Introduction
Penile intraepithelial neoplasia (PIN) is a rare disease that can be associated with
great morbidity and mortality. Historically, the term PIN has been used to refer to
3 premalignant penile lesions: Bowen disease (BD), erythroplasia of Queyrat (EQ),
and Bowenoid papulosis (BP). Although these clinical variants share similar histopathologic
features of squamous cell carcinoma in situ—namely, transepidermal keratinocyte atypia, numerous
mitotic figures, and nuclear crowding—they vary in their clinical presentation. Although
BD typically presents as a well-demarcated, scaly plaque on keratinized penile skin,
EQ is characterized by moist, red plaques located on the mucosal surfaces of the glans
and prepuce. By contrast, BP typically presents with multiple, flesh-colored papillomatous
papules on the penile shaft, glans, or foreskin.
1
Because the risk of progression from PIN to invasive carcinoma is estimated to be
between 10% and 30%, PIN has classically required surgical treatment.
2
However, the resulting morbidity from surgical interventions has led to the judicious
use of non-invasive alternatives to achieve efficacy while preserving appearance and
function. The chemotherapeutic agent 5-fluorouracil (5-FU) has since become a popular,
first-line topical treatment option. However, despite early cohort studies reporting
response rates approaching 100% at 5 years, a more recent study presenting 42 cases
of PIN treated with 5-FU found that only 50% and 31% of patients achieved a complete
and partial response, respectively.
3
Thus, the demand for better cure rates for PIN persists.
Although both cryotherapy and imiquimod have been used to treat PIN, their efficacy
as monotherapies is rather tepid. A study of 299 patients with extragenital BD found
a greater risk of recurrence after cryotherapy (13.4%) compared with 5-FU (9%) and
surgical excision (5.5%).
4
Similarly, a recent literature review highlighting 48 cases of PIN treated with imiquimod
monotherapy found the complete response rate to be 63% and the no-response rate to
be 29% after an average of 8.4 months (range, 1-48 months).
5
However, because cryotherapy and imiquimod have separate mechanisms of action (the
former exerts its therapeutic effect by inducing cellular apoptosis, whereas imiquimod
enhances cell-mediated immune responses), we hypothesized that combining the 2 therapies
might have a complementary effect. Thus, we report our experience with 8 cases of
PIN treated with combined cryotherapy and topical imiquimod.
Materials and methods
A retrospective case study was performed on patients with PIN diagnosed from January
2010 to March 2017 by the Dermatology service at Memorial Sloan Kettering Cancer Center.
Only cases that were subsequently treated with cryotherapy were included. The following
clinical characteristics were assessed: age, anatomic location, lesion type, human
papilloma virus status, HIV status, circumcision status, time to clinical regression,
other concurrent treatment modalities, and follow-up time.
Results
Eight cases were identified that met the aforementioned inclusion criteria. Table
I summarizes their relevant clinical history. The mean age was 45.1 years (range,
26-65). The clinical presentations included BD (5 cases), EQ (2 cases) and BP (1 case),
all of which were histopathologically confirmed. Of the 5 cases tested for HPV, all
were found to be positive for the high-risk subtypes HPV 16/18. Two patients had concurrent
squamous cell carcinoma involving the rectal and anal skin (cases 2 and 6), and in
3 cases, the patients had HIV and were treated with highly active antiretroviral therapy
concomitantly (cases 1, 2, and 6).
Table I
Patient clinical information
Patient no.
Age
Anatomic location
Lesion type
HPV status
HIV status
Foreskin
No. of cryotherapy sessions
Imiquimod
5-FU
Other treatments
Time to clearance (mo)
Follow-up (mo)
Recurrence
1
65
Shaft
EQ
Not tested
+
C
11
2-5 times per wk for 12 mo
bid for 2 wks
None
39
12
No
2
50
Foreskin, shaft
BD
HPV 16/18
+
UC
2
3-5 times per wk for 2 mo
bid for 2 wks
Circumcision
17
40
No
3
28
Base and shaft
BP
HPV 16/18
−
C
5
2-5 times per wk for 7 mo
None
Mohs
14
28
No
4
54
Shaft and glans
EQ
Not tested
−
UC
6
1-5 times per wk for 10 mo
None
None
12
26
No
5
38
Shaft
BD
Not tested
−
C
3
3-5 times per wk for 4 mo
None
None
5
5
No
6
60
Shaft
BD
HPV 16/18
+
C
6
1-5 times per wk for 13 mo
bid for 2 wks
None
20
59
No
7
40
Shaft and glans
BD
HPV 16/18
−
UC
4
2-5 times per wk for 6 mo
bid for 2 wks
Laser, circumcision
17
7
No
8
26
Shaft
BD
HPV 16/18
−
C
4
3 times weekly for 8 mo
None
None
4
24
No
5-FU, 5-fluorouracil; BP, Bowenoid papulosis; BD, Bowen disease; EQ, erythroplasia
of Queyrat; C, circumcised; UC, uncircumcised.
All 8 patients had cryotherapy as frontline therapy. In 1 case (case 3), the patient
first had Mohs micrographic surgery at an outside health care facility, but because
the lesion persisted, cryotherapy was initiated at our institution. In all cases,
the recommended treatment was in-office cryotherapy (2 freeze/thaw cycles consisting
of 10 seconds of funneled spray application of liquid nitrogen per lesion per cycle)
followed by at-home treatment with topical imiquimod 3 to 5 times a week for at least
8 weeks; the frequency of imiquimod administration was reduced to 1 to 3 times per
week in the maintenance phase of the treatment course to prevent recurrence. The average
number of cryotherapy sessions administered was 5.1 (range, 2-11). The average number
of months using topical imiquimod was 7.8 months (range, 2-13). All patients exhibited
a complete response to therapy; additionally, during the follow-up period of 59 months
(range, 5-59 months), none of the patients exhibited signs of recurrence. Of note,
at the conclusion of the case study, cases 1 and 4 were still undergoing maintenance
therapy. The successful resolution of PIN in patient 1 is depicted in Fig 1.
Fig 1
Patient 1. A, Before treatment. EQ lesion on the shaft and glans of the penis of a
65-year-old man. B, After the combination therapy of cryotherapy (11 sessions) and
imiquimod (12 months after initiation of treatment).
Other concurrent treatment modalities used included 5-FU twice daily for 2 weeks (cases
1, 2, 6, and 7), elective circumcision (cases 2 and 7), and laser therapy (case 7).
The median follow-up was 24 months (range, 5-59 months). The median time to clearance
was 15 months (range, 4-39 months). In addition, patients were advised to use concurrent
hydrocortisone 2.5% cream, petroleum jelly, ketoconazole cream, and mupirocin ointment
during the treatment period to decrease skin irritation. Although patients reported
mild redness and irritation at the site of imiquimod application, no severe skin reactions
were reported.
Discussion
PIN has a 10% to 30% rate of advancement to SCC; moreover, the metastatic potential
after advancement to invasive malignancy is 3% to 5%.2, 6 In an effort to eradicate
PIN while limiting anatomic disfigurement and loss of function, clinicians have sought
alternatives to surgical excision, including laser ablation, Mohs micrographic surgery,
electrodessication and curettage, cryotherapy, and chemotherapeutic/immune modulating
topical creams (5-FU and imiquimod). Although the 2014 British Association of Dermatologists'
recommendations for the management of PIN is helpful in guiding the choice of such
noninvasive therapy, there is no gold standard treatment for PIN, nor are there randomized,
controlled trials available upon which to base treatment decisions.7, 8 Moreover,
given the limited efficacy of the most common noninvasive treatment modality, 5-FU,
a clear need for a viable, robust and noninvasive treatment option for PIN remains.
3
Both cryotherapy and topical imiquimod have been evaluated as monotherapies for PIN
in recent years. Cryotherapy exerts its therapeutic effect by inducing ice crystal
formation, vascular stasis, and, ultimately, cellular apoptosis.
9
By contrast, imiquimod acts as an immune response modulator by binding the toll-like
receptor 7 and elaborating interferon-α, interleukin-1α and interleukin-12 production.
10
In a recent review of cryotherapy used for BD (both genital and extragenital), Neubert
and Lehmann
11
identified that lower recurrence rates could be achieved by longer and repeated freezing
cycles but with the increased risk of prolonged wound healing and poor cosmetic outcome
such as scaring and hypopigmentation. Similarly, the utility of imiquimod monotherapy
can be limited by severe skin reactions including severe erythema, superficial erosions,
and tingling/itching/pain at the site of application.
5
Moreover, as was mentioned above, the reported efficacies of both cryotherapy and
imiquimod monotherapy are limited.4, 5
However, given that cryotherapy and immunotherapy have differing mechanisms of action,
we hypothesized that combining the 2 therapies might have a complementary effect.
From the molecular perspective, there seems to be an advantage to combining these
2 methods; while cryotherapy exerts its therapeutic effect by inducing a cellular
stress response and apoptosis, imiquimod simultaneously enhances cell-mediated immune
responses to maximize clearance of dysplastic cells. Additional advantages to combining
said therapies include that both are easily available, inexpensive, noninvasive, and
lack severe systemic toxicity.
Importantly, the clearance rate in our case series exceeds that of the individual
monotherapies. Although it is possible that our robust clearance rate may be attributed
to the concomitant use of 5-FU or laser therapy in 4 of 8 patients, the limited use
of these added therapies (5-FU was applied for a maximum of 2 weeks in 4 patients,
1 session of laser therapy was used in 1 patient) suggests that the observed improvement
in clearance rate is at least in part owing to the synergistic effects of cryotherapy
and imiquimod. Additionally, none of our patients reported any severe skin irritation
secondary to imiquimod application. We speculate that the reason for this favorable
response is 2-fold: not only were our patients instructed to wait at least 3 to 4 days
after cryotherapy before applying the imiquimod, but we advised them to use hydrocortisone
and skin moisturizer during the treatment period to ameliorate any skin irritation.
Given the favorable response and purported benefits of combination therapy, we propose
the use of cryotherapy with topical imiquimod in the treatment of PIN. Given that
this is a small case series, we plan to validate this finding in a larger cohort.