DERMATOPATHOLOGY

The role of immunosuppression in

squamous cell carcinomas arising in
seborrheic keratosis
Ruzica Z. Conic, MD,a,b Karl Napekoski, MD,c Heidi Schuetz, BA,a Melissa Piliang, MD,a Wilma Bergfeld, MD,a
and Natasha Atanaskova Mesinkovska, MD, PhDa,d
Cleveland, Ohio; Naperville, Illinois; and Irvine, California

Background: Seborrheic keratoses (SK) are common skin neoplasms considered to be benign. Reports of
associated squamous cell carcinoma arising within seborrheic keratosis (SCC-SK) have been described.

Objective: To describe the histopathologic characteristics of SCC-SK and identify predisposing factors in
formation of these rare lesions.

Methods: There were 162 cases of SCC-SK in a span of a decade (2003-2014). All of the histopathologic
specimens and medical records were reviewed. Data from these patients were compared to a control group
with seborrheic keratosis who were matched by age, sex, and location of lesion from the same time period
(n = 162).

Results: SCC-SK has the classic histopathologic features of SK, such as hyperkeratosis, parakeratosis,
papillomatosis, and pseudohorn cysts. The areas of squamous cell carcinoma were characterized by areas
of squamous dysplasia (100%), hypogranulosis (79.6%), squamous eddies (79.6%), solar elastosis (80.9%),
and brown pigmentation (59.9%).
Patients with a history of immunosuppression had an increased risk for developing SCC-SK (19% vs 3%;
P \ .01), particularly when inhibition was transplant-associated (10% vs 0%; P \ .01).

Limitations: This was a single center, retrospective study.

Conclusion: SCC-SK occurs more often in elderly men with a history of immunosuppression associated
with organ transplants. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2016.12.002.)

Key words: elderly men; immunosuppression; malignant transformation; SCC-SK; seborrheic keratosis;
squamous cell carcinomas; transplant.

S eborrheic keratoses (SK) are common benign

skin neoplasms that develop from the accu-
mulation of normal keratinocytes between the
basal layer and keratinizing surface. They typically
Abbreviations used:
CI:
OR:
SCC-SK:
confidence interval
odds ratio
squamous cell carcinoma arising in seb-
present as stuck on verrucous plaques with variable orrheic keratosis
thickness and pigmentation. SKs were once consid- SK: seborrheic keratosis
ered senile warts, but their incidence among younger

From the Department of Dermatology and Dermatopathology,
Cleveland Clinic, Clevelanda; Department of Dermatology, Case
Western Reserve University, Clevelandb; Department of Pathol-
ogy, Edward Hospital, Napervillec; and Department of Derma-
tology and Dermatopathology, University of California Irvine.d
Funding sources: None.
Conflicts of interest: None declared.
Accepted for publication December 1, 2016.
Reprint requests: Ruzica Z. Conic, MD, Department of
Dermatology, A61 Cleveland Clinic Foundation, 9500 Euclid
Ave, Cleveland, OH 44195. E-mail: ruzica.conic@gmail.com.
Published online February 2, 2017.
0190-9622/$36.00
2016 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2016.12.002

1
2 Conic et al J AM ACAD DERMATOL
n 2016

patients is rising.1 The etiology of SK remains keratoses were distinguished from squamous cell
unclear, with associations made to human papillo- carcinoma in situ by the presence of mitotic figures,
mavirus, melanocyte hyperplasia, genetic predispo- pleomorphism, and bowenoid dysplasia.
sition, and sun damage.1 Data are presented as mean 6 standard deviation
Patients are typically reassured that these lesions and percentages unless otherwise noted.
are considered benign; however, they mighy not all Comparisons of the clinical variables between
be benevolent. The first report of malignant trans- patients with SCC-SK and SK were performed by
formation of SK into squa- T-test. Categorical variables
mous cell carcinoma was by were calculated by Chi
Civatte in 1954, and since CAPSULE SUMMARY square or Fishers exact test,
then, many case reports and as appropriate.
small studies have been re-
d Squamous cell carcinomas can arise in
ported on the subject.1-7 seborrheic keratoses.
RESULTS
Initially, a question was d Squamous cell carcinoma arising in SCC-SK was more
raised whether these were seborrheic keratosis (SCC-SK) arises on commonly found in men
simply collision tumors due the head and neck of elderly men with a (Table I). Most common lo-
to the relative frequency of history of immunosuppression. cations of SCC-SK were on
both lesions, or if these squa- d Clinicians should be aware of the the head and neck, followed
mous cell carcinomas actu- possibility of malignancy arising in by trunk, lower extremity,
ally arise in the seborrheic seborrheic keratoses of transplant and upper extremity (Figs 1
keratosis.5 To shed light on patients. and 2). The patients who
this issue, we studied the developed SCC-SK were
histopathologic characteris- more likely to have had a
tics of squamous cell carci- prior skin cancer (55.6% vs
nomas arising in seborrheic keratosis (SCC-SK) and 43.8%, P = .03) and to have gotten a diagnosis of skin
analyzed the demographic characteristics of affected cancer at a young age (69.55 vs 7.90, P \.001).
patients. Development of SCC-SK was associated with a
history of immunosuppression in 19% of cases (odds
METHODS AND MATERIALS ratio [OR] 7.43, 95% confidence interval [CI] 2.81-15.5;
This study was approved by the Cleveland Clinic P \.001). Medication-associated immunosuppression
Institutional Board Review. All patients with a histo- was due to prednisone (n = 13) and cyclosporine (n = 1)
logic diagnosis of SCC-SK in the period from 2003 to in the SCC-SK group, while it was due to prednisone
2014 were identified through a computer-generated (n = 3) and methotrexate (n = 2) in the control group.
search by using the phrase seborrheic keratosis and One person in the SCC-SK group was HIV positive.
SCC in pathologic findings from the Cleveland Transplant patients, in particular, developed SCC-
Clinic database (n = 162). Epidemiologic data were SK in much higher numbers compared with the
collected on age, sex, location of lesion, smoking, control group (10% vs 0%, P \.001). The transplants
history of warts, history of immunosuppression, and received by patients in the SCC-SK group were solid
history of skin cancer and other cancers. The organs: kidney (n = 7), heart (n = 6), lung (n = 2), and
epidemiologic findings in the SCC-SK group were liver (n = 1). The immunosuppressants received
compared with a control group of patients with posttransplantation were combination prednisone/
diagnosis of seborrheic keratosis matched by age tacrolimus (n = 7), prednisone/cyclosporine (n = 2),
(within 1 year), sex, and location identified from a prednisone/mycophenolate (n = 2), sirolimus/pred-
computer search by using the phrase seborrheic nisone (n = 2), tacrolimus/mycophenolate (n = 1),
keratosis (n = 162). and cyclosporine/mycophenolate (n = 1). None of
Histologic review of slides was done indepen- these patients had a recorded history of warts or
dently by 3 dermatopathologists (NAM, KN, WFB). human papilloma virus (HPV) infection.
The histologic data collected were examined for the Histologically, SCC-SKs have a combination of SK
presence of hyperkeratosis, parakeratosis, papillo- and SCC features. The growth pattern was most often
matosis, hypergranulosis or hypogranulosis, pseu- a mixture of exophytic and endophytic (40%). The
dohorn cysts, squamous eddies, cytologic atypia, features of SK present in SCC-SK are hyperkeratosis,
mitotic figures, solar elastosis, desmoplasia, acan- parakeratosis, papillomatosis, and pseudohorn cysts
tholysis, presence and type of infiltrate, demarcation, (Table II; Fig 3).
pigmentation, and extension of the squamous cell Associated SCC areas were in situ (49%), invasive
carcinoma invasion. Irritated/inflamed seborrheic (39%), bowenoid (1%), or uncertain because of
J AM ACAD DERMATOL Conic et al 3
VOLUME jj, NUMBER j

Table I. Demographic characteristics of patients with SCC-SK and SK

SCC-SK SK
(n = 162) (n = 162) P value Odds ratio 95% CI
Age 6 SD at diagnosis 72.2 6 12.7 72.3 6 12.7 P = .94
Sex
Male 69.1% (112) 69.1% (112) P \ .99
Female 30.9% (50) 30.9% (50)
Prior skin cancers P = .03 1.6 1.03-2.50
Yes 55.6% (90) 43.8% (71)
None 44.4% (72) 56.2% (91)
Age 6 SD at first skin cancer 69.55 6 14.03 74.9 6 9.9 P \ .001
Immunosuppression P \ .001 7.43 2.81-15.5
Yes 19.1% (31) 3.1% (5)
No 80.9% (131) 96.9% (157)
Organ transplant P \ .001
Yes 9.9% (16) 0% (0)
No 90.1% (146) 100% (162)
Smoking P = .16
Yes 8% (13) 9.1% (7)
No 49.3% (80) 63.6% (95)
Former 42.6% (69) 27.3% (60)

CI, Confidence interval; SCC-SK, squamous cell carcinoma arising in seborrheic keratosis; SD, standard deviation.

Females Males
45
40
35
Percent (%)

30
25
20
15
10
5
0
Upper Lower
Head and Neck Trunk
Extremity Extremity
Females 13 6.2 7.4 4.3
Males 38.9 7.4 14.8 8

Location of SCC-SK
Fig 1. Locations of squamous cell carcinoma arising in seborrheic keratosis by sex.

superficial sampling (11%). Diagnostic SCC areas are
characterized by cytologic atypia, mitosis, hypogra-
nulosis, squamous eddies, and solar elastosis.
Pigmentation, desmoplasia, ulceration, and acan-
tholysis were also prevalent in SCC/SK. Only in
20% of the cases was there an abrupt demarcation
between the SCC area within the SK. An inflamma-
tory infiltrate was present in most SCC-SK lesions
(85%). These infiltrates were lymphocytic (86%),
mixed (13%), or plasmacytic (1%).
DISCUSSION
In this retrospective case control study, we
analyzed the histologic and demographic data from
patients with SCC-SK. SCC-SK was more likely to
occur on the head and neck region of older men.
Among the SCC-SK group, usage of immunosuppres-
sive medication was more likely, particularly when
associated with an organ transplant. SCC-SKs have
been postulated to occur anywhere from 0.2-4.6%.1,3-7
Histologically, SCC-SK lesions have the classic SK
features of hyperkeratosis, parakeratosis, papilloma-
tosis, and pseudohorn cysts and the SCC character-
istics cytologic atypia, mitosis, hypogranulosis,
squamous eddies, and solar elastosis.
SCCs are the most common neoplasms occurring
after organ transplantation, and they tend to be more
severe in transplant patients than in the general
population.8 Relative risk for development of SCC
posttransplant was found to be 108.6 in men and 92.8
4 Conic et al J AM ACAD DERMATOL
n 2016

Fig 2. Clinical images of squamous cell carcinoma arising in seborrheic keratosis (SCC-SK). A,
Invasive SCC-SK on forehead of a man aged 69 years. B, In situ SCC-SK from a pigmented
keratosis on the back of a man aged 73 years. C, In situ SCC-SK from a large, irregular,
pigmented keratosis on the leg of a man aged 70 years.

Table II. Histologic findings in analysis of infiltration, reduced TH1 and IL-17a mRNA, and
squamous cell carcinomas arising in seborrheic reduced paraneoplastic T regulatory cells, thus
keratosis (n = 162) blocking sufficient inflammation to counteract
increased SCC carcinogenesis.12
Histologic features Percentage (n) In addition to immunosuppression caused by
Cytologic atypia 100% (162) medication and transplantation, the older age of the
Hyperkeratosis 97.5% (158) SCC-SK group should be considered. Compared with
Papillomatosis 92.6% (150) people aged 50 to 69 years, the incidence rates of SCC
Parakeratosis 91.9% (149) among people aged 70 to 89 years has been rapidly
Pseudohorn cysts 90.1% (146)
increasing.14 This is likely because during the aging
Mitotic figures 88.3% (143)
process, B and T cells lose their proliferative capacity,
Solar elastosis 80.9% (131)
Squamous eddies 79.6% (129) and T-cell markers are replaced by those of natural
Hypogranulosis 79.6% (129) killer cells, resulting in loss of lymphocyte diversity.15
Pigment 59.9% (97) Squamous cell carcinomas have been described to
Desmoplasia 53.1% (86) arise from seborrheic keratoses because of malignant
Acantholysis 21.6% (35) transformations of the keratinocytes.1-7 There has
Ulceration 17.9% (29) been debate over whether the squamous cell carci-
nomas actually arise in the seborrheic keratoses or are
a collision tumor. SKs usually contain mutations in
oncogenes, such as KRAS, FGFR3, and PI3KCA as well
in women.9 Regardless of transplant site, the risk for as sustained activation of Akt, a pathway that is
SCC increased 20 times.10 Twenty years after trans- involved in apoptosis, proliferation, and cell cycle
plantation, SCCs are diagnosed in 19% of heart and progression.16 Boyd et al suggested malignant trans-
lung, 18% of liver, and 9% of kidney recipients.10 formation to SCC-SK is real and attributes this
The immunosuppressive regiment following organ phenomenon to the enhanced activation of Akt.3
transplantation is a double-edged sword: while it pre- Malignant transformation to SCC has been attrib-
vents rejection, it reduces immunosurveillance, reduces uted to sun exposure, arsenic, ionizing radiation, and
and impairs the function of local plasmacytic dendritic HPV, but thus far there has been no definitive
cells, and reduces CD 4 cell counts, thus allowing conclusion. A recent evaluation of 13 cases of SCC-
mutated cells to persevere and proliferate.11,12 SK did not show the presence of HPV DNA using
Medications used for immunosuppression post- polymerase chain reaction.3 However, HPV has been
transplantation also play an important role in the shown to have an important role in the development
development of SCCs. While medications like the of cutaneous SCCs in organ transplant patients and
calcineurin inhibitors and azathioprine increase the might reveal the presence of SCCs.11 Beta subtypes 5,
risk for the development of SCC, mycophenolate 8, 9, 12, 14, 15, 17, 19-25, 36-38, 47, 49, 75, 76, 80, 92,
mofetil and mTOR inhibitors might decrease it.13 The 93, and 96 have been shown to be associated with
tumor microenvironment in SCCs from organ trans- the development of SCCs, possibly by reducing DNA
plant recipients consists of reduced CD41 repair and inhibiting apoptosis after UV damage.11
J AM ACAD DERMATOL
VOLUME jj, NUMBER j
Fig 3. Histological appearance of squamous cell carcinoma arising in seborrheic keratosis
(SCC-SK). A, Eroded and well-demarcated in situ SCC-SK. B, Well-demarcated, hyperkeratotic,
in situ SCC-SK. C, Pigmented, in situ SCC-SK. D, Inflamed, in situ SCC-SK with features of solar
elastosis. E, Well-demarcated, in situ SCC-SK. (A-E, Hematoxylin-eosin stain; original
magnifications: A, 35; B-D, 310; E, 320.)
There are several limitations of this study. One
limitation was its retrospective study design, which
limited our ability to analyze data. Using electronic
medical records and search engines imposed re-
strictions as well. Additional cases might have
existed that we were unable to identify. The small
sample size of immunosuppressed patients does not
allow for us to make generalized conclusions, in
particular which medications are likely to increase
this risk for malignant transformation. Lastly, we did
not perform studies on HPV viruses in these lesions.
Clinicians and pathologists should be aware of the
possibility for SCCs to arise in SKs and have
increased suspicion when evaluating with these
types of lesions in patients who are immunosup-
pressed. Further studies should be done to further
delineate the immunologic mechanisms that lead to
the formation of SCC-SK in persons on immunosup-
pressive medications. The role of HPV viruses in
SCC-SK should also be examined in greater detail
and compared and contrasted with controls.
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