Perianal Pagets Disease and Malignancies of Lower
Hindgut and Anal Canal
Gianluca Pellino,
Guido Sciaudone, Silvestro Canonico, Francesco Selvaggi
Gianluca Pellino, Guido Sciaudone, Silvestro
Canonico, Francesco Selvaggi, Division of General Surgery, Second University of
Naples, 80122 Naples, Italy
Correspondence to: Francesco Selvaggi, MD, Division of General Surgery, Second University of
Naples, via Francesco Giordani, 42, 80122 Naples, Italy. fselvaggi@hotmail.com Telephone:
+39-335-841-9132 Fax: +39-908-1566-7919
Received: January 5, 2012
Revised: January 25, 2012
Accepted: February 1, 2012
Published online: February 21, 2012
ABSTRACT
Perianal Pagets disease (PPD) consists of a skin
neoplasia which can be either primary or secondary to an underlying internal
malignancy. Treatment of perianal Pagets disease associated with primary
colonic or anal adenocarcinoma is secondary to the treatment of the primary
tumor and, thus, accurate clinical, pathological and immunohistochemical assessment
is essential. Adenocarcinomas are estimated to be only 10% of anal cancer, and
anal mucinous or colloid adenocarcinoma is an even rarer entity. We reviewed
literature concerning the association between malignancies of the lower
gastrointestinal tract and anal canal not associated with a chronic
fistula-in-ano and perianal Pagets disease, focusing on immunohystochemical
differential diagnosis and management. Immunohistochemistry is very useful in
choosing the ideal treatment for perianal Pagets disease; our immunopanel is
useful to classify perianal Pagets disease.
© 2012 Thomson research. All rights reserved.
Keywords: Perianal Pagets disease; Anal mucinous
adenocarcinoma; Immunopanel; Pagetoid spread; Cytokeratine; PPD
Pellino G, Sciaudone G, Canonico S,
Selvaggi F. Perianal Pagets Disease and
Malignancies of Lower Hindgut and Anal Canal. Journal of Gastroenterology
and Hepatology Research 2012; 1(1): 1-4 Available from: URL: http://www.ghrnet.org/index./joghr/
INTRODUCTION
Perianal
Pagets disease (PPD) is a
variant of Extramammary Pagets disease (EMPD). It represents an uncommon
condition which afflicts the perianal
region, consisting in a skin neoplasia which can be either
primary or secondary to an underlying internal malignancy of digestive,
urothelial or genital origin. EMPD seems to be more frequently found between
50-70 years of age, PPD being more common in female gender [1,2].
PPD is characterized by typical histological feature of large, round,
clear-staining cells with large nuclei. Immunohistochemistry is very useful in
differentiating primary PPD from the so called pagetoid phenomena, skin
spreads of internal malignancies. Primary PPD usually shows cytokeratine (CK) 7
positive and CK20 negative pattern whereas anal/colorectal adenocarcinomas are
positive for CK20: several studies demonstrate that CK7-/CK20+ is the most
common secondary PPD pattern [3-5]. Several therapeutic options have
been proposed for primary PPD, such as local excision (LE) or wide local
excision (WLE), with or without flap or graft reconstruction [6-9],
YAG or CO2 laser ablation [10,11], radiotherapy (RT)[12],
photodynamic therapy[13] and the more recent topical Imiquimod 5%[14,15] whereas the treatment of Pagets
disease associated with primary colonic or anal adenocarcinoma is secondary to
that of the primary tumor[2].
PERIANAL PAGETS DISEASE
First described by Crocker in 1888 then by Darier
and Couillaud in 1893, EMPD consists of several forms, of which one is
PPD[16]. PPD is often associated with underlying deep malignancies,
according to Tjandra[17], whose study reported this
association in 38 of 55 (69%) patients affected by PPD: 20 were apocrine or
eccrine carcinoma, 12 were rectal carcinoma, 6 anal carcinoma. The relation
between PPD and malignancies hasnt been clearly understood; if Oster[18]
reported a case of colorectal carcinoma years after the diagnosis of PPD and Koashi[19]
found PPD arising after a rectal carcinoma removal, Marchesa[9]
described 3 cases of primary PPD without invasive tumor at presentation
recurring with cancer. These findings justify the need of submitting all
subjects found with PPD to endoscopic examination and biopsies of the area,
examining them with immunohistochemistry; but it also is very important to carry
out a careful and continuous follow-up either in patients diagnosed with and
treated for PPD or in patients who underwent anorectal cancer removal.
Four main theories are reported to explain the different patterns of PPD
presentation[20]. Pagets cells may arise from underlying carcinoma
of eccrine or apocrine glands, with a secondary epidermal involvement. Second,
Pagets cells may be metastatic from underlying carcinoma cells. It could also
be possible that simultaneous neoplastic changes in epidermis, apocrine
structures and glandular elements of the rectum result in PPD. Another theory
has been hypothesized which would explain those cases without malignancies:
Pagets cells may arise from the pluripotential ectodermal basal cells as an
adenocarcinoma in situ, with a long pre-invasive phase[6,21]. These
theories explain the existence of both primary and secondary PPD.
Treatment of choice has been matter of debate for years. We reviewed
literature to find cases of PPD associated with malignancies of the rectum or
anal canal (Table 1).
Our literature review showed an association of PPD
and rectal or anal adenocarcinoma in 40 patients (1 patient with 2 sigmoid
adenocarcinomas) with only 5 cases of mucinous adenocarcinoma (12.5%). We found
this association more frequent in male gender (M:F=17:8). Procedures outcomes
are summarized in table 2. Adenocarcinomas are estimated to be only 10% of anal
cancer, with approximately 100 case/year of anal adenocarcinoma cancer in the
United States[22]. Anal mucinous or colloid adenocarcinoma is an
even rarer entity which is often associated to a story of chronic
fistula-in-ano, but several cases are today known to occur without;
metastases typically occur to the inguinal
lymph nodes, and treatment of choice is chemo-radiotherapy followed by excision
(for early intercepted lesions) or APR with or without node dissection and
adjuvant chemo-radiation therapy[20,23-25]. We previously reported
the case of a lady with uterine procidentia presenting with a perianal intra-epidermal
pagetoid spread of the anal mucinous adenocarcinoma[26]; we decided
to perform an APR without neoadjuvant therapies because their utility has not
been demonstrated and they are not routinely recommended in literature, further
studies being necessary[25,27]; moreover irradiation of carcinomas
with concomitant uterine prolapse has been associated with high morbidity[28,29].
Shutzes
PPD staging (Table 3)[30], is useful in classifying lesions and in
planning the most appropriate treatment strategy. The treatment of Pagets
disease associated with primary colonic or anal adenocarcinoma is secondary to
the treatment of the primary tumor, depending on the underlying cause and,
thus, accurate clinical, pathological and immunohistochemical assessment is
essential[2].
Several publications focused on distinguishing primary from secondary
agreed in defining an immunopanel for Pagets disease. CK7 positivity is
always present in Pagets disease lesion, CK20 and Gross Cystic Fluid Protein
(GCFP) are helpful to identify secondary PPD. Rectal carcinomas often are
CK7-/CK20+: PPD showing CK7-/CK20+ pattern is the most frequently associated
with it[31]. On the other hand, mucinous anal canal adenocarcinoma
is characterized by a different pattern, showing both CK7 and CK20 positivity[32]:
thats the reason why GCFP test association can be useful. GCFP is always
positive in primary PPD cases[2,5,33]. Recently, the evaluation of
tissue mucine genes (apomucine MUC1, MUC2 and MUC5AC) expression has been advocated
as a useful tool in indentifying primary and secondary PPD, MUC1 always being
present in case of primary PPD, whereas MUC2 is always found in secondary
perianal PPD[26]. However, further studies are needed[34,35].
We recently proposed an immunopanel which could be useful in distinguishing
between primary and secondary PPD (Table 4): this has the advantage of being
easily reproducible, allowing a more reliable differentiation and increasing
the possibility of choosing the right treatment[26].
Le Fur[5] reported the regression of
PPD lesion after adenocarcinoma removals
applying a 5FU cream for 6 weeks, and Ye[36] found 5FU cream
associated with Imiquimod 5% and retinoic acid effective in a case unresponsive
to surgery and Imiquimod alone.
Inguinal node
dissection is another issue. Positron emission tomography (PET) examination
could be useful in identifying patients who could benefit from such an
aggressive approach, however literature survival data show no difference
between patients undergoing nodes dissection and patients not receiving this
procedure in individuals affected by PPD and anorectal carcinoma[30].
Moreover, several reports are highly critical about groin dissection because of
its high morbidity, remarking it is an unnecessary operation in the vast
majority of patients; interval radical groin dissection should be considered if
metastatic inguinal nodes persist or subsequently develop following
chemoradiation therapy[20].
Follow-up of patients
affected by PPD and malignancies hasnt been clearly set; we believe it is an
important part of the management for the reasons previously stated. Biopsies
probably have a role, considering that Beck and Fazio recommended
to take routine biopsy samples 1 cm from the edge of the lesion and in all four
quadrants of the perineum[6].
CONCLUSIONS
The association between
adenocarcinomas of the anal canal without a chronic fistula-in-ano and a
cutaneous pagetoid spread is poorly in literature. Distinguishing primary from secondary PPD (pagetoid
phenomenon) can be very difficult and surely needs further and wider analyses;
as evident, the treatment is markedly different and the achieving of
satisfactory results could be improved. Nevertheless, we believe that both
primary and secondary PPD are similar in needing a rigorous follow-up, with
clinical/instrumental examination, selecting patients requiring periodical
biopsies.
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Peer reviewers: Nivesh Agrawal,
Professor, P.G. Deptement of General Surgery, N.S.C.B. Subharti Medical College
and asociated C.S.S. Hosopital, N.H. 58, Delhi-Dehradoon bypass road, Meerut
(U.P.), 250 002, India; Alejandro Serrablo, MD, PhD, Associate Professor of
Surgery, Hepatopancreatic biliary Surgical Unit, Miguel Servet University
Hospital, Zaragoza 50009, Spain; Dr. Philip H. Gordon, Professor, Surgery and
Oncology, McGill University and Jewish General Hospital, 3755 Cote St Catherine
Road, Montreal Quebec H3T 1E2, Canada.
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