Ultrastructural Observations on a Follicular Carcinoma of the Thyroid Gland SAUL KAY, M.D.,
AND J O S E J. TERZ,
M.D.
Division of Surgical Pathology and Department of Surgery, Medical College of Virginia, Richmond, Virginia
ABSTRACT
of this report is to describe the ultrastructural features of a poorlydifferentiated follicular carcinoma of the thyroid. Various reports concerning ultrastructural studies of thyroid neoplasms have appeared recently. 1,2,4-8 These studies have largely been confined to medullary carcinoma, which has attracted our interest due to the thyrocalcitonin effects and the familial incidence of many tumors. A few reports on papillary carcinomas, Hiirthle cell tumors, follicular adenomas, and anaplastic carcinomas 1,2 ' 4,5,7 are available, but we are unaware of any report of electron-microscopic observations of the purely follicular carcinoma. In our laboratory we rarely see pure follicular carcinoma, as distinguished from the more common mixed follicular and papillary carcinoma. In this regard we concur with Franssila 3 that the distinction between these tumors is of clinical signifi-
T H E PURPOSE
Received May 5, 1975; accepted for publication May 22, 1975. Address reprint request to Dr. Kay: Division of Surgical Pathology, Medical College of Virginia, Richmond, Virginia 23298.
cance. In the case described, the lesion was inoperable at the time of surgery, but sufficient material was available for thorough light- and electron-microscopic study. Report of a Case A 31-year-old black woman was admitted on February 18, 1975, to the Medical College of Virginia, complaining of swelling of the neck, which she had first noticed about two years previously when thyroid medication had been instituted. Pain and discomfort in the neck had begun in July 1974. Hemoptysis and exertional dyspnea had begun 8 days prior to admission. Examination disclosed a large, soft mass, 12 X 5 cm, in the thyroid and cervical regions. A roentgenogram of the chest suggested bilateral pulmonary metastases. A radioiodine scan showed decreased uptake in the left lobe, with a mid-lobe focal "cold" area. The patient was operated upon on the tenth hospital day. T h e left thyroid lobe was removed, and a biopsy of the left supraclavicular area was carried
328
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 7, 2016
Kay, Saul, and Terz, Jose J.: Ultrastructural observations on a follicular carcinoma of the thyroid gland. Am J Clin Pathol 65: 328-336, 1976. Electron microscopic studies were performed on a follicular carcinoma removed from a 31-year-old woman. T h e tumor was poorly differentiated and inoperable but distinctly follicular in pattern. Ultrastructurally, the neoplasm had many of the features of papillary carcinoma, follicular adenoma, and anaplastic carcinoma. Due to the presence of secretory granules it even somewhat resembled medullary carcinoma, but the granules were distinctly larger, and the production of amyloid was definitely excluded. (Key words: Follicular carcinoma of thyroid; Electron microscopy.)
\
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;^-*L. FIG. 2. Low-power view; showing compact tumor cells and fibrous septa. Xote capillary space on the left. Lysosomal granules can be seen at this magnification. X2500.
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 7, 2016
Vi*5i3*sai»*"j
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FIG. 1. Photomicrograph of thyroid neoplasm. T h e tumor cells are compact but show a follicular pattern. Note small colloid droplet in center of field. Hematoxylin and eosin. x240.
330
KAY AND TERZ
A.J.C.P. —Vol. 65
out. She was discharged on March 10,1975, for radiation therapy as an outpatient.
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 7, 2016
They were fixed in 2% cacodylate-buffered glu tar aldehyde for two hours, postfixed in 2% cacodylate-buffered osmic acid for 1 hour, dehydrated in graded alcohols and Pathology Findings propylene oxide, and embedded in Epon Light Microscopy. Gross description (S-75812. Following selection of appropriate 2244). T h e left thyroid lobe consisted of a areas from thin-thick sections, ultrathin mass, 6 x 5 x 3 cm. T h e external surface sections were made with a diamond knife was hemorrhagic and lobulated. Sectioning using an MT-2 ultramicrotome, and the disclosed obvious friable tan tumor with sections stained with uranyl acetate and yellow areas of necrosis, foci of hemorrhage, and fibrous bands. T h e neoplasm appeared lead citrate and examined with an Hitachi to extend through the capsule. A second HS 8F 2 electron microscope. A low-power view showed compact tumor specimen was submitted as a biopsy from the left lobe. Frozen-section examination cells subdivided by fibrous septa and adjawas carried out, and tissue from this biopsy cent to blood vessels (Fig. 2). Even at this specimen, which measured 2 x 1.5 x 0.5 power, lysosomal dense bodies could be cm., was prepared for electron microscopy. seen in many of the tumor cells. T h e plasma It was pink-tan and firm. Finally, a biopsy of membranes were intertwined, and desmothe supraclavicular region was done. T h e somal attachments were seen in many areas tissue was fragmented and 1 cm. in maximal (Figs. 3 and 4). Higher magnifications of dimension. the dense bodies showed that they were membrane-bound, with a narrow, lucent Following routine fixation in Zenker's fluid, the tissue was stained with hematoxylin zone beneath the membrane (Fig. 8). They and eosin, as well as Congo red and crystal ranged from 118 to 455 nm. in diameter. T h e Golgi apparatuses were prominent in violet stains for amyloid. T h e neoplasm consisted of closely- many of the cells (Fig. 7). Mitochondria compacted cells arranged in lobules sep- were scattered, with well-preserved cristae arated by thin capillary spaces. T h e (Fig. 6). Both smooth and rough endotumor cells were cuboidal or low columnar plasmic reticulum were observed, and in with generally clear cytoplasm. They were some areas the rough ER was prominent arranged in a follicular pattern, and fre- and stacked (Figs. 4 and 8). A few cells quently there were distinct lumina filled contained lipid vacuoles (Fig. 6). There was with colloid material (Fig. 1). In some areas evidence of colloid secretion between the follicular pattern was quite prominent, tumor cells (Fig. 5). Occasional nuclei but colloid secretion was minimal. Thick contained a single inclusion body of unand thin fibrous bands traversed the tumor known significance (Fig. 3). Microvilli in irregular fashion. Sometimes these bands could be identified, but were not prominent were prominent and intensely eosin- due to the general compactness of the staining. Amyloid stains were uniformly tumor cells and complicated folding of the negative. T h e supraclavicular biopsy was plasma membrane. A rare cilium was pure tumor, and no lymph node tissue was identified (Fig. 9). In the extracellular space distinct microfibrils with irregular identified. Electron Microscopy. The tissue from the periodicity, approximately 230 A in thickbiopsy was minced into 1 cu. mm. blocks. ness, were seen (Fig. 6). They were pre-
March 1976
FOLLICULAR CARCINOMA OF THYROID
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Fic. 3. More detailed view, showing irregular folds of plasma membranes and desmosomal attachments. Lysosomal dense bodies are prominent, x 11,250.
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 7, 2016
^
332
KAY AND TERZ
A.J.C.P.—Vol. 65
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 7, 2016
FIG. 4. T h r e e adjacent tumor cells with intertwining plasma membranes. Note secretory granules, Golgi apparatus and stacks of rough endoplasmic reticulum, x 1 1,250.
March 1976
333
FOLLICULAR CARCINOMA OF THYROID
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Fie. 5. Two adjacent tumor cells with colloid secretion in center of field. X 15,500.
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 7, 2016
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FIG. 6 (upper). Microfibrils in extracellular space. T h e basal lamina is incomplete and ill-defined. Lipid inclusions and dense bodies can be seen. x21,250. FIG. 7 (lower). T u m o r cell with prominent Golgi apparatus and dense bodies. X27,500.
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*.,
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*,
FIG. 8 (upper). Detailed view of lysosomal granules, showing that they are membrane-bound with a narrow lucent zone beneath the membrane. T h e granules tend to be elongated or oval. Stacks of rough endoplasmic reticulum surround the granules. x 42,500. FIG. 9 (lower). Structure identified as cilium in lower portion of photograph. Vesicular bodies and glycogen granules can also be identified. X50.000.
336
KAY AND TERZ
sumed to represent tropocollagen. Basal laminae were indistinct. Discussion
carcinoma are distinctly smaller, however, and in the absence of amyloid production should pose no problem in histiologic differentiation. References 1. Albores-Saavedra J, Altamirano-Dimas M, Alcorta-Anquizola B, et al: Fine structure of human papillary thyroid carcinoma. Cancer 28: 763-774, 1971 2. Feldman PS, Horvath E, Kovacs K: Ultrastructure of three Hurthle cell tumors of the thyroid. Cancer 30:1279-1285, 1972 3. Franssila KO: Is the differentiation between papillary and follicular thyroid carcinoma valid? Cancer 32:853-864, 1973 4. Gould VE, Gould NS, Bendiu EP: Ultrastructural aspects of papillary and sclerosing carcinomas of the thyroid. Cancer 29:1613-1625, 1972 5. Graham H, Daniel C: Ultrastructure of an anaplastic carcinoma of the thyroid. Am J Clin Pathol 61:690-696, 1974 6. Ibanez ML: Medullary carcinoma of the thyroid gland, Pathology Annual. Appleton, Century, Crofts, 1974, pp 263-290 7. Lupulescu AP, Boyd CB: Follicular adenoma (an ultrastructural and scanning electron microscopy study.) Arch Pathol 93:492-502, 1972 8. Tateishi R, Takahashi Y, Noguchi H: Histologic and ultracytochemical studies on thyroid medullary carcinoma. Cancer 30:755-763, 1972 ADDENDUM
Following submission o f this m a n u s c r i p t , two p e r t i n e n t p a p e r s h a v e a p p e a r e d in t h e l i t e r a t u r e . B o t h deal with t h e u l t r a s t r u c t u r a l f e a t u r e s of t h y r o i d c a r c i n o m a a n d in t h e latter p a p e r follicular c a r c i n o m a is d e s c r i b e d . T h e r e f e r e n c e s follow: 1. Gaal JM, Horrath E, Kovacs K: Ultrastructure of two cases of anaplastic giant cell tumor of the human thyroid gland. Cancer 3 5 : 1 2 7 3 1279, 1975 2. Jao W, Gould VE: Ultrastructure of anaplastic (spindle and giant cell) carcinoma of the thyroid. Cancer 35:1280-1292, 1975
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 7, 2016
The ultrastructural features of a follicular thyroid carcinoma complete information about the various types of thyroid neoplasms as seen with the electron microscope. In actuality the characteristics of follicular carcinoma duplicate some of the findings already reported for papillary carcinoma, 1,4 follicular adenoma, 7 and anaplastic carcinoma. 5 For example, lysosomal bodies were found in all these neoplasms, and, as stated by Graham and Daniel, 5 these bodies in general were larger than those seen in medullary carcinoma. We found cilia in our case of follicular carcinoma. This is not unique, since cilia have been identified in many varieties of neoplasms. With the scanning electron microscope, Lupulescu and Boyd 7 found cilia quite readily in follicular adenomas. We are unable to attach any significance to the presence of nuclear inclusion bodies. They were seen in five papillary thyroid tumors reported by Albores-Saavedra and associates.1 Microfibrils were also found by these investigators in the papillary tumors. Microfibrillary material was present in the stroma in Graham and Daniel's case of anaplastic carcinoma. 5 While collagen production was not in evidence, these fibers had distinct periodicity in our case and were presumed to be tropocollagen. T h e ultrastructures of all thyroid tumors seem to have certain features in common. T h e lysosomal granules of medullary
A.J.C.P. —Vol. 65
AND J O S E J. TERZ,
M.D.
Division of Surgical Pathology and Department of Surgery, Medical College of Virginia, Richmond, Virginia
ABSTRACT
of this report is to describe the ultrastructural features of a poorlydifferentiated follicular carcinoma of the thyroid. Various reports concerning ultrastructural studies of thyroid neoplasms have appeared recently. 1,2,4-8 These studies have largely been confined to medullary carcinoma, which has attracted our interest due to the thyrocalcitonin effects and the familial incidence of many tumors. A few reports on papillary carcinomas, Hiirthle cell tumors, follicular adenomas, and anaplastic carcinomas 1,2 ' 4,5,7 are available, but we are unaware of any report of electron-microscopic observations of the purely follicular carcinoma. In our laboratory we rarely see pure follicular carcinoma, as distinguished from the more common mixed follicular and papillary carcinoma. In this regard we concur with Franssila 3 that the distinction between these tumors is of clinical signifi-
T H E PURPOSE
Received May 5, 1975; accepted for publication May 22, 1975. Address reprint request to Dr. Kay: Division of Surgical Pathology, Medical College of Virginia, Richmond, Virginia 23298.
cance. In the case described, the lesion was inoperable at the time of surgery, but sufficient material was available for thorough light- and electron-microscopic study. Report of a Case A 31-year-old black woman was admitted on February 18, 1975, to the Medical College of Virginia, complaining of swelling of the neck, which she had first noticed about two years previously when thyroid medication had been instituted. Pain and discomfort in the neck had begun in July 1974. Hemoptysis and exertional dyspnea had begun 8 days prior to admission. Examination disclosed a large, soft mass, 12 X 5 cm, in the thyroid and cervical regions. A roentgenogram of the chest suggested bilateral pulmonary metastases. A radioiodine scan showed decreased uptake in the left lobe, with a mid-lobe focal "cold" area. The patient was operated upon on the tenth hospital day. T h e left thyroid lobe was removed, and a biopsy of the left supraclavicular area was carried
328
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 7, 2016
Kay, Saul, and Terz, Jose J.: Ultrastructural observations on a follicular carcinoma of the thyroid gland. Am J Clin Pathol 65: 328-336, 1976. Electron microscopic studies were performed on a follicular carcinoma removed from a 31-year-old woman. T h e tumor was poorly differentiated and inoperable but distinctly follicular in pattern. Ultrastructurally, the neoplasm had many of the features of papillary carcinoma, follicular adenoma, and anaplastic carcinoma. Due to the presence of secretory granules it even somewhat resembled medullary carcinoma, but the granules were distinctly larger, and the production of amyloid was definitely excluded. (Key words: Follicular carcinoma of thyroid; Electron microscopy.)
\
'.'••.^v-'t»m'*'
'"'H.-'
;^-*L. FIG. 2. Low-power view; showing compact tumor cells and fibrous septa. Xote capillary space on the left. Lysosomal granules can be seen at this magnification. X2500.
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 7, 2016
Vi*5i3*sai»*"j
* \V
FIG. 1. Photomicrograph of thyroid neoplasm. T h e tumor cells are compact but show a follicular pattern. Note small colloid droplet in center of field. Hematoxylin and eosin. x240.
330
KAY AND TERZ
A.J.C.P. —Vol. 65
out. She was discharged on March 10,1975, for radiation therapy as an outpatient.
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 7, 2016
They were fixed in 2% cacodylate-buffered glu tar aldehyde for two hours, postfixed in 2% cacodylate-buffered osmic acid for 1 hour, dehydrated in graded alcohols and Pathology Findings propylene oxide, and embedded in Epon Light Microscopy. Gross description (S-75812. Following selection of appropriate 2244). T h e left thyroid lobe consisted of a areas from thin-thick sections, ultrathin mass, 6 x 5 x 3 cm. T h e external surface sections were made with a diamond knife was hemorrhagic and lobulated. Sectioning using an MT-2 ultramicrotome, and the disclosed obvious friable tan tumor with sections stained with uranyl acetate and yellow areas of necrosis, foci of hemorrhage, and fibrous bands. T h e neoplasm appeared lead citrate and examined with an Hitachi to extend through the capsule. A second HS 8F 2 electron microscope. A low-power view showed compact tumor specimen was submitted as a biopsy from the left lobe. Frozen-section examination cells subdivided by fibrous septa and adjawas carried out, and tissue from this biopsy cent to blood vessels (Fig. 2). Even at this specimen, which measured 2 x 1.5 x 0.5 power, lysosomal dense bodies could be cm., was prepared for electron microscopy. seen in many of the tumor cells. T h e plasma It was pink-tan and firm. Finally, a biopsy of membranes were intertwined, and desmothe supraclavicular region was done. T h e somal attachments were seen in many areas tissue was fragmented and 1 cm. in maximal (Figs. 3 and 4). Higher magnifications of dimension. the dense bodies showed that they were membrane-bound, with a narrow, lucent Following routine fixation in Zenker's fluid, the tissue was stained with hematoxylin zone beneath the membrane (Fig. 8). They and eosin, as well as Congo red and crystal ranged from 118 to 455 nm. in diameter. T h e Golgi apparatuses were prominent in violet stains for amyloid. T h e neoplasm consisted of closely- many of the cells (Fig. 7). Mitochondria compacted cells arranged in lobules sep- were scattered, with well-preserved cristae arated by thin capillary spaces. T h e (Fig. 6). Both smooth and rough endotumor cells were cuboidal or low columnar plasmic reticulum were observed, and in with generally clear cytoplasm. They were some areas the rough ER was prominent arranged in a follicular pattern, and fre- and stacked (Figs. 4 and 8). A few cells quently there were distinct lumina filled contained lipid vacuoles (Fig. 6). There was with colloid material (Fig. 1). In some areas evidence of colloid secretion between the follicular pattern was quite prominent, tumor cells (Fig. 5). Occasional nuclei but colloid secretion was minimal. Thick contained a single inclusion body of unand thin fibrous bands traversed the tumor known significance (Fig. 3). Microvilli in irregular fashion. Sometimes these bands could be identified, but were not prominent were prominent and intensely eosin- due to the general compactness of the staining. Amyloid stains were uniformly tumor cells and complicated folding of the negative. T h e supraclavicular biopsy was plasma membrane. A rare cilium was pure tumor, and no lymph node tissue was identified (Fig. 9). In the extracellular space distinct microfibrils with irregular identified. Electron Microscopy. The tissue from the periodicity, approximately 230 A in thickbiopsy was minced into 1 cu. mm. blocks. ness, were seen (Fig. 6). They were pre-
March 1976
FOLLICULAR CARCINOMA OF THYROID
331
^13
Jit
•••'-•• ^- ;v
< W v ; ^
:
Fic. 3. More detailed view, showing irregular folds of plasma membranes and desmosomal attachments. Lysosomal dense bodies are prominent, x 11,250.
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 7, 2016
^
332
KAY AND TERZ
A.J.C.P.—Vol. 65
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 7, 2016
FIG. 4. T h r e e adjacent tumor cells with intertwining plasma membranes. Note secretory granules, Golgi apparatus and stacks of rough endoplasmic reticulum, x 1 1,250.
March 1976
333
FOLLICULAR CARCINOMA OF THYROID
r. ... .»*•>
•v*
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f}$
*-j
iv
•' 4'.'•
* -%
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V
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Fie. 5. Two adjacent tumor cells with colloid secretion in center of field. X 15,500.
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 7, 2016
\j/i
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 7, 2016
FIG. 6 (upper). Microfibrils in extracellular space. T h e basal lamina is incomplete and ill-defined. Lipid inclusions and dense bodies can be seen. x21,250. FIG. 7 (lower). T u m o r cell with prominent Golgi apparatus and dense bodies. X27,500.
Nfe Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 7, 2016
*.,
•*"%4^3& ^> '*iK.-*
*?^U,A'
.KiJ'
*,
FIG. 8 (upper). Detailed view of lysosomal granules, showing that they are membrane-bound with a narrow lucent zone beneath the membrane. T h e granules tend to be elongated or oval. Stacks of rough endoplasmic reticulum surround the granules. x 42,500. FIG. 9 (lower). Structure identified as cilium in lower portion of photograph. Vesicular bodies and glycogen granules can also be identified. X50.000.
336
KAY AND TERZ
sumed to represent tropocollagen. Basal laminae were indistinct. Discussion
carcinoma are distinctly smaller, however, and in the absence of amyloid production should pose no problem in histiologic differentiation. References 1. Albores-Saavedra J, Altamirano-Dimas M, Alcorta-Anquizola B, et al: Fine structure of human papillary thyroid carcinoma. Cancer 28: 763-774, 1971 2. Feldman PS, Horvath E, Kovacs K: Ultrastructure of three Hurthle cell tumors of the thyroid. Cancer 30:1279-1285, 1972 3. Franssila KO: Is the differentiation between papillary and follicular thyroid carcinoma valid? Cancer 32:853-864, 1973 4. Gould VE, Gould NS, Bendiu EP: Ultrastructural aspects of papillary and sclerosing carcinomas of the thyroid. Cancer 29:1613-1625, 1972 5. Graham H, Daniel C: Ultrastructure of an anaplastic carcinoma of the thyroid. Am J Clin Pathol 61:690-696, 1974 6. Ibanez ML: Medullary carcinoma of the thyroid gland, Pathology Annual. Appleton, Century, Crofts, 1974, pp 263-290 7. Lupulescu AP, Boyd CB: Follicular adenoma (an ultrastructural and scanning electron microscopy study.) Arch Pathol 93:492-502, 1972 8. Tateishi R, Takahashi Y, Noguchi H: Histologic and ultracytochemical studies on thyroid medullary carcinoma. Cancer 30:755-763, 1972 ADDENDUM
Following submission o f this m a n u s c r i p t , two p e r t i n e n t p a p e r s h a v e a p p e a r e d in t h e l i t e r a t u r e . B o t h deal with t h e u l t r a s t r u c t u r a l f e a t u r e s of t h y r o i d c a r c i n o m a a n d in t h e latter p a p e r follicular c a r c i n o m a is d e s c r i b e d . T h e r e f e r e n c e s follow: 1. Gaal JM, Horrath E, Kovacs K: Ultrastructure of two cases of anaplastic giant cell tumor of the human thyroid gland. Cancer 3 5 : 1 2 7 3 1279, 1975 2. Jao W, Gould VE: Ultrastructure of anaplastic (spindle and giant cell) carcinoma of the thyroid. Cancer 35:1280-1292, 1975
Downloaded from http://ajcp.oxfordjournals.org/ by guest on June 7, 2016
The ultrastructural features of a follicular thyroid carcinoma complete information about the various types of thyroid neoplasms as seen with the electron microscope. In actuality the characteristics of follicular carcinoma duplicate some of the findings already reported for papillary carcinoma, 1,4 follicular adenoma, 7 and anaplastic carcinoma. 5 For example, lysosomal bodies were found in all these neoplasms, and, as stated by Graham and Daniel, 5 these bodies in general were larger than those seen in medullary carcinoma. We found cilia in our case of follicular carcinoma. This is not unique, since cilia have been identified in many varieties of neoplasms. With the scanning electron microscope, Lupulescu and Boyd 7 found cilia quite readily in follicular adenomas. We are unable to attach any significance to the presence of nuclear inclusion bodies. They were seen in five papillary thyroid tumors reported by Albores-Saavedra and associates.1 Microfibrils were also found by these investigators in the papillary tumors. Microfibrillary material was present in the stroma in Graham and Daniel's case of anaplastic carcinoma. 5 While collagen production was not in evidence, these fibers had distinct periodicity in our case and were presumed to be tropocollagen. T h e ultrastructures of all thyroid tumors seem to have certain features in common. T h e lysosomal granules of medullary
A.J.C.P. —Vol. 65
