T cell chronic lymphocytic leukemia with

bullous manifestations
Jean C6t6, M . D . , Michel Trudel, M.D., and David Gratton, M.D.
Montreal, Quebec, Canada

Among chronic lymphocytic leukemias (CLLs), the B cell variant is the most
common phenotype. The T cell is rare. A variety of cutaneous manifestations
have been reported with B and T cell leukemias. We report a patient who
presented with a bullous eruption and who was found to have T cell CLL.
Despite different therapeutic approaches, the patient died. The cutaneous
histology and autopsy findings are reviewed. (J AM ACAD DERMa'COL
8:874-878, 1983.)

Chronic lymphocytic leukemia (CLL) is the
most common type of chronic leukemia. The ma-
jority o f cases have B cell characteristics. The T
cell variant of C L L is u n c o m m o n , and its true
incidence has not been established. Dermatologic
manifestations occur frequently with C L L , espe-
cially with the T cell variant. These cutaneous
manifestations ~ included nonspecific findings,
such as purpura, ecchymoses, pruritus, erythro-
derma, viral eruptions, bullous eruptions, and
p y o d e r m a gangrenosum. Specific cutaneous in-
volvement is manifested by papules, nodules,
tumors, and exfoliative erythroderma, all of which
represent leukemic infiltrates.
The association of T cell chronic lymphocytic
leukemia and a bullous eruption is u n c o m m o n .
We report a case and review the literature.
CASE REPORT
A 63-year-old man was admitted in December,
1980, for a bullous eruption involving the hands and
feet, Six weeks prior to this, he had noted several bul-
]ae on the dorsa and sides of his feet. These were large,
From the Departments of Dermatology (C8t6 and Gratton) and
Pathology (Trudel), The Montreal General Hospital, McGill Uni-
versity.
Reprint requests to: Dr. Jean C6t~, M.D., Dermatology Department,
The Montreal General Hospital, 1650 Cedar Ave., Montreal,
Quebec, H3G IA4/514-937-601 I.
874
tense, and contained clear fluid. Ten days later, the
face, hands, and feet became swollen. Infiltrated
plaques appeared on his trunk. He was given predni-
sone, 30 mg daily, by his physician without improve-
ment. His general health had been satisfactory, except
for a past history of depression which was treated with
lithium.
The physical examination revealed mobile nontender
adenopathy, measuring 1 3 cm, in the right axilla,
and a moderately enlarged spleen. The liver measured
13 cm. The cutaneous findings were polymorphous: the
face was erythematous and swollen; pruritic plaques
with pinch-purpura were present on the temporal areas,
shoulders, anterior portion of the chest, and abdomen;
the hands were exquisitely tender, swollen, erythema-
tous, and fissured; tense bullae filled with clear fluid
were located on the dorsal, medial, and lateral aspects
of the hands and feet (Fig. 1).
The hematocrit was 40%, with a hemoglobin of 14.0
gm/dl; the leukocyte count was 56,600/mm 3, with 79%
lymphocytes, 14% neutrophils, and 2% basophils. The
platelet count was 232,000/mm a. The peripheral smear
confirmed the marked lymphocytosis; the lymphocytes
were small and monotonous, with slightly irregular
nuclear outlines. The bone marrow aspirate demon-
strated 38% small lymphocytes in keeping with a
chronic lymphocytic leukemia. Chromosome analysis
and Q banding studies on bone marrow cells showed no
significant abnormality. Skin tests to purified protein
derivative (PPD), Candida, mumps, and trichophyton
showed cutaneous anergy. Immunologic typing of pe-
ripheral blood lymphocytes showed 47% sheep red
Volume 8
Number 6
June, 1983
hyperpigmentation of the face without involvement of
the eyes or ears (Figs. 1 and 2). The hyperpigmentation
was relatively uniform, with some accentuation on the
malar eminences and the skin creases of the cheeks and
forehead. The remainder of the physical examination
was unremarkable.
Laboratory investigations, including a chemistry
profile, complete blood cell count, urinalysis, and
Fe/TIBC (total iron binding capacity) were all normal
except for a mildly elevated serum creatinine of 1.7
mg/dl. A urine screen for HGA was negative. Methemo-
globlin levels were normal.
A 2-ram punch biopsy was taken from the right
cheek. With hematoxylin-eosin staining, the biopsy
demonstrated a yellow-brown pigment present within
homogenized and swollen collagen bundles in the
upper dennis. Most of these collagen bundles were
broken and formed irregular, almost banana-shaped,
clumps (Figs. 3 and 4). The pigment stained black
with methylene blue. Elastic tissue stains revealed
no abnormalities. These findings were interpreted as
ochronosis.
Electron microscopy revealed large ochronotic fibers
deposited as irregular fibrillar electron-dense areas sur-
rounded by normal collagen bundles (Fig. 5). These
findings were similar to those reported by Attwood et
alz in their ultrastructural study of dermal ochronosis in
a patient with alkaptonuria, except that the electron-
dense deposits were homogeneous in their patient.
The patient was advised to discontinue the use of any
bleaching cream. She was conservatively treated with a
topical 21A% hydrocortisone cream to her face twice
daily and cautioned to protect her face from sun expo-
sure. Follow-up of this patient after 18 months showed
remarkable clearing of the hyperpigmentation, except
for some residual changes in the periorbital areas
(Fig. 6).
DISCUSSION
The differential diagnosis of cutaneous blue-
black hyperpigmentation is summarized in Table
I. The history and physical examination, labora-
tory data, and appropriate biopsy specimens usu-
ally pinpoint the etiology. The mechanism for the
blue-black coloration o f dermal hyperpigmenta-
tion due to the Tyndall effect has been beautifully
detailed in the classic paper by Jeghers,a and more
recently by other workers. 4.5 An excellent review
of drug and heavy metal-induced hyperpigmenta-
tion has recently appeared. 6 The following discus-
sion elaborates on the various causes ofochronosis.
Localized exogenous ochronosis 883
Ochronotic pigmentation of the connective tis-
sues of patients with alkaptonuria is believed to
result from the accumulation of HGA, with sub-
sequent oxidation and polymerization. However,
the biochemical mechanism responsible for the
production of the pigmentation has not been de-
termined, and it is not clear w h y ochronosis leads
to arthritis o f the large joints. In a series of inter-
esting papers, Zannoni et al T'~ studied the distri-
bution of H G A and its corresponding quinone,
benzoquinoneacetic acid. They found them mainly
in skin and cartilage, with the quinone chemically
binding to the sulfhydryl and amino groups of the
connective tissue substrates. Moreover, the en-
zyme HGA polyphenoloxidase, implicated in the
subsequent oxidation and polymerization, has its
highest activity in skin and cartilage, which may
explain the distribution of ochronotic pigmenta-
tion and arthropathy.
Other research groups, noting that solutions of
HGA darken on exposure to air or upon addition
of alkali, proposed a straightforward nonenzy-
matic oxidation for the formation ofochronotic pig-
ment.9-11 These workers showed that both the ul-
traviolet and infrared spectra of pigment prepared
by air oxidation of HGA and ochronotic pigment
extracted from the hip of an Egyptian mummy
were nearly identical. Hence, our present knowl-
edge of the chemical structure and the production
(whether enzymatic or nonenzymatic) o f the ochro-
notic pigment in patients with alkaptonuria is in-
complete.
One of the earliest reports of exogenous ochro-
nosis noted hyperpigmentation secondary to the
prolonged use of carbolic acid (phenol) dressings
for chronic cutaneous ulcers.'" Twenty cases of
phenol-induced ochronosis can be found in the
older literaturela'~'t; the course o f disease and clin-
ical picture were very uniform. The disorder oc-
curred in patients who for many years (10 to 40)
had treated leg ulcers with applications of wet
dressings containing phenol in various concentra-
tions. The pigmentation of phenol ochronosis does
not essentially differ from that observed in the
endogenous type, with the skin, sclerae, and carti-
lage being affected. Many patients with phenol
ochronosis were noted to have dark urine, much
like patients with alkaptonuria. Moreover, autopsy
 Journal of the
884 Cullison et al American Academyof
Dermatology

T a b l e I . Differential diagnosis o f cutaneous blue-black hyperpigmentation*

I. Dermal melanoses
A. Mongolian spots
B. Nevus of Ota and Ito
C. Blue nevus
D. Demaal melanocyte hamartoma a~
E. Incontinentia pigmenti
II. Drugst
A. Fixed drug
B. Phenothiazines
C. Antimalarials
D. Heavy metals
1. Localized-topical mercurials
2. Diffuse
E. Tetracyclines
1. Localized
2. Diffuse-minocycline
F. Clofazimine
G. Amiodarone
H. Chemotherapeutic agents
III. Metabolic disorders
A. Ochronosis
1, Endogenous
2. Exogenous
B. Hemochromatosis
C. Gaucher's disease a~
D. Addison's disease
E. Nutritional deficiencies
F. Carcinoid
G. Cyanosis/pseudocyanosis
IV. Infections
A. Pinta
B. Pediculosis pubis (maculae caeruleae)
C. H. influenzae (buccal cellulitis)zr
V. Neoplasms
A. Melanoma
1. Localized
2. Diffuse-metastatic a
B, Vascular lesions
1. Venous lake
2. Blue rubber bleb nevus
C, Neuroblastoma-metastatic '~s
VI. Miscellaneous
A. Ashy dermatosis
B. Riehl's melanosis
C. Erythema ab igne
D. Traumatic tattoo
E. Cullen/Gray-Tumer sign
*As a general reference, see Ref. 34.
tSee Ref. 6.
Volume 8
Number 6
June, 1983
of a 73-year-old man who had phenol-induced
ochronosis showed the knee joint to have the color
"of a well-polished black boot"; the stemocla-
vicular joint was also black. 12 Reportedly, in phe-
nol ochronosis there is no discoloration of sweat
and cerumen, which frequently is noted in cases of
alkaptonuria. Apart from cessation of the use of
phenol, there is no method of treatment, and the
pigmentation persists for life. Another example of
exogenous ochronosis due to phenolic compounds
is the report by Howard and Mills la of bluish hy-
perpigmentation in a patient following prolonged
use of picric acid in the treatment of extensive
bums.
The antimalarials, a group of acridines and
4-aminoquinolones, have been reported infre-
quently to cause an ochronosis-like pigmentation
on the anterior shins, hard palate, face, and sub-
ungal areas. 16-j~ Characteristically, in antimalar-
ial ochronosis, the hyperpigmentation is first noted
on the hard palate. No patient with antimalarial
ochronosis has been reported to have dark urine.
One patient with quinacrine ochronosis complained
of low back pain and had roentgenographic evi-
dence of a degenerative type of arthritis involving
the lumbar spine. ~7 However, examination of
synovium, cartilage, and bone from a 58-year-old
woman with quinacrine ochronosis who under-
went surgical repair of a hammer toe showed no
evidence of abnormal pigmentation. 1~ Although
initial reports implicated only quinacrine, most
antimalarials, including quinine, quinacrine, chlo-
roquine, hydroxychoroquine, and amodiaquine,
are capable of producing this hyperpigmentation.
Tuffanelli's extensive description of twenty-five
patients with antimalarial hyperpigmentation indi-
cated the mean duration of therapy was 25 months
before pigmentation occurred.iS Cessation of ther-
apy led to decreased intensity of the pigmentation,
but no patient cleared completely. Histologic
examination of skin in these patients revealed
yellow-brown pigment granules in the mid dermis
consistent with ochronosis.
The exact nature of the pigment in these cases
secondary to antimalarial therapy is not known.
When metabolized, the basic ring structure of the
antimalarials is not altered; only minor changes,
Localized exogenous ochronosis 885
such as dealkylation of the amino group or de-
methylation of the methoxy group (quinacrine),
are found, z" Therefore, it is difficult, except in the
case of quinacrine, to postulate phenolic interme-
diates or a chromophore (Fig. 7; dotted lines) simi-
lar to any melanin precursor. Sams and Epstein '-'1
showed that chloroquine not only has a remarkable
affinity for cutaneous melanin, but that it also is
not readily released from the pigmented tissues.
Studies suggest that the chloroquine may bind to
melanin by a charge transfer process. Hence, the
pigmented polymer in antimalarial ochr0nosis is
probably melanin itself. This provides chemical
support for those who object to an expansion of
the term "ochronosis" beyond its original use by
Virchow to describe hyperpigmentation due to the
deposition of polymers of phenolic derivatives in
connective tissue. 22
Although not causing confetti-like leukoderma
or depigmentation at distant sites like its mono-
benzyl ether, hydroquinone can cause a peculiar
hyperpigmentation. First recognized by Findlay
et al,2a-25 exogenous ochronosis may be caused by
the continuous use of bleaching creams containing
hydmquinone. This outbreak of exogenous ochm-
nosis was first noted when creams containing
6.0% to 8.0% hydroquinone were introduced in
South Africa. These authors described observa-
tions in thirty-five patients collected over a 5-year
period (1969-1974). Their clinical and histologic
findings are similar to those o f our patient, except
that the hyperpigmentation in their patients did not
tend to clear. Subsequently, another South African
group reported forty-three additional black women
with exogenous ochronosis secondary to hydro-
quinone bleaching creams 26 Four of these patients
had granulomas resembling sarcoidal lesions ap-
parently developing as a reaction to the ochronotic
particles. None of these cases of hydroquinone
ochronosis was reported to have dark urine or ar-
thritis.
Common to exogenous ochronosis, caused by
phenols and hydroquinone bleaching creams, and
endogenous ochronosis (alkaptonuria) are phe-
nolic intermediates (Fig. 7). Phenol is readily ab-
sorbed from the surface of wounds and even
through intact skin. 2~ It forms compounds with
 Journal of the
886 Cullison et al American Academyof
Dermatology

Fig. 5. Electron micrograph of the ochronotic dermis demonstrating irregular electron-

dense areas of ochronotic fibers surrounded by normal collagen bundles. (Original mag-
nification, 36,000.)

sulfuric and glucuronic acids and is excreted in the
urine in the form o f the alkali salts of these com-
pounds. A portion o f the absorbed phenol is oxi-
dized within the body into hydroquinone. 2s In-
deed, Berry and Pear a isolated hydroquinone
from one sample of urine of their patient with
phenol-induced ochronosis. The metabolism of
hydroquinone involves oxidation to quinone and
its derivatives, with all being excreted unchanged
or in the form of sulfates or glucuronates. 29 Hy-
droquinones, including HGA, when oxidized to
quinones, can readily add nucleophiles such as
amines. Stoner and Blivaiss a~ showed that ben-
zoquinoneacetic acid forms a stable adduct when
incubated with various biologic amines such as
spermine, tyrosine, glycine, taurine, and lysine?~
All of these reactions produced compounds dis-
playing various shades of red, except spermine,
the adduct of which was golden yellow. Quinones
do not have characteristics of aromatic compounds
but behave chemically more like unsaturated
aliphatic ketones. This property would allow
electron-donating groups (such as primary or sec-
ondary amines) to be added in either a 1,2 or 1,4
fashion. Either mode of addition, followed by
cyclization, could ultimately lead to a hydrox-
ylated indole similar to melanin precursors (Fig.
8). Support for this scheme can be found in a

Fig. 1. Localized exogenous ochronosis. Sooty blue-black hyperpigmentation with some

accentuation in skin creases on the chin, cheeks, and periorbital area.
Fig. 2. Side view of patient shown in Fig. 1.
Fig. 3. Photomicrograph of a skin biopsy from the patient's right cheek. The yellow-brown
ochronotic pigment is deposited as homogenized bundles. The ochronotic bundles assume
bizarre curled shapes. (Hematoxylin-eosin stain; original magnification, 40.)
Fig. 4. Higher magnification of Fig. 3 further demonstrating the dermal ochronosis.
(Hematoxylin-eosin stain; original magnification, 100.)
Fig. 6. Eighteen-month follow-up visit after discontinuing use of the hydroquinone bleach-
ing cream and applying hydrocortisone cream; only residual periorbital hyperpigmentation
remains.
Volume 8
Number 6 Localized exogenous ochronosis 887
June, 1983

Figs. 1, 2, 3, 4, and 6. For legends, see opposite page.

 Journal of the
888 Cullison et al American Academy of
Dermatology

OH OH OH OH OH

~ hydroquinone
OH OH NO2 OH
hydroquinone HGA picrie acid
,Oxldation

.j~.ik,.,,1,2
NHR NHFI
i~ ........ ! ~. ~ ,,2 additlon o, ( )J,,t 1,4 addltion of

L_~J ___ c~
<,L2.cJ 0
5,8-dlhydroxlndole
(a melanogen)
qulnacrl.ne chloroqulne
N
...H CO2H
qulnone OH

C02H

Fig. 7. Structural formulas for phenols, indoles, and

antimalarials.
OH
O i ~ cyellzation

report on the interaction of thiols and quinones, OH

where a similar conjugate addition and cyclization

was noted, al Prota a' recently described analogous
addition/cyclization reactions between cysteine
and dopaquinone.
A recent review of bleaching creams concluded
with the statement, "Bleaching creams containing
hydroquinone are modestly effective and generally
safe."az The number of such products, both pre-
scription and proprietary, and the market for such
products are increasing. This patient's problem
OH
expands the arena for exogenous ochronosis due to hydroxlndole
hydroquinone bleaching creams from South Africa
and emphasizes that the safety of a hydroquinone Fig. 8. Proposed mechanism for indole formation from
hydroquinones.
preparation may not be ascertainable solely by
concentration, but also requires consideration of
the amount, frequency, and vigor of application.
8.
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Volume 8
Number 6
June, 1983
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