Case Reports

Clear Cell Hidradenoma

A Mimic of Metastatic Clear Cell Tumors
Keith E. Volmar, MD; Thomas J. Cummings, MD; Wei Hua Wang, MD, PhD; Andrew J. Creager, MD;
Douglas S. Tyler, MD; H. Bill Xie, MD, PhD

Clear cell hidradenoma is a benign skin appendage tumor

that may mimic conventional-type renal cell carcinoma.
Histologically, clear cell hidradenoma contains small ductular lumens, focal apocrine and squamoid change, and a
less prominent vascular pattern than renal cell carcinoma.
Furthermore, immunohistochemical studies can aid in distinguishing the 2 tumors. Knowing the cytologic features
of primary skin adnexal neoplasms helps distinguish them
from cutaneous metastases, which are more commonly referred for fine-needle aspiration biopsy evaluation. Detailed clinical history, physical findings, and ancillary studies are essential for correct diagnosis and categorization of
these tumors. We report the rare case of a patient with
renal cell carcinoma who underwent excision of an axillary
clear cell hidradenoma, which was clinically suggestive of
cutaneous metastatic disease.
(Arch Pathol Lab Med. 2005;129:e113e116)

lear cell hidradenoma (CCH) is a benign skin appendage tumor that most often presents as a small, firm,
solitary dermal nodule. At times, CCH shows striking cytologic and histologic similarity to other clear cell neoplasms, including malignancies such as conventional-type
renal cell carcinoma. We report a case of CCH arising in
the axilla of a man with renal cell carcinoma. The case
illustrates a rare but important potential diagnostic pitfall
in the evaluation of patients with clear cell malignancies.
REPORT OF A CASE
A 59-year-old man presented to the emergency department
complaining of multiple episodes of bloody stools and generalized abdominal discomfort for 1 day. He denied any nausea,
vomiting, fevers, or chills. The patient denied any history of gastrointestinal bleeding. His past medical history included appendectomy and a 40-pack-year smoking history. A family history
of prostate carcinoma was also noted. Physical examination revealed a well-developed, well-nourished man in no acute distress, with normal vital signs. His abdomen was soft and nonAccepted for publication December 7, 2004.
From the Departments of Pathology (Drs Volmar, Cummings, Wang,
Creager, and Xie) and Surgery (Dr Tyler), Duke University Medical Center, Durham, NC. Dr Volmar is now with the Department of Pathology,
University of North Carolina, Chapel Hill.
The authors have no relevant financial interest in the products or
companies described in this article.
Corresponding author: Keith E. Volmar, MD, Department of Pathology, University of North Carolina, Chapel Hill, CB 7525, Chapel Hill,
NC 27599 (e-mail: kevolmar@yahoo.com).
Arch Pathol Lab MedVol 129, May 2005

tender to deep palpation, and no masses were present. The remainder of the physical examination was unremarkable. Laboratory studies revealed minimal anemia with normal coagulation
indices and normal serum amylase and lipase levels. Total serum
prostate-specific antigen (1.0 ng/mL) and carcinoembryonic antigen (2.3 ng/mL) levels were normal. The patients gastrointestinal bleeding ceased spontaneously, and colonoscopy revealed
multiple hyperplastic polyps and diverticulosis. The colonic mucosa was otherwise normal. Digital rectal examination was abnormal, with a distinct firmness in the anterior rectal wall.
A computed tomographic scan revealed 3 distinct lesions. The
largest was a 10 3 7-cm soft tissue mass in the pelvis, abutting
the sigmoid colon and in apparent continuity with the prostate
and seminal vesicles. Additionally, a 1.9 3 1.0-cm mass was evident in the lower pole of the left kidney, with contrast appearances consistent with renal cell carcinoma, and a low-attenuation,
indeterminate, 1-cm lesion occupied the posterior aspect of the
right lobe of the liver. Ultrasound-guided core biopsy of the pelvic mass revealed smooth muscle with abnormal architecture and
nuclear pleomorphism. The neoplastic cells were positive for
smooth muscle actin and muscle-specific actin, but negative for
desmin and S100 protein (all from DakoCytomation, Carpinteria,
Calif). No mitoses were noted, but leiomyosarcoma could not be
excluded on such a small biopsy.
The patient was referred to the surgical oncology clinic for resection of the pelvic and renal masses. An extensive physical
examination revealed a 2-cm, rubbery, mobile, subcutaneous nodule in the right axillary region, which had gone previously unnoticed but was assumed to be a lymph node. According to the
patient, the nodule had been present for several years. No adenopathy was noted in the axilla, neck, or groin. A fine-needle
aspiration biopsy was performed to rule out metastatic disease.

PATHOLOGIC FINDINGS
Fine-needle aspiration of the right axillary nodule was
performed. The aspirate smears were hypercellular and
predominated by single cells and cohesive groups (Figure
1, A). The cells were bland, containing oval nuclei with
smooth nuclear membranes and distinct but small nucleoli
(Figure 1, B). Some of the cells had moderate cytoplasm,
which varied from clear to eosinophilic with fine granules.
Occasional cells had less cytoplasm and a more basaloid
appearance. No mitotic figures were identified. A few
macrophages and multinucleated giant cells were scattered about in the background. Immunohistochemical
stains performed on cell block material showed that the
tumor cells were positive for cytokeratin (CK; Zymed,
South San Francisco, Calif) and negative for the following:
TTF-1 (DakoCytomation), BRST-2 (Signet, Dedham, Mass),
HMB-45 (DakoCytomation), S100 protein, and vimentin
(DakoCytomation). The immunostaining profile of the tuClear Cell HidradenomaVolmar et al e113

Figure 1. Fine-needle aspiration cytology of clear cell hidradenoma.

A, Cells with bland nuclei and clear cytoplasm (Diff-Quik, original
magnification 3250). B, In some groups there is a suggestion of tubular
structure (Papanicolaou, original magnification 3250).

mor supported an epithelial origin, and a diagnosis of

skin appendage tumor was favored. It should be noted
that the cytopathologist had no knowledge of the patients
renal tumor.
The patient underwent a complex surgical procedure
involving resection of the pelvic mass, left partial nephrectomy, and excisional biopsy of the right axillary nodule.
The pelvic tumor proved to be associated with a loop of
small bowel and was not attached to the rectum, sigmoid
colon, prostate, or seminal vesicles. The small bowel resection specimen contained an 11.3 3 9.5 3 6.8-cm, redtan mass with a smooth external surface. On cut section,
the mass was white-tan and predominately solid. The
overlying mucosa was unremarkable. Immunohistochemical stains showed the tumor was positive for CD117
(DakoCytomation) and negative for S100 protein, smooth
muscle actin, and CD34 (Becton Dickinson, Franklin
Lakes, NJ), consistent with a gastrointestinal stromal tumor. The mitotic index was 3 to 5 mitoses per 50 highpower fields, and there was no evidence of necrosis. The
partial nephrectomy specimen contained a 1.5 3 1.3 3
1.0-cm, well-circumscribed, round tumor. Histologic exe114 Arch Pathol Lab MedVol 129, May 2005

Figure 2. Histology of axillary clear cell hidradenoma. A, One population of cells has clear cytoplasm and small bland nuclei (hematoxylin-eosin, original magnification 3150). B, A second cell type has
larger nuclei and eosinophilic cytoplasm (hematoxylin-eosin, original
magnification 3150).

amination disclosed a renal cell carcinoma, conventional

type, with Fuhrman nuclear grade 2/4. There was no capsular penetration, no vascular invasion, and the resection
margin was negative.
The specimen labeled as right axillary lymph node consisted of an ellipse of skin with a 1.5-cm, well-circumscribed, round nodule that focally contained bloody fluid. Histologic examination (Figure 2, A) revealed clear
cells with abundant cytoplasm and low-grade nuclei, virtually identical to the renal tumor. However, additional
histologic sections (Figure 2, B) revealed small ductular
lumens, focal apocrine and squamoid change, and a less
prominent vascular pattern than that seen in the renal tumor. Extensive sampling revealed no lymph node tissue
surrounding the axillary nodule. An immunohistochemical battery was performed on the axillary nodule and renal tumor, as summarized in the Table and illustrated in
Figure 3. The axillary nodule was positive for carcinoembryonic antigen (DakoCytomation; Figure 3, A), CK5/6
(DakoCytomation; Figure 3, C), pan-CK (Becton Dickinson), CK7 (DakoCytomation), and high-molecular-weight
Clear Cell HidradenomaVolmar et al

Figure 3. Comparison of clear cell hidradenoma and conventional-type renal cell carcinoma. Immunohistochemical stains show the clear cell
hidradenoma to be reactive for carcinoembryonic antigen (A) and for cytokeratin 5/6 (C) (original magnifications 3100). Immunohistochemical
stains show the renal cell carcinoma to be positive for vimentin (B) and CD10 (D) (original magnifications 3100).

Immunohistochemical Findings
Antibody*

Axillary Nodule

Renal Tumor

Pan-CK
1
1
CK5/6
1
2
CK7
1
2
CK20
2
2
34bE12
1
2
Vimentin
2
1
SMA
2
2
CEA
1
2
CD10
2
1
* CK indicates cytokeratin; SMA, smooth muscle actin; and CEA, carcinoembryonic antigen.

CK (34bE12; DakoCytomation). The nodule was negative

for CD10 (NCL/Vector, Burlingame, Calif), vimentin, and
CK20 (DakoCytomation). Conversely, the renal tumor was
positive for vimentin (Figure 3, B), CD10 (Figure 3, D),
and pan-CK, and negative with all of the other antibodies.
These findings in the right axillary nodule were interpreted as clear cell nodular hidradenoma, cystic variant.
Arch Pathol Lab MedVol 129, May 2005

COMMENT
Hidradenoma is a generally benign, dermal appendage
tumor that usually presents as a solitary unencapsulated
dermal nodule, with occasional extension into the subcutaneous fat. There is some disagreement as to the differentiation of hidradenoma, but it has been regarded as an
eccrine sweat gland tumor on the basis of enzyme histochemical and electron microscopic features, which include
microvillus processes, abundant glycogen granules, and
numerous mitochondria.1 Clear cell hidradenoma is a variant of hidradenoma with several other designations, including clear cell myoepithelioma, nodular hidradenoma,
eccrine sweat gland adenoma of clear cell type, solid cystic
hidradenoma, and eccrine acrospiroma.1,2 Oncocytic, epidermoid, and pigmented variants of hidradenoma have
also been reported.3,4
Clear cell hidradenoma presents as a solitary, firm nodule with a slight predilection for the head, face, and upper
extremities. A review of nodular hidradenomas by Hernandez-Perez and Cestoni-Parducci5 revealed a female
predominance (1.7:1), with a mean age at presentation of
Clear Cell HidradenomaVolmar et al e115

37.2 years. Sites of involvement were the head (30.3%),

upper limb (25.8%), and trunk (20.2%). The overlying skin
is generally intact, although ulceration with leakage of serous fluid may be seen. Histologically, CCH is a well-circumscribed dermal tumor with a grenz zone between the
tumor and the epidermis. Cytologically, hidradenomas are
composed of 2 types of cells, the proportion of which
varies a great deal between tumors. One cell type is polyhedral with a rounded nucleus and slightly basophilic cytoplasm. The second cell type is generally round with
clear cytoplasm.6 A preponderance of clear cells, as seen
in CCH, is noted in less than one third of hidradenomas.
The clear cells contain glycogen and periodic acid-Schiff
positive, diastase-resistant material, but no lipid.3 It has
been suggested that the clear cells are a metabolic variant
of epidermoid cells, rather than a peculiar form of tumor
differentiation.7 Ductlike structures are often present,
some of which resemble eccrine ducts, while others consist
of slitlike spaces lined by concentric layers of squamous
cells. It has been suggested that the cystic spaces form as
a result of tumor cell degeneration.1 The intervening stroma varies from delicate vascularized cords of fibrous tissue to dense hyalinized collagen. Myxoid and chondroid
stroma are less frequent.3
Although regarded as benign, nodular hidradenoma
can recur after inadequate excision.8 Malignant transformation of CCH is rare; in one review, 6.7% of CCHs were
malignant and were histologically characterized by nuclear atypia, necrosis, and abnormal mitoses.5 An aggressive
course with widely disseminated disease and death has
been reported. The histologic appearance does not always
predict the behavior of CCH.5
Immunohistochemical studies may be vital in distinguishing CCH from its mimics. Clear cell hidradenomas
react with different monoclonal antibodies that label both
eccrine and apocrine secretory elements. Biernat et al9 determined cytokeratin expression in CCH and found that
the most keratin expression was noted in squamoid cells
and tubule lining cells, primarily with keratins to simple
epithelia, such as CK6/18, CK7, and CK8/18. Clear cells
were the most consistently positive for epithelial membrane antigen and showed staining for CK10/17/18. None
of the tumor cells stained for S100 protein. Some authors
have noted positive staining for CK19 and 34bE12, and
variable staining for CAM 5.2.7,10
The differential diagnosis of clear cell tumors in the dermis includes metastatic disease and primary skin tumors
with follicular differentiation, sebaceous differentiation, or
sweat gland differentiation. Cutaneous metastases from
renal cell carcinoma can be somewhat unusual in presentation. Metastases have been noted in the skin in 2.8% to
6.3% of renal cell carcinoma patients, but the finding is
rare at the time of presentation.11 The most common sites
are the scalp and face, followed by the chest and abdomen.11
We report a case of an axillary nodule discovered in a
patient with conventional-type renal cell carcinoma. Fine-

e116 Arch Pathol Lab MedVol 129, May 2005

needle aspiration biopsy of the nodule showed somewhat

equivocal findings, and a skin appendage tumor was favored. The axillary nodule was excised at the time of partial nephrectomy and was submitted as a lymph node. At
initial examination, the 2 tumors showed remarkable histologic similarity. The proximity of the 2 specimens and
the assumption of lymph node tissue contributed to the
clinical suggestion of the axillary nodule as metastatic renal cell carcinoma. However, in the full context of the patients clinical picture, it became apparent that this interpretation required review. First, the renal cell carcinoma
was quite small, lacked vascular or capsular invasion, and
offered no evidence of regional adenopathy. Second, the
axillary nodule was solitary and contralateral to the renal
tumor. Nonetheless, small renal cell carcinomas are known
to metastasize. Immunohistochemical studies are valuable
in distinguishing CCH from renal cell carcinoma. Clear
cell hidradenoma is generally positive for cytokeratins 5,
6, 7, and 34bE12, and may be positive for carcinoembryonic antigen. Conversely, renal cell carcinoma is positive for
vimentin and CD10.
The patient was referred to medical oncology for adjuvant therapy. A patient with a gastrointestinal stromal tumor plus another metastatic disease presents 2 dilemmas
to the medical oncologist: (1) there is no defined role for
imatinib mesylate in such a patient, and (2) the patient is
not eligible for many clinical chemotherapy trials. The
presence of metastasis in such a small, apparently innocuous renal cell carcinoma was also unusual. This led to
reevaluation of the patients axillary mass. Imatinib mesylate chemotherapy was initiated, and the patient had no
evidence of disease by imaging or clinical examination after 24 months of follow-up. Thus, recognition of CCH and
avoiding the pitfall of renal cell carcinoma was critical to
patient management. The case illustrates a rare but potential pitfall in evaluating patients with clear cell malignancies for metastatic disease.
References
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5. Hernandez-Perez E, Cestoni-Parducci R. Nodular hidradenoma and hidradenocarcinoma: a 10-year review. J Am Acad Dermatol. 1985;12:1520.
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