ARTICLE
Auteur(s) : Sadhanna Badeloe, Jorge Frank
Department of Dermatology and Maastricht University
Center for Molecular Dermatology (MUCMD) and GROW -
School for Oncology and Developmental Biology, Maastricht
University Medical Center, P. Debyelaan 25; Postbus 5800, 6202 AZ
Maastricht, The Netherlands
accepté le 15 Mai 2009
Leiomyomas of the skin were first described by Virchow in 1854
[1]. Cutaneous leiomyomas are rare benign tumors arising from
smooth muscle cells. According to their site of origin they can be
classified into three types, i) those derived from the arrector
pili muscle of hair follicles (piloleiomyomas); ii) those
originating from the vascular smooth muscle (angioleiomyomas); and
iii) those arising from the smooth muscle of genital skin (dartoic
leiomyomas). Piloleiomyoma is the most common type among cutaneous
leiomyomas [1, 2]. In contrast to the mainly solitary
angioleiomyomas and dartoic leiomyomas, piloleiomyomas
predominantly manifest as multiple tumors, referred to as
leiomyomatosis. In 1958 Kloepfer et al. described for the
first time, in an Italian family with cutaneous leiomyomatosis, an
autosomal dominant inheritance pattern with incomplete penetrance
[3]. Subsequently, different authors reported several families with
autosomally dominant inherited cutaneous leiomyomatosis [4-6].
Furthermore, in some of these families, affected female individuals
also exhibited uterine leiomyoma [4, 6]. In 1973, Reed et al.
were the first to emphasize the association with leiomyoma of the
uterus and, therefore, this syndrome was known as Reed’s syndrome
for many years [7]. Currently this syndrome is referred to as
multiple cutaneous and uterine leiomyomatosis syndrome (MCUL; OMIM
150800). In 2001, Launonen et al. reported that a small
proportion of families with MCUL also cluster renal cell cancer
(RCC) [8]. The latter disease variant is referred to as hereditary
leiomyomatosis and renal cell cancer (HLRCC; OMIM 605839). In 2002,
Tomlinson et al. showed that germline mutations in the
fumarate hydratase (FH) gene underlie hereditary cutaneous
leiomyomatosis and its associated features [9].
Clinical features
Cutaneous leiomyomas and leiomyosarcoma
Cutaneous leiomyomas typically present in the second to fourth
decade of life as skin colored or brown-reddish grouped papules or
nodules localized on the trunk and limbs (figure 1A). These benign
tumors are characteristically painful in response to pressure or
low temperature. While the exact pathophysiological origin of pain
in leiomyomas has not yet been elucidated, different authors have
proposed theories, including contraction of smooth muscle cells,
compression or invasion of cutaneous nerve bundles, and an
increased number of nerve elements within the tumors [2, 10-16].
Leiomyomas gradually increase in size and number and the extent of
the skin lesions is variable, even within one family. Some patients
suffer from extensive disease, with multiple leiomyomas covering
large areas of the body, whereas others only have a few
inconspicuous papules.
Interestingly, multiple cutaneous leiomyomas do not exclusively
manifest in a diffuse and symmetric fashion (figure 1B). Rather
frequently, a segmental or band-like manifestation pattern of these
tumors can be observed, most likely reflecting mosaicism [17-39]
(figure 1C).
Already 12 years ago, Happle postulated a genetic concept for the
segmental manifestation of dominantly inherited skin diseases [23].
Whenever the segmental skin lesions reveal the same degree of
severity as that found in the corresponding non-mosaic trait and a
germline mutation is absent, a type 1 segmental involvement is
present. Occasionally, however, the severity of cutaneous
involvement observed in the segmentally affected skin areas is far
more pronounced. Happle suggested that this phenomenon can be
explained by loss of heterozygosity (LOH) at the same locus that
caused the phenotypically less severe, diffuse involvement [23].
Although the type 2 segmental manifestation is usually only rarely
observed, he noted that in cutaneous leiomyomatosis the type 2
segmental manifestation occurs rather frequently. Recently, the
hypothesis for the type 2 segmental manifestation of autosomal
dominant skin disorders has been confirmed on the cellular and
molecular level in Hailey-Hailey disease [40]. In hereditary
cutaneous leiomyomatosis though, this concept has not yet been
demonstrated to be valid.
Malignant transformation of cutaneous leiomyoma is rare.
However, two cases of cutaneous leiomyosarcoma in two different,
apparently unrelated families with hereditary cutaneous
leiomyomatosis and renal cell cancer (HLRCC) have been reported
[41, 42].
Uterine leiomyomas and leiomyosarcoma
Uterine leiomyomas occur in more than 90% of females with MCUL.
These patients may have a medical history of menorrhagia and pelvic
pressure or pain, frequently requiring a hysterectomy before the
age of 30 years [43]. A minority of patients with MCUL/HLRCC
are predisposed to the development of highly aggressive uterine
leiomyosarcoma before the age of 30. Interestingly, this disease
variant has only been observed in the Finnish population to date
[8, 44, 45].
Renal cancer
Type II papillary RCC is the predominant type of kidney cancer in
HLRCC [46]. These tumors tend to be very aggressive. Metastases are
seen in more than 50% of affected individuals, even in those with
relatively small primary tumors. Furthermore, sporadic cases of
collecting duct carcinoma, oncocytoma, and clear cell carcinoma
have been described [46]. Recently, we described a patient with
cutaneous and uterine leiomyoma carrying a heterozygous FH mutation
who also had a history of a metastasizing Wilms tumor (WT) at the
age of 2 years [47]. RCCs in HLRCC are typically solid and
unilateral, although in exceptional cases bilateral renal tumors
have been reported [46, 48].
Other associated tumors
Infrequently, a broad range of other benign and malignant tumors
has also been observed in MCUL/HLRCC families, including breast
carcinoma, prostate carcinoma, bladder carcinoma, testis Leydig
cell tumors, cerebral cavernomas, ovarian and kidney cysts, and
adrenal gland adenomas [48-53]. Some of these tumors showed
biallelic FH inactivation, indicating that they are associated with
MUCL/HLRCC. However, the majority of tumors observed in these
families most probably occurred by coincidence and, thus, it seems
rather unlikely that they are pathogenetically associated with
hereditary cutaneous leiomyomatosis.
Histopathological findings
Cutaneous leiomyomas and leiomyosarcoma
Piloleiomyomas are poorly circumscribed lesions consisting of
interlacing bundles of smooth muscle fibers intermingled with
varying amounts of collagen bundles (figure 2A). The neoplasms
are located in the dermis and may encroach upon the subcutaneous
tissue. The smooth muscle fibers usually show an eosinophilic
cytoplasm with typical cigar shaped nuclei (figure 2B).
Immunohistochemistry reveals positive staining with anti-desmin and
anti-α-smooth muscle actin [10] (figure 2C).
Similarly to cutaneous leiomyomas, cutaneous leiomyosarcoma show
a poorly demarcated dermal tumor composed of proliferative bundles
of spindle cells intermingled with collagen fibers with positive
immunohistochemical staining for anti-α-smooth muscle actin and
desmin. Additionally, however, mitotic figures and atypical cells
are present [10].
Uterine leiomyomas and leiomyosarcoma
Uterine leiomyosarcoma are characterized by whirled bundles of
elongated smooth-muscle cells that are closely packed so that the
tumor appears to be more cellular. The nuclei of cells are
elongated and uniform. Mitosis figures are absent or sparse [54].
In contrast, uterine leiomyosarcoma show mitotic activity, nuclear
atypia, and tumor necrosis [55].
Renal cancer
Type II papillary RCC is characterized by a papillary growth
pattern with thick, lengthened papillae. The cells lining the
papillae are large with abundant cytoplasm and display a high
Fuhrman nuclear grade (3 or 4) with large and prominent
“owl-eye-like” nuclei [8, 46, 56, 57]. Furthermore,
tubulo-papillary, tubular, and cystic growth patterns can be found
in HLRCC related kidney malignancies. Recently, Merino et al.
reviewed 40 RCCs from HLRCC patients. According to their
observations, the hallmark of these tumors is the presence of large
eosinophilic nucleoli with a clear perinuclear halo, regardless of
the prevailing histological pattern. Moreover, they state that this
feature is not only seen in the majority of the tumor cells but is
unique to HLRCC kidney tumors [46]. Although a specific
immunophenotype has not yet been established for HLRCC-associated
renal tumors, absent expression of cytokeratin 7 (CK7) and Ulex
europeaus agglutinin (UEA-1) may support the diagnosis [46].
Utilization of FH antibodies could also contribute to the diagnosis
of an HLRCC-related malignant tumor.
Diagnosis
All patients with a tentative diagnosis of cutaneous leiomyomatosis
should be examined by a dermatologist. To exclude the differential
diagnoses of eruptive syringoma, neurofibroma, neurinoma or eccrine
spiradenoma, a biopsy for histopathological examination must be
obtained to confirm the diagnosis because the histological features
of cutaneous leiomyomas are highly specific and will help to
differentiate it from other tumors with similar clinical
appearances. In a patient with histologically confirmed cutaneous
leiomyomas, taking a detailed family history is mandatory to
identify putative relatives at risk and arrange for genetic
counseling and additional screening for uterine leiomyomas and
kidney cancer. DNA mutation analysis of the FH gene is compulsory
in order to confirm the diagnosis on the molecular genetic level
and should nowadays be considered as a state-of-the-art diagnostic
technique.
Gene and function
In 2001, Alam and colleagues reported linkage of MCUL to chromosome
1q42.3-q43 [32, 58]. Subsequently, heterozygous germline mutations
in the fumarate hydratase (FH) gene were detected in both MCUL and
HLRCC, confirming that these disorders are allelic [9, 41]. The FH
gene spans 22 kb and contains 10 exons. To date, approximately 73
different mutations distributed throughout the FH gene have been
reported in cutaneous leiomyomatosis [9, 19, 20, 26, 31, 41, 42,
45, 48-53, 59-73]. These sequence deviations include missense,
nonsense, frameshift, and splice-site mutations as well as whole
gene and exonic deletions and, together, demonstrate the molecular
heterogeneity associated with disorders caused by FH mutations
(figure 3).
Currently, there is no strong evidence for a putative
genotype-phenotype correlation in cutaneous leiomyomatosis.
Previous reports suggested that FH mutations occurring at 5’ of
codon 250 of FH could be associated with an increased risk of
developing renal cell cancer [9]. However, a subsequent study from
Toro et al. showed that only 55% of FH mutations in HLRCC were
indeed located at 5’ of codon 250, a notion that was confirmed by
Wei et al. who reported on FH mutations distributed over the
entire gene in HLRCC families. Of these mutations, only a few were
located upstream of codon 250 of FH [41, 42]. In addition, there
are no reports on families in which more than one individual
developed kidney cancer. Therefore, a heterozygous germline
mutation alone is most likely not sufficient to give rise to renal
cancer, suggesting an important role of additional genetic
inactivation by, e.g. LOH or a second hit mutation in the
development of kidney cancer.
Homozygous or compound heterozygous FH germline mutations cause
autosomal recessive fumarate hydratase deficiency (FHD) (OMIM
136850), a severe metabolic disease characterized by neurological
impairment and encephalopathy [74]. To date, neither the occurrence
of leiomyomas nor renal cancer has been reported in individuals
affected with FHD. This may be due to the fact that most
individuals suffering from FHD only live a few months and do not
reach early adulthood [74]. FH codes for the enzyme fumarate
hydratase (FH) that catalyzes the conversion of fumarate to malate
in the Krebs cycle [9]. FH is thought to act as tumor suppressor
since loss of the wild-type allele has been found in cutaneous,
uterine, and renal tumors of patients with MCUL and HLRCC [9, 41].
Furthermore, enzymatic FH activity was low or absent in tumors from
affected individuals [75].
The exact mechanism by which improper FH function leads to tumor
formation has not yet been defined. However, recent studies suggest
a pseudohypoxic drive in the pathogenesis of tumors in HLRCC [76,
77]. Considering the position of the enzyme in the Krebs cycle,
loss of mitochondrial FH leads to an intracellular accumulation of
fumarate. Elevated intracellular levels of fumarate have been shown
to stabilize the transcription factors hypoxia-inducible factor
(HIF-1α and HIF-2α) [77]. HIF proteins are key regulators of oxygen
homeostasis and act via transcriptional regulation of
anti-apoptotic and proliferative genes, such as vascular
endothelial growth factor (VEGF), platelet derived growth factor
(PDGF), endothelial growth factor receptor (EGFR), glucose
transporter protein 1 (Glut-1), and transforming growth factor-α
(TGF-α). Overexpression of these gene products is associated with
improved vascularity, autocrine stimulation, uncontrolled growth,
and survival of the cell [76, 78, 79]. This phenomenon has been
described as the “pseudohypoxia” and shows remarkable similarities
with von Hippel Lindau (VHL) syndrome [80-82]. Increased expression
of HIF-1α, HIF-2α and Glut-1 was recently detected in kidney tumors
from patients with HLRCC [77]. Additional studies on leiomyomas
occurring in the context of HLRCC revealed an enhanced expression
of VEGF, further supporting the role of a pseudohypoxic drive as
the link between mitochondrial FH dysfunction and tumor formation
in HLRCC [76].
Multidisciplinary management
Genetic counseling of patients and their relatives should be
self-evident. Once the diagnosis of hereditary cutaneous
leiomyomatosis is made, affected individuals must be considered at
risk for the occurrence of other tumors. Women with MCUL/HLRCC have
a high chance of developing uterus leiomyomas at young age, often
necessitating hysterectomy. Further, they have a slightly increased
risk for the occurrence of highly aggressive uterine
leiomyosarcoma. Therefore, referral of all female patients with FH
mutations to a gynecologist for annual evaluation seems justified
in our eyes. Additionally, adequate counseling for family planning
is advisable, considering that in these patients uterine leiomyomas
usually develop early.
The precise risk for the development of renal cancer in HLRCC is
not known. The overall frequency of malignant kidney tumors in
familial cutaneous leiomyoma is variable, ranging from 1-14% when
looking at different studies [41, 60, 62]. Likewise, age of onset
varies from 16 to 90 years [41, 46, 60, 62]. Renal malignancies in
HLRCC are associated with a poor prognosis and frequently
metastasize to regional lymph nodes. Of note though, there are no
specific screening guidelines for HLRCC, most likely due to the
rareness of the disease. We suggest that annual abdominal
computational tomography could serve as a screening procedure for
both the detection of kidney tumors and uterine changes. Magnetic
resonance imaging and ultrasound could serve as alternative
techniques if contrast-enhanced computational tomography cannot be
performed. However, ultrasound alone cannot be considered an
adequate screening technique since lesions may be isoechoic and
therefore, may be missed. Magnetic resonance imaging of the uterus
is particularly helpful in detecting and characterizing uterine
leiomyomas and leiomyosarcoma [83].
Therapy
Cutaneous leiomyoma and leiomyosarcoma
On the one hand, cutaneous leiomyomas may cause cosmetic
discomfort. Moreover, recurrent pain arising in these tumors can
cause serious complaints and disturb daily activities, sometimes
even leading to suicidal thoughts. While solitary leiomyomas can be
easily treated by surgical excision, multiple leiomyomas covering
large surfaces of the body are difficult to manage. Several
different treatment modalities have been hitherto described for
symptomatic pain relief or tumor destruction in cutaneous
leiomyomatosis, including pharmacological agents such as
nifedipine, gabapentine, doxasozine, phenoxybenzamine, hyoscine,
hydrobromide, and nitroglycerine or invasive therapy consisting of
extensive surgical excision, CO2 laser ablation and
cryotherapy, all with variable success [2, 7, 11, 12, 14, 37,
84-93]. Unfortunately, some patients with severe complaints do not
respond to any of these treatment modalities. Hence, there is a
need for additional therapeutic strategies, particularly for
patients suffering from extensive painful leiomyomas.
Most of the current therapeutic recommendations for cutaneous
leiomyosarcoma include a wide surgical excision. Routine lymph node
excision is not indicated unless lymph node invasion is evident.
Radiotherapy could be an option if surgery is unfeasible. However,
recurrence rates are very high [10, 94].
Uterine leiomyoma and leiomyosarcoma
Different surgical approaches, including myomectomy, hysterectomy
or abdominal uterus extirpation can be considered. Prior to
recommending a specific therapy the patient’s individual concerns
should always be respected though, in particular the specific
symptoms and their effect on quality of life and the possible
request to preserve fertility [95, 96].
As a general rule, hysterectomy is the first treatment of choice
for patients with uterine malignancies. Peritoneal washing and
omentectomy are indicated if the diagnosis of leiomyosarcoma is
sure. The role of prophylactic lymphadenectomy is limited since a
high percentage of patients without lymph node metastases will
still experience a recurrence. Myomectomy may be considered in
patients with low stage leiomyosarcoma who strongly desire future
fertility [97].
Renal cancer
Only little is known about the treatment of kidney malignancies in
HLRCC but since these tumors behave aggressively, total nephrectomy
at early stage is indicated. Recent advances in the understanding
of the molecular pathways involved in the etiopathogenesis of RCC
have led to the early development of promising targeted therapies
in hereditary malignant kidney tumors [98, 99].
Acknowledgements
JF is a board member of the Dutch working group on hereditary
leiomyomatosis and a member of the Network for Ichthyoses and
Related Keratinization Disorders (NIRK) that is supported by the
German Federal Ministry of Education and Research (BMBF). We thank
Dr. A. van Marion, MD, for providing the histological pictures.
Financial support: none. Conflict of interest: none.
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