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Reciprocal skin grafts in systemic sclerosis scleroderma.

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Reciprocal Skin Grafts in Systemic Sclerosis (Scleroderma)
James F. Fries, John
E. Hoopes and Lawrence E. Shulman
Full-thickness skin grafts were exchanged between involved forearm skin and
uninvolved abdominal skin in patients with systemic sclerosis. Eight of 10 grafts
healed well. The course of the grafts was evaluated clinically, and after seven to
nine months the grafts and adjacent skin were examined histologically. When
clinically normal skin is placed in a sclerodermatous bed, it becomes sclerodermatous. If sclerodermatous skin is placed in a normal bed, it remains sclerodermatous. These data suggest that skin involvement in systemic sclerosis is
generalized or irreversible, in contrast to reported findings in morphea, where
the disorder was found to be localized and reversible.
In 1946, Haxthausen described the results of reciprocal skin transplantation experiments in localized scleroderma or morphea (1). He reported transformation of all
grafts; the normal skin grafted into a lesion
became abnormal, and the diseased skin
grafted into a normal region became normal. The changes were complete in six to
nine months. No attempt was made at
systematic histologic evaluation. Whether
because Haxthausen freely interchanged
the words “morphea” and “scleroderma” or
because of a general confusion about the
relationships of “localized” and “generalized” scleroderma, the misconception that
his results are applicable to systemic sclerosis has been widespread.
From the Connective Tissue Division, Department of Medicine, and the Plastic Surgery Department, T h e Johns Hopkins Hospital and the Johns
Hopkins University School of Medicine. Baltimore,
Maryland 21205.
Supported by Grant 5T01-AM-05033-13 of the
Training Grant in Arthritis, National Institutes of
Health, US Public Health Service.
Address reprint requests to Dr. Fries, Department
of Medicine, Stanford University Hospital, Stanford,
California 94305.
Submitted for publication Dec 28, 1970; accepted
March 18, 1971.
Over 90% of patients with generalized
scleroderma have an “acrosclerotic” distribution of skin lesions, in which the skin
involvement is distal in distribution rather
than uniform and diffuse throughout the
body (2). These patients exhibit Raynaud’s
phenomenon. Typically, they have sclerodactyly, and the skin of the dorsum of the
hand, the forearm, the face and the upper
chest is also involved. The skin on other
parts of the body may be involved later in
the course of the disease, but is often
spared clinically. The reason for this characteristic distribution of skin lesions is urn
known.
This study evaluated the fate of r e c i p e
cal skin autografts in patients with systemic
sclerosis and acrosclerotic skin lesions.
METH0 DS
Full-thickness skin grafts were exchanged in five
patients under local anesthesia. Grafts, 2 to 3 cm
in diameter, were exchanged between clinically involved mid-forearm skin, and uninvolved abdominal
skin under 1% Xylocaine anesthesia (Fig 1). Subcutaneous fat was trimmed to ensure good contact
with the new bed. Skin was cloeed with 5-0 n y b n
sutures and a pressure dressing applied for five days.
Arthritis and Rheumatism, Vol. 14, No. 5 (September-October 1971)
m
FRIES E l A 1
Biopsies were taken from the initial grafts and
re-biopsy of both of the grafts and of the adjacent
skin was performed 7 to 9 months after grafting.
All patients had definite clinical scleroderma in
an acrosclerotic distribution. All had Raynaud’s
phenomenon, and all had typical internal organ
involvement of gastrointestinal tract, lungs or kidneys (3) Severity of disease, however, varied widely, with one patient exhibiting mild disease after 15
years, and another progressing to terminal renal
failure within 18 months (Table 1 ) .
Clinical evaluation of the course of the grafts was
performed monthly. Particular attention was paid
to induration, thickness, pigmentation, and attachment of the skin to underlying structwes. Clinical
grading was done with an arbitrary scale of zero to
4+, by a varying group of eight observers. T h e
authors graded each case. Agreement was excellent
between observers, and each of the patients independently made similar assessments. T h e final
grades represented a consensus of all observers.
Six tissue specimens from each patient were
evaluated histologically. These consisted of biopsies
from the grafts at time of transplantation, and
biopsies from the grafts and the adjacent skin 7
.
to 9 months later. Slides were stained with
Hematoxylin and Eosin, Verhoff-Van Giesen, and
Masson stains: they were coded and evaluated in
the blind by four observers according to a predetermined evaluation sheet. T h e obsenws consisted of
a dermatopathologist, a surgical pathologist, and
two of the authors. Slides were graded for thickness
of the dermis in tenths of millimeters, the number
of cell layers in the epidermis, “entrapment” of skin
appendages by collagen, extension of dermal connective tissue into fat, collagen staining characteristics, organization or disorganization of collagen
bundles, presence or absence of rete pegs, absence of
sweat glands or hair follicles, number of capillaries
in the subepidermal region per highpower field,
presence of intimal arteriolar sclerosis, and presence
of a perivascular infiltrate.
R ES ULTS
Eight of the 10 grafts healed well. Both
of the graft failures occurred in one patient. This patient had particularly severe
peripheral vascular disease, and had previ-
Table 1. Summary of Cases
~
~
Case
~~
AperiPulmonary
Duration
Acrostalsis of diffusion Renal
(yr)
sclerosis esophagus capacity disease
1. 54 WF
9
2. 34 WF
20
3. 41 WM
2
Marked
Yes
4. 59 WM
2
Marked
No
5. 39 NF
7
Severe
Yes
572
Marked
Yes
Normal
Moderate Equivocal 60% of
predicted
50% of
predicted
60% of
predicted
30% of
predicted
Fluorescent
antinuclear
antibody
Comments
Scleroderma, typical
postsyrnpathectorny
No Negative
Scleroderma, typical
mild, postsympathectorny
No 1: 10 Speckled Scleroderma, myositis, on steroids
Yes 1:lOO Speckled: Scleroderrna, accelerated renal disease
and malignant hypertension leading to
death three months
after study completed
No Negative
Scleroderma, marked
peripheral vascular
disease and digital
amputations, postsyrnpathectomy, graft
failure at both sites,
patient not included
No
1:lO Speckled
Arthritis and Rheumatism, Vol. 14, No. 5 (September-October 1971)
Fig 1. Reciprocal skin graft procedure. Full-thickness grafts from the forearm (A) were exchanged with those from the abdomen (6). Appearance of the grafts after
five days is shown in C and D.
FRIES ET A 1
Fig 4. Photomicrographs (original magnifiiation x 60) from Case 3. A Original clinkally normal abdominal skin. B. Abdominal skin after nine months in sclerodermatour site on forearm. C. Original clinically
sclerodermatous (3 +) forearm skin. D. Forearm skin after nine months in normal site on abdomen.
574
Arthritis and Rheumstism, Voi. 14, No. 5 (September-October 1971)
SKIN GRAFTS IN SCLERODERMA
Arthritis and Rheumatism, Vol. 14, No. 5 (September-October 1971)
575
FRIES E l
ously required multiple digital amputations for gangrene.
Clinical evaluation of the grafts during
the study revealed different courses at the
two sites (Fig 2). Initially, grafts from both
sites were edematous and indurated to clinical examination, but after the first 4 to
6 weeks these changes resolved. At this
point, all of the grafts resembled their original site, and several patients suggested that
perhaps more of their “bad” skin should be
replaced by this “good” skin. However, the
abdominal-to-forearm grafts then began to
insidiously assume a sclerodermatous character. In terms of thickness of the skin, the
difficulty in “picking it up,” and an indurated “feel,” these grafts progressively came
to resemble the surrounding sclerodermatous forearm.
On the other hand, the transplanted
sclerodermatous skin failed to change significantly after an initial period of postoperative edema. All grafts remained definitely involved with scleroderma throughout the period of observation.
Figure 3 shows the results in the individual cases. On the left, no significant
changes are seen to occur in the transplanted sclerodermatous skin. On the right,
sclerodermatous changes were striking ,in
three patients, and mild in one. Interestingly, these changes occurred most slowly
Forearm-to- A bdomenGraft
0
I
2
3
4
MONTHS
5
6
7
8
9
1
OF OBSERVATION
Fig 2. Composite course of grafts with time.
576
0
AL
4t
3t
2t
L
It
0
W
1
u
cn
Initial
Final
Foreorm To Abdominal
Graft
Fig 3.
lnitiol
Abdomen
To
Final
Forearm
Graft
Interval changes with grafts.
in the patient with the mildest clinical
disease.
Blind histologic evaluation of the graft,
forearm, and abdominal skin gave results
compatible with the clinical evaluation.
However, disagreement between observers
was frequent. The microscopist was not
always convinced of sclerodermatous changes even when clinical scleroderma was
marked. It was only possible to correctly
identify a given slide as grafted or nongrafted skin about two-thirds of the time.
The mean histologic ratings paralleled exactly the clinical findings of Figure 3,
but variation of at least one grade from the
mean occurred in 53y0 of the 288 individual observations, and variation of two or
more grades on 20y0 of the observations.
No clue to the degree of clinical scleroderma was given by the thickness of the
dermis, the number of cell layers in the
epidermis, “entrapment” of skin appendages, extension of dermal connective tissue
into fat, collagen staining characteristics,
collagen organization, appearance of
subepidermal collagen, or absence of sweat
glands and hair follicles. Presence of a
perivascular round-cell infiltrate correlated
to some degree, but not significantly, with
Arthritis and Rheumatism, Vol. 14, No. 5 (September-October 1971)
SKIN GRAFTS IN SCLERODERMA
the degree of clinical scleroderma. Crude
capillary counts and intimal arteriolar
sclerosis could not be significantly correlated with clinical involvement. T h e most
reliable histologic predictor of clinical
scleroderma was atrophy of the rete pegs.
Figure 4 illustrates the histologic changes
in the patient in whom they were most
evident. On the upper left, normal abdominal skin with a lacy collagen organization is shown. After nine months (at
upper right), collagen has become dense
and homogeneous, both in superficial and
deep layers of the dermis. On the lower
left, sclerodermatous forearm skin with
dense collagen and epidermal atrophy has
not changed after nine months i n an abdominal site (shown at lower right). T h e
abdominal skin did not change clinically or
histologically during the course of the
study in any patient.
DISCUSSION
In contrast to Haxthausen’s findings in
morphea, we did not observe a return of
sclerodermatous skin to normal. On the
other hand, normal skin readily became
sclerodermatous in a sclerodermatous site.
We considered the possibility that scarring
from the graft procedure might have obscured our perception of improvement in
the grafts, but the transplanted normal
skin often remained normal for months
before undergoing gradual sclerodermatous
change. If scarring were pronounced, it
should have been maximal within a few
weeks. Moreover, scarring from the graft
procedure was minimal or undetectable
histologically in many specimens, and located only in the deepest portions of the
dermis.
T h e obvious difference between systemic
sclerosis and morphea is the widespread,
multi-organ character of systemic sclerosis.
It may be questioned whether any skin in a
patient with systemic sclerosis may be considered normal, and whether any areas of
the body are actually uninvolved. With a
“generalized” skin disease one would not
expect a graft to return to normal even on
a n “uninvolved” area. T h e failure of
sclerodermatous skin to return to normal
in an “uninvolved’ area suggests that the
skin disease is, in fact, generalized, that it is
irreversible, or both. T h e delineation of
morphea and systemic sclerosis as distinct
and separate disease entities is strengthened by these observations.
Skin biopsy, to ourselves and to others,
has been a disappointing method for diagnosing systemic sclerosis. Inter-observer
disagreements, noted in this study, would
indicate that histopathologic grading of
scleroderma is no more satisfactory. Blindslide review emphasizes the lack of reliable
histologic criteria which parallel clinical
sclerodermatous involvement.
Few reports of successful skin grafting in
systemic sclerosis appear in the literature
(4-6). During the execution of this study,
both full-thickness grafts healed well in
four of five patients, including one patient
on high-dose corticosteroid therapy. Failures occurred only in the patient with the
most pronounced peripheral vascular insufficiency; this patient had previously required multiple digital amputations for
gangrene. Full-thickness skin grafting a p
pears feasible in scleroderma, with little
increased risk of graft failure as compared
with other patients.
REFERENCES
1. Haxthausen H: Studies on the pathogenesis
of morphea. vitiligo, and acrodermatitis
atrophicans by means of transplantation
experiments. Acta Derm Vener 27352-368,
1946
2. Tuffanelli DL, Winkelman RK: Systemic
Arthritis and Rheumatism, Vol. 14, No. 5 (September-October 1971)
577
FRIES El AL
scleroderma: A clinical study of 727 cases.
Arch Derm 84:359-371, 1961
3. D'Angelo WA,'Fries JF, Masi AT, et al:
Pathologic observations in systemic sclerosis
(Scleroderma): A study of 58 autopsied
cases and 58 matched controls. Amer J
Med 46:428-440, 1969
4. Gordon S: The hand in scleroderma. Plast
578
Reconstr Surg 23:240-244, 1959
5. Herman BE, Fischl R, Frankel A, et al:
Successful skin graft in patient with generalized scleroderma. JAMA 182:578-579,
1962
6. Cramer LM: The management of the extravisceral manifestations of scleroderma.
Plast Reconstr Surg 28:166-182, 1961
Arthritis and Rheumatism, Vol. 14, No. 5 (September-October 1971)
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