ORIGINAL ARTICLE
Papillary Squamous Cell Carcinoma, Not Otherwise
Specified (NOS) of the Penis: Clinicopathologic Features,
Differential Diagnosis, and Outcome of 35 Cases
Alcides Chaux, MD,* Fernando Soares, MD,w Ingrid Rodrı´guez, MD,* Jose´ Barreto, MD,*
Cecilia Lezcano, MD,* Jose´ Torres, MD,* Elsa F. Velazquez, MD,z and Antonio L. Cubilla, MD*
Abstract: There is a group of low-grade papillomatous
squamous cell carcinomas (SCC) of the penis, collectively
designated as ‘‘verruciform,’’ that are difficult to classify. A
proposal of classification grouped these tumors in warty
(condylomatous), verrucous, and papillary carcinomas. Papil-
lary SCC, not otherwise specified is the third distinctive type of
penile low-grade verruciform neoplasms. We are presenting
clinicopathologic features of 35 cases from 2 institutions. All
specimens were penectomies or circumcisions. Mean age was 57
years. Sites of involvement were glans alone in 18 cases (51%),
glans, coronal sulcus and foreskin in 13 cases (37%), glans and
sulcus in 3 cases (9%), and foreskin in 1 case (3%). Papillary
carcinomas were large (mean 5.6 cm) exophytic low-grade
squamous neoplasms with hyperkeratosis and papillomatosis.
Papillae were variable in length and shape. The tip was straight,
undulated, spiky, or blunt. There was no koilocytosis. The
interface between tumor and stroma was characteristically
jagged and a moderate stromal reaction was evident in most
cases. The majority of the tumors (94%) showed a low-grade
histology with focally present poorly differentiated areas in 6%
of the cases. The mean thickness of the tumor was 9.4 mm.
The most commonly invaded anatomic levels were the corpus
spongiosum and/or dartos (77% cases). Corpus cavernosum
was invaded in 8 cases (23%). Vascular and perineural invasion
were unusual. Frequent associated lesions were squamous
hyperplasia, differentiated penile intraepithelial neoplasia,
and lichen sclerosus (74%, 46%, and 34%, respectively). Nodal
metastases were identified in 3 of 12 patients with bilateral groin
dissections. Of the 20 patients followed, 18 were either with no
evidence of disease (15 cases) or died from unrelated causes
(3 cases). One patient was alive with evidence of systemic
metastases and 1 died from disseminated penile cancer 32
months after original penectomy. In conclusion, papillary
carcinomas were exophytic albeit, often deeply invasive low-
From the *Instituto de Patologı́a e Investigación, Asunción, Paraguay;
wHospital do Cancer A. C. Camargo, São Paulo, Brazil; and
zBrigham and Women’s Hospital, Harvard Medical School, Boston,
MA.
Disclosure: No financial support was received for this work.
Correspondence: Antonio L. Cubilla, MD, Instituto de Patologı́a e
Investigación, Martin Brizuela 325, Asuncion, Paraguay (e-mail:
acubilla@institutodepatologia.com.py).
Copyright r 2010 by Lippincott Williams & Wilkins
Am J Surg Pathol  Volume 34, Number 2, February 2010
grade neoplasms, with a low rate of nodal metastasis char-
acterized by complex papillae, irregular fibrovascular cores, and
jagged tumor base. Papillary SCC should be distinguished from
other penile verruciform tumors, including verrucous and
variants, warty and papillary basaloid carcinomas, and carci-
noma cuniculatum. Helpful morphologic features for differential
diagnosis are provided.
Key Words: penile cancer, squamous cell carcinoma, papillary
carcinoma, verruciform tumor, HPV, prognosis
(Am J Surg Pathol 2010;34:223–230)
T here is a distinct geographic distribution of penile
cancer, with a low incidence in the United States,
Europe, Japan, Korea, and Israel, with an age-standard-
ized rate of 0.1 to 1.0/100.000 inhabitants, and a high
incidence in tropical regions of America, Africa, and
Asia, with an age-standard rate of 1.0 to 4.0/100.000
inhabitants. Highest rates are reported in Paraguay and
Northern Brazil.11,18 A vast majority of penile carcino-
mas, except rare cases of Paget disease or basal cell
carcinomas, are squamous cell carcinomas (SCC). About
one third of them are represented by grossly exophytic
and microscopically low-grade papillomatous tumors,
collectively designated as ‘‘verruciform’’ that are proble-
matic to classify.3,4,16 There has been some confusion
in the nomenclature of these neoplasms. A proposal
classified these tumors in condylomatous (warty), verru-
cous, papillary not otherwise specified (NOS), and giant
condylomas.3 A recently described tumor, the carcinoma
cuniculatum, also belongs to the verruciform group.1
Distinguishing morphologic features are related to the
pattern of papillae, presence of koilocytosis, and the
appearance of the interface between the tumor and the
underlying stroma.5,13 Papillary SCC, NOS was originally
mentioned with other penile tumors in a study evaluating
the presence of HPV in penile carcinomas15 and in other
series,3,4,16 but we found no specific clinical or morpho-
logic description and outcome features of this tumor
entity. The aims of this study were to characterize these
features in 35 papillary carcinomas and to discuss the
differential diagnosis of penile verruciform tumors.
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Chaux et al Am J Surg Pathol  Volume 34, Number 2, February 2010

MATERIALS AND METHODS Statistical Analysis

Among a cohort of 500 cases with invasive penile
SCC from 2 institutions about one-third exhibited low-
grade exophytic ‘‘verruciform’’ morphology and from
this group 35 cases of papillary, NOS carcinomas
were selected. Cases were from the pathology files of
the Instituto de Patologı́a e Investigación, Asuncion,
Paraguay (18 cases) and the Hospital do Cancer A. C.
Camargo, São Paulo, Brazil (17 cases). Specimens were
partial or total penectomies and circumcisions, and there
were 12 inguinal bilateral groin dissections. Criteria for
inclusion were the presence of hyperkeratosis, papilloma-
tosis, jagged or irregular limits in the interface between
tumor and stroma, and the absence of koilocytosis.
Clinical and pathologic information obtained from
charts and pathologic reports were: age, tumor site, size,
grade, thickness, anatomic level of invasion, associated
epithelial lesion, inguinal node status, and the outcome of
the patient. Associated epithelial lesions corresponded to
epithelial abnormalities, precancerous lesions, and lichen
sclerosus. Nomenclature and morphologic criteria for
precursor lesions were those recently reported,13 and
included squamous hyperplasia and penile intraepithelial
neoplasia (PeIN). Follow-up was available in 20 patients
and ranged from 3.7 to 453 months (mean 140 mo,
median 79 mo).
Clinicopathologic Comparison With Other
Squamous Cell Carcinoma Subtypes
Clinicopathologic features of papillary, NOS carci-
nomas were compared with similar features of warty,
verrucous, and usual squamous cell carcinoma, using
earlier reported series of cases that included 34 cases
of warty SCC (11 from Cubilla et al3 and 23 from
Guimaraes et al16), 24 cases of verrucous SCC (from
Guimaraes et al16), and 215 cases of usual SCC (from
Guimaraes et al16).
Contingency analyses were carried out using the
w2 or the Fisher exact test. For continuous variables, the
Bartlett test for equal variances was used to set the type of
population distribution. For Gaussian distributions, the
one-way ANOVA with the Tukey multiple comparison
tests were preferred. For non-Gaussian distributions
the Kruskal-Wallis with the Dunn multiple comparison
tests were carried out. In all cases, a 2-tailed P<0.05 was
required for statistical significance. Data were analyzed
using the software GraphPad Prism version 5.0 (Graph-
Pad Software, Inc., La Jolla, CA) and Epi-Info version
3.5.1 (Centers for Disease Control and Prevention,
Atlanta, GA).
RESULTS
Clinical Data
Age ranged from 26 to 84 years (mean 57 y and
median 61.5 y). Tumors were large (range of 1 to 9 cm,
average of 5.5 cm) involving the glans exclusively in 18
cases (51%), diffuse and continuously glans, coronal
sulcus and foreskin in 13 cases (37%), glans and sulcus
in 3 cases (9%), and the foreskin, 1 case (3%). Comparing
tumors affecting only 1 anatomic compartment the
majority of papillary, NOS SCC was localized in the
glans (95%) and less frequently (5%) in the foreskin
(Table 1).
Pathologic Features
Grossly, papillary carcinomas were exophytic white
gray irregular neoplasms. The cut surface showed a pearly
white papillomatous tumor with a ‘‘serrated’’ surface
appearance and a poorly delineated interface between
tumor and stroma (Fig. 1). Microscopically, the low
power appearance was that of a well to moderately
differentiated papillary squamous cell outgrowth with
hyperkeratosis, acanthosis, and papillomatosis (Figs. 2A,
B). Papillae were complex and nondistinct, variable in

TABLE 1. Comparison of Clinicopathologic Features of Papillary, Warty, Verrucous, and Usual Penile Carcinomas
Papillary NOS Warty SCC Verrucous SCC Usual SCC P
No. cases 35 34 24 215
Age (y) 57 57 58 54 0.3937
Site (%) 0.0118
Glans 18 (95) 12 (75) 16 (94) 139 (96)
Foreskin 1 (5) 4 (25) 1 (6) 6 (4)
Size (cm) 5.6 5.8 4.2 4.6 0.0665
Histologic grade* <0.0001
Low grade 33 (94) 26 (76) 24 (100) 114 (53)
High grade 2 (6) 8 (24) 0 (0) 101 (47)
Anatomic level 0.0001
LP 0 (0) 2 (6) 4 (17) 6 (3)
CS/DT 27 (77) 15 (44) 14 (58) 96 (45)
CC/SK 8 (23) 17 (50) 6 (25) 113 (53)
Thickness (mm) 9.4 6.5 5.5 7.3 0.0024
Inguinal nodal metastasis 3/12 (25) 6/18 (33) 0/3 (0) 60/106 (57) 0.0200
*Low-grade tumors include grade 1 and 2 tumors. High-grade tumors include all grade 3 tumors, regardless of the proportion of anaplastic cells.
CC indicates corpus cavernosum; CS, corpus spongiosum; DT, dartos; LP, lamina propria; NOS, not otherwise specified; SCC, squamous cell carcinoma; SK, preputial
skin.

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Am J Surg Pathol  Volume 34, Number 2, February 2010 Penile Papillary Squamous Cell Carcinoma

FIGURE 1. Papillary, not otherwise specified (NOS) carcinoma. Left: Gross picture of a penectomy specimen showing an
exophytic papillomatous tumor extending through the glans, coronal sulcus, and inner foreskin. Tumor base is jagged and
irregular. Right: Diagrammatic representation of the gross specimen highlighting the papillary carcinoma (in white) with its
verruciform pattern of growth affecting multiple anatomic compartments. CA indicates papillary carcinoma; CC, corpus
cavernosum; COS, coronal sulcus; DT, preputial dartos; F, foreskin; GL, glans; TA, tunica albuginea.

length, and shape; some harbored central fibrovascular
cores and others were separated by irregular wide areas
of keratinization or ‘‘keratin lakes’’ (Figs. 2C, 3). The
former simulated the papillae of warty carcinomas and
the latter of verrucous carcinomas. Unlike other more
homogeneous verruciform tumors, the tip of the papillae
was characteristically polymorphic: straight, undulated,
spiky, rounded, or blunt. There were no koilocytosis
and a granular cell or parakeratotic layer was often
present (Fig. 4). The interface between tumor and stroma
was characteristically irregular or jagged (Figs. 2D, 3).
Histologically, most of the tumors were well or moder-
ately differentiated. The distribution by histologic grades
was: grade 1 in 20 cases (57%), grade 2 in 13 cases (37%),
and grade 3 in 2 cases (6%). Papillary carcinomas
classified as grade 3 presented anaplastic cells focally
distributed in a minor proportion of the tumor and in
none of the cases they predominated. Tumor thickness
ranged from 4 to 43 mm (mean 9.4 mm, median 7.0 mm).
The most commonly involved anatomic levels were the
corpus spongiosum and dartos (27 cases, 77%). Corpora
cavernosa were affected in 8 cases (33%). We found no
superficial tumors involving only lamina propria. Vascu-
lar and perineural invasion were unusual and observed in
2 cases each (6%).
Associated Lesions
There were 55 lesions found in 26 patients.
Squamous hyperplasia was the commonest (74%), fol-
lowed by differentiated (‘‘simplex’’) PeIN (46%), and
lichen sclerosus (34%). Basaloid PeIN was very unusual
(3%). Most of the lesions were found in association with
each other (Table 2). The most frequent combination was
that of squamous hyperplasia with differentiated PeIN
followed by that of squamous hyperplasia, differentiated
PeIN, and lichen sclerosus (Fig. 5). Areas of squamous
hyperplasia alone represented about one-fifth of all the
lesions. In 1 case, we found a multicentric and coexisting
differentiated-basaloid PeIN associated with lichen scler-
osus and squamous hyperplasia.
Nodal Metastasis and Outcome
Bilateral inguinal lymphadenectomy was carried
out in 12 patients. Nodal metastasis was identified in
3 of these patients (25% of nodal dissections, 15% of all
followed cases, and 9% of all patients). Tumors asso-
ciated with groin metastases were large (mean 7.5 cm) and
invaded 6, 8, and 18-mm deep into corpus spongiosum (2
cases) or corpus cavernosum (1 case). Of the 2 patients
with tumors harboring focal histologic grade 3, 1
developed groin nodal metastasis. In the other, no lymph
node dissection was carried out. The outcome of the 3
patients with inguinal involvement was as follows: 1 was
alive with no evidence of disease 245 months after original
surgery, another was alive 13 months after diagnosis but
with evidence of metastatic disseminated disease, and the
third was lost to follow-up.
Of the 20 patients followed, 18 were either with no
evidence of disease (15 cases) or died from unrelated
causes (3 cases). One patient was alive with evidence of
systemic metastases and 1 died from disseminated penile
cancer 32 months after original penectomy. The primary
tumor of this last patient was a large neoplasm affecting
multiple compartments (glans, coronal sulcus, and fore-
skin) with deep invasion of corpus cavernosum and
vascular/perineural invasion. However, the tumor was
well differentiated. No groin dissection was carried out in
this case.
Comparison of Papillary Carcinomas With Other
Subtypes of Squamous Cell Carcinoma
Comparison of clinicopathologic features of papillary
and other verruciform tumors and usual SCC are depic-
ted in Table 1. Papillary carcinomas were preferentially
located in the glans, similarly to the other subtypes,
whereas warty carcinomas tended to be visible in the

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Chaux et al Am J Surg Pathol  Volume 34, Number 2, February 2010

FIGURE 2. Papillary, not otherwise specified (NOS) carcinoma. A and B, Low-power view depicting the papillomatous exophytic
pattern of growth of papillary carcinomas. Papillae are variable in size and shape with irregular fibrovascular cores. Note the
jagged interface between tumor and stroma. C, Mild-to-moderate acanthosis and hyperkeratosis are typical features of papillary
carcinoma. Keratin lakes or plugs are commonly found. D, Tumor base showing irregular nests of neoplastic cells and an intense
inflammatory reaction in the surrounding stroma.

foreskin in up to one-quarter of the cases. Papillary DISCUSSION

carcinomas showed a low-grade histology, similar to the
other verruciform tumors, whereas almost half of the
cases of usual SCC were of high grade. Papillary SCC
tended to invade up to corpus spongiosum, similarly to
verrucous carcinomas, whereas warty and usual carcino-
mas invaded up to corpus cavernosum in one-half of the
cases. Tumor thickness was greater in papillary carcino-
mas when compared with other subtypes. The metastatic
rate of inguinal involvement was similar to warty
carcinomas, higher than verrucous carcinomas but lower
than usual SCCs.
Papillary SCC is the third and less distinctive type of
penile verruciform tumors and should be distinguished
from other carcinomas depicting similar patterns of
growth, mainly verrucous and warty carcinomas. Verru-
cous carcinomas exhibit a morphologic spectrum includ-
ing its classical or pure form, a minimally invasive variant
and a mixed category. Carcinoma cuniculatum, a recently
described SCC variant, could be also regarded as a
verrucous carcinoma variant.1 In its classical presenta-
tion verrucous carcinoma is characterized by its extreme
degree of differentiation and a broad base between tumor

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Am J Surg Pathol  Volume 34, Number 2, February 2010
FIGURE 3. Papillary, not otherwise specified (NOS) carcinoma. Left: Papillae are complex and fibrovascular cores are irregular.
Tumor base is jagged and the stromal reaction intense. Right: Tips of papillae depict a broad spectrum of shapes. Acanthosis
ranges from mild-to-moderate.
and stroma (Fig. 6, left); diagnosis is straightforward in
most cases.4,5,13,16 However, some verrucous carcinomas,
instead of this regular interface, may present thin finger-
like epithelial extensions or exhibit ‘‘serrated’’ features
that may be considered to the inexperienced eye as an
irregular tumor front. Careful examination of this area
would disclose an intact basement membrane and a
sharply defined bulbous base with a reactive under-
lying stroma. Focally infiltrative, microinvasive verrucous
carcinoma shows microscopic foci of invasive tumor
(none beyond 2 mm from the limits of lamina propria)
detached from the broad base but the predominant tumor
feature is that of a classical verrucous carcinoma.13,16 In
mixed (hybrid) verrucous carcinomas, at least 20% of
the tumor is composed of usual SCC intermingled with
typical areas of verrucous carcinoma. Tumor invasion,
associated with the former subtype, is overt and may
even predominate over the classical verrucous compo-
nent.14,16,17 Carcinoma cuniculatum shows deep tumor
invaginations that are broadly based, whereas in papillary
carcinomas the front of the invasion is characteristically
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Penile Papillary Squamous Cell Carcinoma
jagged. In addition, no sinuses and fistulae are found in
papillary carcinomas. The differential diagnosis between
these verrucous lesions and papillary carcinomas is
crucial, as pure and microinvasive verrucous carcinoma
and carcinoma cuniculatum, are not associated with
nodal metastasis and their prognosis is excellent.1,4,16 The
hybrid variant of verrucous carcinoma, however, carries a
metastatic potential that is probably higher than that
presented by papillary SCC.14,16,17 Finally, in rare
occasions a penile tumor may show features of both
classical verrucous and papillary, NOS carcinoma, named
mixed verrucous-papillary carcinoma.
In warty SCC, such as in papillary carcinomas,
the interface of tumor and stroma is irregular, but the
prominent condylomatous papillae and conspicuous pleo-
morphic koilocytosis, hallmarks of warty tumors, are
absent in papillary SCC (Fig. 6, right).2–4,16 In some
cases immunohistochemistry for p16INK4a or HPV iden-
tification and genotypification may be required for the
distinction.9,10 An earlier study evaluating the presence of
HPV in subtypes of penile SCC showed negativity for the
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Chaux et al Am J Surg Pathol  Volume 34, Number 2, February 2010

FIGURE 4. Papillary, not otherwise specified (NOS) carcinoma. Left: Papillae are lined by keratinizing cells with retained epithelial
maturation showing mild-to-moderate nuclear atypia. Note the parakeratotic layer and the irregular fibrovascular cores. Right:
Papillae can be spiky and parakeratotic but no koilocytic changes are seen in the neoplastic cells.

virus in 10 cases classified as papillary SCC.15 In another

series 11 of 13 cases were HPV negative.10 Although
morphologically quite different, the papillary variant of
basaloid carcinoma, given its exophytic configuration,
should also be considered in the differential diagnosis.13
This unusual tumor is similar to urothelial carcinomas
and it is composed of papillae with central fibrovascular
cores lined by poorly differentiated and uniform cells

TABLE 2. Precursor Lesions Found in Association With

Papillary, NOS SCC
No. Cases
Precursor Lesion (%)
Squamous hyperplasia alone 5 (19)
Squamous hyperplasia+lichen sclerosus 5 (19) FIGURE 5. Penile intraepithelial neoplasia (PeIN), differen-
Squamous hyperplasia+differentiated PeIN 9 (35) tiated (‘‘simplex’’) type. Neoplastic cells exhibiting mild
Squamous hyperplasia+differentiated PeIN+lichen 6 (23) nuclear atypia are evident throughout the entire epithelium.
sclerosus
Cytoplasm is ample and keratinized and epithelial maturation
Squamous hyperplasia+differentiated PeIN+basaloid 1 (4)
PeIN+lichen sclerosus is retained. Morphologic changes of lichen sclerosus are
observed underneath the neoplastic epithelium.

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Am J Surg Pathol  Volume 34, Number 2, February 2010
FIGURE 6. Morphologic features of other verruciform tumors. Left: In warty carcinoma; papillae are condylomatous, fibrovascular
cores are prominent, and tumor base is jagged. Note infiltrative tumor nests underneath. Koilocytosis (inset) are readily found.
Right: Verrucous carcinoma shows papillae with prominent acanthosis without fibrovascular cores. Neoplastic cells are extremely
well differentiated. Tumor base is regular, broad, and pushing. No koilocytes are identified.
similar to those of basaloid penile carcinomas.8,13 This
papillary small cell pattern may superficially be part of
basaloid or warty-basaloid invasive carcinomas.13 Para-
keratosis and focal koilocytosis at the surface may be
present. A single case was recently evaluated for HPV
presence and it was positive for genotype 16.5 We have
observed similar tumors in the uterine cervix, vagina, and
vulva and they share with their penile tumor counter-
part the positivity for HPV (ALC, unpublished observa-
tions). This tumor, despite its papillomatous pattern, is
a distinctive HPV-related neoplasm of the family of
basaloid carcinomas and should not be classified in the
group of highly keratinized papillary, NOS carcinomas.
Sometimes a low-grade usual SCC may superficially
resemble papillary carcinoma, but the former usually
do not exhibit a verruciform pattern of growth and
papillomatosis is not a prominent feature.4,16 Finally, a
pseudohyperplastic carcinoma may exhibit a focal papil-
lary configuration.7
Owing to its complex and exuberant papillomatous
pattern of growth, papillary carcinomas were found to
be among the largest and thicker of penile tumors. How-
ever, these features were not associated with a dismal
prognosis. The most likely explanation for this is the
protective effect of the low-grade histology, among the
lowest in penile carcinomas, considering the irregular
and fairly deep invasive features of papillary carcinomas.
Although in penile carcinomas there is a gradual asso-
ciation of higher histologic grades and deeper invasion
of anatomic levels there are exceptions.19 In these cases
of deeply infiltrative low-grade tumors and superficially
invasive high-grade tumors, the histologic grade will
influence the prognosis because it is a stronger predictor
of adverse outcome than depth of invasion.12,20 Tumor
behavior of papillary carcinomas is similar to that of
other verruciform tumors, especially warty carcinoma,
with a low but unequivocal potential for metastatic
dissemination.
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Penile Papillary Squamous Cell Carcinoma
The unusual presence of basaloid PeIN, a purported
HPV-related lesion, and the frequent association with
squamous hyperplasia, differentiated PeIN, and lichen
sclerosus seems to indicate an HPV-independent patho-
genetic pathway for papillary carcinoma. The differen-
tiated PeIN would more likely represent the precursor of
this histologic variant of penile SCC.6 These findings are
in consonance with the paucity of HPV DNA positive
cases identified in papillary carcinomas.10,15
In summary, papillary carcinomas are large and
exophytic albeit often deeply invasive low-grade penile
neoplasms with a low-rate of inguinal nodal metastasis
and low mortality. Papillary carcinomas should be distin-
guished from other penile verruciform tumors, including
verrucous and variants, warty and papillary basaloid
carcinomas, and carcinoma cuniculatum. They are fre-
quently associated with squamous hyperplasia, differen-
tiated PeIN, and lichen sclerosus, probable precursor
lesions of papillary carcinomas, suggesting that this SCC
variant follows an HPV-independent oncogenic pathway.
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