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Uhlenhake et al.
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Nuclear factor XIIIa is sensitive and specific for sebaceous proliferations
(7), desmoplastic trichilemmoma (2), trichilem- XIIIa (AC-1A1) staining in sebaceous prolifer-
moma (10), trichilemmal carcinoma (3), clear ations and in non-sebaceous clear cell tumors.
cell acanthoma (9), atypical fibroxanthoma Only strong nuclear staining was considered
(AFX) (1), syringoma (8), trichoepithelioma a positive result for purposes of statistical
(1), metastatic renal cell carcinoma (2) and calculation; negative and weak staining both
melanocytic nevi with balloon cell change (8). were considered as negative. Sensitivity was
The 27 sebaceous proliferations were taken from calculated as (strong staining of sebaceous
our previously characterized cohort as reported proliferations)/[(strong staining of sebaceous
by Clark et al. and included sebaceous hyperpla- proliferations) + (negative or weak staining
sia (7), sebaceous adenoma (8), sebaceoma (5) of sebaceous proliferations)]. Specificity was
and sebaceous carcinoma (7).17 calculated as (negative or weak staining of
non-sebaceous clear cell tumors)/[(negative
or weak staining of non-sebaceous clear cell
Immunohistochemical staining
tumors) + (strong staining of non-sebaceous
Histologic sections were placed on positively clear cell tumors)].
charged glass slides (Thermo Shandon; Thermo
Fisher Scientific, Pittsburgh, PA, USA). Stain-
ing was performed in a Ventana Benchmark Results
Ultra automated immunostainer (Ventana Med- Nuclear factor XIIIa (AC-1A1) staining was
ical Systems, Tucson, AZ, USA) with factor present in 100% (27/27) of sebaceous prolifer-
XIIIa antibody according to standard protocols ations, of which 96% (26/27) displayed strong
(prediluted to 0.05 μg/ml, AC-1A1 monoclonal staining (23 diffuse strong, 3 focal strong)
mouse; Ventana Medical Systems, Inc.). Appro- (Figs. 1A,B and 2A,B); these are the same data
priate positive controls were included for each we presented in Clark et al.17 Non-sebaceous
run of immunostaining and cases were stained clear cell tumors were negative or focal weak pos-
in batches to minimize the number of runs. itive in 70% (47/67) or diffuse weak positive in
Non-neoplastic sebaceous glands and dermal 25.5% (17/67). Only 4.5% (3/67) of the entire
dendritic cells within background skin on the non-sebaceous clear cell tumor group showed
sections also served as internal positive controls. strong staining with factor XIIIa (AC-1A1), and
these three cases with strong staining were all
Scoring different tumor types: one clear cell hidrade-
Nuclear factor XIIIa (AC-1A1) staining intensity noma (diffuse strong), one trichilemmoma
was graded by four separate dermatopathologists (diffuse strong) and one clear cell BCC (focal
(EEU, BRS, SCS and JMG) as strong, weak or strong) (Figs. 3–6). Detailed data are presented
negative and distribution was scored as diffuse in Tables 1 and 2.
(the majority of tumor cells) or focal (a minor- When the group of sebaceous proliferations
ity of tumor cells). Pure cytoplasmic staining was compared with the group of clear cell
only was regarded as negative. This tier system tumors, strong nuclear staining of factor XIIIa
was chosen for clinical ease and more practical (AC-1A1) was more frequently seen in the seba-
applicability than a 0–4+ grading system. The ceous lesions than in the non-sebaceous clear
nuclear factor XIIIa (AC-1A1) staining results of cell tumors (p < 0.0001). Strong nuclear stain-
the 67 clear cell tumors were tabulated and were ing of factor XIIIa (AC-1A1) had a sensitivity of
then compared with the dataset of nuclear factor 96% for sebaceous proliferations and a speci-
XIIIa (AC-1A1) staining results for the 27 seba- ficity of 96% for sebaceous proliferations vs. the
ceous proliferations from our previous study.17 non-sebaceous clear cell tumor group.
As we noted in our previous study, factor XIIIa
(AC-1A1) again displayed a gradient staining
Statistical analysis pattern within the nuclei of normal squamous
The statistical association between the factor epithelium, hair follicular epithelium, and sweat
XIIIa (AC-1A1) staining and the tumors tested ducts and glands.17 This staining was accentu-
was analyzed using Fisher’s exact test with a ated toward the terminally differentiated epithe-
p value <0.05 considered to be statistically lial and follicular cells and secretory units of
significant (conducted via http://graphpad. eccrine glands and diminished toward the less
com/quickcalcs/contingency1.cfm; accessed differentiated basaloid cells and periphery of
on 7 February 2016). The sensitivity and speci- eccrine ducts/glands (Figs. 7–9). Nuclear fac-
ficity were manually calculated with factor tor XIIIa (AC-1A1) staining in these normal
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Uhlenhake et al.
Fig. 1. A) Sebaceous hyperplasia stained with factor XIIIa (AC-1A1). There is strong diffuse nuclear staining of mature sebocytes,
×100 magnification. B) Differential staining of more mature sebocytes. Nuclei of mature sebocytes stain strongly with factor XIIIa
(AC-1A1), but less mature peripheral basaloid cells (right and bottom left) are negative, ×400 magnification.
Fig. 2. A) Sebaceous carcinoma. Hematoxylin & eosin stain, 200× magnification. B) Sebaceous carcinoma showing strong diffuse
nuclear staining with factor XIIIa (AC-1A1). The strong staining is particularly prominent in the more mature vacuolated sebocytes.
The basaloid cells are weakly staining or negative, ×200 magnification.
epithelia was usually much weaker than the red O and Sudan black IV are histochemical
nuclear staining seen in normal and neoplastic stains for lipid; they are the classically described
sebocytes. ancillary tests for the diagnosis of sebaceous
carcinoma, but their utility is limited due to
suboptimal specificity and the requirement
Discussion for fresh or frozen tissue.8 Other investigators
Sebaceous carcinoma is an uncommon but have attempted to find a specific and reliable
aggressive, potentially fatal malignancy that immunohistochemical marker that can detect
may mimic other benign or malignant tumors sebaceous differentiation on formalin-fixed
histologically when not well differentiated. Oil paraffin-embedded tissue sections. A variety
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Nuclear factor XIIIa is sensitive and specific for sebaceous proliferations
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Uhlenhake et al.
Numbers represent the number of cases for a given staining intensity and distribution pattern. The most common staining pattern for each tumor
is presented in bold. Adapted from Table 1 in our previous study of nuclear factor XIIIa (AC-1A1) staining in sebaceous proliferations.17
Table 2. Nuclear factor XIIIa (AC-1A1) staining of non-sebaceous tumors with clear cell features
BCC (8) 0 1 0 3 4
SCC (8) 0 0 2 1 5
Trichilemmal carcinoma (3) 0 0 2 1 0
Clear cell AFX (1) 0 0 0 0 1
Metastatic RCC (2) 0 0 0 0 2
Clear cell acanthoma (9) 0 0 2 5 2
Clear cell trichoepithelioma (1) 0 0 0 1 0
Trichilemmoma (10) 1 0 2 5 2
Desmoplastic trichilemmoma (2) 0 0 0 1 1
Clear cell hidradenoma (7) 1 0 5 0 1
Clear cell syringoma (8) 0 0 0 6 2
Balloon cell nevi (8) 0 0 4 1 3
AFX, atypical fibroxanthoma; BCC, basal cell carcinoma; RCC, renal cell carcinoma; SCC, squamous cell carcinoma.
Numbers in brackets represent the number of cases for a given staining intensity and distribution pattern. The most common staining pattern for
each tumor is presented in bold.
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Nuclear factor XIIIa is sensitive and specific for sebaceous proliferations
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Uhlenhake et al.
nuclear factor XIIIa (AC-1A1) staining may also other sebaceous neoplasms from their mimics.
have utility in evaluating cutaneous epithelial It is readily available in most laboratories and
maturation in general. Further investigation of its nuclear staining pattern makes for easy inter-
this is needed. pretation. As such, it may be a useful adjunct
In conclusion, strong nuclear factor XIIIa to the histologic evaluation of poorly differ-
(AC-1A1) staining is highly sensitive and specific entiated neoplasms with suspected sebaceous
in differentiating sebaceous carcinoma and differentiation.
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