Hashimoto's Thyroiditis Presenting as a Solitary Functioning Thyroid Nodule PAUL BIALAS, STANLEY MARKS, ANDREW DEKKER, AND JAMES B. FIELD Clinical Research Unit and Departments of Medicine and Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 sented Hashimoto's thyroiditis with more extensive destruction of the remaining gland. Although it is unusual, Hashimoto's disease should be considered in the differential diagnosis of functioning thyroid nodules, and both anti-thyroglobulin and antimicrosomal antibodies should be obtained in such circumstances. (J Clin Endocrinol Metab 43: 1365, 1976)
ABSTRACT. A case of hypothyroidism is described in a young woman who on thyroid scan had a discrete functioning "nodule" with homogeneous radioactive iodine uptake, and surrounded by atrophic non-functioning thyroid tissue. Antithyroglobulin antibodies were not demonstrable, but anti-microsomal antibodies were positive at a titer of 1:25,600. Histologically, the "nodule" repre-
C
LINICALLY patients with Hashimoto's thyroiditis may be euthyroid, hypothyroid or rarely hyperthyroid (1,2). Although the thyroid gland is usually diffusely enlarged and of firm consistency, other presentations are also seen. In younger individuals the gland may not be firm and in others the diagnosis is established following surgery for a well-defined palpable nodule. Characteristically, the radioactive iodine scan of the thyroid gland reveals a nonhomogeneous, patchy uptake of the isotope. The appearance may occasionally suggest a discrete non-functioning area raising the possibility of underlying malignancy. Described below is a patient with Hashimoto's disease and hypothyroidism, with a functioning single thyroid "nodule," in which the uptake of radioactive iodine was homogeneous and limited to this area. Case History A 21-year-old white, single, female college student noticed symptoms of weakness, fatigue, lethargy, cold intolerance, depression, and 4.1
Received June 1, 1976. Supported by USPHS Grant AM 06865 and Clinical Research Center Grant RR-00056 from the National Institutes of Health. Reprint requests to: James B. Field, M.D., Director, Clinical Research Unit, 3304 Presbyterian-University Hospital, 230 Lothrop Street, Pittsburgh, Pennsylvania 15261.
kg weight gain in March, 1974, while assigned as a foreign exchange student. She was seen by a physician abroad who diagnosed hypothyroidism. Upon return to the United States in December 1974, she was seen at the outpatient facility of the University of Pittsburgh. She again related her previous symptoms. In addition, her menses had become scant and irregular. She denied constipation, dysphagia, paresthesias, galactorrhea, periorbital edema, or voice or skin changes. There was no family history of thyroid disease and she had never received radiation to the neck area. On physical examination the patient was well developed and in no distress. The blood pressure was 90/60 and the pulse 64 and regular, without orthostatic changes. Temperature was 37 C. The skin was cool and dry. Her hair was dry and somewhat thin with a normal female escutcheon. The entire left thyroid lobe was non-palpable. A 1 cm firm "nodule" was palpable low in the right lobe. It was movable and rubbery in consistency. The remainder of the right lobe felt lobulated and small. There was no expressible galactorrhea. The deep tendon reflexes were characterized by a delayed relaxation phase. The rest of the physical examination was normal. Routine urinalysis and hematologic examinations were normal. Serum thyroxine was 1.5 jig/dl (normal 4.0-10.1 /ng/dl). The estimated free thyroxine was reduced to 0.15 ng/dl (normal 0.95-2.13 ng/dl). The serum TSH was elevated to 250 /-lU/ml (normal less than 10). Antithyroglobulin antibodies were negative at a dilution of 1:10 using the tanned rbc agglutination technique. Anti-microsomal antibodies were
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BIALAS ET AL.
JCE & M • 1976 Vol 43 • No 6
FIG. 1. I123 thyroid scan performed at time of presentation with myxedema. Note discreet nodular area of homogeneous radioactive iodine uptake.
not determined. Serum cholesterol was 275 mg/dl and serum calcium 10.0 mg/dl. Radioactive iodine uptake was 5.1% at 6 h and 3.9% at 24 h. The scan (Fig. 1) revealed nearly absent uptake with the exception of one functional area approximately 1 cm x 1 cm corresponding to the palpable nodule in the right lobe. The uptake in this area was homogeneous. The clinical diagnosis was myxedema, probably due to Hashimoto's thyroiditis. The patient was initially treated with sodium levothyroxine (Synthroid®) 50 mg daily. She became euthyroid while receiving 100 mg daily. On June 10, 1975, the serum thyroxine was 9.6 jUg/dl and the estimated free thyroxine was 1.12 ng/dl. Since the thyroid nodule appeared unchanged to palpation while she was receiving replacement therapy, she was admitted to the Presbyterian-University Hospital on August 11, 1975,
for elective resection of a possible malignant nodule. The hemoglobin was 12.9 g/dl, the hematocrit was 39.1 vol/dl and the cholesterol was 197 mg/dl. A 2 h thyroid scan was performed using technetium and revealed partial suppression of the previously functioning nodular area (Fig. 2). The patient underwent partial right thyroidectomy on August 13, 1975, with removal of the nodule in the right lobe. The left lobe was described by the surgeon as "paper thin and leathery." No tissue from this area was removed. She had an uneventful post-operative recovery and was discharged on sodium levothyroxine 100 /jig daily. Six months after discharge, antithyroglobulin antibodies were determined and found to be negative at a dilution less than 1:10, and anti-microsomal antibodies were positive at a titer of 1:25,600.
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HASHIMOTO'S FUNCTIONING NODULE
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• f J*
FlG. 2. Technetium 99 thyroid scan performed during the time the patient was being treated with Synthroid®. Note nearly total absence of radioactive uptake.
Results The specimen from the right lobe of the thyroid was a round nodule which measured 2.5 x 1.5 x 0.8 cm, weighed 2.0 g, and was completely surrounded by a thin capsule. The cut surface was pale tan. Microscopically, lymphoid follicles with prominent germinal centers were present diffusely throughout the nodule (Fig. 3). The
parenchyma was disrupted by large collections of chronic inflammatory cells consisting of lymphocytes and plasma cells. The thyroid follicles appeared irregular and decreased in number. The follicular cells demonstrated an eosinophilic cytoplasm and irregular nuclei with prominent nucleoli. Colloid material in the follicles was present but decreased. Chronic inflammatory cells occasionally were seen within the
FIG. 3. Thyroid nodule with diffuse interstitial infiltration by chronic inflammatory cells and lymphoid follicles with prominent germinal centers. Inset: Eosinophilic metaplastic change of the follicular epithelial is illustrated (Hematoxylin and Eosin; X200; inset X450).
•t*
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JCE & M • 1976 Vol 43 • No 6
BIALAS ET AL.
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colloid material. A thin fibrous tissue capsule surrounded the entire specimen, but no other evidence of fibrosis was present. Discussion The diagnosis of Hashimoto's thyroiditis is suggested clinically when there is evidence of a goiter of firm or lobular consistency in a patient who manifests hypothyroidism. The diagnosis is confirmed by demonstrating a high titer of circulating thyroid autoantibodies or by thyroid biopsy (1). The thyroid scan usually demonstrates "patchy" uptake of radioactive iodine (3-6). The patient presented here was unusual because her thyroid scan suggested a functioning "nodule" and anti-thyroglobulin antibodies were not demonstrable on two separate occasions. Although occasional patients with Hashimoto's thyroiditis present with a localized palpable "nodule," these are usually hypofunctioning or "cold" areas on the scan. Presentation as a functioning "nodule" is extremely unusual. We are aware of only one previously reported case of Hashimoto's thyroiditis presenting as a solitary functioning thyroid "nodule" (7). Despite adequate thyroid hormone replacement, the size of the "nodule" did not change. Comparison of the two scans before and after thyroid administration suggests that the functioning tissue in the "nodule" was under TSH stimulation since the area of radioactivity was much less prominent while she was on thyroid medication. However, this interpretation might be criticized because 123I was used before and technetium after thyroid suppression. It has been demonstrated that disparate thyroid imaging may occur between radioactive iodine and pertechnetate (8,9). At the time of clinical presentation, we did not determine antimicrosomal antibodies, and we were surprised to find a titer of this antibody postoperatively in view of persistently negative anti-thyroglobulin antibodies. Over 90% of patients with Hashi-
moto's disease will have positive thyroid autoantibodies (10). Hashimoto's thyroiditis, which is increasingly being designated as autoimmune thyroiditis, occurs in two main forms: i.e., the goitrous and atrophic types. Very little is known of the natural course of these two variants although the work of Vickery and Hamlin seems to establish that the goitrous variety does not progress to atrophy (11). A further difference between the two is that the sex and age incidence is different (12). Both types, however, develop hypothyroidism and have essentially identical microscopic features, although sclerosis is usually predominant in the atrophic type (13). Intermediate forms have rarely been reported (13). Our case, with a 2 g palpable "nodule" in the right lobe and severe atrophy of the left, might represent another such instance. This case is important for two reasons. First, it demonstrates the need to consider Hashimoto's disease when there is evidence of a functioning thyroid "nodule," even though the radioactive iodine uptake is homogeneous and not "patchy." Secondly, it illustrates the need to obtain both antithyroglobulin and anti-microsomal thyroid antibodies when considering this diagnosis. References 1. Williams, R. H., Textbook of Endocrinology, W. B. Saunders Co., Philadelphia, 1974, p. 224. 2. Block, M. A., R. C. Horn, and J. M. Miller, Unilateral thyroid nodules with lymphocytic thyroiditis, Arch Surg 86: 280, 1963. 3. Hung, W., and J. M. LoPresti, Thyroid scintiscans in children and adolescents with chronic lymphocytic thyroiditis,/ Pediatr 77: 302, 1970. 4. Paull, B. R., P. O. Alderson, B. A. Siegel, W. C. Bauer, and R. G. Evens, Thyroid imaging in lymphocytic thyroiditis, Radiology 115: 139, 1975. 5. Boyle, J. A., J. A. Thompson, W. R. Greig, I. M. D. Jackson, and I. T. Boyle, The thyroid scan in patients with Hashimoto's disease, Ada Endocrinol (Kbh) 51: 337, 1966. 6. Hauser, W., H. L. Atkins, W. C. Eckelman, and P.
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HASHIMOTO'S FUNCTIONING NODULE Richard, Thyroid pertechnetate uptake in Hashimoto's disease, Am J of Roentgenol Radium Ther Nucl Med 112: 720, 1971. 7. Werner, S. C , and S. H. Ingbar, The Thyroid, ed. 3, Harper and Row, New York, 1971, p. 227. 8. Shambaugh, G. E., J. L. Quinn, R. Oyasu, and N. Freinkel, Disparate thyroid imaging, JAMA 228: 866, 1974. 9. Usher, M. S., and A. Y. Arqoumanian, Thyroid nodule scans made with pertechnetate and iodine may give inconsistent results, Case report, J Nucl Med 12: 136, 1970.
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10. Werner, S. C , and S. H. Ingbar, The Thyroid, ed. 3, Harper and Row, New York, 1971, p. 864. 11. Vickery, A. L., and E. Hamlin, Jr., Struma lymphomatosa (Hashimoto's thyroiditis): Observations on repeated biopsies in sixteen patients, N EnglJ Med 264: 226, 1961. 12. Bastenie, P. A., M. Bonnyns, and L. Vanhaelst, In Bastenie, P. A., and A. M. Ermans (eds.) Thyroiditis and Thyroid Function, Pergamon Press, Oxford, 1972, p. 211. 13. Sclare, G., The thyroid in myxedema, / Pathol 85: 263, 1963.
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ABSTRACT. A case of hypothyroidism is described in a young woman who on thyroid scan had a discrete functioning "nodule" with homogeneous radioactive iodine uptake, and surrounded by atrophic non-functioning thyroid tissue. Antithyroglobulin antibodies were not demonstrable, but anti-microsomal antibodies were positive at a titer of 1:25,600. Histologically, the "nodule" repre-
C
LINICALLY patients with Hashimoto's thyroiditis may be euthyroid, hypothyroid or rarely hyperthyroid (1,2). Although the thyroid gland is usually diffusely enlarged and of firm consistency, other presentations are also seen. In younger individuals the gland may not be firm and in others the diagnosis is established following surgery for a well-defined palpable nodule. Characteristically, the radioactive iodine scan of the thyroid gland reveals a nonhomogeneous, patchy uptake of the isotope. The appearance may occasionally suggest a discrete non-functioning area raising the possibility of underlying malignancy. Described below is a patient with Hashimoto's disease and hypothyroidism, with a functioning single thyroid "nodule," in which the uptake of radioactive iodine was homogeneous and limited to this area. Case History A 21-year-old white, single, female college student noticed symptoms of weakness, fatigue, lethargy, cold intolerance, depression, and 4.1
Received June 1, 1976. Supported by USPHS Grant AM 06865 and Clinical Research Center Grant RR-00056 from the National Institutes of Health. Reprint requests to: James B. Field, M.D., Director, Clinical Research Unit, 3304 Presbyterian-University Hospital, 230 Lothrop Street, Pittsburgh, Pennsylvania 15261.
kg weight gain in March, 1974, while assigned as a foreign exchange student. She was seen by a physician abroad who diagnosed hypothyroidism. Upon return to the United States in December 1974, she was seen at the outpatient facility of the University of Pittsburgh. She again related her previous symptoms. In addition, her menses had become scant and irregular. She denied constipation, dysphagia, paresthesias, galactorrhea, periorbital edema, or voice or skin changes. There was no family history of thyroid disease and she had never received radiation to the neck area. On physical examination the patient was well developed and in no distress. The blood pressure was 90/60 and the pulse 64 and regular, without orthostatic changes. Temperature was 37 C. The skin was cool and dry. Her hair was dry and somewhat thin with a normal female escutcheon. The entire left thyroid lobe was non-palpable. A 1 cm firm "nodule" was palpable low in the right lobe. It was movable and rubbery in consistency. The remainder of the right lobe felt lobulated and small. There was no expressible galactorrhea. The deep tendon reflexes were characterized by a delayed relaxation phase. The rest of the physical examination was normal. Routine urinalysis and hematologic examinations were normal. Serum thyroxine was 1.5 jig/dl (normal 4.0-10.1 /ng/dl). The estimated free thyroxine was reduced to 0.15 ng/dl (normal 0.95-2.13 ng/dl). The serum TSH was elevated to 250 /-lU/ml (normal less than 10). Antithyroglobulin antibodies were negative at a dilution of 1:10 using the tanned rbc agglutination technique. Anti-microsomal antibodies were
1365
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1366
BIALAS ET AL.
JCE & M • 1976 Vol 43 • No 6
FIG. 1. I123 thyroid scan performed at time of presentation with myxedema. Note discreet nodular area of homogeneous radioactive iodine uptake.
not determined. Serum cholesterol was 275 mg/dl and serum calcium 10.0 mg/dl. Radioactive iodine uptake was 5.1% at 6 h and 3.9% at 24 h. The scan (Fig. 1) revealed nearly absent uptake with the exception of one functional area approximately 1 cm x 1 cm corresponding to the palpable nodule in the right lobe. The uptake in this area was homogeneous. The clinical diagnosis was myxedema, probably due to Hashimoto's thyroiditis. The patient was initially treated with sodium levothyroxine (Synthroid®) 50 mg daily. She became euthyroid while receiving 100 mg daily. On June 10, 1975, the serum thyroxine was 9.6 jUg/dl and the estimated free thyroxine was 1.12 ng/dl. Since the thyroid nodule appeared unchanged to palpation while she was receiving replacement therapy, she was admitted to the Presbyterian-University Hospital on August 11, 1975,
for elective resection of a possible malignant nodule. The hemoglobin was 12.9 g/dl, the hematocrit was 39.1 vol/dl and the cholesterol was 197 mg/dl. A 2 h thyroid scan was performed using technetium and revealed partial suppression of the previously functioning nodular area (Fig. 2). The patient underwent partial right thyroidectomy on August 13, 1975, with removal of the nodule in the right lobe. The left lobe was described by the surgeon as "paper thin and leathery." No tissue from this area was removed. She had an uneventful post-operative recovery and was discharged on sodium levothyroxine 100 /jig daily. Six months after discharge, antithyroglobulin antibodies were determined and found to be negative at a dilution less than 1:10, and anti-microsomal antibodies were positive at a titer of 1:25,600.
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HASHIMOTO'S FUNCTIONING NODULE
1367
• f J*
FlG. 2. Technetium 99 thyroid scan performed during the time the patient was being treated with Synthroid®. Note nearly total absence of radioactive uptake.
Results The specimen from the right lobe of the thyroid was a round nodule which measured 2.5 x 1.5 x 0.8 cm, weighed 2.0 g, and was completely surrounded by a thin capsule. The cut surface was pale tan. Microscopically, lymphoid follicles with prominent germinal centers were present diffusely throughout the nodule (Fig. 3). The
parenchyma was disrupted by large collections of chronic inflammatory cells consisting of lymphocytes and plasma cells. The thyroid follicles appeared irregular and decreased in number. The follicular cells demonstrated an eosinophilic cytoplasm and irregular nuclei with prominent nucleoli. Colloid material in the follicles was present but decreased. Chronic inflammatory cells occasionally were seen within the
FIG. 3. Thyroid nodule with diffuse interstitial infiltration by chronic inflammatory cells and lymphoid follicles with prominent germinal centers. Inset: Eosinophilic metaplastic change of the follicular epithelial is illustrated (Hematoxylin and Eosin; X200; inset X450).
•t*
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JCE & M • 1976 Vol 43 • No 6
BIALAS ET AL.
1368
colloid material. A thin fibrous tissue capsule surrounded the entire specimen, but no other evidence of fibrosis was present. Discussion The diagnosis of Hashimoto's thyroiditis is suggested clinically when there is evidence of a goiter of firm or lobular consistency in a patient who manifests hypothyroidism. The diagnosis is confirmed by demonstrating a high titer of circulating thyroid autoantibodies or by thyroid biopsy (1). The thyroid scan usually demonstrates "patchy" uptake of radioactive iodine (3-6). The patient presented here was unusual because her thyroid scan suggested a functioning "nodule" and anti-thyroglobulin antibodies were not demonstrable on two separate occasions. Although occasional patients with Hashimoto's thyroiditis present with a localized palpable "nodule," these are usually hypofunctioning or "cold" areas on the scan. Presentation as a functioning "nodule" is extremely unusual. We are aware of only one previously reported case of Hashimoto's thyroiditis presenting as a solitary functioning thyroid "nodule" (7). Despite adequate thyroid hormone replacement, the size of the "nodule" did not change. Comparison of the two scans before and after thyroid administration suggests that the functioning tissue in the "nodule" was under TSH stimulation since the area of radioactivity was much less prominent while she was on thyroid medication. However, this interpretation might be criticized because 123I was used before and technetium after thyroid suppression. It has been demonstrated that disparate thyroid imaging may occur between radioactive iodine and pertechnetate (8,9). At the time of clinical presentation, we did not determine antimicrosomal antibodies, and we were surprised to find a titer of this antibody postoperatively in view of persistently negative anti-thyroglobulin antibodies. Over 90% of patients with Hashi-
moto's disease will have positive thyroid autoantibodies (10). Hashimoto's thyroiditis, which is increasingly being designated as autoimmune thyroiditis, occurs in two main forms: i.e., the goitrous and atrophic types. Very little is known of the natural course of these two variants although the work of Vickery and Hamlin seems to establish that the goitrous variety does not progress to atrophy (11). A further difference between the two is that the sex and age incidence is different (12). Both types, however, develop hypothyroidism and have essentially identical microscopic features, although sclerosis is usually predominant in the atrophic type (13). Intermediate forms have rarely been reported (13). Our case, with a 2 g palpable "nodule" in the right lobe and severe atrophy of the left, might represent another such instance. This case is important for two reasons. First, it demonstrates the need to consider Hashimoto's disease when there is evidence of a functioning thyroid "nodule," even though the radioactive iodine uptake is homogeneous and not "patchy." Secondly, it illustrates the need to obtain both antithyroglobulin and anti-microsomal thyroid antibodies when considering this diagnosis. References 1. Williams, R. H., Textbook of Endocrinology, W. B. Saunders Co., Philadelphia, 1974, p. 224. 2. Block, M. A., R. C. Horn, and J. M. Miller, Unilateral thyroid nodules with lymphocytic thyroiditis, Arch Surg 86: 280, 1963. 3. Hung, W., and J. M. LoPresti, Thyroid scintiscans in children and adolescents with chronic lymphocytic thyroiditis,/ Pediatr 77: 302, 1970. 4. Paull, B. R., P. O. Alderson, B. A. Siegel, W. C. Bauer, and R. G. Evens, Thyroid imaging in lymphocytic thyroiditis, Radiology 115: 139, 1975. 5. Boyle, J. A., J. A. Thompson, W. R. Greig, I. M. D. Jackson, and I. T. Boyle, The thyroid scan in patients with Hashimoto's disease, Ada Endocrinol (Kbh) 51: 337, 1966. 6. Hauser, W., H. L. Atkins, W. C. Eckelman, and P.
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HASHIMOTO'S FUNCTIONING NODULE Richard, Thyroid pertechnetate uptake in Hashimoto's disease, Am J of Roentgenol Radium Ther Nucl Med 112: 720, 1971. 7. Werner, S. C , and S. H. Ingbar, The Thyroid, ed. 3, Harper and Row, New York, 1971, p. 227. 8. Shambaugh, G. E., J. L. Quinn, R. Oyasu, and N. Freinkel, Disparate thyroid imaging, JAMA 228: 866, 1974. 9. Usher, M. S., and A. Y. Arqoumanian, Thyroid nodule scans made with pertechnetate and iodine may give inconsistent results, Case report, J Nucl Med 12: 136, 1970.
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10. Werner, S. C , and S. H. Ingbar, The Thyroid, ed. 3, Harper and Row, New York, 1971, p. 864. 11. Vickery, A. L., and E. Hamlin, Jr., Struma lymphomatosa (Hashimoto's thyroiditis): Observations on repeated biopsies in sixteen patients, N EnglJ Med 264: 226, 1961. 12. Bastenie, P. A., M. Bonnyns, and L. Vanhaelst, In Bastenie, P. A., and A. M. Ermans (eds.) Thyroiditis and Thyroid Function, Pergamon Press, Oxford, 1972, p. 211. 13. Sclare, G., The thyroid in myxedema, / Pathol 85: 263, 1963.
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