Chi nese Med i cal Jour nal (Taipei) 2001;64:101-107
Original
Clinical and Histopathological Characteristics
of Primary Cutaneous Amyloidosis in 794
Chinese Patients
Wen-Jen Wang
Yun-Ting Chang
Chun-Yu Huang
Ding-Dar Lee
De part ment of Der ma tol ogy, Tai pei
Vet erans Gen eral Hos pi tal; and
Na tional Yang-Ming Uni ver sity School of
Med i cine, Tai pei, Tai wan, R.O.C.
Key Words
am y loid; amyloidosis; pa thol ogy
Background. Primary cutaneous amyloidosis (PCA) is not un common in Chi nese pa tients. The dis ease is usu ally per sis tent and quite
pruritic. Pa tients who suf fer from this dis ease usu ally re spond poorly
to con ven tional treat ment. We thus re viewed our cases of PCA to discuss the clin i cal and patho log i cal char ac ter is tics.
Methods. Seven hun dred and ninety-four Chi nese pa tients with PCA
who vis ited the De part ment of Der ma tol ogy, Tai pei Vet erans Gen eral
Hos pi tal dur ing the last 26-year pe riod were ex am ined and ret ro spectively studied. The diagnosis in these patients was confirmed by
histopathological stud ies.
Results. Among the many types of PCA, li chen amyloi dosus was the
most com mon clin i cal vari ant (67%). Pure cases of macular amyloidosis ac counted only 8% and were of ten as so ci ated with lichenoid lesions to form biphasic amyloidosis, which was com posed of 25% in
our se ries. Other rare types of PCA, such as nod u lar, anosacral, and
vitiliginous amyloidosis, al ways re quired a care ful dif fer en tial di agno sis clin i cally from other sim i lar skin dis or ders. In ad di tion, 56 famil ial cases were found. Histopathologically, the most com mon epidermal findings of PCA were hyperkeratosis, irregular acanthosis
with thin ning of rete ridges, and ex pan sion of der mal papillae by amy loid de po si tion. Spe cial histochemical stains were help ful for confirm ing the ex is tence of am y loid.
Conclusions. Our study represents the largest number of cases of
PCA col lected to date. Based on the data, most cases are spo radic, except 56 familial cases which may suggest the pos si ble ge netic role.
Rare types of PCA, such as anosacral and vitiliginous amyloidosis
which need special attention, compose a diagnostic challenge to a
dermatologist. Histochemically, H&E stain can give a pri mary clue
for the di ag no sis of amyloidosis and crys tal vi o let stain is a very simple and sen si tive method to de tect the ex is tence of am y loid.
[Chin Med J (Taipei) 2001;64:101-107]
C
utaneous am y loid de pos its may ap pear in the
skin in both pri mary and sec ond ary cu ta ne ous
amyloidosis. Pri mary cu ta ne ous amyloidoses (PCA)
can be clas si fied into three ma jor types: (1) lichenoid
or pap u lar type: li chen amyloidosus (LA); (2) macular
type: macular amyloidosis (MA); and (3) nodular
type: amyloidosis cutis nodularis atrophicans.1,2 LA is
the most com mon vari ant among PCA.3 Poi kiloderma-
Re ceived: March 29, 2000. Ac cepted: December 2, 2000.
Cor re spon dence to: Ding-Dar Lee, MD, De part ment of Der ma tol ogy, Tai pei Vet erans Gen eral Hos pi tal, 201, Se c. 2, Shih-Pai Road,
Tai pei 112, Tai wan. Fax: 886-2-28753136; E-mail: ddlee@vghtpe.gov.tw
102
Wen-Jen Wang, et al.
like cu ta ne ous amyloidosis, bullous amy loidosis,
vitili ginous amyloidosis and anosacral amyloidosis
have been re ported oc ca sion ally. Sec ond ary lo calized cu ta ne ous amyloid deposits can be detected
patho log i cally and histochemically in var i ous ep ithe lial tu mors, so lar keratosis, and psoriatic le sion
af ter PUVA ther apy. 1-4 There is a high in ci dence of
PCA, such as lichenoid or macular amyloidosis, in
South east Asia5 as well as in some South Amer i can
countries.6
It is well known that LA is a rel a tively com mon
skin dis or der in Tai wan,7,8 and in the im mi grant Chinese re sid ing in Sin ga pore. 5 In the De part ment of Derma tol ogy, Tai pei Vet erans Gen eral Hos pi tal, we have
col lected 794 cases of PCA dur ing the pe riod be tween
1973 and 1999 to an a lyze its male-female ra tio, on set
of the le sions, the du ra tion of ill ness, the sites of the lesions, the clin i cal types, fa mil ial cases, and the histopathological fea tures.
Chi nese Med i cal Jour nal (Taipei) Vol. 64 No. 2
our out-patient De part ment of Der ma tol ogy was approx i mate 41,600. Thus, an av er age of 30.5 new cases
with PCA can be en coun tered ev ery year, ac count ing
for 1.9% of the to tal num ber of new out-patients seen
in our clinic each year.
Clinical features
We an a lyzed the male-female ra tio, on set of the lesions, the du ra tion of ill ness, the dis tri bu tion of skin
le sions, the clin i cal types, and fa mil ial cases.
Histopathological studies
In ad di tion to rou tine haematoxyline-eosin stain,
spe cial stains in clud ing Congo red, crys tal vi o let and
Pa goda red were also per formed to con firm the ex istence of am y loid.
Results
Clinical features
Methods
Seven hun dred and ninety-four Chi nese pa tients
with PCA were ex am ined and ret ro spec tively stud ied
at Tai pei Vet erans Gen eral Hos pi tal, from Aug. 1973
through Sep. 1999. The di ag no sis in these pa tients was
con firmed by histopathological stud ies. Dur ing this
pe riod, the to tal num ber of new pa tients who vis ited
Age and sex
From Aug. 1973 through Sep. 1999, to tally 794
pa tients with PCA were en coun tered (532 males and
262 fe males). The male-female ra tio was 2.026. The
age of youngest and oldest patient was 11 and 92
years, re spec tively (me dian, 53 years). The peak in cidence was be tween 51-60 years of age, fol lowed by inter val 61-70 (Fig. 1).
Fig. 1. Age when seen of pri mary cu ta ne ous amyloidosis (n = 794)
Feb ru ary 2001
Pri mary Cu ta ne ous Amyloidosis 103
Table 1. Clinical features of primary cutaneous amyloidosis in different areas
Features
Case number
Sex ratio (M:F)
Peak incidence
(age interval, years)
Duration of illness
(years)
Distribution (%)
Lower legs
Thighs
Forearms
Back
Frequency of
Clinical type (%)
LA
MA
BA
Family history (%)
Tan 5
(Singapore)
Ollague et al.6
(South America)
Present study
(Taiwan, ROC)
265
1:3
30-50
604
1:3
35-44
794
2:1
51-60
1-30
ND
1-40
53
15
32.8
14.2
ND
ND
ND
ND
75.5
20.0
62.3
49.2
80
6
14
ND
32.15
35.71
15.71
33.86
67
8
25
7.06
BA = biphasic amyloidosis; LA = lichen amyloidosus; MA = macular amyloidosis; ND = no available data.
Duration of illness
The du ra tion of PCA var ied from 6 months to 40
years (me dian, 14 years). Most cases had the con di tion
for 2 to 20 years.
Distribution of skin lesions
As shown in Ta ble 1, the extensor as pects of the
pretibial re gion and fore arms were the most fre quent
sites to be af fected, al though other parts of the body,
such as the face, neck, trunk and anosacral area could
also be oc ca sion ally in volved.
Clinical types
In our study, “li chen amyloidosus” was the most
com mon type of skin le sions (Fig. 2), fol lowed by biphasic amyloidosis, and macular amyloidosis (Fig. 3).
Fig. 2. Clin i cal pic ture of li chen amyloidosus.
Fig. 3. Clin i cal pic ture of macular amyloidosis
104
Wen-Jen Wang, et al.
Fig. 4. Crys tal vi o let stain of cu ta ne ous amyloidosis (100×).
Rare types e.g. nod u lar amyloidosis (2 cases), anosacral
amyloidosis (10 cases), vitiliginous amy loidosis (9
cases), could also be seen.
Familial Cases
In our se ries, 56 pa tients had a pos i tive fam ily history. The fa mil ial mem bers showed sim i lar skin lesions.
Histopathological Features
In PCA (MA & LA), subepidermal de po si tion of
am y loid was de tected only in the der mal papillae and
the subpapillary lay ers by crys tal vi o let stain (Fig. 4).
The most com mon epi der mal changes of PCA were
hyperkeratosis, ir reg u lar acanthosis, thin ning of rete
ridges, and ex pan sion of the der mal papillae by am yloid ma te rial. Other less com mon histopatholo gical
find ings were pig ment in con ti nence, and in crease of
epi der mal mel a nin. The sim i lar ity of am y loid dis tri bution made it dif fi cult to dif fer en ti ate LA from MA in
pathology, since amyloid deposition was dem onstrated only in the up per por tion of dermis in both conditions.
Discussion
Many reviews of PCA, including the statistical
anal y sis of sex ra tio, the age in ci dence, and the clin i cal
Chi nese Med i cal Jour nal (Taipei) Vol. 64 No. 2
types of PCA, have been pub lished.1-9 The clin i cal features of PCA in dif fer ent ar eas are sum ma rized in Table 1. Al though PCA was com mon in women with female to male ra tio of 3:1 in Sin ga pore and in South
Amer ica, from our se ries, the fe male to male ra tio was
1:2. Since our hos pi tal served mainly male vet eran patients, the sex dif fer ence in in ci dence was not meaningful.
PCA usu ally oc curred dur ing the fourth or fifth decade of age. In our se ries, the peak in ci dence was between 51-60 years of age, older than the re port from
Sin ga pore and South Amer ica se ries. No pa tient was
youn ger than 11 years old. The du ra tion of ill ness varied from 6 months to 40 years. This find ing was consis tent with other pre vi ous stud ies and con firmed the
chronicity of this dis or der.
As shown in Table 1, the extensor aspects of
pretibial re gion and fore arms were the most fre quent
sites to be af fected, which was also con sis tent with
other re ports.5,6 The ma jor ity of our pa tients pre sented
with lichenoid type of PCA (LA). Pa tients in this cat egory usu ally showed per sis tent pruritic erup tions on
both shins. As shown in Fig. 2, the le sions were discrete, firm, nonelastic, nontender, scaly, closely set,
matchhead to pea-sized, skin-colored or brownish,
dome-shaped or hemi spheric papules. Ul cer ation and
purpura were not the usual features. Al though the
pretibial area was the most com monly in volved site,
the thighs, calves, an kles, and dorsa of the feet were
also oc ca sion ally se verely af fected. Small keratotic
papules be came larger and con flu ent to form verrucoid
plaques with a rough crater-like surface. Large iso lated nod ules re sem bling prurigo nodularis were seen
as the re sult of se vere pru ri tus, af ter re peated ex co ri ation. In the se vere cases, ex ten sive le sions could be
found on the face, chest, ab dom i nal wall and anosacral
re gion. Li chen sim plex chronicus, prurigo sim plex,
prurigo nodularis, keratosis pilaris, pap u lar mucinosis,
and colloid milium, etc. were the main skin dis or ders
which re quired a care ful con sid er ation in dif fer en tial
diagnosis.
In macular type of PCA (MA), the up per back and
extensor as pect of lower legs were the com monly involved sites, al though le sions might also be seen on
the arms and thighs. The le sions dem on strated poorly-
Feb ru ary 2001
de lin eated brown ish pig mented patches or lin ear rippling of the skin with closely aggregated grayish
brown macules. A follicular con fig u ra tion was frequently found and the papular lesions of LA often
co-existed with the macular lesion, thus the term
“biphasic amyloidosis” (LA + MA) was coined.10 In
our se ries, the biphasic amyloidosis con sisted of 25%
of the to tal cases.
In our series, only two cases of nodular amyloidosis were found, the rare type of PCA. 11 Al though
nod u lar amyloidosis might oc cur ei ther as a pri mary
con di tion lo cal ized in the skin or as a man i fes ta tion of
sys temic amyloidosis, our cases only dem on strated as
a pri mary lo cal ized con di tion af ter ex ten sive in ves tigations.
Ten cases of anosacral amyloidosis, an other rare
type of PCA, were seen in our se ries. The skin le sion
radiated from the anus as scaly, dark-brown linear
macules or lichenoid papules in which a thin layer of
am y loid deposition was eas ily proved in skin bi opsy
spec i men by crys tal vi o let and other spe cial am y loid
stains. The dif fer en tial di ag no sis should in clude li chen
sim plex chronicus, postinflammatory hyperpigmentation, tinea cruris, and pru ri tus ani.
Nine cases of vitiliginous amyloidosis were found
in our se ries. It ac counted for about 10% of the cases
in a study from Ec ua dor.6 Al though it pre sented as typi cal vitiligo le sions, in histopathology, ac cu mu la tion
of am y loid sub stance in the pap il lary dermis be neath
the basal layer of epidermis was still found.
Melanocytes were damaged and de gen er ated, lead ing
to a loss of pigment in the lesion and clinically a
vitiligo-like ap pear ance.
In our se ries, most cases were spo radic but 56 patients had a fam ily his tory, sug gest ing that ge netic factors might play an im por tant role in its pathogenesis.
On the other hand, about one-third of the South Ameri can cases had a fam ily his tory of this dis or der. 6 In the
re ported cases of fa mil ial PCA, the dis ease was in herited as a Mendelian autosomal dominant trait with
vari able penetrance.12 Some pa tients with mul ti ple endo crine neo pla sia type 2A also had a clin i cal pic ture of
PCA. 13 It was thus sug gested that the gene of fa mil ial
PCA was linked to the pericentromeric re gion of chromo some 10, the lo ca tion of the RET proto-oncogene.
Pri mary Cu ta ne ous Amyloidosis 105
We have car ried out link age anal y sis in seven fam i lies
us ing four dinucleotide re peat mark ers from the RET
region and found no evidence for linkage between
Chi nese fam i lies with PCA and the pericentromeric
re gion of chro mo some 10.14 The dis tinct ge netic ba sis,
plus their ap par ent phenotypic dif fer ence in sex ra tio,
age of on set and sites of cu ta ne ous le sions, sug gested
that fa mil ial PCA was at trib ut able to ge netic het er o geneity.
From histopathological and histochemical points
of view, it is well known that cu ta ne ous amyloidosis
did not re veal much dif fer ences from other types of
amyloidosis.3,15 Am y loid in haematoxylin-eosin stain
showed amor phous eosinophilic masses. If there was
only a small amount of amyloid, such as in MA,
histochemical stains might make it eas ier to be iden tified. Three classes of histochemical stains were em ployed for the dem on stra tion of am y loid in tis sue sections: (1) metachromatic stains, such as methyl vi o let
and crys tal vi o let; (2) fluorecence with thioflavin T;
and (3) stains with cot ton dyes, such as Congo red and
Pa goda red. 16 Among these stains, Crys tal vi o let was
rou tinely used in the de tec tion of am y loid de pos its and
was a rel a tively sim ple and sen si tive method. Congo
red had been widely applied for staining, which
stained am y loid red and pro duced a green bi refringence under a polarizing microscope. However, it
stained col la gen, and elas tic tis sue as well as am y loid,
with or with out po lar iza tion mi cros copy. 16 Be sides, in
some dermatoses such as colloid milium and lipoid
proteinosis, amor phous ma te ri als sim i lar to amyoid
can be seen in the up per dermis histopathologically.
Both crys tal vi o let and Congo red may stain colloid
milium and lipoid proteinosis pos i tively. 1 An other cotton dye, Pa goda red, had been re ported to stain am yloid brighter and was long last ing and quite spe cific.
Un like crys tal vi o let and Congo red, it did not re act
with colloid of colloid milium and hyaline of lipoid
proteinosis.16
Westermark17 had pre vi ously re ported that liquefactive de gen er a tion and pig ment in con ti nence were
spe cific find ings in PCA. In our se ries, how ever, we
sel dom found liquefactive de gen er a tion of the basal
cell layer in PCA, but pigment incontinence was a
quite fre quent find ing.
106
Wen-Jen Wang, et al.
Al though the true pathogenesis of PCA is yet to be
de ter mined, some prog ress has been made re cently. In
one study, Epstein-Barr virus (EBV) genome was
found in 40.7% cases of PCA.18 It is sug gested that
EBV may be as so ci ated with some cases of PCA. Another study tried to elu ci date the role of apoptosis in
PCA. 19 Their re sults pro posed that the keratinocyte destruction in PCA may occur as an initial result of
apoptosis, which in turn leads to am y loid for ma tion.
How ever, more in ves ti ga tions are re quired to fur ther
clar ify the mech a nism of cu ta ne ous am y loid de pos its.
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