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Leiomyoma of the thyroid gland
Pathology (1999) 31, pp. 64± 66
LEIOMYOMA OF THE THYROID GLAND S ANDRA A. B IANKIN AND A DRIAN R. C ACHIA Department of Tissue Pathology, Institute of Clinical Pathology and M edical Research, Westmead Hospital, New South Wales, Australia
Summary Primary smooth muscle tumors of the thyroid gland are very rare neoplasms, leiomyosarcomas comprising the majority of these. Only three cases of primary leiomyoma have been reported to date, all of which have occurred in females of varying ages. We present the morphological, immunohistochemical and ultrastructural features of a fourth case of leiomyoma of the thyroid gland, occurring in a postmenopausal woman with a history of uterine leiomyomas. Key words: Immunohistochemistry, leiomyoma, leiomyosarcoma, thyroid gland.
with a maximum diameter of 28 mm. Preoperative FNA sm ears (Fig. 1) and frozen section (Fig. 2) of the lesion revealed a spindle cell neoplasm which was regarded as consistent with the FNA diagnosis of medullary carcinoma. Paraffin sections showed a well circumscribed tumor with an incomplete fibrous pseudocapsule, comprised of interlacing fascicles of relatively monotonous, spindle cells with oval nuclei and pale eosinophilic cytoplasm with indistinct cytoplasmic membranes (Fig. 3). Nucleoli were not prominent and no areas of hemorrhage or necrosis were seen. No mitotic figures were identified. The tumor cells were individually invested by reticulin fibres. Their cytoplasm was red on trichrome staining. Immunohistochemistry was performed using a modified streptavidin± biotin± peroxidase complex method.4 The antibodies used and results obtained are shown in Table 1. Antigen retrieval was performed either by
Accepted 5 October 1998
INTRODUCTION Although leiomyoma is a common tumor, leiomyoma of the thyroid gland is exceptionally rare. Only three cases of primary leiomyoma have been reported to date, all of which have occurred in females of varying ages.1±3 The following case dem onstrates the m orphological, imm unohistochemical and ultrastructural properties of an otherwise typical leiomyoma occurring in an unusual location.
CASE REPORT A 61 yr old Caucasian wom an presented with a lump in her anterior neck, immediately to the right of the midline, that had gradually increased in size over the previous 6 wks. She was clinically and biochemically euthyroid. Her past medical history included osteoarthritis of the lumbar spine, treated with ibuprofen, and hormone replacement therapy with conjugated estrogens for the previous 5 yrs. She had undergone a total abdominal hysterectomy and previously bilateral salpingoophorectomy for menorrhagia secondary to uterine leiomyomas 16 yrs previously. Physical examination revealed a 3 cm diameter nodule in the right lobe of the thyroid gland. This nodule was ªcoldº on a radioisotopic scan with Technetium-99 oxide and homogeneously solid to ultrasonography. Preoperative FNA, performed at another institution, yielded uniform oval to spindle cells and a diagnosis of medullary carcinoma was suggested. Immunocytochemistry for calcitonin was performed on one sm ear from the FNA, however there was insufficient material in this sm ear and surgery was recommended for a definitive diagnosis. At operation, the right lobe of the thyroid was enlarged but there was no adhesion of the gland to adjacent structures. Following frozen section, a total thyroidectomy was performed without complication. The patient was subsequently placed on thyroid hormone replacement therapy and is well 6 mo post-surgery.
PATHOLOGY The capsular surface of the thyroid gland was intact. The cut surface of the right lobe revealed a well circumscribed, apparently encapsulated tumor
Fig. 1 FNA demonstrated uniform oval to spindle cells singly (left frame) and in larger tissue fragments (right frame). (Left frame, Giemsa; right frame, Papanicolaou. Original magnification 3 150.)
Fig. 2 Frozen section revealed an intrathyroidal, solid, non-follicular, non-papillary, spindle cell neoplasm (H& E, original magnification 3 150).
0031±3025/99/010064± 03 1999 Royal College of Pathologists of Australasia
65
LEIOM YOMA OF THE THYR OID GLAND
Fig. 3 Interlacing fascicles of uniform oval to spindle cells are present throughout the lesion (H& E, original magnification 3 50).
treatment of deparaffinised sections by 0.05% pronase in Tris± HCL at pH 7.6 for 5±10 min, or by a recently described microwave pressure cooker method. 5 Appropriate positive and negative (primary antibody deficient) controls were used in all cases. Tissue for electron microscopy was fixed overnight in Karnovsky’s fixative, post-fixed in 2% osm ium tetroxide in 0.1 M cacodylate buffer, alcohol dehydrated and embedded in Spurr epoxy resin. The tissue was sectioned, stained with uranyl acetate and lead citrate, and examined with a Philips 1L CM 10 electron microscope at 70 kV. The cytoplasm of the tumor cells contained many thin actin filaments with focal densities, clustering of organelles around the nuclear poles and many subplasmalemmal pinocytotic vesicles (Fig. 4). Fig. 4 The tumor cells have abundant thin actin filaments with focal densities ( Ý) and subplasmalemmal pinocytotic vesicles ( Þ) (electron micrograph, original magnification 3 42,000).
DISCUSSION Leiomyomas are characterised by intersecting fascicles of spindle cells which have monotonous, round ended nuclei, minimal atypia and scarce m itotic figures. Imm unohistochemically, they express desmin, sm ooth muscle actin and vim entin but are negative for cytokeratin, carcinoembryonic antigen, S-100 protein and epithelial membrane antigen.6 The typical ultrastructural features are those of normal smooth muscle, namely the clustering of Golgi apparatus, sparse mitochondria and a small amount of rough endoplasmic reticulum at the nuclear poles, presence of abundant TABLE 1
intracytoplasmic thin filaments with focal densities and presence of pinocytotic vesicles at the cytoplasmic membrane.7 The intrathyroidal neoplasm reported here, conformed to all these characteristics of leiomyoma as seen in other sites. Although the histogenesis of intrathyroidal leiomyoma is uncertain, it has been postulated that this tumor m ay arise from the smooth muscle of blood vessels or from isolated smooth muscle cells scattered along slender fibrous septa
Immunohistochemistry: materials and results
Antigen
Antibody (clone)
Source
Antibody type
Antigen retrieval method
Result
Desmin
33
Biogenex, CA
Mouse monoclonal
Microwave
+++
Actin
HHF 35
Biogenex, C A
Mouse monoclonal
Nil
+++
Cytokeratin
AE1/AE3
Dako, CA
Mouse monoclonal
Protease
±
Cytokeratin
NCL-5D3
Novocastra, UK
Mouse monoclonal
Protease
±
Estrogen receptor
ID5
Dako, CA
Mouse monoclonal
Microwave
+++
Progesterone receptor
hPRa 2 & hPR a 3
NeoM arkers, CA
Mouse monoclonal
Microwave
+++
Chromogranin
LK2H10
Biogenex, CA
Mouse monoclonal
Microwave
±
Carcinoembryonic antigen
COL-1
Zymed, San Francisco, CA
Mouse monoclonal
Nil
±
S-100 protein
Anti-S-100
Immunotech, France
Rabbit polyclonal
Microwave
±
Calcitonin
Anti-calcitonin
Signet, M A
Rabbit polyclonal
Microwave
±
66
Pathology (1999), 31, February
BIANKIN AND CACHIA
normally present in the thyroid gland. The three previously reported cases have all occurred in females. Although one previously reported case of leiomyosarcom a documented a history of uterine leiomyom as,3 ours is the first case of thyroid leiomyom a with such an association. Uterine leiomyom as are well known to be estrogen sensitive and commonly express both estrogen and progesterone receptors,8 and it is of interest that our patient, with a proven capacity to develop such lesions, also acquired her intrathyroidal leiomyoma while on ovarian hormone replacement therapy, particularly as the tumor was strongly positive for both estrogen and progesterone receptors. However, as the three previously reported intrathyroidal leiomyomas have occurred in pre-pubertal, reproductive age and post-menopausal patients, the role that estrogen plays in the etiology and natural history of this lesion in the thyroid remains uncertain. Furtherm ore, as up to 40% of women have uterine leiomyom as at some time, and there are only four reported cases of intrathyroidal leiomyoma, any association may well be coincidental. On the basis of the presence of a solid, non-follicular and non-papillary, spindle cell neoplasm on frozen section, with small groups and singly dispersed spindle cells on cytological imprints, com bined with the clinical history of a preoperative FN A having suggested m edullary carcinoma, this lesion was reported by one of us (ARC) to be consistent with medullary carcinoma. Although spindle cell variants of medullary carcinoma exist, the lack of any discrete nesting of cells, lack of amyloid, lack of any metachromatic intracytoplasmic granules on the Giemsa stained imprints, good circumscription of the lesion and absence of any mitotic activity were clues, which were available at the tim e of frozen section, that the current lesion was not typical of medullary carcinom a. W hile a definitive diagnosis of leiomyoma may not be possible on frozen section, we suggest that the presence of these clues should prompt
deferral of definitive diagnosis on an intrathyroidal spindle cell neoplasm until thorough morphological and im munohistochemical examination of the paraffin em bedded tissue can be performed. Obtaining sufficient m aterial at preoperative FNA of the thyroid for im munocytochemical staining for calcitonin would also contribute significantly to an accurate diagnosis. In the three previously reported cases of leiomyom a the patients have been free of morbidity following primary resection, as has our patient in the six months since her lesion was excised. Knowledge of the rare occurrence of benign leiomyoma of the thyroid gland m ay help to prevent misdiagnosis of spindle cell neoplasms in this organ. Address for correspondence: ARC, Department of Tissue Pathology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, NSW 2145, Australia.
References 1. Hendrick J, Tuscaloosa A. Leiomyoma of thyroid gland: report of a case. Surgery 1957; 42: 597± 9. 2. Andrion A, Bellis D, Delsedime L, Bussolati G, M azzucco G. Leiomyoma and neurilemoma: report of two unusual non-epithelial tumours of the thyroid gland. Virchows Arch A Pathol Anat 1988; 413: 367± 2. 3. Thompson L, Wenig B, Adair C, Shm ookler B, Heffess C. Primary sm ooth muscle tumours of the thyroid gland. Cancer 1997; 79: 579 ±987. 4. B oenisch T. Staining methods In: Naisch SJ, editor. Dako handbook of immunohistochemical staining methods. Carpinteria, CA: Dako C orporation, 1989. 5. B rassil KE. Antigen retrieval in immunohistochemistry ± a new method using a domestic microwave pressure cooker. Aust J M ed Sci 1997; 18: 84 ± 6. 6. Enzinger FM, Weiss SW. Soft tissue tumours, 3rd ed. St. Louis: Mosby, 1995; Chapter 18, Benign tumours of sm ooth muscle. 7. Ghadially FN. Ultrastructural pathology of the cell and matrix. 3rd ed. London: B utterworths, 1988; 860 ± 4. 8. Wilson E, Yang F, Rees E. Estradiol and progesterone binding in uterine leiomyomata and in normal uterine tissues. Obstet Gynaecol 1980; 1: 20 ± 4.
LEIOMYOMA OF THE THYROID GLAND S ANDRA A. B IANKIN AND A DRIAN R. C ACHIA Department of Tissue Pathology, Institute of Clinical Pathology and M edical Research, Westmead Hospital, New South Wales, Australia
Summary Primary smooth muscle tumors of the thyroid gland are very rare neoplasms, leiomyosarcomas comprising the majority of these. Only three cases of primary leiomyoma have been reported to date, all of which have occurred in females of varying ages. We present the morphological, immunohistochemical and ultrastructural features of a fourth case of leiomyoma of the thyroid gland, occurring in a postmenopausal woman with a history of uterine leiomyomas. Key words: Immunohistochemistry, leiomyoma, leiomyosarcoma, thyroid gland.
with a maximum diameter of 28 mm. Preoperative FNA sm ears (Fig. 1) and frozen section (Fig. 2) of the lesion revealed a spindle cell neoplasm which was regarded as consistent with the FNA diagnosis of medullary carcinoma. Paraffin sections showed a well circumscribed tumor with an incomplete fibrous pseudocapsule, comprised of interlacing fascicles of relatively monotonous, spindle cells with oval nuclei and pale eosinophilic cytoplasm with indistinct cytoplasmic membranes (Fig. 3). Nucleoli were not prominent and no areas of hemorrhage or necrosis were seen. No mitotic figures were identified. The tumor cells were individually invested by reticulin fibres. Their cytoplasm was red on trichrome staining. Immunohistochemistry was performed using a modified streptavidin± biotin± peroxidase complex method.4 The antibodies used and results obtained are shown in Table 1. Antigen retrieval was performed either by
Accepted 5 October 1998
INTRODUCTION Although leiomyoma is a common tumor, leiomyoma of the thyroid gland is exceptionally rare. Only three cases of primary leiomyoma have been reported to date, all of which have occurred in females of varying ages.1±3 The following case dem onstrates the m orphological, imm unohistochemical and ultrastructural properties of an otherwise typical leiomyoma occurring in an unusual location.
CASE REPORT A 61 yr old Caucasian wom an presented with a lump in her anterior neck, immediately to the right of the midline, that had gradually increased in size over the previous 6 wks. She was clinically and biochemically euthyroid. Her past medical history included osteoarthritis of the lumbar spine, treated with ibuprofen, and hormone replacement therapy with conjugated estrogens for the previous 5 yrs. She had undergone a total abdominal hysterectomy and previously bilateral salpingoophorectomy for menorrhagia secondary to uterine leiomyomas 16 yrs previously. Physical examination revealed a 3 cm diameter nodule in the right lobe of the thyroid gland. This nodule was ªcoldº on a radioisotopic scan with Technetium-99 oxide and homogeneously solid to ultrasonography. Preoperative FNA, performed at another institution, yielded uniform oval to spindle cells and a diagnosis of medullary carcinoma was suggested. Immunocytochemistry for calcitonin was performed on one sm ear from the FNA, however there was insufficient material in this sm ear and surgery was recommended for a definitive diagnosis. At operation, the right lobe of the thyroid was enlarged but there was no adhesion of the gland to adjacent structures. Following frozen section, a total thyroidectomy was performed without complication. The patient was subsequently placed on thyroid hormone replacement therapy and is well 6 mo post-surgery.
PATHOLOGY The capsular surface of the thyroid gland was intact. The cut surface of the right lobe revealed a well circumscribed, apparently encapsulated tumor
Fig. 1 FNA demonstrated uniform oval to spindle cells singly (left frame) and in larger tissue fragments (right frame). (Left frame, Giemsa; right frame, Papanicolaou. Original magnification 3 150.)
Fig. 2 Frozen section revealed an intrathyroidal, solid, non-follicular, non-papillary, spindle cell neoplasm (H& E, original magnification 3 150).
0031±3025/99/010064± 03 1999 Royal College of Pathologists of Australasia
65
LEIOM YOMA OF THE THYR OID GLAND
Fig. 3 Interlacing fascicles of uniform oval to spindle cells are present throughout the lesion (H& E, original magnification 3 50).
treatment of deparaffinised sections by 0.05% pronase in Tris± HCL at pH 7.6 for 5±10 min, or by a recently described microwave pressure cooker method. 5 Appropriate positive and negative (primary antibody deficient) controls were used in all cases. Tissue for electron microscopy was fixed overnight in Karnovsky’s fixative, post-fixed in 2% osm ium tetroxide in 0.1 M cacodylate buffer, alcohol dehydrated and embedded in Spurr epoxy resin. The tissue was sectioned, stained with uranyl acetate and lead citrate, and examined with a Philips 1L CM 10 electron microscope at 70 kV. The cytoplasm of the tumor cells contained many thin actin filaments with focal densities, clustering of organelles around the nuclear poles and many subplasmalemmal pinocytotic vesicles (Fig. 4). Fig. 4 The tumor cells have abundant thin actin filaments with focal densities ( Ý) and subplasmalemmal pinocytotic vesicles ( Þ) (electron micrograph, original magnification 3 42,000).
DISCUSSION Leiomyomas are characterised by intersecting fascicles of spindle cells which have monotonous, round ended nuclei, minimal atypia and scarce m itotic figures. Imm unohistochemically, they express desmin, sm ooth muscle actin and vim entin but are negative for cytokeratin, carcinoembryonic antigen, S-100 protein and epithelial membrane antigen.6 The typical ultrastructural features are those of normal smooth muscle, namely the clustering of Golgi apparatus, sparse mitochondria and a small amount of rough endoplasmic reticulum at the nuclear poles, presence of abundant TABLE 1
intracytoplasmic thin filaments with focal densities and presence of pinocytotic vesicles at the cytoplasmic membrane.7 The intrathyroidal neoplasm reported here, conformed to all these characteristics of leiomyoma as seen in other sites. Although the histogenesis of intrathyroidal leiomyoma is uncertain, it has been postulated that this tumor m ay arise from the smooth muscle of blood vessels or from isolated smooth muscle cells scattered along slender fibrous septa
Immunohistochemistry: materials and results
Antigen
Antibody (clone)
Source
Antibody type
Antigen retrieval method
Result
Desmin
33
Biogenex, CA
Mouse monoclonal
Microwave
+++
Actin
HHF 35
Biogenex, C A
Mouse monoclonal
Nil
+++
Cytokeratin
AE1/AE3
Dako, CA
Mouse monoclonal
Protease
±
Cytokeratin
NCL-5D3
Novocastra, UK
Mouse monoclonal
Protease
±
Estrogen receptor
ID5
Dako, CA
Mouse monoclonal
Microwave
+++
Progesterone receptor
hPRa 2 & hPR a 3
NeoM arkers, CA
Mouse monoclonal
Microwave
+++
Chromogranin
LK2H10
Biogenex, CA
Mouse monoclonal
Microwave
±
Carcinoembryonic antigen
COL-1
Zymed, San Francisco, CA
Mouse monoclonal
Nil
±
S-100 protein
Anti-S-100
Immunotech, France
Rabbit polyclonal
Microwave
±
Calcitonin
Anti-calcitonin
Signet, M A
Rabbit polyclonal
Microwave
±
66
Pathology (1999), 31, February
BIANKIN AND CACHIA
normally present in the thyroid gland. The three previously reported cases have all occurred in females. Although one previously reported case of leiomyosarcom a documented a history of uterine leiomyom as,3 ours is the first case of thyroid leiomyom a with such an association. Uterine leiomyom as are well known to be estrogen sensitive and commonly express both estrogen and progesterone receptors,8 and it is of interest that our patient, with a proven capacity to develop such lesions, also acquired her intrathyroidal leiomyoma while on ovarian hormone replacement therapy, particularly as the tumor was strongly positive for both estrogen and progesterone receptors. However, as the three previously reported intrathyroidal leiomyomas have occurred in pre-pubertal, reproductive age and post-menopausal patients, the role that estrogen plays in the etiology and natural history of this lesion in the thyroid remains uncertain. Furtherm ore, as up to 40% of women have uterine leiomyom as at some time, and there are only four reported cases of intrathyroidal leiomyoma, any association may well be coincidental. On the basis of the presence of a solid, non-follicular and non-papillary, spindle cell neoplasm on frozen section, with small groups and singly dispersed spindle cells on cytological imprints, com bined with the clinical history of a preoperative FN A having suggested m edullary carcinoma, this lesion was reported by one of us (ARC) to be consistent with medullary carcinoma. Although spindle cell variants of medullary carcinoma exist, the lack of any discrete nesting of cells, lack of amyloid, lack of any metachromatic intracytoplasmic granules on the Giemsa stained imprints, good circumscription of the lesion and absence of any mitotic activity were clues, which were available at the tim e of frozen section, that the current lesion was not typical of medullary carcinom a. W hile a definitive diagnosis of leiomyoma may not be possible on frozen section, we suggest that the presence of these clues should prompt
deferral of definitive diagnosis on an intrathyroidal spindle cell neoplasm until thorough morphological and im munohistochemical examination of the paraffin em bedded tissue can be performed. Obtaining sufficient m aterial at preoperative FNA of the thyroid for im munocytochemical staining for calcitonin would also contribute significantly to an accurate diagnosis. In the three previously reported cases of leiomyom a the patients have been free of morbidity following primary resection, as has our patient in the six months since her lesion was excised. Knowledge of the rare occurrence of benign leiomyoma of the thyroid gland m ay help to prevent misdiagnosis of spindle cell neoplasms in this organ. Address for correspondence: ARC, Department of Tissue Pathology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, NSW 2145, Australia.
References 1. Hendrick J, Tuscaloosa A. Leiomyoma of thyroid gland: report of a case. Surgery 1957; 42: 597± 9. 2. Andrion A, Bellis D, Delsedime L, Bussolati G, M azzucco G. Leiomyoma and neurilemoma: report of two unusual non-epithelial tumours of the thyroid gland. Virchows Arch A Pathol Anat 1988; 413: 367± 2. 3. Thompson L, Wenig B, Adair C, Shm ookler B, Heffess C. Primary sm ooth muscle tumours of the thyroid gland. Cancer 1997; 79: 579 ±987. 4. B oenisch T. Staining methods In: Naisch SJ, editor. Dako handbook of immunohistochemical staining methods. Carpinteria, CA: Dako C orporation, 1989. 5. B rassil KE. Antigen retrieval in immunohistochemistry ± a new method using a domestic microwave pressure cooker. Aust J M ed Sci 1997; 18: 84 ± 6. 6. Enzinger FM, Weiss SW. Soft tissue tumours, 3rd ed. St. Louis: Mosby, 1995; Chapter 18, Benign tumours of sm ooth muscle. 7. Ghadially FN. Ultrastructural pathology of the cell and matrix. 3rd ed. London: B utterworths, 1988; 860 ± 4. 8. Wilson E, Yang F, Rees E. Estradiol and progesterone binding in uterine leiomyomata and in normal uterine tissues. Obstet Gynaecol 1980; 1: 20 ± 4.