Secondary Localized Cutaneous Amyloidosis is not Rare in Bowen’s Disease and Bowenoid Papulosis
Can BAYKAL1, Ozge HURDOGAN2, Goncagul BABUNA KOBANER1, Algun POLAT EKINCI1, Nesimi BUYUKBABANI2
1Department of Dermatology &Venereology, Istanbul University, Istanbul Faculty of Medicine, ISTANBUL, TURKEY
2Department of Pathology, Istanbul University, Istanbul Faculty of Medicine, ISTANBUL, TURKEY
Keywords: Bowen’s disease, Cutaneous amyloidosis, Regression, Bowenoid papulosis
Secondary localized cutaneous amyloidosis is a histopathological finding seen in the dermis, in various benign, premalignant, and malignant
skin conditions, without clinical significance. The real incidence is not known. We aimed to investigate the phenomenon of secondary localized
cutaneous amyloidosis in Bowen’s disease and Bowenoid papulosis. We retrospectively evaluated the data of all cases with histopathological
confirmation of Bowen’s disease and Bowenoid papulosis between 2006 and 2017 in our Dermatovenereology and/or Pathology departments.
Secondary localized cutaneous amyloidosis was observed in three patients with Bowen’s disease (3/52; 5.8%) and in three patients with Bowenoid
papulosis (3/18; 16.7%). Herein, we present the demographic, clinical and histopathological features of these six cases of secondary localized
cutaneous amyloidosis in detail. Although the occurrence of secondary localized cutaneous amyloidosis in epithelial tumors is a well-known
phenomenon, its incidence has not been previously reported in Bowen’s disease and Bowenoid papulosis. Therefore, our results indicating a
high incidence may be particularly important for Bowenoid papulosis, as its association with secondary localized cutaneous amyloidosis has
only been shown in one case before. Moreover, in three of six cases, we histologically observed areas of regression with a marked prominence of
amyloid deposition. Remarkably, two of these patients had a history of topical application of destructive agents which reveals a possible etiologic
relationship between secondary localized cutaneous amyloidosis and cellular apoptosis/necrosis induced by these external agents.
Besides the involvement of the skin in primary systemic
amyloidosis, amyloid deposition may be seen in primary
localized cutaneous amyloidosis (PLCA) causing
specific macular or papular skin lesions, and in various
benign and malignant skin conditions as a “secondary”
histopathological finding without clinical significance.
In cases with secondary localized cutaneous amyloidosis
(SLCA), the amount of amyloid deposition is usually scant
and hard to visualize, and thus susceptible to be overlooked
in routine hematoxylin and eosin (H&E) stained sections
In our practice over the past 11 years, we observed SLCA in
tissue specimens of six patients with Bowen’s disease (BD)
or Bowenoid papulosis (BP), raising the question whether
this association may be more common than estimated.
Moreover, in three of these cases (two with BD and one
with BP), we histologically observed areas of regression
in which amyloid deposition in the papillary dermis
paralleled partial regression of the lesion. As two of these
patients had a history of topical application of destructive
agents (silver nitrate stick and quicklime based ointment), a possible etiologic relationship between SLCA and cellular
apoptosis/necrosis induced by these agents is suggested.
We retrospectively evaluated the data of 70 consecutive
patients who were diagnosed with BD (52 patients)
or BP (18 patients) on the basis of typical clinical and
histopathological features between 2006 and 2017 at the
Dermatovenereology and/or Pathology departments. All
tissue specimens were examined by the same experienced
dermatopathologist. Secondary localized amyloid
deposition was observed in a total of six patients, three with
BD and three with BP.
All patients showed classical clinical features of BD (Figure
1A-C) or BP (Figure 1D-F) and in one patient with BD, a
raised nodule representing superficially invasive squamous
cell carcinoma (SCC) had developed in one area of the
plaque (Figure 1C). The presence of amyloid deposition
was incidentally detected as an eosinophilic material in
the papillary dermis during routine histopathological
examination, and was further confirmed with special stains,
Congo red and crystal violet. Congo red stained sections were examined under polarized light and birefringence
confirmed the presence of amyloid (Figures 2B,C, 2E,F and
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|Figure 1: A) (Case 1) A 3 cm-sized, irregular pigmented, slightly hyperkeratotic solitary plaque of Bowen’s disease on left groin. B) (Case
2) A 2-cm sized, erythematous slightly raised solitary flat plaque of Bowen’s disease, showing foci of regression on posterior aspect of
right leg. C) (Case 3) A 2-cm sized plaque of Bowen’s disease with development of superficially invasive squamous cell carcinoma on
the left side of the lesion as a crusted area on the anterior aspect of left lower leg. D) (Case 4) A hyperpigmented flat plaque of bowenoid
papulosis on penile shaft. E) (Case 4) Two small hyperpigmented papules of bowenoid papulosis, developed after the excision of the
initial plaque lesion. F) (Case 5) Multiple clustered hyperpigmented dome-shaped papules of bowenoid papulosis on penile shaft.
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|Figure 2: Bowen’s disease: A) (Case 1) Parakeratosis, acanthosis and full thickness keratinocyte atypia in the epidermis, increased mitosis,
diskeratosis, eosinophilic homogeneous globular material deposition and mononuclear inflammatory infiltrate in the papillary dermis
(H&E; x200). B) (Case 1) Congophilic droplets in the papillary dermis (Congo red; x200). C) (Case 1) Droplets showing birefringence
under polarized light (Congo red-polarized light; x200). D) (Case 3) Area of regression showing epidermal keratinocyte atypia and
homogeneous eosinophilic material deposition in papillary dermis (H&E; x200). E) (Case 3) Congophilic droplets in the papillary dermis
(Congo red; x200). F) (Case 3) Deposits showing birefringence (Congo red-polarized light; x200).
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|Figure 3: Bowenoid papulosis: A) (Case 4) Bowenoid histopathology and eosinophilic substance accumulation filling the dermal
papillae (H&E; x200). B) (Case 4) Congophilic material accumulation in the papillary dermis (Congo red; x200). C) (Case 4) Deposits
showing birefringence (Congo red-polarized light; x200). D) (Case 5) Atypical keratinocytes, mitoses and apoptotic cells in the epidermis
and eosinophilic material in the papillary dermis (H&E; x200). E) (Case 5) Deposits are congophilic (Congo red; x200). F) (Case 5)
Birefringence under polarized light (Congo red-polarized light; x200).
Case 1 was a 73-year-old woman who had a 3 cm-sized,
irregular pigmented, slightly hyperkeratotic solitary plaque
of BD on the right groin that had developed 6 months ago
(Figure 1A). A punch biopsy showed hyperkeratosis, lack
of maturation, loss of polarity in all epidermal layers, and
apoptotic keratinocytes, consistent with BD. There were
congophilic droplets in the papillary dermis (Figure 2B).
Case 2, a 58-year-old man, had a 3-year history of an erythematous
slightly raised, solitary flat plaque of BD with a
diameter of approximately 2 cm on the posterior aspect of
the right leg (Figure 1B). There were skin-colored flat areas
suggesting regression. The patient mentioned application of silver nitrate stick to the lesion, upon the recommendation
of a friend, approximately one month ago. A punch biopsy
showed epidermal keratinocyte atypia consistent with
BD and the lesion was completely excised. Histopathological
examination of the excision revealed typical BD showing
also an area of regression with a slightly atrophic epidermis
lacking findings reminiscent of BD. Papillary dermis was
full of homogeneous eosinophilic material deposition, later
proven to be amyloid.
Case 3 was a 76-year-old man presented with a 2 cmsized
plaque of BD associated with the development of
superficially invasive squamous cell carcinoma on the
anterior aspect of the left lower leg. The lesion was slightly
raised and crusted on the left side (Figure 1C). The patient
mentioned that his lesion first appeared 40 years ago and that recently upon recommendation of a friend, he applied
quicklime base ointment. Last application was 15 days
prior to his admission. A punch biopsy revealed epidermal
keratinocyte atypia consistent with BD and the lesion was
completely excised. In addition to the typical features of BD
and invasive carcinoma, a sample taken from the area of
regression showed epidermal keratinocyte atypia in a small
focus and amyloid accumulation in the papillary dermis as
aggregates of eosinophilic droplets (Figure 2D-F).
Case 4, a 64-year-old man, had a 2-year history of hyperpigmented
flat plaque of BP (Figure 1D) which was accompanied
by pigmented papules (Figure 1E) on the penile
shaft. A punch biopsy from the plaque revealed Bowenoid
epidermal histopathology and eosinophilic substance
accumulation in the papillary dermis, showing birefringence
under polarized light (Figure 3A-C).
Case 5 was a 66-year-old man who had experienced multiple,
clustered hyperpigmented dome-shaped papules of
BP on the penile shaft (Figure 1F) for the last 3 years. An
excisional biopsy of a papular lesion revealed few dispersed
atypical keratinocytes. Mitoses and apoptotic cells were
visible with a prominent basal layer pigmentation. Eosinophilic
substance accumulation filling the dermal papilla was also observed (Figure 3D-F).
Case 6, a 59-year-old man, presented with two hyperpigmented
flat plaques of BP on the pubic and scrotal areas
which appeared 27 years ago, and showed a persistent
course. A punch biopsy revealed Bowenoid epidermal
histopathology with keratinocyte atypia associated with
hyperkeratosis. The papillary dermis contained aggregates
of amyloid. Edema, scattered melanophages and band-like
lymphocytic infiltration, more intense in the lesional area,
were highly suggestive of regression. However, the patient
could not clearly remember whether he had applied a topical
destructive agent to the lesion.
The demographic, clinical and histopathological features of
these six cases with SLCA are summarized in Table I.
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|Table I: The demographic, clinical and histopathological features of the patients with Bowen’s disease and Bowenoid papulosis
associated with secondary localized cutaneous amyloidosis.
SLCA is most commonly associated with skin tumors
of epithelial origin such as seborrheic keratosis, actinic
keratosis, BD, basal cell carcinoma (BCC), and SCC 1
these epithelial tumors, amyloid deposition is restricted to
the dermo-epidermal junction / papillary dermis or to the
tumoral stroma, similar to our observations in our six cases
with BD and BP 1,2
The mechanism of amyloid deposition in PLCA and
SLCA has been postulated to be similar. Literature
findings suggest that amyloid is derived from degenerated
epidermal cells and keratin released from apoptotic basal
keratinocytes or colloid bodies is the precursor protein
3. Keratin tonofilaments of epidermal keratinocytes
undergo “filamentous degeneration” resulting in amyloid
formation. Moreover, two β-sheet-rich proteins, galectin-7
and actin, were recently suggested to be the components of
amyloid deposition in localized cutaneous amyloidosis 2.
SLCA may also be associated with local, chronic
inflammatory conditions that may also induce apoptotic
processes 4,5. It is hypothesized that “drop off” of
epidermal keratinocytes into the dermis and the interaction
between epidermal components and fibroblasts are essential
for the formation of amyloid precursors 3. In accordance
with current hypothesis, Cases 2 and 3 with BD, who used
topical agents with tissue destructive effects (silver nitrate
and quicklime based ointment, respectively), showed
conspicuous regression as well as marked prominence of
amyloid deposition in the areas of regression. To the best of
our knowledge, amyloid deposition in the papillary dermis
which paralleled areas of regression, probably induced by
application of tissue destructive agents, has not previously been reported in BD and BP. A similar regression associated
with amyloid deposition observed in one of our BP patients
(Case 6) comforts the same hypothesis. In this patient, the
reason for regression could not be identified.
There is a paucity of studies investigating the incidence
of amyloid deposition in epithelial tumors. In one series
of 199 BCCs, the frequency of amyloid deposition was
found to be only 8% in H&E stained sections, but increased
to 51% using special stains 6. In these series, the solid,
adenoid and cystic types of BCC were found to be more
commonly associated with SLCA 6. Additionally, a rarer
association without a clinical significance of SLCA with
other skin conditions like disseminated superficial actinic
porokeratosis, melanocytic nevi, mycosis fungoides,
PUVA-exposed skin, discoid lupus erythematosus, and
dermatofibroma has also been reported 1,4,5.
BD, an in-situ SCC, presents typically with a slow-growing
erythematous patch or plaque of a few centimeters. Cumulative
risk for invasive SCC within 5 years of a diagnosis of
BD has been reported to be 11.7% and 6.9% in men and
women, respectively 7. Although the association of SLCA
with BD is considered to be a well-known phenomenon,
literature data regarding this association is only restricted to a few cases or small case series 1,8. Furthermore, no
secondary amyloid deposition was observed in a series of
six cases with BD 9.
BP is an uncommon sexually transmitted disease induced by
human papilloma virus infection. BP manifests as multiple
or solitary, asymptomatic, brownish-violaceous pigmented
dome-shaped papules or flat plaques in the anogenital
area, with a variable course. Clinically, the most common
differential diagnosis includes condyloma acuminata,
whereas histopathological features resemble SCC in-situ, namely BD. Therefore, the distinction between BP and BD
is usually based on clinical findings, especially location. In
BP, association with SLCA has only been reported in one
case so far 10. Remarkably, in our large series with BD
and BP, the incidence of SLCA was found to be 5.8% in BD
and 16.7% in BP. Furthermore, the real incidence of SLCA
association may be higher in both diseases as amyloid stains
are not routinely performed in all cases.
In conclusion, our results may be particularly important
for BP, as its association with SLCA is not well-known and thus maybe an under-reported phenomenon in the
literature. As all of our patients with SLCA showed clinical
features typical for BD or BP, this rare association seems
to be clinically insignificant. Moreover, amyloid deposition
in the papillary dermis showing a marked prominence
in the areas of regression reveals a possible etiologic
relationship between SLCA and therapeutic or destructive
agents inducing cellular apoptosis/necrosis which has not
previously been reported in the literature.
CONFLICT of INTEREST
The authors declare no conflict of interest.
Concept: CB, NB, Design: CB, GBK, NB, Data collection
or processing: CB, ÖH, GBK, APE, NB, Analysis or
Interpretation: CB, GBK, APE, NB, Literature search: CB,
ÖH, GBK, Writing: CB, ÖH, GBK, Approval: CB, ÖH,
GBK, APE, NB.
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