Case 2 -
Clear Cells of Toker in the Nipple Epidermis
Timothy W. Jacobs
Virginia Mason Medical Center
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A 39 year old woman underwent prophylactic mastectomy. The nipple was unremarkable
clinically, as well as on gross pathologic examination. Images are from a routine section of the nipple.
The nipple was grossly unremarkable, and routine sections were taken. Photomicrographs provided are
from two separate fields of a hematoxylin and eosin (H&E) stained slide (figures 1 through 3, and 4
through 7). At low power in both areas, "clear" or pale staining cells can be appreciated at various
levels within the epidermis. At intermediate and high power the cells appear slightly larger than
surrounding keratinocytes, with pale/clear cytoplasm, but with bland appearing nuclei, with smooth
nuclear membranes and small inconspicuous nucleoli (even at high power). Occasional clusters of these
pale cells are seen, some with abortive tubule formation.
An immunostain shows the cells in question to be positive for cytokeratin 7 (figure 8). By
immunohistochemistry (not shown), these cells were also positive for cytokeratin Cam 5.2, variably
positive for estrogen receptor; the cells were negative for HER2, cytokeratin 5/6, S100 protein and gross
cystic disease fluid protein (GCDFP). The cells were also negative for cytokeratin 20.
Of note, the mastectomy specimen was negative for in situ or invasive carcinoma.
This case raises diagnostic issues regarding clear cells in the epidermis of the nipple. In addition,
issues pertaining to the judicious use of immunohistochemistry in this context will be considered.
The differential diagnosis of intraepidermal clear cells is theoretically quite wide, and includes
epithelial, melanocytic, neuroendocrine and lymphoid lesions (for an excellent comprehensive review, see
. However in practice, the entities to consider in the nipple skin are fewer and can be
conceptually divided into malignant lesions (which have overtly atypical cells) and benign entities (with
bland appearing cells) :
Of note, malignant lesions are much rarer than benign entities. Malignant melanoma and squamous cell
carcinoma primarily involving the nipple are exceedingly rare (essentially confined to individual case
), while Paget's disease of the nipple accounts for approximately 1-4% of breast cancer cases
. In contrast, benign entities are common. Cleared keratinocytes are a relatively frequent artifact,
not unique to the skin of the nipple. Clear cells of Toker are found in up to 10-12% of nipples on
routine hematoxylin and eosin stains , with a higher percentage when immunohistochemistry is used
(specifically cytokeratin 7.)
- Malignant entities:
- Paget's disease of the nipple
- Malignant melanoma
- Squamous cell carcinoma in situ
- Benign entities:
- Cleared keratinocytes
- Clear cells of Toker
The differential diagnosis of cells in the nipple skin which are positive for cytokeratin 7 by
immunohistochemistry includes Paget's disease of the nipple, clear cells of Toker and Merkel cells .
Clear Cells of Toker in the Nipple Epidermis
The case presented here has classic clinical, morphologic and immunohistochemical features of clear
cells of Toker. The intraepidermal clear cells originally described by Dr. Cyril Toker in 1970 and
which bear his name are an incidental microscopic finding .
(Our patient had no clinical symptoms
attributable to her nipple, and as noted, the nipple was grossly unremarkable.) Similar to the cells
shown in this case, Toker cells have a bland cytologic appearance, are slightly larger than surrounding
keratinocytes, with pale staining ("clear") cytoplasm. The nuclei are similar in size to those of
surrounding keratinocytes with inconspicuous or small nucleoli, fine chromatin and smooth nuclear
contours. Toker cells may be seen at any level within the epidermis. Of note, they are often found near
openings of major lactiferous ducts. They may be present scattered singly or in clusters, with
occasional lumen or abortive tubule formation, as in our case. Definitions of what constitutes so-called
"Toker cell hyperplasia" vary widely (e.g. clusters of >3 cells, 7 cells, 20 cells or glands), however
the relative number of cells and/or degree of clustering do not appear to have clinical
Immunohistochemistry results for our case were as described for Toker cells. Toker
cells are currently considered to be derived from ductal epithelium. Consequently, their immunophenotype
is similar to normal breast ductal epithelium, including positive immunostaining for cytokeratin 7,
cytokeratin Cam 5.2 and epithelial membrane antigen (EMA.)
Estrogen and progesterone receptor
immunostaining is variable, and usually reflects that seen in the underlying benign lactiferous ducts.
Toker cells are negative for HER2 (an important distinguishing feature from Paget cells which frequently
are positive.) The cells are usually negative for GCDFP by immunohistochemistry, and mucin
histochemistry (not done in our case) is also usually negative. In addition Toker cells are negative for
cytokeratin 20. In contrast, Merkel cells are cytokeratin 20 positive, but may also be cytokeratin 7
positive. Merkel cells also differ from Toker cells in that they are restricted to the basal layer, have
small round nuclei, scant cytoplasm , do not occur in clusters and are not easily seen on routine H&E
(In addition to being cytokeratin 20 negative, the cells in our case were seen on H&E
and had none of the morphologic features of Merkel cells.)
In contrast to the bland appearing Toker cells, the cells of Paget's disease of the nipple are
pleomorphic and obviously malignant appearing; (this point seems obvious, but it is key to their
distinction from Toker cells.) Paget cells are large, usually with round to oval nuclei which have
irregular nuclear contours, and prominent nucleoli. Their cytoplasm is eosinophilic or amphophilic,
often abundant and may contain mucin. Paget cells are usually present singly or in small aggregates,
very rarely forming glands
Paget cells may take up melanin pigment released by epidermal cells
or melanocytes, mimicking melanoma
Paget's disease of the nipple is associated with underlying
breast carcinoma in ~95% of cases (ductal carcinoma in situ, usually high grade and/or invasive
carcinoma.) In addition, unlike Toker cells which are an incidental finding, Paget's disease may present
clinically with a scaly nipple lesion, redness, mass or discharge. (Absence of a clinical lesion however
does not preclude the diagnosis of Paget's disease which may be clinically occult.)
are glandular in origin by immunohistochemistry and ultrastructurally and consequently they are positive
for cytokeratin 7, Cam 5.2 and EMA (just like Toker cells!)
Paget cells are usually positive for
CEA and may be GCDFP positive. They are negative for high molecular weight cytokeratin and CK5/6, in
contrast to pagetoid squamous cell carcinoma which would be CK5/6 positive. Unlike extramammary Paget's
disease which may be cytokeratin 20 positive, Paget's disease of the nipple is usually cytokeratin 20
negative (akin to the usual CK7 positive/CK20 negative breast phenotype.)
Paget cells are
usually similar morphologically and by immunostaining profile to the underlying carcinoma present
Because associated carcinomas are usually high grade (particularly DCIS), Paget cells are often
estrogen and progesterone receptor (ER/PR) negative (95% of cases) and often HER2 positive (79-100% of
Therefore, negative ER/PR immunostaining certainly does not preclude the diagnosis.
However, HER2 staining if positive is particularly useful (especially in the differential diagnosis with
melanoma, squamous cells carcinoma and Toker cells, which are all negative.) S100 immunostaining is
variable in Paget's disease of the nipple (0-26% of cases positive, depending on the study)
Positive S100 staining therefore does not preclude the diagnosis of Paget's or rule in melanoma (a
pitfall, particularly in Paget cells which have taken up pigment.) Paget cells will be negative for
other melanocytic markers, e.g. HMB45. Although melanoma and squamous cell carcinoma were not serious
considerations in our case based on H&E morphology, the cells were also negative by
immunohistochemistry for S100 and cytokeratin 5/6 ruling out these entities. (See Table below for
With regard to "bland" appearing cells, rare reports of Paget's disease of the nipple have been
attributed to lobular carcinoma in situ (LCIS) (as opposed to the usual DCIS, with pleomorphic cells). A
recent interesting case report describes a patient with bland clear intraepidermal cells in both nipples,
with LCIS involving nearby lactiferous ducts in a pagetoid fashion . By immunohistochemistry the
intraepidermal cells were positive for cytokeratin 7 and estrogen receptor and negative for HER2 and
e-cadherin. (Toker cells in contrast appear to be positive for e-cadherin; personal experience.) This was considered to be case of Paget's disease due to
LCIS. In practice, the distinction between LCIS involving the nipple skin versus Toker cells may be
difficult as both have quite bland appearing cells. In addition, e-cadherin immunostaining may be
difficult to interpret on these single cells in a background of strongly positive keratinocytes.
Pragmatically, the distinction may be moot as the management implications for either are not that of
classic Paget's disease of the nipple with malignant appearing cells and underlying DCIS and/or invasive
Lastly, "atypical" Toker cells have also been described. Recently, 12.5% Toker cells in one study
were considered "atypical" and reported to have slightly larger nuclei and more cytoplasm (but preserved
nuclear-cytoplasmic ratio), slightly irregular nuclear membranes, and with more prominent eosinophilic
(Of note, our case did not have these morphologic features.) These authors found that
immunostains for CD138 and p53 were useful adjuncts for distinguishing Toker cells from Paget cells. All
Toker cells were p53 negative and 18/19 were CD138 negative, while amongst Paget's cases, 6/10 were p53
positive and 7/10 were CD138 positive. Of note, all Toker cells in this study were HER2 negative and
9/10 Paget's cases were HER2 positive. The clinical significance of so called "atypical" Toker cells
remains to be determined.
Differential Diagnosis of Clear Cells in Nipple Epidermis
| ||Paget's disease ||Toker cells ||Squamous cell carcinoma in situ ||Melanoma|
|Cytokeratin 7 ||Positive ||Positive ||Negative ||Negative|
|Cam 5.2 ||Positive ||Positive ||Negative ||Negative|
|EMA ||Positive ||Positive ||Positive or Negative ||Negative|
|CK5/6 ||Negative ||Negative ||Positive ||Negative|
|S100 ||Positive or Negative ||Positive or Negative ||Negative ||Positive|
|HMB45 ||Negative ||Negative ||Negative ||Positive|
|ER/PR ||Usually negative, (may be positive) ||Variably positive or negative ||Negative ||Negative|
|HER2 ||Often Positive, (may be negative) ||Negative ||Negative ||Negative|
|Mucin ||May be positive ||Negative ||Negative ||Negative|
|Morphology ||Malignant ||Bland ||Malignant ||Malignant|
Clear cells of Toker are an incidental and benign microscopic finding, without specific clinical
significance. However, their importance lies in the recognition of these mimickers by pathologists, to
avoid misdiagnosis of malignant entities, particularly Paget's disease of the nipple. A key diagnostic
feature of Toker cells is their bland cytologic appearance as opposed to the overtly atypical cells found
in malignant lesions. Judicious use of immunohistochemistry as an adjunct necessitates familiarity with
immunostaining profiles common to benign and malignant entities (e..g. Toker and Paget's both are
cytokeratin 7 positive) as well as knowledge of useful contrasting features (e.g. frequent HER2
positivity of Paget's, while Toker cells, melanoma and squamous carcinoma are negative.) Above all, a
diagnostic approach which integrates clinical and imaging findings, H&E morphology and
immunophenotype is most prudent in this challenging area.
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