OBSERVATION
Specific Nail Alterations in Cutaneous
T-Cell Lymphoma
Successful Treatment With Topical Mechlorethamine
Laurent Parmentier, MD, PhD; Caroline Dürr, MD; Erik Vassella, PharmD;
Helmut Beltraminelli, MD; Luca Borradori, MD; Eckart Haneke, MD
Background: Cutaneous T-cell lymphoma can be associated with clinically significant nail alterations, the presentation of which can be protean and misleading. To date,
only a few reports have demonstrated direct specific tumor infiltration of the nail bed, while little is known about
the efficacy of topical treatments.
Observations: We describe the case of a 93-year-old
man presenting with Sézary syndrome who developed
clinically significant nail alterations. Light microscopy
studies and T-cell receptor rearrangement analysis
demonstrated the presence of a specific lymphocytic
infiltrate within the nail bed. The patient was given
N
Author Affiliations:
Department of Dermatology,
Inselspital, Berne University
Hospital (Drs Parmentier, Dürr,
Beltraminelli, Borradori, and
Haneke), and Institute of
Pathology, University
of Berne (Dr Vassella), Bern,
Switzerland.
repeated courses of topical mechlorethamine, leading to
a sustained complete remission of both skin and nail
alterations.
Conclusions: Specific nail involvement should be recognized and considered in all patients with cutaneous
T-cell lymphomas. Topical mechlorethamine remains an
attractive therapeutic option in cases of specific nail
alterations, especially for situations in which systemic
therapies are either not indicated or unlikely to be well
tolerated.
Arch Dermatol. 2010;146(11):1287-1291
AIL ABNORMALITIES ARE A
rare accompanying sign of
both localized and erythrodermic forms of cutaneous T-cell lymphoma
(CTCL). Their presentation can be very
pleomorphic and misleading. Demonstration of specific infiltration of the nail apparatus by histologic examination and/or
T-cell receptor (TCR) clonality has been
very rarely reported. Moreover, although
systemic therapies of CTCL are likely to improve specific nail lesions, little is known
about the effect of topical treatments.
Among them, mechlorethamine is an attractive alternative to use in situations in
which the disease has spared lymph nodes
or other hematopoietic organs.
We report the case of a patient with Sézary syndrome (SS) who developed specific nail abnormalities, confirmed histologically, immunohistochemically, and by
clonal T-cell rearrangement studies, who
was successfully treated with topical mechlorethamine. This observation demonstrates the usefulness for nail involvement in CTCL.
(REPRINTED) ARCH DERMATOL/ VOL 146 (NO. 11), NOV 2010
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REPORT OF A CASE
A 93-year-old male patient with suspected CTCL presented at our department. He had complained of generalized
and recurrent eczematous lesions for 3
years and had been treated with intermittent topical steroids. The first histologic
evaluation in January 2008 showed features compatible with small-plaque parapsoriasis. Psoralen–UV-A (PUVA) therapy
had no effect. Five months later, the eruption had spread to more than 80% of the
body surface and had become partially infiltrated. Findings from a new biopsy specimen revealed a subepidermal infiltrate
composed of atypical small lymphocytes
with a clinically significant degree of epidermotropism but no genuine abscess formation. The infiltrate consisted mainly of
CD3⫹ T lymphocytes (with a CD4 to CD8
ratio of 1:2), and a clonal rearrangement
for the ␥-chain of TCR (TCR-␥) was observed. Findings from a screening for
lymph nodes or visceral and bone marrow involvement were negative. No circulating Sézary cells could be detected, but
the same clonal rearrangement of the
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A
A
B
B
Figure 2. Histopathologic specimen. A, Atypical lymphocyte infiltration of the
nail bed. Hematoxylin-eosin, original magnification ⫻5. B, Lining-up of
lymphocytes along the basal membrane and Pautrier abscess formation.
Hematoxylin-eosin, original magnification ⫻20.
C
Figure 1. A 93-year-old patient with Sézary syndrome who developed
clinically significant nail alterations. A, Marked nail alterations of all but 1 nail
on both hands. B, Detailed view of right hand fingernails 3 and 4, showing
onychomadesis. C, Detailed view of both thumbnails, showing marked
thickening and subungual hyperkeratosis. A nail biopsy specimen was
obtained from fingernail 1, left lateral.
TCR-␥ was observed in the blood. The patient was considered to have stage IIIA CTCL (stage T4N0M0B0b according to the 2007 European Organisation for Research and Treatment of Cancer /International Society
for Cutaneous Lymphoma criteria). In addition, he had
complained of nail alterations over a 1-year period, which
involved 9 of the 10 fingernails (Figure 1). Careful examination revealed anonychia (fingernail 2, right and left),
onychomadesis (fingernails 1, 3, and 4, right; and fingernails 3 and 5, left), subungual distal hyperkeratosis
(fingernail 1, left) and onycholysis (fingernail 5, right).
Neither paronychium nor perionychium alterations were
observed. There was also no discoloration or growth arrest, and the fourth left digit was normal. The patient de-
nied any intake of systemic drugs, especially no cyclins.
Histopathologic examination of a longitudinal nail biopsy (fingernail 1, left), involving the proximal nail matrix, revealed a horizontal bandlike lymphocytic infiltrate localized in the dermis of the nail bed and at the
junction with the hyponychium. The atypical lymphocytes showed clinically significant epidermotropism with
Pautrier microabscesses formation. No relevant modification of the proximal matrix was observed. The nail plate
was proximally thin and became steadily substituted by
hyperkeratosis distally ( Figure 2 ). Periodic acid–
Schiff (PAS) stains were negative for fungi. Immunostaining revealed a CD3⫹ lymphocytic infiltrate within
the distal matrix, the nail bed, and the hyponychium. CD4
stained only one-third of the cells, whereas CD8 showed
marked staining of the majority. The TCR-␥ rearrangement showed identical clones in blood as well as in skin
and nail materials (Figure 3).
Because previous PUVA therapy was ineffective, local therapy with topical mechlorethamine ointment
(chlormethin hydrochloride) was started. A 0.02% ointment-based mechlorethamine preparation was obtained according to the recommended procedure.1 It was
applied 3 times weekly, used in alternation during the
first 2 weeks, with clobetasol propionate on all the skin
surface except the head. Mechlorethamine was also directly applied on the whole nail apparatus (nail plates
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A
150
170
190
210
230
250
270
290
Intensity of Fluorescence
1200
150
170
190
210
230
250
270
290
150
170
190
210
230
250
270
290
230
250
270
290
900
800
700
600
500
400
300
200
100
0
1000
800
600
400
200
0
B
150
170
190
210
230
250
270
290
Intensity of Fluorescence
1400
500
1200
400
1000
800
300
600
200
400
100
200
0
0
244.92
22 084
209.72
6932
247.77
12 916
212.69
7468
C
150
170
190
210
230
250
270
Intensity of Fluorescence
150
290
170
190
210
3200
3200
2800
2800
2400
2400
2000
2000
1600
1600
1200
1200
800
800
400
400
0
0
209.77
53 400
245.08
57 025
171.97 183.94
42 274 16 718
212.71
32 582
247.91
22 759
Nucleotides, No.
Nucleotides, No.
Figure 3. Identical clonal rearrangement for T-cell receptor ␥ in the skin and nails. A, Polyclonal; B, D9014-08 skin abdominal biopsy specimen; C, D10439-08 nail
biopsy specimen. Arrowheads indicate the direction of the major peaks.
and lateral and proximal nail folds). At 6 months, the skin
and nails appeared to be completely healed (Figure 4).
Maintenance of the success was obtained for more than
6 months while decreasing the application frequency to
twice weekly.
6-carboxy-fluorescein. Polymerase chain reaction products
were analyzed by capillary electrophoresis using an ABI PRISM
3100 Avant genetic analyzer (Applied Biosystems, Foster City,
California).
COMMENT
METHODS
The skin and nail biopsy specimens were fixed in formalin
and processed as usual. Staining with hematoxylin-eosin,
PAS, Giemsa, and elastic–van Gieson stains was performed.
Immunophenotyping was performed according to routine
methods for skin lymphomas. For TCR-rearrangement study,
genomic DNA was extracted from formalin-fixed, paraffinembedded tissue sections. Amplification was performed using
2 different sets of specific consensus primers that bind to different zones of the variable (V) regions in combination with consensus primers from the joining ( J) regions of the TCR ␥-chain
gene.2-4 The 2 sets of variable region primers (consensus primers Vg1-8 and specific primers Vg9, Vg10, and Vg11) were
either 5⬘ end-labeled with 5-carboxyfluorescein or hexachloro-
Though not uncommon, nail alterations in CTCL have
been rarely described. Nail involvement is seen in mycosis fungoides (MF), usually in advanced stages, as well
as in true SS.
Ungueal involvement in plaque and tumoral stages of
MF was first described as “yellow nail syndrome” of the
20 nails with pleural effusion and marked lower leg lymphedema.5 Yellow discoloration, slowed growth, nail thickening, and increased curvature, together with onychomadesis, were also reported in a multiple-plaque–stage MF.6
Yellow nails with thickening accompanied a vesiculopustular variant of palmoplantar MF, in which tumoral infiltration of the nail bed was confirmed histologically, im-
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A
B
C
Figure 4. The same patient as in Figure 1. A-C, The same views as in Figure
1 after 6 months of treatment, showing complete healing of the lesions.
munohistochemically, and by TCR rearrangement study.7
Paronychia, trachyonychia, onycholysis, and subungual
hyperkeratosis were observed as a direct consequence of
infiltration by a folliculotropic MF, affecting all fingernails.8 More recently, nail alterations in a single finger were
reported in tumor-stage MF as nail plate thinning and partial obliteration of the proximal and lateral nail folds, together with soft-tissue swelling of the entire segment.9 Eight
cases of nail alterations have been described in patients
with SS. Tomsick10 reported isolated rough subungual hyperkeratosis of the 20 nails in a patient with circulating
Sézary cells and multiple MF plaques, whereas Dalziel et
al11 observed a similar presentation in a patient with true
erythrodermic SS. The patient described in a report by Tosti
et al12 had nonspecific thickening and discoloration of the
nail plates. In a series of 5 SS cases,13 all patients presented
with splinter hemorrhages, 3 with subungual hyperkera-
tosis and/or onycholysis and 4 with distal yellow-brown
discoloration.
Our case shows the coexistence of marked onychomadesis, previously undescribed, to our knowledge, involving 9 of the 20 nails. There was neither a yellow nail
discoloration nor a generalized subungual hyperkeratosis. The possibility that phototherapy was responsible for
the nail alterations seems very unlikely because (1) nail
changes started prior to PUVA therapy, (2) 1 finger was
completely spared, and (3) onycholysis remains very rare
during PUVA therapy and then induces more homogeneous alterations.14
To our knowledge, treatment of nail alterations in CTCL
have never been specifically studied. In the several cases
reported to date, patients received a systemic treatment, resulting in partial or total improvement of the nail lesions.
Topical therapies in CTCL, besides phototherapy as standalone or add-on treatment, rely mainly on local application of cytostatics, such as topical nitrogen mustard.15,16
Topical mechlorethamine has proved to be an efficient treatment in MF, alone15,16 or associated with topical steroids.17 A response was even reported in patients with a poor
prognosis, such as CTCL in organ transplant recipients.18
However, the specific efficacy on nail alterations was never
mentioned, except in the original report by Tomsick,10 who
wrote that nitrogen mustard diluted in water induced resumption of normal nail growth. Because systemic absorption of mechlorethamine is negligible after topical administration,15 the observed response is likely to result from a
local cytostatic effect on tumor cells infiltrating the hyponychium and/or the nail bed and/or the matrix. Topical
mechlorethamine might be effective by various mechanisms of action: (1) diffusion through the nail plate, although this is likely to be minimal; (2) effect on the matrix via penetration of the proximal nail fold; and (3) direct
diffusion to the nail bed favored by the distal onycholysis.
In brief, this case illustrates the wide spectrum of specific nail abnormalities that can occur in CTCL. In addition, it provides evidence for the excellent effect of topical mechlorethamine and suggests that nail involvement
per se in CTCL should not be regarded as an independent criterion to start a systemic treatment if otherwise
not required
Accepted for Publication: May 15, 2010.
Correspondence: Laurent Parmentier, MD, PhD, Department of Dermatology, Inselspital, Berne University
Hospital, CH-3010-Bern, Switzerland (laurent.parmentier
@insel.ch).
Author Contributions: Drs Parmentier and Haneke had
full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of
the data analysis. Study concept and design: Parmentier
and Haneke. Acquisition of data: Parmentier, Dürr, Vassella, and Haneke. Analysis and interpretation of data: Parmentier and Haneke. Drafting of the manuscript: Parmentier, Vassella, Borradori, and Haneke. Critical revision
of the manuscript for important intellectual content: Parmentier, Beltraminelli, Borradori, and Haneke. Administrative, technical, and material support: Parmentier, Dürr,
Beltraminelli, and Borradori.
Financial Disclosure: None reported.
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Arch Dermatol. 2006;142(8):1071-1073.
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mycosis fungoides confined to a single digit: report of a case and review of nail findings in cutaneous T-cell lymphoma. J Am Acad Dermatol. 2008;59(1):154-157.
10. Tomsick RS. Hyperkeratosis in mycosis fungoides. Cutis. 1982;29(6):621-623.
11. Dalziel KL, Telfer NR, Dawber RP. Nail dystrophy in cutaneous T-cell lymphoma.
Br J Dermatol. 1989;120(4):571-574.
12. Tosti A, Fanti PA, Varotti C. Massive lymphomatous nail involvement in Sézary
syndrome. Dermatologica. 1990;181(2):162-164.
13. Sonnex TS, Dawber RP, Zachary CB, Millard PR, Griffiths AD. The nails in adult
type 1 pityriasis rubra pilaris: a comparison with Sézary syndrome and psoriasis.
J Am Acad Dermatol. 1986;15(5, pt 1):956-960.
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15. Estève E, Bagot M, Joly P, et al; French Study Group of Cutaneous Lymphomas.
A prospective study of cutaneous intolerance to topical mechlorethamine therapy
in patients with cutaneous T-cell lymphomas. Arch Dermatol. 1999;135(11):13491353.
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Notable Notes
Articles of Faith Variant Lighten Up Babe!
This little cherub was inspired by
various folk and home remedies
that have been recommended to
lighten skin color (Figure). From
the top, the components are saffron for its little curl; a potato for
its head; plum tomatoes for its
ears; almonds for its eyes; a red
onion for its howling mouth (it
is a baby after all); a milk bottle
for its body; pieces of aloe for its
arms and slices of lime for its
hands; pieces of cucumber for its
legs and slices of lemon for its feet;
and an orange peel for its diaper.
Mark S. Bernhardt, MD
Contact Dr Bernhardt at 1601 E
Broward Blvd, Ft Lauderdale, FL
33301 ([email protected]).
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