when combined with external radiation therapy. Eleven of the 12 subjects died of disease, and one was alive at 120 months of follow-up. Junor and colleagues16reported on 91 patients with anaplastic thyroid cancer. The female-to-male ratio was 2.4:1, and the median age was 70 years with a range of 38 to 92 years. Presenting symptoms commonly included an enlarging thyroid mass, dyspnea, dysphagia, or dysphonia. Their review showed that a partial thyroidectomy was performed in 31% of patients ( n = 28) and a total resection in 5% (n = 5); 63% underwent a biopsy without further surgical approach. A total of 86 patients received further therapy in addition to surgery or biopsy, and 18 (21%) also received adjunctive chemotherapy. The overall survival was poor, as the average length of survival was 21 weeks with 45% alive at 6 months; 32% survived for 9 months, and 11%survived for 3 years. In contrast to the earlier mentioned studies, 60% of patients seemed to respond to radiation therapy, and it was concluded that a thyroidectomy was associated with enhanced survival. Additional chemotherapy did not appear to increase survival. Hadar and co-workersl0 found comparable results; only 28% of 48 patients with anaplastic thyroid cancer were alive 2 years after the diagnosis.
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It is difficult to make conclusions from these studies as they are generally retrospective in nature and contain relatively few patients; there are no controlled studies. Nevertheless, it seems that a thorough discussion with the patient and his or her family is indicated to arrive at a mutually conceived treatment plan. If all other factors are equal, it is reasonable to perform a total thyroidectomy with surgical removable of local lymph nodes and mass lesions, followed by external radiation therapy and chemotherapy, but it is not possible to prove that this approach will prolong survival and decrease morbidity. LYMPHOMA
Primary thyroid lymphoma represents a distinct entity that has recently been recognized more frequently (Fig. 6). Matsuzuka et alZ3 reviewed their institutional experience with 119 cases of thyroid lymphoma seen during a 27-year period. Thirty-three patients were men, and 68 were women. The average age was 60 years with a range of 26 to 82 years. They could find no significant association of the development of thyroid lymphoma with a prior history of head and neck irradiation or with HIV infection. The presenting signs or symptoms of patients with thyroid lymphoma included the presence of a goiter (100%), recent rapid growth of a goiter (78%), hoarseness (13%), dysphagia (7%), and fever (7%).Positive serum antimicrosomal and thyroglobulin antibody titers, were found in 68% and 34% of patients respectively, and every patient had histologic evidence of Hashimoto’s thyroiditis in
Figure 6. Primary lymphoma of the thyroid. This tumor is characterized by a diffuse infiltrate of monotonous, atypical lymphocytes with extensive obliteration of thyroid architecture. The presence of lymphoma cells within a follicle is typically observed. This tumor also frequently arises from or is associated with the presence of Hashimoto’s thyroiditis. (H and E, original magnification x 70)
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peritumor tissue. Fifty-eight percent of patients were euthyroid, 14% were clinically hypothyroid, and an additional 27% had subclinical hypothyroidism. The preoperative diagnostic evaluation of patients with suspected thyroid lymphoma remains difficult and controversial. Although not universally accepted, Matsuzuka and c o - ~ o r k e r sbelieve ~~ that ultrasound examination can suggest the presence of thyroid lymphoma. Ninety-three percent of the patients with this tumor had what these investigators called a ”pseudocystic pattern,” which was found in only 11% of patients with Hashimoto’s thyroiditis alone. It was suggested that fine-needle aspiration of the thyroid gland was helpful if obtained from these cystic areas, even without flow cytometry for monoclonality. Of 83 patients with thyroid lymphoma who had fine-needle aspiration, 65 (78%)were accurately diagnosed, 10 subjects (12%) had indeterminate or borderline results, and 8 patients (9.6%)had results that were read as benign or had no evidence of malignancy. As a result of their experience, Matsuzuka and colleagues do not believe, as has been suggested previously, that large-bore needle biopsies need to be routinely employed to diagnose thyroid lymphoma. They suggest that, in rare instances of borderline fine-needle results, an open core biopsy may be indicated. Although Matsuzuka did not need to employ immunotyping to make the diagnosis, others have suggested that flow cytometry, even when obtained from a fine-needle aspiration, can be very helpful, as there is a clonal proliferation rather than a heterogeneous cell population as observed in Hashimoto’s thyroiditis. The treatment of patients with thyroid lymphoma is controversial. In Matsuzuka’s the cause-specific mortality rate was 35% before the advent of fine-needle aspiration and decreased to 5% after the institution of this procedure, although, of course, there have also been concomitant advances in the use of chemotherapy. It was suggested that combined external radiation and adjuvant chemotherapy with six courses of CHOP (cyclophosphamide, Adriamycin, vincristine, Adriamycin, and prednisolone) resulted in 100% survival at 8 years. This group of subjects contained 16 individuals who had not undergone a thyroidectomy and who had stage 2 lymphoma. The results in Matsuzuka’s study are better than those reported earlier. Survival rates have ranged from approximately 30% to 80%.6,7, 36, 3R, 41, 43 Although these reports usually included a thyroidectomy in addition to radiotherapy and chemotherapy, the studies vary in how extensively they used contemporary techniques of diagnosis and chemotherapy and also in the ability to diagnose stage 3 or 4 disease. Currently, the most important elements of approach include early suspicion and diagnosis, with rapid institution of therapy. Although our own approach may be controversial, if one is suspicious for thyroid lymphoma, we suggest a fine-needle aspiration with cytologic analysis and performance of flow cytometry with immunotyping for monoclonality. Further preoperative assessment may include neck, chest, and abdominal CT scan or MR imaging and, on occasion, a gallium scan which may be able to
UNUSUAL TYPES OF THYROID NEOPLASMS
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suggest lymphomatous deposits both within the thyroid and extrathy roidally. We generally recommend a near-total thyroidectomy if technically feasible, especially if the results of fine-needle aspiration are unclear. This approach allows not only determination of the extent of cervical involvement with lymphoma but also removal of the majority of abnormal tissue. In experienced hands, we believe the potential adverse effects of a near-total thyroidectomy may not be significantly higher than that of a core biopsy, and that the procedure is more likely to render a definitive and representative diagnosis. In some instances, the thyroidectomy can easily be performed, whereas, in others, the tumorous involvement is such that there is extensive fibrosis. Analysis of the surgical options with consideration of the potential benefits and adverse effects must be made by a surgeon experienced in this area and discussed candidly with the patient and his or her family. As described by Matsuz~ka?~ after surgery and a histologic diagnosis, the first course of CHOP therapy is given, followed by external radiation (total dose, 40 to 60 Gy) and then the remaining five courses of chemotherapy. Doria and co-workers7analyzed a total of 211 reported subjects and 11 patients seen at their institution. They noted the potential problems in analyzing such literature, such as varying diagnostic procedures and changes in chemotherapy and external radiation procedures. Approximately 30% of patients with stage 1E and IIE disease had distant relapse, and their review suggests that combined external radiation with adjuvant chemotherapy was most likely beneficial in patients with thyroid lymphoma. Skarsgard and co-workers3*reviewed the records of 27 patients with thyroid lymphoma (stage I and 11) and agreed that combined external radiation therapy and chemotherapy improved survival. They did not believe a total thyroidectomy was necessary and that an incisional biopsy would suffice. Improved survival was associated with the absence of dysphagia at presentation, a primary thyroid tumor less than 10 cm, restriction of disease to within the thyroid gland, and the lack of mediastinal involvement. Histologic diagnosis, whether highgrade or intermediate cellular characteristics, did not correlate with overall survival. Earlier in 1983, Hamburger and co-workers’2reviewed their experience with 30 patients with primary thyroid lymphoma. Their clinical findings were comparable with those we have reviewed; 13 of 30 subjects were aged more than 60 years, 12 had hypothyroidism, and 24 had coexistent Hashimoto’s thyroiditis. In findings somewhat different from that in other reports, 19 of 30 subjects presented with a solitary or dominant thyroid nodule. Thyroid lymphoma is commonly observed in a background of autoimmune thyroiditis. Early clinical suspicion and diagnosis followed by prompt multimodality treatment results in higher cure rates. Clinically, attention should be paid to patients with chronic Hashimoto’s thyroiditis with high-titer antithyroid antibodies, especially if the thyroid gland is enlarging and local symptoms are present, such as tenderness, dysphagia, hoarseness, and fever.
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SUMMARY
This article discusses several unusual forms of primary thyroid neoplasms. The TCV of PTC and insular thryoid carcinoma appears to have a more aggressive clinical behavior than DTC in most patient groups and may respond to thyroid hormone suppression and radioiodine. Anaplastic thyroid carcinoma, which may develop from differentiated thyroid tumors, has a poor prognosis which may be altered by surgery and radiation therapy but not typically by radioiodine and thyroid hormone suppression. Primary squamous cell carcinoma of the thyroid is an unusual entity that may be associated with a clinical syndrome that includes leukocytosis, fever, and hypercalcemia. Primary thyroid lymphoma is frequently associated with Hashimoto’s thyroiditis and should be considered especially in older patients with rapidly enlarging thyroid masses. Although there are no studies assessing this issue, it seems reasonable that patients who have undergone thyroidectomy for neoplasms of thyroid cells that are poorly differentiated and do not concentrate radioiodine (e.g., squamous cell, anaplastic) should receive sufficient thyroid hormone suppression, if tolerated, to reduce TSH (third-generation assay) to approximately 0.1 to 0.3 pU/mL, because TSH may be a growth factor. If, however, the tumor concentrates or responds to radioiodine, suggesting more differentiated cells (e.g., TCV, insular carcinoma), the target TSH level (third-generation assay) should range from 0.01 to 0.1 pU/mL, as tolerated. Patients with primary thyroid neoplasms arising from cells other than thyrocytes (e.g., lymphoma) can be maintained at a TSH level of 0.5 to 1.5 FU/mL. Our conclusions and analyses are often based upon small, retrospective, poorly controlled reports, and further studies are required to allow a better understanding of the evaluation and treatment of these neoplasms. ACKNOWLEDGMENTS The authors are grateful to Dr. Barry Shmookler, who reviewed the pathologic material, Dr. James Oertel, who provided the slides and their interpretation, and Dr. Harold Carlson, who provided the photographs of the patient with Cowden’s syndrome.
References Ashfaq R, Vuitch F, Delgado R, et a1 Papillary and follicular thyroid carcinomas with an insular component. Cancer 73:416, 1994 Bakri K, Shimaoka K, Rao U, et al: Adenosquamous carcinoma of the thyroid after radiotherapy for Hodgkin’s disease. Cancer 52:465-470, 1983 Bell 8, Mazzaferri EL: Familial adenomatous polyposis (Gardner’s syndrome) and thyroid carcinoma: A case report and review of the literature. Dig Dis Sci,38:185-190, 1993 Budd DC, Fink DL, Rashti MY, et al: Squamous cell carcinoma of the thyroid. J Med SOCNJ 79:838, 1982
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5. Carcangiu ML, Zampi G, Rosai J: Poorly differentiated (”insular”) thyroid carcinoma: A reinterpretation Langhans’ “Wuchernde Struma.” Am J Surg Pathol 8:655, 1984 6. Devine RM, Edis AJ, Banks PM: Primary lymphoma of the thyroid: A review of the Mayo Clinic experience through 1978. World J Surg 5:33, 1981 7. Doria R, Jekel JF, Cooper D Thyroid lymphoma: The case for combined modality therapy. Cancer 73:20&206, 1994 8. Egea Moreno A, Rodriguez Gonzalez JM, Sola Perez J, et al: Prognostic value of the tall cell variety of papillary cancer of the thyroid. Eur J Surg Oncol 19:517-521, 1993 9. Flint A, Davenport RD, Lloyd RV The tall cell variant of papillary thyroid carcinoma of the thyroid gland: Comparison with the common form of papillary carcinoma by DNA and morphometric analysis. Arch Pathol Lab Med 115:169-171, 1991 10. Hadar T, Mor C, Shvero J, et al: Anaplastic carcinoma of the thyroid. Eur J Surg Oncol 19:511-516, 1993 11. Haibach H, Burman TW, Carlson HE, et al: Multiple hamartoma syndrome (Cowden’s disease) associated with renal cell carcinoma and primary neuroendocrine carcinoma of the skin (Merkel cell carcinoma). Am J Clin Pathol 97705-712, 1992 12. Hamburger JI, Miller JM, Kini SR Lymphoma of the thyroid. Ann Intern Med 99:685693, 1983 13. Harada T, Shimaoka K, Yakumaru K, et al: Squamous cell carcinoma of the thyroid gland-transition from adenocarcinoma. J Surg Oncol 19:3643, 1982 14. Hawk WA, Hazzard JB: The many appearances of papillary carcinoma of the thyroid. Cleveland Clin Q 43:207, 1976 15. Johnson TL, Lloyd RV, Thompson NW, et al: Prognostic implications of the tall cell variant of papillary thyroid carcinoma. Am J Surg Pathol 12:22, 1988 16. Junor EJ, Paul J, Reed NS: Anaplastic thyroid carcinoma: 91 patients treated by surgery and radiotherapy. Eur J Surg Oncol 18:83-88, 1992 17. Justin EP, Seabold JE, Robinson RA, et al: Insular carcinoma: A distinct thyroid carcinoma with associated iodine-131 localization. J Nucl Med 32:1363, 1992 18. Klinck GH, Menk K F Squamous cells in the thyroid gland. Mil Surg 109:406, 1951 19. Lampertico P: Anaplastic (sarcomatoid) carcinoma of the thyroid gland. Semin Diagn Pathol 10259-168, 1993 20. Langhans T Uber die epithelialen Formen der malignen Struma. Virchows Arch (Pathol Anat) 385:125, 1907 21. Lee JR, Vohman MD, Pendergast WJ: Squamous cell carcinoma of the thyroid gland. J Med Assoc Ga 69:755, 1980 22. Levendag PC, De Porre PM, van Putten WL: Anaplastic carcinoma of the thyroid gland treated by radiation therapy. Lnt J Radiat Oncol Biol Phys 26:125-128, 1993 23. Matsuzuka F, Miyauchi A, Katayama S, et al: Clinical aspects of primary thyroid lymphoma: Diagnosis and treatment based on our experience of 119 cases. Thyroid 3193-99, 1993 24. Mazzaferri E L Thyroid Cancer. In Becker KL (ed): Principles and Practice of Endocrinology and Metabolism, ed 2. Philadelphia, JB Lippincott, 1995, p 354 25. Mazzaferri EL, Jhiang SM: Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97418, 1994 26. Mobini J, Krouse TB, Klinghoffer J F Squamous cell carcinoma arising in a thyroglossal duct cyst. Am Surg 40:290, 1974 27. Nicolosi A, Addis E, Massidda B, et a1 Anaplastic carcinoma of the thyroid: Our experience. Minerva Chir 47:1161, 1992 28. Okabe T, Nomura H, Oshawa N: Establishment and characterization of a human colony-stimulating factor-producing cell line from a squamous cell carcinoma of the thyroid gland. J Natl Cancer Inst 69:1235-1241, 1982 29. Papotti M, Botto Micca F, Favero A, et al: Poorly differentiated thyroid carcinomas with primordial cell component A group of aggressive lesions sharing insular, trabecular and solid patterns. Am J Surg Pathol 17291, 1993 30. Penn I, First MR: Development and incidence of cancer following cyclosporine therapy. Transplant Proc 18 (2 suppl 1):210, 1986 31. Plail RO, Bussey HJ, Glazer G, et al: Adenomatous polyposis: An association with carcinoma of the thyroid. Br J Surg 74:377, 1987
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32. Riddle PE, Dincsoy HP: Primary squamous cell carcinoma of the thyroid associated with leukocytosis and hypercalcemia. Arch Pathol Lab Med 111:373-374, 1987 33. Robbins J, Merino MJ, Boice JD, et al: Thyroid cancer: A lethal endocrine neoplasm. Ann Intern Med 115133, 1991 34. Saito K, Kuratomi Y, Yamamoto K, et al: Primary squamous cell carcinoma of the thyroid associated with marked leukocytosis and hypercalcemia. Cancer 48:2080, 1981 35. Sat0 K, Fujii Y, Ono M, et al: Production of interleukin 1 alpha-like factor and colonystimulating factor by a squamous cell carcinoma of the thyroid (T3M-5) derived from a patient with hypercalcemia and leukocytosis. Cancer Res 476474-6480, 1987 36. Sessions RB, Davidson BJ: Thyroid cancer. Med Clin North Am 77:517-538, 1993 37. Simpson WJ, Carruthers J: Squamous cell carcinoma of the thyroid gland. Am J Surg 156:4446, 1988 38. Skarsgard ED, Connors JM, Robins RE: A current analysis of primary lymphoma of the thyroid. Arch Surg 1261199-1204, 1991 39. Sobrinho-Simoes M, Sambade C, Nesland JM: Tall cell papillary carcinoma [letter]. Am J Surg Pathol 12:79, 1989 40. Starink Th M, van der Veen JPW, de Waal LP, et al: The Cowden syndrome: A clinical and genetic study in 21 patients. Clin Genet 29:222-233, 1986 41. Tennvall J, Lundell G, Hallquist A, et al: Combined doxorubicin, hyperfractionated radiotherapy, and surgery in anaplastic thyroid carcinoma. Cancer 74:1348-1354, 1994 42. Terry JH, St. John SA, Karkowski FJ, et al: Tall cell papillary thyroid cancer: Incidence and prognosis. Am J Surg 168:459, 1994 43. Tupchong L, Phil D, Hughes F, et al: Primary lymphoma of the thyroid gland: Clinical features, prognostic factors, and results of treatment. Int J Radiat Oncol Biol Phys 12:1813, 1986
Address reprint requests to Kenneth D. Burman, MD Endocrine Section Department of Medicine Washington Hospital Center 110 Irving Street, NW Washington, DC 20010
THYROID CANCER I1
+ .20
UNUSUAL TYPES OF THYROID NEOPLASMS Kenneth D. Burman, MD, Matthew D. Ringel, MD, and Leonard Wartofsky, MD
This review describes the clinical diagnosis, presentation, and treatment of several unusual types of thyroid neoplasms. The discussion focuses on the tall cell variant (TCV) of thyroid cancer, insular thyroid cancer, anaplastic thyroid cancer, and lymphoma of the thyroid gland. The clinical entities of Cowden’s syndrome and familial adenomatous polyposis (FAP) also are reviewed as they relate to thyroid neoplasms. We have chosen these disorders because of their importance clinically, and because the ability to recognize these thyroid cancer subtypes or variants may influence patient management and outcome. Unfortunately, long-term prospective controlled studies of these neoplasms do not exist, and, therefore, the clinician must frequently render management decisions without strong literature support. In addition, for several of the tumors discussed, such as the TCV and columnar thyroid cancer, there has been no critical evaluation of either intraobserver or interobserver variation in the ability to recognize these tumors. TALL CELL VARIANT OF PAPILLARY THYROID CANCER
Histologic characterization and identification of the TCV of papillary carcinoma were established by Hawk and Hazzard in 1976.14 Although relatively subjective, the following criteria apply: (1) there must From the Section of Endocrinology (KDB), Department of Medicine (LW), Washington Hospital Center, Washington, DC; the Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda (KDB);and the Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland (MDR) ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA VOLUME 25 * NUMBER 1 MARCH 1996
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be a papillary thyroid cancer (PTC) component in which the cell height is at least twice the width; (2) oxyphilic cells must be present; (3) microfollicles may be formed; and (4) tall cells must encompass at least 30% of the tumor (Fig. 1). It may be difficult to assess whether tall cells are found in more than 30% of the entire tumor, as this observation depends on many factors including the diligence of the pathologist and the number of sections fixed and analyzed. Hawk and H a ~ z a r d believed ’~ that 18 of 197 of their PTCs fulfilled these criteria, and these tumors were labeled as TCV. These patients tended to have large tumors, and the average age of the patients was 57 years. Four of the 18 subjects (22%) died within 7 years of diagnosis. TCV may be confused with Hurthle cell neoplasms, because an oxyphilic cell component may be observed in both tumors. Johnson and cow o r k e r ~compared ~~ patients with TCV with a control group of patients with PTC matched for tumor size, age, sex, and disease duration. Between 1972 and 1986,12 patients were identified with TCV out of more than 300 cases of differentiated thyroid cancer (DTC). The patients with TCV had a mean age of 49.4 years, were predominately female (10 females to 2 males), had an average tumor size of 2.8 cm, and were followed up for 68 months. In comparison, control patients with PTC had an average age of 48.3 years, the identical gender ratio, a tumor size of 2.3 cm, and were followed up for 80 months. Tumor in cervical nodes was found in 9 of 12 patients (75%) with TCV compared with 5 of 12 patients (42%) with PTC. Distant metastases were found in 2 of 12
Figure 1. Tall cell variant of papillary thyroid cancer. Tall cell variant of papillary thyroid cancer is characterized by papillae lined by columnar cells with at least twice the height as width, eosinophilic granular cytoplasm, and predominantly basally located nuclei. Although these criteria are relatively subjective, this tall cell variant does seem to have a poorer prognosis in patients more than age 50 years. In patients fewer than 50 years old, the stage at diagnosis and tumor behavior seems similar to well-differentiated cancer. (Hematoxylin and eosin [H and El,original magnification, x 50.)
UNUSUAL TYPES OF THYROID NEOPLASMS
51
patients (17%) with TCV and in none of 12 patients with PTC, and recurrent disease was identified in 7 of 12 of the TCV group compared with 1 of 12 of the PTC group. Mortality due to the tumor was noted in 3 of 12 patients (25%) with TCV, whereas none of 12 patients with PTC died of thyroid disease during follow-up (mean, 68 months). In the same time period, 7 of 12 patients with TCV had no evidence of disease despite the fact that four of these seven patients had extrathyroidal disease at surgery. It is difficult to define the criteria necessary to identify a tumor variant as inherently possessing a greater tendency toward invasion, metastasis, recurrence, and death, but matching tumors for stage at the time of presentation may be an important variable. Statistical evaluation showed that the frequencies of soft-tissue involvement, tumor recurrence, and metastases were more common for TCV. Tumor size and age greater than 50 years correlated with a higher frequency of death in patients with TCV disease. No differences were found in patients younger than 50 years regarding mortality or returrence rates at the end of the follow-up period. Sobrinho-Simoes and co-~orkers"~ agreed that TCV is associated with a poor prognosis and suggested that mitotic rates were related to invasiveness. Flint and co-workers9compared 11 patients with TCV with eight patients with DTC, these patients were matched for age and sex. There were no significant differences in the two groups; 6 of 11 of the TCV tumors and four of eight of the DTC tumors were aneuploid. Terry and ~ o - w o r k e r sin~ ~a recently published article noted that TCV accounted for approximately 10% of all thyroid papillary cancers. In 19 such tumors, the average tumor size was about 4.2 cm compared with 2.8 cm for customary differentiated PTC. Patients with TCV who were aged more than 50 years had larger tumors (5.6 versus 2.7 cm) and also a higher likelihood of having stage 3 and 4 disease. They also noted increased recurrence rates with TCV when compared with DTC. Specifically, none of six patients aged less than 50 years with tumors less than 4 cm in size had recurrences in the TCV group compared with 1 of 63 patients in the PTC group. Similarly, if the tumor was less than 4 cm and the patients were aged more than 50 years, two of four and 1 of 33 patients had recurrences in the TCV and PTC groups, respectively. Of patients aged less than 50 years with tumors greater than 4 cm, none of two and none of 22 had recurrences in the groups with TCV and PTC, respectively. However, four of five patients aged more than 50 years with TCV had recurrences compared with 2 of 14 patients with PTC. When all of the patients were grouped together, the presence of adenopathy at surgery and multicentricity of tumors did not vary significantly between the TCV and PTC groups. Age was significantly greater in the TCV group, and there was a significantly greater ratio of males with TCV when compared with patients with PTC. Extrathyroidal invasion, vascular invasion, recurrences, and mortality were significantly more frequent in the TCV group. It was concluded that PTC in patients aged more than 50 years and with larger tumors had a significantly worse prognosis than more customary PTC, but these differences in
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clinical outcome seemed to be less important in patients with smaller tumors who were younger. Egea and co-workers8 studied five patients with TCV and noted vascular invasion in two, multicentricity in four, recurrences in four, and metastasis and mortality in one patient. Ain and Merino33 have retrospectively reviewed 25 patients with TCV seen at the National Institutes of Health (NIH) between 1976 and 1990. The reader is referred to Dr. Ain’s article on papillary carcinoma in the preceding issue of Endocrinology and Metabolism Clinics of North America for further detailed information. He reports that 23 patients had extensive disease at the time of initial diagnosis; 32% had local nodal metastasis at the time of surgery. Pulmonary metastasis developed in 36% and bone metastasis in three patients. There was a 16% mortality rate in this group, who were followed up for an average of 5 years with a maximum time interval of 14 years. In our opinion, these earlier studies seem difficult to interpret given the varying time of follow-up, the relatively small number of patients, and the seemingly discrepant outcomes. In an attempt to understand this disease entity better, and realizing that the evaluation period was variable in the patients with TCV, we have summarized the results found in the total number of patients with reported clinical follow-up in the literature thus far, including Dr. Ain’s analysis of 25 new patients with TCV. We found 76 patients with TCV for whom data could be analyzed. We compared the results with that in 1355 patients with DTC recently reported on by Mazzaferri and Jhiang,25with specific attention to stage at presentation and patient outcome by age. Although the mean age of the patients with TCV was greater (53 versus 36 years) and the size of the tumor was relatively larger (3.7 versus 2.5 cm), there were no apparent differences in the frequency of regional invasion (51% versus 50%); the frequency of metastasis was higher (19% versus 2%), and intrathyroidal tumors were less common (30% versus 38%) (Table 1). Clinical outcomes are summarized in Table 2. When all of the patients are combined, those with TCV had higher mortality and a higher rate of recurrent or persistent disease. However, in patients aged less than 50 years, the prognosis seems comparable with that for welldifferentiated thyroid cancer. Our review of the literature suggests that, in comparison with welldifferentiated thyroid cancer, TCV has a worse prognosis in patients Table 1. CLINICAL PRESENTATION OF TCV COMPARED WITH WELLDIFFERENTIATEDTHYROID CARCINOMA Tall Cell Variant ( n = 76) Age (years) Size (cm) lntrathyroidal Regional (neck) Metastases Female
53 3.7 30% 51% 19% 69%
Differential Thyroid Cancer ( n = 1355) 36 2.5 48% 50% 2% 67%
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53
Table 2. CLINICAL OUTCOMES OF TCV COMPARED WITH WELL-DIFFERENTIATED THYROID CARCINOMA All Patients
Outcomes
Dead Alive with disease Alive without disease
Over Age 50 Years
Differentiated (%) (fl = 1355)
TCV (%) (fl = 19)
42
0 29
26 42
29
63
32
TCV (%) (n = 76) 29
Under Age 50 Years TCV (%) (n = 14)
Differentiated (%) ( n = 1133)
23
0 21
2 21
58
79
77
Differentiated (fl
(“h) = 222) 19
older than 50 years. These patients often present with large, more advanced tumors. In patients aged less than 50 years, the stage at diagnosis and tumor behavior appear similar to that with well-differentiated cancer, with the caveat of a much shorter reported follow-up period and no standardized treatment regimen. These tumors tend to concentrate radioiodine and respond to thyrotropin as a growth factor, and, when possible, the use of radioiodine therapy and thyroid-stimulating hormone (TSH) suppression is encouraged. Further studies will help to clarify the clinical characteristics and outcomes of the TCV. INSULAR THYROID CANCER
Insular thyroid cancer, originally described as “Wuchernde struma” by LanghansZ0in 1907, represents approximately 5% of all thyroid cancers. This entity was renamed insular thyroid cancer in 1984 by Carcangiu and colleagues.5Histologically, the tumor has solid clusters of tumor cells with small follicles that resemble pancreatic islet cells; these cells stain positively with thyroglobulin antibodies but do not stain with calcitonin antibodies (Fig. 2). At the time of diagnosis, there usually is vascular and capsular invasion, frequently accompanied by necrotic foci; insular thyroid cancer also may be seen to a variable extent in typical papillary or follicular thyroid cancer. To date, there are 141 cases of insular thyroid carcinoma published in the world literature. In 1984, Carcangia and colleagues5 reported 25 cases of histopathologically defined insular thyroid cancer (8 men, 17 women). The average age was 55 years and the follow-up period 1 to 8 years (average, 3.5 years). Tumor size at surgery was about 4 cm. At presentation, 10 of 25 patients (40%) had intrathyroidal disease; 11 of 25 (44%) had regional spread, and 4 of 25 (16%) had metastatic disease. In terms of outcome, 11 of 25 patients (44%) died of disease; 7 of 25 (28%) were alive with disease, and 4 of 25 (16%) had no evidence of disease (when analyzed at follow-up; mean, 3.5 years). Three of 25 patients (12%) died of non-cancer-related causes with their disease. Three of four patients who presented with metastasis died of disease. It was appropriately concluded that insular thyroid cancer is a very aggressive variety of thyroid cancer.
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Figure 2. Insular thyroid cancer. Insular thyroid cancer is typically characterized by infiltrating sheets and nests of cohesive cells without evidence of either follicular or papillary differentiation. Insular thyroid cancer seems to have a poorer prognosis than differentiated thyroid cancer, including a higher recurrence rate and, in all likelihood, a higher mortality. A tumor that contains only a minor component of insular carcinoma in an otherwise welldifferentiated tumor is probably not associated with an adverse outcome. (Hand E, original magnification, x 50)
Ashfaq and co-workers' recently published a study of 41 patients with insular thyroid cancer with a male-to-female ratio of 1:1.6. Average age was 52 years; follow-up period was 1 to 12 years, with an average of 4 years. Interestingly, the prognosis seemed comparable regardless of the extent of the insular component in the histologic specimen. Increased age was predictive of tumor recurrence. At presentation, there were intrathyroidal metastases in 15 of 37 patients in whom clinical data were reported (41%). Regional invasion was found in 13 of 37 (%YO), and metastatic disease in 9 of 37 (24%). In terms of outcome, 5 of 28 patients (18%) were dead of disease, 6 of 28 (21%) alive with disease, and 14 of 28 (50%) had no evidence of disease. Three of 28 (11Y0) died of other causes with their disease. Follow-up data were not reported in nine patients. When insular cancer was located within follicular or PTC, the clinical outcome of the well-differentiated component did not seem to be adversely influenced. Papotti and co-workersz9studied 63 persons with thyroid cancer. Eighteen were male and 45 female. Average age was 55 years, and the follow-up evaluation period ranged from 3 months to 16 years, with an average of about 4.6 years. Average tumor size was 5.9 cm. A total of 31 subjects had insular thyroid cancer as the major component of the tumor, and the remaining 32 patients had DTC (follicular with minor insular component). The only difference between patients with a minor insular component ( n = 32) and those with a tumor that was mainly insular cancer was a higher tumor recurrence rate in the latter. At presentation, 46 of 62 patients (74%) were free of disease following thyroidectomy, and 16 of 62 (26%) had metastasis at the time of surgery.
UNUSUAL TYPES OF THYROID NEOPLASMS
55
Ten patients with metastatic or recurrent disease were treated with 1-131 after surgery and followed up for 4 to 15 years (average, 8 years). Two of ten patients had no evidence of disease, four of ten were alive with disease, and the remaining four of ten died of disease at an average time of 7 years' follow-up. None of the tumors proved fatal within 6 months, and most seemed to respond to 1-131 therapy. Although there were no differences in survival, insular thyroid cancer was associated with a higher recurrence rate and an increased frequency of distant metastases. In an effort to compare the characteristics of insular thyroid cancer with those of DTC, we reviewed the literature and compiled Table 3. We again utilized the recently published work of Mazzaferri and JhiangZ5 to provide comparison data for DTC, again noting the shorter follow-up time and variable therapies in the insular carcinoma group. In analyzing stage 4 metastatic disease, 9 of 15 patients (60%) with insular thyroid cancer died with disease (at 0-15 years) compared with 65% with differentiated cancer (at 30 years). In the group with insular cancer, 3 of 15 patients (20%) were alive with disease, and 3 of 15 (20%) were alive without evidence of disease. A total of 39 of the 77 patients with insular cancer (51%) thought to be cured at surgery had a recurrence of tumor, whereas patients with DTC with stage 1 to 3 disease had a combined recurrence rate of 21% (stage 3 was associated with a rate of 26%). Justin and colleagues17reported on five cases and reviewed the ability of insular carcinomas to concentrate radioactive iodine. Each of these five patients had a large neck mass; one had local invasion, one had vascular invasion, and one had tracheal invasion. Radioiodine screening detected thyroid tissue in the neck bed and humerus area in the patient with vascular invasion; it showed cervical node uptake in the patient with tracheal invasion and neck bed concentration in a patient without known invasion. It is a complex issue to analyze and make clinically relevant comparisons regarding the behavior of insular thyroid cancer and more customary DTC, especially considering the difficulty in controlling for size of tumor and age of onset. Nevertheless, insular thyroid cancer appears to have a worse prognosis than DTC, including a higher recurrence rate and, in all likelihood, a higher mortality. Most tumors concentrate radioTable 3. COMPARISON OF CHARACTERISTICS OF INSULAR THYROID CANCER AND DIFFERENTIATED THYROID CANCER Presentation Insular Age (yr) Size (crn) lntrathyroid Regional (neck) Metastases
Differentiated 36 2.5 48%
54
4.7 38% 36% 26%
DOD = dead of disease; AWD died with disease.
Outcome
50% 2% =
alive with disease; NED
Insular
Differentiated
DOD 25% AWD 29% NED 41% DWD 5%
8% 29% 63%
=
-
no evidence of disease; DWD
=
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iodine, supporting this modality of therapy as possibly effective, even for patients with metastatic disease. When analyzed at 5 years, there may be a 20% cure rate for adults with stage 4 insular thyroid cancer. Apparently, in an otherwise well-differentiated tumor, having a minor component showing insular carcinoma does not adversely influence outcome. SQUAMOUS CELL CARCINOMA
In endocrine textbooks, thyroid cancer is classically divided into papillary, follicular, medullary, and anaplastic, with thyroid lymphomas being prominently mentioned.24However, primary squamous cell carcinoma of the thyroid gland also is an important variant (Fig. 3). This disease accounts for approximately 1% of thyroid cancers, but it possesses unique clinical and biochemical characteristics that should be recognized. Once again, there are scant numbers of case reports of this entity and a lack of large-scale studies that have been reported and analyzed. This section discusses several of these case studies and emphasizes important or relevant aspects. Riddle and D i n ~ s o ydescribed ~~ a 66-year-old woman with primary squamous cell carcinoma of the thyroid. Frequently, this tumor occurs in elderly males with a long history of a goiter. This particular patient had a large goiter with dyspnea and chest pain; bilateral cervical adenopathy was present. The white blood cell count was 28,400/mm3 with 84%
Figure 3. Squamous cell thyroid cancer. This squamous cell thyroid cancer displays infiltrating nests of cohesive polygonal cells. Within the center of these nests are eosinophilic cells with keratinization. This tumor can be associated with a systemic syndrome characterized by leukocytosis, hypercalcemia, and fever, possibly mediated by colonystimulating factor or interleukin 1. (Original magnification, x 50)
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polymorphonuclear lymphocytes; serum calcium was elevated to 13 mg/dL; T3, T4, and TSH were normal. Chest radiography showed bilateral interstitial edema and nodular densities. At autopsy, the thyroid weighed 450 g, and histology showed a moderately differentiated squamous cell carcinoma with keratin pearl formation, necrotic areas, and giant and spindle cells. The larynx, trachea, hyoid, esophagus, and submandibular glands were normal on extensive sectioning. This case report illustrates the rapid clinical course of this disease-3 months in this patient. The precise cellular source of this tumor has been under considerable debate, as the presence of squamous cells within the thyroid gland is controversial. Squamous metaplasia of follicular epithelium of the thyroid does occur, especially in patients with chronic thyroid disease. Furthermore, squamous cell thyroid carcinoma has been described in remnant thyroid tissue, for example, a thyroglossal duct cyst.26It is likely that malignant transformation of benign metaplastic squamous cells arising from the thyroid is the histologic basis for squamous cell carcinoma of the thyroid. Patients with squamous cell carcinoma of the thyroid may present with systemic symptoms of hypercalcemia, fever, and leukocytosis as 21, 28, 32, 34, 35, 37 This exemplified in case reports described previ~usly.~, thyroid tumor has been successfully transplanted into athymic nude mice and resulted in leukocytosis and hypercalcemia. It was believed that colony-stimulating factor and interleukin 1-alpha had a role in mediating the leukocytosis and hypercalcemia, as the injection of interleukin 1 antibodies in these mice decreased thymocyte proliferation and bone resorption.28,34, 35 Furthermore, the tumor did not stain with parathyroid hormone antiserum, suggesting that nonparathyroid-mediated mechanisms are involved in the hypercalcemia. Harada and c o - ~ o r k e r s studied ’~ eight thyroid glands at autopsy obtained from patients with squamous cell carcinoma of the thyroid. Several of these patients were treated with bleomycin or external radiation or both to no avail. Histologically, all eight of these cases showed a major component in which squamous cell carcinoma of the thyroid was predominant, whereas, elsewhere in the tumor, there was primarily PTC. In addition, there was a third broad area of overlap and transition. Histologic examination of the metastases could demonstrate any of these patterns. Tumor metastases usually occurred in the lungs, nodes, liver, or mediastinums, in some cases, there was extensive local invasion. The mean age at diagnosis was 66 years. Half of the patients were male. Four of seven patients had soft-tissue calcification on radiography. Mucin staining in adenocarcinoma can help differentiate it from squamous cell carcinoma of the thyroid, although some believe that there are no squamous cells in the normal thyroid gland. Squamous metaplasia, if present, could represent a transition stage to squamous cell carcinoma of the thyroid. Klinck and Menkl* at the Armed Forces Institute of Pathology suggest that this mechanism is unlikely, because no other tissue or organ has been documented to show the transition of squamous metaplasia into squamous cell carcinoma, although they did
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identify thyroidal squamous cells in a wide variety of conditions, including DTC, thyroiditis, and Riedel’s struma. In a study of squamous cell carcinomas Harada and colleague^^^ did not find any areas of squamous metaplasia, whereas they identified 19 instances of squamous metaplasia in 480 cases of thyroid adenocarcinoma. The relationship between squamous cell carcinoma of the thyroid and therapy for other medical conditions has been evaluated. Bakri and co-workers2 described one patient who underwent x-ray therapy for Hodgkin’s disease and in whom 48 years later squamous cell carcinoma of the thyroid developed. Penn and First30observed patients after transplantation. A total of 2511 malignancies arose after transplantation in 2347 patients; 88 tumors developed after cyclosporine therapy. Although no pathophysiologic link between this agent and the development of squamous cell carcinoma of the thyroid has been established, this tumor developed in one patient. Diagnostic radioiodine scans of patients with squamous cell carcinoma of the thyroid show either a cold nodule or, surprisingly in some instances, a functional area. Gallium 67 does not concentrate well in differentiated adenocarcinoma but may do so in patients with squamous cell carcinoma of the thyroid and may be helpful in monitoring disease recurrence. Simpson and car rut her^^^ reported 17 cases of squamous cell carcinoma of the thyroid in 2214 patients with thyroid malignancy (0.8%). Between 1977 and 1984, they found eight cases of squamous cell carcinoma of the thyroid; only two patients were considered to have undergone a reasonably complete resection. X-ray therapy was given to six patients, and one received 5-fluorouracil and mitomycin C. The two patients who had surgical completions were alive 4 years after operation, whereas each of the other patients had died. Lee and co-workersZ1also reported on one patient who was alive several years after operations. These results suggest that complete surgical resection of tumor mass represents the best chance for cure. Radioiodine and thyroid hormone suppression are probably less helpful in patients with this neoplasm, but, in selected instances, it may be reasonable to perform a diagnostic radioiodine neck and chest scan and to determine the potential avidity of the tumor for radioiodine.* Squamous cell carcinoma of the thyroid is a rare disorder, that is most frequently observed in older patients with a history of thyroid gland enlargement. Metastasis to the thyroid from another site (e.g., lung, upper respiratory tract) must be excluded. It is usually a rapidly progressive malignancy with a predilection for local invasion and metastasis; early detection and extensive surgery represent the best chance for palliation and cure. It is speculated that squamous cell carcinoma of the thyroid may arise more frequently in a thyroid gland that has been exposed to radiation. The precise pathophysiologic mechanism by which squamous cell carcinoma of the thyroid arises has not been defined, but it is possible that it may arise from cellular transformation from squa“References2, 4, 13, 18, 21, 26, 28, 30, 32, 34, and 37.
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mous metaplasia. Squamous cell carcinoma of the thyroid usually is associated with a distinct clinical syndrome characterized by leukocytosis and hypercalcemia, probably mediated by the production and secretion of colony-stimulating factor and interleukin 1. Patients presenting with a thyroid nodule and these associated clinical parameters should be evaluated for squamous cell carcinoma of the thyroid gland. The finding of squamous cell carcinoma on biopsy or histology should prompt consideration of whether this tumor represents metastasis to the thyroid gland from another site or is primarily originating within the thyroid gland. COWDEN'S SYNDROME
Although not strictly considered an unusual cause of thyroid cancer, Cowden's syndrome deserves to be mentioned because of its coincidence with thyroid carcinoma, because of the recent developments in our understanding of the clinical manifestations of this syndrome, and because of the relevance to early clinical diagnosis. Cowden's syndrome is characterized by multiple mucocutaneous hamartomas, keratoses, and fibrocystic disease of the breast. In a study by Starink and co-workers,4" mucocutaneous hamartomas were found in each of 21 patients, most commonly on the face (Fig. 4).The keratoses are most prominent on the hands, feet, and mouth. Many of these lesions are actually trichilemmomas. Perhaps the most serious associated abnormalities are fibrocystic disease or cancer of the breast and gastrointestinal polyps. Skeletal and facial abnormalities and mucocutaneous neuromas and neurofibromas also may be present. Serum calcitonin and chromogranin A may be elevated, reflecting, perhaps, the Merkel cell origin of the tumors that are found throughout the body rather than the coexistence of medullary thyroid carcinoma. The most commonly associated thyroid cancer is well-differentiated thyroid cancer. Haibach and colleagues" reviewed the literature on Cowden's syndrome and found that 8 of 26 patients had thyroid carcinoma. Very little is known about the pathologic characteristics and the clinical aggressiveness of the thyroid carcinoma associated with Cowden's syndrome, but patients with this syndrome should be carefully evaluated for thyroid nodules. FAMILIAL ADENOMATOUS POLYPOSIS (GARDNER'S SYNDROME)
Familial adenomatous polyposis is a syndrome consisting of multiple adenomatous polyps frequently in conjunction with osteomas, epidermoid cysts, desmoid tumors, retinal pigmentation, and, more rarely, with adenomas in the upper gastrointestinal tract and pancreas and hepatobla~tomas.~ The disease is inherited as an autosomal dominant disorder, although there are isolated or sporadic cases as well. In their
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Figure 4. Facial lesions in a typical patient with Cowden’s disease. Multiple small papular lesions are observed in the temporal region and on the eyelids and nose (A), and gingivae (6).(From Carlson HE, et al: Cowden’s disease: Gene marker studies and measurements of epidermal growth factor. Am J Hum Genet 38:908-917, 1986; with permission.)
review, Bell and Mazzaferri3 documented the association of FAP with thyroid carcinoma. Plail and c o - w ~ r k e r sbelieved ~~ that the risk of thyroid cancer in young female patients may be enhanced about 160 times when compared with normal subjects. Bell and Mazzaferri3 found 37 reported cases of thyroid cancer in patients with FAP; 26 were PTC (88%), and the remaining 12% were follicular thyroid cancer. There were markedly more females than males with thyroid cancer (94% female, 6% male). Interestingly, the thyroid cancer appeared at a relatively young age, with patients averaging 23 years in age, and was diagnosed before the recognition of FAP in 30% of patients. Histologically, the thyroid tumors were frequently multicentric, and, in other patients with PTC, this represents a significant risk of tumor recurrence. The thyroid tumor
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seemed to have relatively low aggressiveness, as 4% of patients had distant metastases and local nodal disease was found in only 1 of the 37 patients. The average follow-up time was 7.2 years in 21 patients. More information relative to the nature and aggressiveness of the thyroid cancer that occurs in association with FAP needs to be obtained. Currently, however, it is important clinically to recognize this association and to perform appropriate studies, such as thyroid biopsies, sonograms, and scans, in patients with known FAP. If there is a dominant nodule that can be aspirated, this should be performed, but it is slightly more difficult to interpret a benign result because the thyroid cancer may be multicentric. Close clinical observation for neoplasia in the thyroid gland in patients who have a personal or family history of FAP is important. Conversely, clinical follow-up including questioning for a family or personal history of gastrointestinal polyps, bleeding, or cancer in patients who have had thyroid cancer, particularly if it presented at an early age, is appropriate. It is unknown whether patients with PTC should have earlier or more frequent examinations, sigmoidoscopy, or examinations for stooI blood than the general population or what the effect would be on clinical outcome or cost effectiveness. ANAPLASTIC THYROID CANCER
Anaplastic carcinoma is the most aggressive type of thyroid cancer. This disease occurs more frequently in older individuals and usually presents as a rapidly enlarging thyroid or neck mass in association with dysphagia, neck tenderness, and, occasionally, superior vena cava syndrome. Lampertico19has suggested that there has been a three- to four-fold decrease in reported cases of anaplastic cancer compared with several decades earlier, although the aggressive nature of the disease has not seemed to change. Virtually all patients with anaplastic cancer die from the progression of this tumor. Histologically, anaplastic cancer invades locally but may also metastasize distantly. Upon microscopic examination, there are giant cells, intranuclear cytoplasmic invaginations, and usually residual elements of more differentiated thyroid cancer (Fig. 5). It is suspected, but not proven, that anaplastic thyroid cancer arises or evolves from DTC, and it is hypothesized that prior radioiodine therapy may have a role in this process. Radioiodine therapy does not help in this tumor as the anaplastic cells do not concentrate radioiodine. Levendag and retrospectively reviewed 51 patients with anaplastic thyroid cancer who were treated with external beam radiation therapy in the presence or absence of adjunctive chemotherapy. Metastases without significant local invasion were associated with a median survival of 7.5 months, whereas patients with local disease had a mean survival of 1.6 months. External beam radiation in conjunction with Adriamycin did not seem to be effective, and the most appropriate therapy rests with early diagnosis and aggressive surgical management.
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Figure 5. Anaplastic thyroid cancer. This tumor consists of pleomorphic spindle cells containing hyperchromatic nuclei. The portion of the tumor shown contains numerous dispersed multinucleated giant cells. In contrast with the undifferentiated insular type, the cells show increased pleomorphism and a more haphazard pattern. Anaplastic thyroid cancer is associated with a very poor prognosis. (H and E, original magnification x 20.)
Nicolosi and co-workersZ7studied 19 patients, average age 66 years, with anaplastic thyroid carcinoma. Four patients had disease presenting as an intrathyroidal mass, 11 had local infiltration, and four had distant metastases. Seven subjects had a history of thyroid enlargement. All of the patients with anaplastic thyroid carcinoma received external radiation therapy, and the median survival was 6 months. Thyroidectomy or only diagnostic thyroid biopsy did not seem to alter prognosis when combined with external radiation therapy. Eleven of the 12 subjects died of disease, and one was alive at 120 months of follow-up. Junor and colleagues16reported on 91 patients with anaplastic thyroid cancer. The female-to-male ratio was 2.4:1, and the median age was 70 years with a range of 38 to 92 years. Presenting symptoms commonly included an enlarging thyroid mass, dyspnea, dysphagia, or dysphonia. Their review showed that a partial thyroidectomy was performed in 31% of patients ( n = 28) and a total resection in 5% (n = 5); 63% underwent a biopsy without further surgical approach. A total of 86 patients received further therapy in addition to surgery or biopsy, and 18 (21%) also received adjunctive chemotherapy. The overall survival was poor, as the average length of survival was 21 weeks with 45% alive at 6 months; 32% survived for 9 months, and 11%survived for 3 years. In contrast to the earlier mentioned studies, 60% of patients seemed to respond to radiation therapy, and it was concluded that a thyroidectomy was associated with enhanced survival. Additional chemotherapy did not appear to increase survival. Hadar and co-workersl0 found comparable results; only 28% of 48 patients with anaplastic thyroid cancer were alive 2 years after the diagnosis.
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It is difficult to make conclusions from these studies as they are generally retrospective in nature and contain relatively few patients; there are no controlled studies. Nevertheless, it seems that a thorough discussion with the patient and his or her family is indicated to arrive at a mutually conceived treatment plan. If all other factors are equal, it is reasonable to perform a total thyroidectomy with surgical removable of local lymph nodes and mass lesions, followed by external radiation therapy and chemotherapy, but it is not possible to prove that this approach will prolong survival and decrease morbidity. LYMPHOMA
Primary thyroid lymphoma represents a distinct entity that has recently been recognized more frequently (Fig. 6). Matsuzuka et alZ3 reviewed their institutional experience with 119 cases of thyroid lymphoma seen during a 27-year period. Thirty-three patients were men, and 68 were women. The average age was 60 years with a range of 26 to 82 years. They could find no significant association of the development of thyroid lymphoma with a prior history of head and neck irradiation or with HIV infection. The presenting signs or symptoms of patients with thyroid lymphoma included the presence of a goiter (100%), recent rapid growth of a goiter (78%), hoarseness (13%), dysphagia (7%), and fever (7%).Positive serum antimicrosomal and thyroglobulin antibody titers, were found in 68% and 34% of patients respectively, and every patient had histologic evidence of Hashimoto’s thyroiditis in
Figure 6. Primary lymphoma of the thyroid. This tumor is characterized by a diffuse infiltrate of monotonous, atypical lymphocytes with extensive obliteration of thyroid architecture. The presence of lymphoma cells within a follicle is typically observed. This tumor also frequently arises from or is associated with the presence of Hashimoto’s thyroiditis. (H and E, original magnification x 70)
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peritumor tissue. Fifty-eight percent of patients were euthyroid, 14% were clinically hypothyroid, and an additional 27% had subclinical hypothyroidism. The preoperative diagnostic evaluation of patients with suspected thyroid lymphoma remains difficult and controversial. Although not universally accepted, Matsuzuka and c o - ~ o r k e r sbelieve ~~ that ultrasound examination can suggest the presence of thyroid lymphoma. Ninety-three percent of the patients with this tumor had what these investigators called a ”pseudocystic pattern,” which was found in only 11% of patients with Hashimoto’s thyroiditis alone. It was suggested that fine-needle aspiration of the thyroid gland was helpful if obtained from these cystic areas, even without flow cytometry for monoclonality. Of 83 patients with thyroid lymphoma who had fine-needle aspiration, 65 (78%)were accurately diagnosed, 10 subjects (12%) had indeterminate or borderline results, and 8 patients (9.6%)had results that were read as benign or had no evidence of malignancy. As a result of their experience, Matsuzuka and colleagues do not believe, as has been suggested previously, that large-bore needle biopsies need to be routinely employed to diagnose thyroid lymphoma. They suggest that, in rare instances of borderline fine-needle results, an open core biopsy may be indicated. Although Matsuzuka did not need to employ immunotyping to make the diagnosis, others have suggested that flow cytometry, even when obtained from a fine-needle aspiration, can be very helpful, as there is a clonal proliferation rather than a heterogeneous cell population as observed in Hashimoto’s thyroiditis. The treatment of patients with thyroid lymphoma is controversial. In Matsuzuka’s the cause-specific mortality rate was 35% before the advent of fine-needle aspiration and decreased to 5% after the institution of this procedure, although, of course, there have also been concomitant advances in the use of chemotherapy. It was suggested that combined external radiation and adjuvant chemotherapy with six courses of CHOP (cyclophosphamide, Adriamycin, vincristine, Adriamycin, and prednisolone) resulted in 100% survival at 8 years. This group of subjects contained 16 individuals who had not undergone a thyroidectomy and who had stage 2 lymphoma. The results in Matsuzuka’s study are better than those reported earlier. Survival rates have ranged from approximately 30% to 80%.6,7, 36, 3R, 41, 43 Although these reports usually included a thyroidectomy in addition to radiotherapy and chemotherapy, the studies vary in how extensively they used contemporary techniques of diagnosis and chemotherapy and also in the ability to diagnose stage 3 or 4 disease. Currently, the most important elements of approach include early suspicion and diagnosis, with rapid institution of therapy. Although our own approach may be controversial, if one is suspicious for thyroid lymphoma, we suggest a fine-needle aspiration with cytologic analysis and performance of flow cytometry with immunotyping for monoclonality. Further preoperative assessment may include neck, chest, and abdominal CT scan or MR imaging and, on occasion, a gallium scan which may be able to
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suggest lymphomatous deposits both within the thyroid and extrathy roidally. We generally recommend a near-total thyroidectomy if technically feasible, especially if the results of fine-needle aspiration are unclear. This approach allows not only determination of the extent of cervical involvement with lymphoma but also removal of the majority of abnormal tissue. In experienced hands, we believe the potential adverse effects of a near-total thyroidectomy may not be significantly higher than that of a core biopsy, and that the procedure is more likely to render a definitive and representative diagnosis. In some instances, the thyroidectomy can easily be performed, whereas, in others, the tumorous involvement is such that there is extensive fibrosis. Analysis of the surgical options with consideration of the potential benefits and adverse effects must be made by a surgeon experienced in this area and discussed candidly with the patient and his or her family. As described by Matsuz~ka?~ after surgery and a histologic diagnosis, the first course of CHOP therapy is given, followed by external radiation (total dose, 40 to 60 Gy) and then the remaining five courses of chemotherapy. Doria and co-workers7analyzed a total of 211 reported subjects and 11 patients seen at their institution. They noted the potential problems in analyzing such literature, such as varying diagnostic procedures and changes in chemotherapy and external radiation procedures. Approximately 30% of patients with stage 1E and IIE disease had distant relapse, and their review suggests that combined external radiation with adjuvant chemotherapy was most likely beneficial in patients with thyroid lymphoma. Skarsgard and co-workers3*reviewed the records of 27 patients with thyroid lymphoma (stage I and 11) and agreed that combined external radiation therapy and chemotherapy improved survival. They did not believe a total thyroidectomy was necessary and that an incisional biopsy would suffice. Improved survival was associated with the absence of dysphagia at presentation, a primary thyroid tumor less than 10 cm, restriction of disease to within the thyroid gland, and the lack of mediastinal involvement. Histologic diagnosis, whether highgrade or intermediate cellular characteristics, did not correlate with overall survival. Earlier in 1983, Hamburger and co-workers’2reviewed their experience with 30 patients with primary thyroid lymphoma. Their clinical findings were comparable with those we have reviewed; 13 of 30 subjects were aged more than 60 years, 12 had hypothyroidism, and 24 had coexistent Hashimoto’s thyroiditis. In findings somewhat different from that in other reports, 19 of 30 subjects presented with a solitary or dominant thyroid nodule. Thyroid lymphoma is commonly observed in a background of autoimmune thyroiditis. Early clinical suspicion and diagnosis followed by prompt multimodality treatment results in higher cure rates. Clinically, attention should be paid to patients with chronic Hashimoto’s thyroiditis with high-titer antithyroid antibodies, especially if the thyroid gland is enlarging and local symptoms are present, such as tenderness, dysphagia, hoarseness, and fever.
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SUMMARY
This article discusses several unusual forms of primary thyroid neoplasms. The TCV of PTC and insular thryoid carcinoma appears to have a more aggressive clinical behavior than DTC in most patient groups and may respond to thyroid hormone suppression and radioiodine. Anaplastic thyroid carcinoma, which may develop from differentiated thyroid tumors, has a poor prognosis which may be altered by surgery and radiation therapy but not typically by radioiodine and thyroid hormone suppression. Primary squamous cell carcinoma of the thyroid is an unusual entity that may be associated with a clinical syndrome that includes leukocytosis, fever, and hypercalcemia. Primary thyroid lymphoma is frequently associated with Hashimoto’s thyroiditis and should be considered especially in older patients with rapidly enlarging thyroid masses. Although there are no studies assessing this issue, it seems reasonable that patients who have undergone thyroidectomy for neoplasms of thyroid cells that are poorly differentiated and do not concentrate radioiodine (e.g., squamous cell, anaplastic) should receive sufficient thyroid hormone suppression, if tolerated, to reduce TSH (third-generation assay) to approximately 0.1 to 0.3 pU/mL, because TSH may be a growth factor. If, however, the tumor concentrates or responds to radioiodine, suggesting more differentiated cells (e.g., TCV, insular carcinoma), the target TSH level (third-generation assay) should range from 0.01 to 0.1 pU/mL, as tolerated. Patients with primary thyroid neoplasms arising from cells other than thyrocytes (e.g., lymphoma) can be maintained at a TSH level of 0.5 to 1.5 FU/mL. Our conclusions and analyses are often based upon small, retrospective, poorly controlled reports, and further studies are required to allow a better understanding of the evaluation and treatment of these neoplasms. ACKNOWLEDGMENTS The authors are grateful to Dr. Barry Shmookler, who reviewed the pathologic material, Dr. James Oertel, who provided the slides and their interpretation, and Dr. Harold Carlson, who provided the photographs of the patient with Cowden’s syndrome.
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5. Carcangiu ML, Zampi G, Rosai J: Poorly differentiated (”insular”) thyroid carcinoma: A reinterpretation Langhans’ “Wuchernde Struma.” Am J Surg Pathol 8:655, 1984 6. Devine RM, Edis AJ, Banks PM: Primary lymphoma of the thyroid: A review of the Mayo Clinic experience through 1978. World J Surg 5:33, 1981 7. Doria R, Jekel JF, Cooper D Thyroid lymphoma: The case for combined modality therapy. Cancer 73:20&206, 1994 8. Egea Moreno A, Rodriguez Gonzalez JM, Sola Perez J, et al: Prognostic value of the tall cell variety of papillary cancer of the thyroid. Eur J Surg Oncol 19:517-521, 1993 9. Flint A, Davenport RD, Lloyd RV The tall cell variant of papillary thyroid carcinoma of the thyroid gland: Comparison with the common form of papillary carcinoma by DNA and morphometric analysis. Arch Pathol Lab Med 115:169-171, 1991 10. Hadar T, Mor C, Shvero J, et al: Anaplastic carcinoma of the thyroid. Eur J Surg Oncol 19:511-516, 1993 11. Haibach H, Burman TW, Carlson HE, et al: Multiple hamartoma syndrome (Cowden’s disease) associated with renal cell carcinoma and primary neuroendocrine carcinoma of the skin (Merkel cell carcinoma). Am J Clin Pathol 97705-712, 1992 12. Hamburger JI, Miller JM, Kini SR Lymphoma of the thyroid. Ann Intern Med 99:685693, 1983 13. Harada T, Shimaoka K, Yakumaru K, et al: Squamous cell carcinoma of the thyroid gland-transition from adenocarcinoma. J Surg Oncol 19:3643, 1982 14. Hawk WA, Hazzard JB: The many appearances of papillary carcinoma of the thyroid. Cleveland Clin Q 43:207, 1976 15. Johnson TL, Lloyd RV, Thompson NW, et al: Prognostic implications of the tall cell variant of papillary thyroid carcinoma. Am J Surg Pathol 12:22, 1988 16. Junor EJ, Paul J, Reed NS: Anaplastic thyroid carcinoma: 91 patients treated by surgery and radiotherapy. Eur J Surg Oncol 18:83-88, 1992 17. Justin EP, Seabold JE, Robinson RA, et al: Insular carcinoma: A distinct thyroid carcinoma with associated iodine-131 localization. J Nucl Med 32:1363, 1992 18. Klinck GH, Menk K F Squamous cells in the thyroid gland. Mil Surg 109:406, 1951 19. Lampertico P: Anaplastic (sarcomatoid) carcinoma of the thyroid gland. Semin Diagn Pathol 10259-168, 1993 20. Langhans T Uber die epithelialen Formen der malignen Struma. Virchows Arch (Pathol Anat) 385:125, 1907 21. Lee JR, Vohman MD, Pendergast WJ: Squamous cell carcinoma of the thyroid gland. J Med Assoc Ga 69:755, 1980 22. Levendag PC, De Porre PM, van Putten WL: Anaplastic carcinoma of the thyroid gland treated by radiation therapy. Lnt J Radiat Oncol Biol Phys 26:125-128, 1993 23. Matsuzuka F, Miyauchi A, Katayama S, et al: Clinical aspects of primary thyroid lymphoma: Diagnosis and treatment based on our experience of 119 cases. Thyroid 3193-99, 1993 24. Mazzaferri E L Thyroid Cancer. In Becker KL (ed): Principles and Practice of Endocrinology and Metabolism, ed 2. Philadelphia, JB Lippincott, 1995, p 354 25. Mazzaferri EL, Jhiang SM: Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97418, 1994 26. Mobini J, Krouse TB, Klinghoffer J F Squamous cell carcinoma arising in a thyroglossal duct cyst. Am Surg 40:290, 1974 27. Nicolosi A, Addis E, Massidda B, et a1 Anaplastic carcinoma of the thyroid: Our experience. Minerva Chir 47:1161, 1992 28. Okabe T, Nomura H, Oshawa N: Establishment and characterization of a human colony-stimulating factor-producing cell line from a squamous cell carcinoma of the thyroid gland. J Natl Cancer Inst 69:1235-1241, 1982 29. Papotti M, Botto Micca F, Favero A, et al: Poorly differentiated thyroid carcinomas with primordial cell component A group of aggressive lesions sharing insular, trabecular and solid patterns. Am J Surg Pathol 17291, 1993 30. Penn I, First MR: Development and incidence of cancer following cyclosporine therapy. Transplant Proc 18 (2 suppl 1):210, 1986 31. Plail RO, Bussey HJ, Glazer G, et al: Adenomatous polyposis: An association with carcinoma of the thyroid. Br J Surg 74:377, 1987
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32. Riddle PE, Dincsoy HP: Primary squamous cell carcinoma of the thyroid associated with leukocytosis and hypercalcemia. Arch Pathol Lab Med 111:373-374, 1987 33. Robbins J, Merino MJ, Boice JD, et al: Thyroid cancer: A lethal endocrine neoplasm. Ann Intern Med 115133, 1991 34. Saito K, Kuratomi Y, Yamamoto K, et al: Primary squamous cell carcinoma of the thyroid associated with marked leukocytosis and hypercalcemia. Cancer 48:2080, 1981 35. Sat0 K, Fujii Y, Ono M, et al: Production of interleukin 1 alpha-like factor and colonystimulating factor by a squamous cell carcinoma of the thyroid (T3M-5) derived from a patient with hypercalcemia and leukocytosis. Cancer Res 476474-6480, 1987 36. Sessions RB, Davidson BJ: Thyroid cancer. Med Clin North Am 77:517-538, 1993 37. Simpson WJ, Carruthers J: Squamous cell carcinoma of the thyroid gland. Am J Surg 156:4446, 1988 38. Skarsgard ED, Connors JM, Robins RE: A current analysis of primary lymphoma of the thyroid. Arch Surg 1261199-1204, 1991 39. Sobrinho-Simoes M, Sambade C, Nesland JM: Tall cell papillary carcinoma [letter]. Am J Surg Pathol 12:79, 1989 40. Starink Th M, van der Veen JPW, de Waal LP, et al: The Cowden syndrome: A clinical and genetic study in 21 patients. Clin Genet 29:222-233, 1986 41. Tennvall J, Lundell G, Hallquist A, et al: Combined doxorubicin, hyperfractionated radiotherapy, and surgery in anaplastic thyroid carcinoma. Cancer 74:1348-1354, 1994 42. Terry JH, St. John SA, Karkowski FJ, et al: Tall cell papillary thyroid cancer: Incidence and prognosis. Am J Surg 168:459, 1994 43. Tupchong L, Phil D, Hughes F, et al: Primary lymphoma of the thyroid gland: Clinical features, prognostic factors, and results of treatment. Int J Radiat Oncol Biol Phys 12:1813, 1986
Address reprint requests to Kenneth D. Burman, MD Endocrine Section Department of Medicine Washington Hospital Center 110 Irving Street, NW Washington, DC 20010