The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 8 2653-2657
Copyright © 1998 by The Endocrine Society
Hypercalcemia Caused by Ectopic Production of Parathyroid Hormone in a Patient with Papillary Adenocarcinoma of the Thyroid Gland
Haruo Iguchi,
Chisato Miyagi,
Kichinobu Tomita,
Shigeto Kawauchi,
Yoko Nozuka,
Masazumi Tsuneyoshi and
Hideyuki Wakasugi
Department of Biochemistry (H.I.), Division of Head and Neck
Surgery (C.M., K.T.), Department of Pathology (S.K.), Division of
Gastroenterology (H.W.), National Kyusyu Cancer Center, Second
Department of Pathology, Faculty of Medicine, Kyusyu University (Y.N.,
M.T.), Fukuoka 815, Japan
Address all correspondence and requests for reprints to: Haruo Iguchi, Department of Biochemistry, National Kyusyu Cancer Center, Notame 3–1-1, Minami-ku, Fukuoka 815, Japan. E-mail:
highuchi{at}nk-cc.go.jp
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Abstract
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Hypercalcemia and elevation of a serum PTH level (9800 pg/mL (normal:
160–520) were found in a 72-yr-old woman who had a lung cancer. She
underwent pulmonary lobectomy for a suspected PTH-producing lung
cancer. However, hypercalcemia and elevation of the serum PTH level
were persistent postoperatively. Subsequent examination, using
parathyroid scintiscanning, revealed a hot spot in the right lower part
of the thyroid gland, suggesting hypercalcemia caused by a parathyroid
tumor. She underwent bilateral exploration of the neck; however, four
apparently normal parathyroid glands were seen. Therefore,
hemithyroidectomy was performed for the possibility of an
intrathyroidal parathyroid adenoma. Serum calcium and PTH levels
declined after this operation. A nodular lesion was found in the cut
sections of the resected specimen, which was consistent with the result
of the scintiscanning. Histological examinations revealed a papillary
adenocarcinoma of the thyroid gland, and the PTH-immunoreactivity in
the tumor cells was confirmed. These findings strongly suggest that PTH
could be produced ectopically by the papillary adenocarcinoma of the
thyroid gland.
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Introduction
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IN CANCER-ASSOCIATED hypercalcemia (CAH),
humoral factors produced by cancer cells act on bone and kidney, which
increase bone resorption and impair calcium excretion. This concept was
first proposed by Albright (1) in 1941, and PTH has been considered as
a candidate that causes hypercalcemia. However, PTH-related protein
(PTHrP) has been isolated and cloned from several tumors in 1987 (2),
and subsequent studies revealed that PTHrP is the main humoral factor
in CAH (3, 4, 5, 6). In contrast, ectopic production of PTH in cancer cells
is very rare, and only six cases have been reported to date (7, 8, 9, 10, 11, 12). We
describe here a patient with hypercalcemia and elevation of serum PTH
concentration caused by thyroid papillary adenocarcinoma.
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Case Report
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A 72-yr-old woman was admitted to our hospital in September, 1993,
because of cough. Laboratory data on admission are shown in Table 1
. Serum calcium was increased (11.5
mg/dL, normal: 8.4–9.8 mg/dL), and serum phosphorus was decreased (2.0
mg/dL, normal: 2.7–4.5 mg/dL). A serum PTH level, determined by an RlA
kit specific for the midregion of PTH (Yamasa Shouyu Co. Ltd., Chiba,
Japan), was increased (9800 pg/mL, normal: 160–520 pg/mL); and a serum
PTHrP level, determined by an RlA kit specific for the C-terminal
portion of PTHrP (Daiichi RI Co. Ltd., Tokyo, Japan), remained in the
normal range (26 pmol/L, normal: 13–55 pmol/L). The other
abnormal data included serum alkaline phosphatase (175 IU/L,
normal: 45–130 IU/L) and serum potassium (3.0 mEq/L, normal:
3.5–4.6 mEq/L). Chest x-ray (Fig. 1) and
computed tomography (CT) disclosed an abnormal mass in the right lower
lung field. She underwent right pulmonary lobectomy for suspected
PTH-producing lung cancer in October, 1993. The histological diagnosis
was that an alveolar cell carcinoma existed. However, hypercalcemia and
elevation of the serum PTH level were persistent postoperatively. Based
on these findings, together with that of a tumor mass in the right
adrenal gland on CT (Fig. 2), further
evaluation of the neck was performed for suspected MEN,
including primary hyperparathyroidism caused by parathyroid adenoma.
Although US and CT failed to identify a putative parathyroid
gland, technetium-thallium scanning revealed a hot spot in the right
lower part of the thyroid gland (Fig. 3).
She underwent bilateral exploration of the neck in January, 1994;
however, four apparently normal parathyroid glands were seen.
Therefore, we considered the possibility of an intrathyroidal
parathyroid adenoma, although palpation of the thyroid gland during
operation failed to identify the presence of a tumor, and we performed
a hemithyroidectomy. Serum levels of calcium, phosphorus, and PTH
during a clinical course are shown in Fig. 4. Serum PTH levels declined, to near the
normal range, after the removal of the right lobe of the thyroid gland.
Tetany was observed immediately after the hemithyroidectomy, and serum
calcium levels were maintained at approximately 9.0–10.0 mg/dL, under
oral treatment with calcium and vitamin D. Serum phosphorus levels also
returned to the normal range after this.
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Figure 3. Parathyroid scintiscanning using
technetium-thallium. A hot spot ( ) was seen in the right lobe of the
thyroid gland.
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After she was discharged in February, 1994, serum levels of calcium,
phosphorus, and PTH had been varied, closer to or within the normal
range (Fig. 4
), until she died of recurrence of the lung cancer in
September 1997.
Histological examination
Cut sections of the resected specimen of the thyroid gland are
shown in Fig. 5. A nodular lesion is seen
in the section closer to isthmus. Histological examination revealed
proliferation of cuboidal carcinoma cells in a papillary and/or
follicular fashion (Fig. 6a). Nuclear
grooves and ground-glass nuclear and intranuclear cytoplasmic inclusion
were observed in the tumor cells (Fig. 6, b and c). Thyroglobulin was
positively stained in the tumor cells (data not shown). Based on these
findings, diagnosis of papillary adenocarcinoma of the thyroid gland
was done.
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Figure 5. Cut sections of the resected specimen (right
lobe of the thyroid gland). A nodular lesion of about 0.4-cm diameter
is indicated by an arrow ().
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Immunohistochemistry of PTH was performed on formalin-fixed
paraffin-embedded sections of the patient’s surgical specimen of the
hemithyroid. Five-micrometer sections were dewaxed and rehydrated with
phosphate-buffered saline. Endogenous peroxidase was blocked by 3%
hydrogenous peroxide. Then, the sections were cooked in an ordinary
kitchen-style microwave oven for 20 min in citrate buffer containing
1% Tween 20 and 6 mol/L urea (pH 6.0), and incubated with a monoclonal
rat anti-PTH (1–34) antibody (Dako, Kyoto, Japan) at 4 C overnight.
The labeled streptavidin-biotin system (Dako) was used to detect
the antibodies. Nuclei were stained with Mayer’s hematoxylin.
Parathyroid adenoma and papillary adenocarcinoma of the thyroid served
as positive and negative controls, respectively.
In this system of the PTH immunohistochemistry, PTH was positively
stained in the parathyroid adenoma (positive control) (Fig. 7a), whereas it was not stained in the
papillary adenocarcinoma of the thyroid (negative control) (Fig. 7b)
and adjacent normal thyroid tissue to the parathyroid adenoma (data not
shown). The tumor cells showed positive staining of PTH (Fig. 7c).
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Figure 7. Immunohistochemical analysis of PTH. a,
Parathyroid adenoma (positive control) (x125); b, papillary
adenocarcinoma of the thyroid (negative control) (x125); c, the
patient’s surgical specimen of the hemithyroid (x200). Positive
staining was found in the parathyroid adenoma (a), whereas PTH was not
stained in the papillary adenocarcinoma of the thyroid (b) and adjacent
normal thyroid tissue to the parathyroid adenoma (data not shown). The
tumor cells showed positive staining of PTH (c).
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Discussion
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CAH is usually ascribed to PTHrP produced by cancer cells, and
that caused by ectopic production of PTH is very rare. In the present
study, we describe a case of ectopic PTH producing thyroid carcinoma.
In our patient, the serum level of PTH was elevated, whereas that of
PTHrP remained in the normal range. After the removal of the
right lobe of the thyroid gland, tetany was observed, and decline of
the serum PTH level closer to the normal range was confirmed. The hot
spot on the technetium-thallium scanning, which was observed in the
right lower part of the thyroid gland before the operation, disappeared
after the hemithyroidectomy was performed. These findings suggest that
PTH was produced in the tissues included in the right lobe of the
thyroid gland other than the parathyroid gland. In fact, a nodular
lesion was found in the lower part of the resected specimen, which was
consistent with the result on the technetium-thallium scanning.
Histological examination revealed papillary and follicular
proliferation of cuboidal carcinoma cells with nuclear grooves and
ground-glass nuclear and intranuclear cytoplasmic inclusion.
Thyroglobulin was present in these carcinoma cells. These findings
indicate that the nodular lesion in the resected specimen was papillary
adenocarcinoma of the thyroid gland. To confirm that tumor cells indeed
produce PTH, PTH mRNA could be identified in the tumor tissue. In our
case, however, a tumor was not found, even by the palpation of the
right lobe of the thyroid gland during operation; therefore, we did not
keep the tumor tissue frozen for Northern blot analysis of the PTH
mRNA. Thus, we performed immunohistochemical analysis using
formalin-fixed paraffin-embedded sections to elucidate production of
PTH in the tumor cells. Positive staining with the anti-PTH antibody
was found in most tumor cells of the papillary adenocarcinoma of the
thyroid gland. All of these findings indicate that PTH was produced by
the thyroidal papillary adenocarcinoma cells, although expression of
the PTH gene in the tumor tissue was not examined. As to the ectopic
PTH-producing tumor, only six cases [i.e. two small cell
lung carcinomas (7, 8), one ovarial cancer (9), one malignant
neuroectodermal tumor (10), one thymoma (11), and one squamous cell
lung carcinoma (12)] were reported to date. The present report is the
first description of ectopic PTH production by papillary adenocarcinoma
of the thyroid gland.
Technetium-thallium scanning is a useful diagnostic tool for the
parathyroid tumor. This scanning also reveals a hot spot in the thyroid
cancer; however, it is easy to distinguish them if serum PTH levels are
determined. In the present case, the papillary adenocarcinoma in the
right lobe of the thyroid gland produced PTH, and a hot spot was
observed on the scanning. This makes it very difficult to distinguish
the thyroid cancer from the parathyroid tumor. The present study
warrants attention in the diagnosis using the parathyroid
scintiscanning.
Received August 6, 1997.
Revised March 18, 1998.
Accepted May 1, 1998.
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Top
Abstract
Introduction
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—
1993–1997). Operation 1, Right middle and lower lobectomy of the
lung (removal of lung cancer); Operation 2, right lobectomy of the
thyroid gland (removal of thyroidal cancer).
), ground-glass nuclear (
) are seen (b and c).