ARTICLE
In patients with DD, mucous membrane involvement is recognized as white
umblicate or cobblestone papules, especially in more readily accessible
areas such as the oral cavity [1]. Some reports mention mucosal lesions
in the pharynx, larynx [2], esophagus [3], and rectum [4], that are normally
only discovered by more detailed examinations such as endoscopy. We were
able to examine the esophageal mucosa of a patient with DD who underwent
subtotal esophagectomy for esophageal carcinoma.
Some cases of DD have been reported to be associated with carcinogenesis
[5]. Investigations of those cases have uncovered the presence of human
papillomavirus (HPV) DNA, which has a role in the carcinogenesis. However,
alteration of the immune state by DD is likely to be an additional factor.
The development of cutaneous carcinoma in the area involved by DD has
been reported in some cases. In this study, we examined the pathogenic
relationship between esophageal carcinoma and DD.
Desmosomes, the prime cell-cell adhesion junctions in the epidermis,
consist of desmosomal cadherins [desmogleins (Dsgs) and desmocollins]
and also desmosomal attachment plaques (desmoplakins and plakoglobins)
that bind the desmosomal cadherins to intermediate filaments [6, 7]. Variations
in intracellular Ca2+ are thought to be important in regulating
epithelial cell-cell adhesion [7]. Sakuntabhai et al. identified
mutations in the ATP2A2 gene, which encodes the sarco/endoplasmic
reticulum Ca2+ ATPase isoform 2 (SERCA2), in DD and postulated
that altered Ca2+ signaling may result in impaired desmosomal
assembly or altered anchorage of intermediate filaments to the desmosomal
plaques [8]. Previous immunohistochemical studies demonstrated loss of
the dotted pattern on the plasma membrane and diffusion of desmoplakins
1 + 2, plakoglobin, and Dsg into the cytoplasm of keratinocytes in the
acantholytic lesions [9-11]. We examined lesional skin with monoclonal
antibody against Dsgs 1 + 2.
Case report
A 59-year-old Japanese man with a history of DD from the age of 15 was
admitted to our hospital to undergo bilateral vitrectomy for fungal endophthalmitis,
a condition he developed one month after a subtotal esophagectomy for
esophageal carcinoma in February 1999. Physical examination revealed discrete
and confluent brownish keratotic papules and plaques on the scalp, trunk,
axillae (Fig. 1), extremities,
and perianal region. In addition, there were white umblicate papules on
the hard palate. The patient had been treated with topical emollients
and occasional oral etretinate. There was a history of DD in his family
with his father and one brother. A biopsy specimen of a keratotic papule
from his chest revealed acantholytic cells, dyskeratotic cells and focal
suprabasal clefts (Fig. 2).
In the lesional skin, we used antibody against Dsgs 1 + 2 (DG 3.10). Most
of the suprabasal acantholytic cells showed a diffuse cytoplasmic pattern,
whereas some of the spherical acantholytic cells showed a ring pattern
surrounding the nucleus (Fig.
3). Electron microscopy revealed dispersed tonofibrils in most
of the suprabasal acantholytic cells and perinuclear aggregation of tonofibrils
in the spherical acantholytic cells (Fig.
4).
Gross features of the esophagus demonstrated an ulcerative, localized,
well-demarcated tumor measuring 2.0 X 1.4 cm in the middle part
of the thoracic esophagus, surrounded by a number of small white plaques,
resembling those seen in the preoperative endoscopy. Histopathology of
the main tumor confirmed a poorly differentiated squamous cell carcinoma
limited to the submucosa with no conspicuous findings of DD. The histopathological
findings of the specimens near the carcinoma showed suprabasal clefts
and villi formation, features consistent with DD, with no evidence of
malignancy (Fig. 5). Neither
immunohistochemistry using anti human papillomavirus (HPV) antibody nor
in situ hybridization for HPV 16, 18 identified HPV in the esophageal
carcinoma in this patient. Moreover, no apparent alteration in the immune
state was revealed in laboratory studies on this patient.
Discussion
Histopathological changes, suprabasal clefts and villi formation were
clearly observed in the esophageal mucosal epithelium of our patient.
In the rare reports of esophageal lesions examined histologically [3],
gross features were reported to be clusters of hard, white, round nodules
and verrucous plaques, or scattering of irregular ulcers on whitish, edematous
esophageal mucosa [3]. There were several small white plaques in our patient
that we later decided were the same as the white plaques detected in the
preoperative endoscopy. Histologically, earlier reports have described
clefts and villi formation, epithelial proliferation, acantholysis, and
dyskeratosis [3]. An absence of corps ronds and grains has been observed
in the oral cavities and other mucosal areas [1, 2]. In our patient we
found the epithelial proliferation and suprabasal clefts and villi formation.
However, dyskeratotic cells such as corps ronds and grains were not observed.
We were unable to elucidate any of the likely associations of DD with
the esophageal carcinoma, such as the presence of HPV, an altered immune
state, or the direct involvement of DD in the carcinoma. However, we presume
that altered calcium signaling might have resulted in an aberrant gene
expression that caused the carcinoma in this patient [12]. At present,
no treatment for esophageal mucous membrane lesions is indicated, but
it is advisable to perform endoscopy, if available, in cases of this type
to obtain a more accurate evaluation of this manifestation in DD. Endoscopy
is especially recommendable for DD cases with mucosal or perianal lesions,
since pharyngeal and laryngeal involvement has been found in DD cases
with oral mucosa involvement [2], and rectal mucosa involvement has been
found in DD cases with perianal lesions [4].
The distribution of Dsg in lesional skin of DD examined with DG 3.10
which recognizes Dsgs 1 + 2 was reported to be diffuse throughout the
cytoplasm in most of the acantholytic cells [9-11]. In our case we confirmed
similar findings. Furthermore, some of the spherical acantholytic cells
showed a ring pattern surrounding the nucleus. In electron microscopy,
these areas corresponded to perinuclear aggregation of tonofibrils. Burge
reported a perinuclear ring obtained by staining anti-desmoplakin antibody
in a few acantholytic cells [9], and Hashimoto observed this ring with
anti-plakoglobin antibody [10]. Perinuclear distribution of Dsg was previously
reported only using immunoelectron microscopy [11]. Hashimoto postulated
that the intracellular minor components of Dsg and desmocollins are dissolved
in DD since the attachment plaque is primarily affected and there is some
diffusion into the cytoplasm [10]. Our results imply that some affinity
remains after acantholysis between Dsgs and intermediate filaments, possibly
via other desmosomal components such as desmoplakin and/or plakoglobin
under altered Ca2+ signaling.
Article accepted on 5/6/00
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