Water-Clear Cell Adenoma of the Mediastinal Parathyroid Gland
Deniz ARIK1, Emine DÜNDAR1, Evrim YILMAZ1, Cumhur SİVRİKOZ2
1Department of Pathology, Eskisehir Osmangazi University, Medicine Faculty, ESKİŞEHİR, TURKEY
2Department of Thorax Surgery, Eskisehir Osmangazi University, Medicine Faculty, ESKİŞEHİR, TURKEY
Keywords: Water-clear cell, Adenoma, Ectopic tissue, Mediastinum, Parathyroid gland
Water-clear cell adenoma of the parathyroid gland is a rare neoplasm that consists of cells with abundant clear-pink cytoplasm. There have
only been 19 cases reported in the English literature. Here we report a case of water-clear cell adenoma of the mediastinal parathyroid gland.
A 70-year-old male patient presented to the hospital with back pain and a mediastinal mass 6 cm in size was detected. After excision and
microscopic evaluation, uniform, large clear cells with fine cytoplasmic vacuolization, without nuclear atypia, and arranged in solid and acinar
patterns were revealed. The cells formed nests that were separated by fine fibrovascular septae and stained positively with anti-parathyroid
hormone. To the best of our knowledge, this has not been previously reported in this location. In the differential diagnosis of clear cell lesions of
the mediastinum, water-clear cell parathyroid adenoma should be considered.
Water-clear cell parathyroid adenoma (WCCA) is very
rare. Only nineteen cases have been reported in the English
. Water-clear cells (WCCs) are large
polygonal cells with a small nucleus and large optically
clear cytoplasm. Albright first described these histological
features in 193418
. WCCs are not seen in normal human
parathyroid glands. Their presence has been associated
with parathyroid hyperfunction. These cells are considered
to represent an end stage of hyperplastic chief cells19
In relation to embryological migration patterns, abnormal
parathyroid tissues can occur in ectopic locations. Ectopic
locations include the superior mediastinum and thymus
and areas behind the esophagus or within the thyroid20.
Here, we present a 70-year-old man with WCCA presenting
as a mediastinal mass. To the best of our knowledge, this
is the first reported case of WCCA with a mediastinal
location. In the differential diagnosis of clear cell lesions of
the mediastinum, WCCA should be considered.
A 70-year-old man presented to the hospital with back
pain. On computed tomography, a mediastinal mass,
6 cm in size, was detected between the esophagus and
trachea (Figure 1
). There were mild osteoporotic changes
at the thoracal vertebrae. Positron emission tomography
computed tomography (PET-CT) revealed that the mass did not have high glycolytic activity. The serum calcium and
parathyroid hormone levels were not evaluated. Surgical
excision was planned by the initial diagnosis of a bronchial
cyst, pathological lymph node or low-grade malignancy.
In open surgery, by intraoperative consultation (frozen
section) of the biopsy, a lesion with clear cells was seen, but
the biologic behavior of the lesion could not be assessed.
The mass was excised, and the operation was finished.
Macroscopically, the specimen measured 6x2.5x2
cm in size. It was soft, brown, and almost completely
encapsulated. Upon microscopic evaluation, uniform,
large clear cells with fine cytoplasmic vacuolization,
arranged in solid and acinar patterns, were revealed
(Figure 2). There was no lymphatic or vascular invasion,
extracapsular extension, pleomorphism, necrosis or
mitotic activity. A rim of compressed parathyroid tissue
was identified at the periphery of the tumor (Figure 3). In
the immunohistochemical evaluation, the tumor cells were
positive for cytokeratin (Ventana, AE1/AE3/PCK26, USA),
chomogranin (Ventana, LK2H10, USA), synaptophysin
(Ventana, SP11, USA) and parathyroid hormone (Ventana,
MRQ-31, USA) (Figure 4), but the cells were negative for
TTF-1 (Ventana, SP141, USA), and thyroglobulin (Ventana,
2H11+6E1, USA), vimentin (Ventana, v9, USA), CD10
(Ventana, SP67, USA), and the RCC marker (Ventana, PN-
15, USA). The tumor was diagnosed as Water-clear cell
adenoma of the ectopic parathyroid gland. Two weeks after
surgery, the serum parathyroid hormone level was 63.3 pg/ ml (reference range 15-65) and the calcium level was 9.3
mg/dL. At 50 months of follow-up, there is no evidence of
Click Here to Zoom
|Figure 3: Compressed parathyroid tissue identified at the
periphery of the tumor (H&E; x100).
The adult parathyroid predominantly consists of chief and
oxyphilic cells. The water-clear cells are not part of the
normal histology of the parathyroid gland. Roth suggested
that WCCs are transformed from chief cells, and the
presence of these cells is most commonly associated with
. Miettinen et al. postulated that
all types of parathyroid parenchymal cells, including chief
cells, oxyphilic cells and WCCs, are variants of a single
. Chen et al. considered that the occurrence
of water-clear cells might represent hyperfunction of the parathyroid glands in SAMP6 (Senescence-accelerated
mouse prone 6) mice22
Most of the cases of WCCA have presented with
hyperparathyroidism. Kanda et al. hypothesized that
due to the large size of the adenoma compared with the
biochemical and clinical features, WCC adenomas have
a low endocrinological activity and that the calcium
level is not elevated until the adenoma has reached a
considerable size6. In our case, the adenoma was 6 cm in
one dimension, making it one of the largest WCCAs ever
Primary hyperparathyroidism is characterized by the
autonomous production of parathyroid hormone, resulting
in hypercalcemia. It is most commonly seen with sporadic adenomas, which is followed by hyperplasia, multiple
adenomas, and carcinoma. Water-clear cell parathyroid
adenoma is extremely rare. There have only been 19 cases
reported in the English literature (Table I). In 20 cases
(including the present case), the mean age is 57.4 (18-81).
In 10 cases, adenomas were seen at the lower left lobe (one
of them is a double adenoma). Five were located in the
upper right (one of them is a double adenoma) and, 3 were
at the upper left lobe. Only three of the 20 adenomas were
ectopic. Two of them were intrathyroidal4,17 and one
was mediastinal WCCA (the present case).
Click Here to Zoom
|Table I: Summary of reported cases of water-clear cell adenoma of the parathyroid gland
The presence of ectopic parathyroid tissue has been
attributed to abnormal migration during embryogenesis.
The superior parathyroids develop from the fourth
pharyngeal pouch, and the inferior parathyroids develop
from the third. The inferior parathyroids migrate a greater
distance, and they do so in conjunction with thymic
tissue. Therefore, these are more likely to be found in ectopic sites23. Phitayakorn and McHenry reported
that 37 (16%) of 231 patients who underwent operations
for hyperparathyroidism had ectopic parathyroid glands.
Ectopic parathyroid glands were superior in 14 (38%)
and inferior in 23 (62%) patients. Superior glands were
found in the tracheoesophageal groove in 6 (43%), in
the retroesophageal in 3 (22%), in the posterosuperior
mediastinum in 2 (14%), in the intrathyroidal area in
1 (7%), within the carotid sheath in 1 (7%), and in the
paraesophageal area in 1 (7%) patient. Inferior glands were
found in the thymus in 7 (30%), in the anterosuperior
mediastinum in 5 (22%), in the intrathyroidal area in
5 (22%), in the thyrothymic ligament in 4 (17%), and
undescended in a submandibular location in 2 (9%)
patients24. Of these locations, our case is consistent with
the posterosuperior mediastinal location. Only two of the
tumors were ectopic (intrathyroidal) in 19 reported cases of
WCCA4. Our case is the third case located at an ectopic
site, and it is unique according to its mediastinal location.
The differential diagnosis of WCCA includes WCC
hyperplasia of the parathyroid, parathyroid chief cell
adenoma with focal clear cell change, clear cell changes
in a thyroid tumor, clear cell lung tumors, paraganglioma,
metastatic renal cell carcinoma, clear cell sarcoma,
thymic carcinoma of rare clear cell type, germ cell
tumors (seminoma and dysgerminoma) and parathyroid
carcinoma. Classic WCC hyperplasia is a diffuse lesion in
which all glands are enlarged20. Foci of WCCs can be
seen in chief cell adenoma of the parathyroid, but they are
admixed with chief cells2. Clear cell changes can occur in
thyroid neoplasms of various microscopic types, including
Hurthle cell tumors, follicular adenomas, papillary
carcinomas, and anaplastic carcinomas25. Paraganglioma
may be diagnosed based on the presence of rosettes and
Zellballen structures. In metastatic renal cell carcinoma,
the useful histologic features in the differential diagnosis
with WCCA include multiplicity of the nodules, optically
clear cytoplasm, sinusoidal type blood vessels, intraluminal
hemorrhage, and high levels of cytoplasmic glycogen and
fat25. In clear cell sarcoma, nuclear pleomorphism and
prominent nucleoli may be useful in differential diagnosis.
Thymic carcinoma consists of spindle shaped or epithelioid
cells. Carcinoma of the thymus with clear cell features is
composed of cells with clear cytoplasm and rather bland
nuclear features, and shows a lobular or occasionally
sheet-like growth pattern26. Seminoma have polygonal
shaped nuclei and thin fibrous bands with lymphocytes.
Parathyroid carcinoma is rare but should be included in
the differential diagnosis. Water-clear cell carcinoma of the
parathyroid gland has also been reported25. Unequivocal
vascular invasion, perineural invasion, gross invasion into
adjacent anatomic structures and metastases are features
of carcinoma27. The methylation profile of parathyroid
tumors has been shown to distinguish adenoma from
carcinoma28. In the differentiation of parathyroid
carcinoma from benign tumors, decreased expression of parafibromin, Bcl-2a, retinoblastoma (Rb), and p27 with
PGP9.5 positivity may be helpful29-31. In addition to
being useful, immunohistochemical stains are essential for
avoiding a misdiagnosis (Table II).
Click Here to Zoom
|Table II: Useful immunohistochemical panel in differential diagnosis of WCCA
In conclusion, even though water-clear cell lesions of
the parathyroid are rare, they should be considered in
the differential diagnosis of clear cell lesions of the neck.
Additionally the ectopic location should be considered for
1) Kovacs K, Horvath E, Ozawa Y, Yamada S, Matushita H. Large
clear cell adenoma of the parathyroid in a patient with MEN-
1 syndrome. Ultrastructural study of the tumour exhibiting
unusual RER formations. Acta Biol Hung. 1994;45:275-84.
2) Grenko RT, Anderson KM, Kauffman G, Abt AB. Waterclear
cell adenoma of the parathyroid. A case report with
immunohistochemistry and electron microscopy. Arch Pathol
Lab Med. 1995;119:1072-4.
3) Begueret H, Belleannée G, Dubrez J, Trouette H, Parrens M, Velly
JF, de Mascarel A. Clear cell adenoma of the parathyroid gland: A
rare and misleading lesion. Ann Pathol. 1999;19:316-9.
4) Dundar E, Grenko RT, Akalin A, Karahuseyinoglu E, Bildirici
K. Intrathyroidal water-clear cell parathyroid adenoma: A case
report. Hum Pathol 2001;32:889-92.
5) Kuhel WI, Gonzales D, Hoda SA, Pan L, Chiu A, Giri D, DeLellis
RA. Synchronous water-clear cell double parathyroid adenomas
a hitherto uncharacterized entity? Arch Pathol Lab Med.
6) K anda K, Okada Y, Tanikawa T, Morita E, Tsurudome Y, Konishi
T, Tanaka Y. A rare case of primary hyperparathyroidism with
clear cell adenoma. Endocr J.2004; 51:207-12.
7) Prasad KK, Agarwal G, Krishnani N. Water-clear cell adenoma
of the parathyroid gland: A rare entity. Indian J Pathol Microbiol.
8) K odama H, Iihara M, Okamoto T, Obara T. Water-clear cell
parathyroid adenoma causing primary hyperparathyroidism in
a patient with neurofibromatosis type 1: Report of a case. Surg
9) Liang Y, Mojica W, Chen F. Water-clear cell adenoma of
parathyroid gland: A case report and literature review. N A J Med
Sci. 2010; 3:194-8.
10) Papanicolau-Sengos A, Brumund K, Lin G, Hasteh F. Cytologic
findings of a clear cell parathyroid lesion. Diagn Cytopathol.
11) Bai S, LiVolsi VA, Fraker DL, Bing Z. Water-clear parathyroid
adenoma: Report of two cases and literature review. Endocr
12) Murakami K, Watanabe M, Nakashima N, Fujimori K, Ishida K,
Ohuchi N, Sasano H. Water-clear cell adenoma associated with
primary hyperparathyroidism: Report of a case. Surg Today.
13) Piggott RP, Waters PS, Ashraf J, Colesky F, Kerin MJ. Water-clear
cell adenoma: A rare form of hyperparathyroidism. Int J Surg
Case Rep. 2013;4:911-3.
14) Ezzat T, Maclean GM, Parameswaran R, Phillips B, Komar V,
Mihai R, Sadler G, Courtney S. Primary hyperparathyroidism
with water clear cell content: The impact of histological diagnosis
on clinical management and outcome. Ann R Coll Surg Engl.
15) Tassone P, Kaplan S, Kenyon L, David R, Pribitkin E. Water clear
cell parathyroid adenoma: Case report and literature review.
Thyroid Disorders Ther. 2014;3:160.
16) Chou YH, Jhuang JY, Hsieh MS. Water-clear cell parathyroid
adenoma in a patient with acute pancreatitis. J Formos Med
17) Pirela D, Treitl D, El Hussein S, Poppiti R, Mesko T, Manzano A.
Intrathyroidal clear cell tumor of parathyroid origin with review
of literature. Case Rep Pathol. 2016;2016:7169564.
18) Albright F, Bloomberg E, Castleman B, Churchill ED.
Hyperparathyroidism due to diffuse hyperplasia of all parathyroid
glands rather than adenoma of one: Clinical studies on three such
cases. Arch Intern Med. 1934;54:315-29.
19) Roth SI. The ultrastructure of primary water-clear cell hyperplasia
of the parathyroid glands. Am J Pathol. 1970;61:233-48.
20) LiVolsi VA, Hamilton R. Intraoperative assessment of parathyroid
gland pathology. A common view from surgeon and the
pathologist. Am J Clin Pathol. 1994;102:365-73.
21) Miettinen M, Clark R, Lehto VP, Virtanen I, Damjanov I.
Intermediate-filament proteins in parathyroid glands and
parathyroid adenomas. Arch Pathol Lab Med. 1985;109:986-9.
22) Chen H, Emura S, Shoumura S. Ultrastructure of the waterclear
cell in the parathyroid gland of SAMP6 mice. Tissue Cell.
23) Carlson D. Parathyroid pathology: Hyperparathyroidism and
parathyroid tumors. Arch Pathol Lab Med. 2010;134:1639-44.
24) Phitayakorn R, McHenry CR. Incidence and location of ectopic
abnormal parathyroid glands. Am J Surg. 2006;191;418-23.
25) Carcangiu ML, Sibley RK, Rosai J. Clear cell change in primary
thyroid tumors. A study of 35 cases. Am j Surg Pathol. 1985;9:705-22.
26) Hasserjian RP, Klimstra DS, Rosai J. Carcinoma of the thymus
with clear-cell features. Report of eight cases and review of the
literature. Am J Surg Pathol. 1995;19:835-41.
27) Duan K, Mete Ö. Parathyroid carcinoma: Diagnosis and clinical
implications. Turk Patoloji Derg. 2015;31 Suppl 1:80-97.
28) Starker LF, Svedlund J, Udelsman R, Dralle H, Akerström
G, Westin G, Lifton RP, Björklund P, Carling T. The DNA
methylome of benign and malignant parathyroid tumors. Genes
Chromosomes Cancer. 2011;50:735-45.
29) Kruijff S, Sidhu SB, Sywak MS, Gill AJ, Delbridge LW. Negative
parafibromin staining predicts malignant behavior in atypical
parathyroid adenomas. Ann Surg Oncol. 2014;21(2):426-33.
30) Howell VM, Gill A, Clarkson A, Nelson AE, Dunne R, Delbridge
LW, Robinson BG, Teh BT, Gimm O, Marsh DJ. Accuracy of
combined protein gene product 9.5 and parafibromin markers
for immunohistochemical diagnosis of parathyroid carcinoma. J
Clin Endocrinol Metab. 2009;94:434-41.
31) Erovic BM, Harris L, Jamali M, Goldstein DP, Irish JC, Asa SL,
Mete O. Biomarkers of parathyroid carcinoma. Endocr Pathol.