1. Introduction
Multiple cutaneous and uterine leiomyomatosis (MCUL: OMIM 150800), which is also known as Reed syndrome, is an autosomal dominant disorder in which benign skin tumors arising from the arrector pili muscle and uterine fibroids typically develop in the third and fourth decades [1, 2]. Reed
2. Clinical manifestations
2.1. Cutaneous leiomyomas
The most prominent feature of MCUL/HLRCC is the occurrence of solitary or multiple cutaneous leiomyomas, which appear as firm skin-colored or pink-brown papules or nodules up to 2cm in diameter and are often associated with pain (Figure 1) [1]. The distribution of skin lesions shows approximately equal numbers of patients with clustered leiomyomas only, scattered leiomyomas only, and a combination of clustered and scattered lesions. Clustered lesions are most common on the trunk, followed by the lower limb(s), upper limb(s), and head and neck. Scattered lesions are most often found on the the upper limb(s), followed by the trunk, lower limb(s), and head and neck. A small proportion of patients have symmetrically distributed or unilaterally distributed lesions. In addition, band-like or type 2 segmental manifestations have also been reported [8]. Skin leiomyomas are reported to develop at a mean age of 24.1 years (median, 25 years; range, 9-45 years), although the mean ages of symptom onset and diagnosis are 31.4 and 36.6 years, respectively. These tumors seem to remain benign. Only two cases of skin leiomyosarcoma in association with an
2.2. Uterine fibroids
Uterine fibroids (leiomyomas) are benign tumors that develop from the smooth muscle cells of the uterus. The common symptoms including irregular menses, menorrhagia, pain and defects in the reproductive functions, show no difference between uterine fibroids in MCUL/HLRCC and those of sporadic cases; however, the clinical features in MCUL/HLRCC are different from those in sporadic cases. Many uterine fibroids are observed in MCUL/HLRCC and the size of tumors in MCUL/HLRCC is larger than that of sporadic cases [9, 10]. The mean age at the time of diagnosis of uterine fibroids with MCUL/HLRCC is around 30 years (range 18-53) and it is approximately 10 years before the diagnosis in sporadic cases. Most female patients (79-100%) with an
2.3. Renal cell carcinoma
Renal cell carcinoma (RCC) is a tumor arising from the epithelium of the renal tubules. RCC can be classified into morphological subtypes including clear cell, papillary, chromophobe and collecting duct carcinoma [15, 16]. The most frequent type of RCC in HLRCC is a type 2 papillary RCC [17]. The tumor histologically shows a papillary growth pattern. The tumor cells show a large nucleus with a prominent eosinophilic nucleus surrounded by a clear halo. Cystic components also seem to be typical findings [18, 19]. These features are suggested to be characteristic of a RCC in HLRCC. In addition, collecting duct tumors, oncocytic tumors and clear cell tumors have also been reported [9, 10, 18, 20]. An immunohistochemical study of RCC in HLRCC showed the absence of the cytokeratin (CK) 7 and the expression of UEA-a protein. In addition, the absence of mucin, CK20 and CD10 is considered to be typical of the tumors [19, 21]. RCC in HLRCC is commonly solitary and unilateral. RCC is found in about 20-25% of the
2.4. Fumarate hydratase
Heterozygous germline mutations in
2.5. Mutations in FH gene
Approximately 100 different mutations have been reported in the
mutations on human FH [33]. These missense mutations paradoxically cause marked reduction in the FH enzyme activity in comparison to truncated mutations [8, 13]. In addition, a hypothesis of the dominant negative effect of missense mutations has also been reported [34]. There appears to be no specific genotype-phenotype correlation with regard to which combination of these tumors develops in MCUL/HLRCC [32]. However, cases with RCC in HLRCC are mainly found in Finnish and North American families. This suggests that either environmental or additional genetic factors might be related to the induction of the malignant phenotype [2, 4-6, 10, 18]. Several other tumors have also been reported In the
2.6. Molecular mechanism of MCUL/HLRCC tumorigenesis
Individuals with MCUL/HLRCC inherit one loss-of function allele and somatically lose the other allele in the tumor. The inherited
2.7. Diagnosis
No diagnostic criteria for MUUL/HLRCC have been established; however, practical criteria for the clinical diagnosis of MUUL/HLRCC have been proposed [56]. Multiple cutaneous leiomyoma which is histologically confirmed is proposed as a major criterion. The minor criteria included uterine fibroids, papillary type 2 RCC or positive familial history. A molecular genetic analysis should be conducted to confirm the diagnosis when the clinical features are suggestive of MCUL/HLRCC. Direct sequencing of the
3. Treatment and management
3.1. Cutaneous leiomyomas and uterine fibroids
Cutaneous leiomyomas are commonly benign, and thus, the treatment for these tumors may be only improvement of cosmetic and pain related complications. Surgical excision is usually performed for the solitary tumors. The multiple painful lesions are generally treated with medications, such as nitoglycerol, calcium channel blockers, alpha-adrenoreceptor blockers, which have been reported to be occasionally successful to relieve pain [8]. Surgical approaches including hysterectomy are typically needed for uterine fibroids, based on the number and size of the tumors and the severity of the symptoms caused by the tumors [13, 57]. Furthermore, myomectomy, uterine artery embolization or pharmaceutical treatment with gonadotropin-releasing hormone agonist is also performed as an optional treatment for uterine fibroids.
3.2. Renal cell carcinoma
RCCs commonly acquires metastatic potential after exceeding the size of 3-7 cm [59]. Renal lesions can be observed until they reach the size of 3 cm, at which point they should be removed, and nephron sparing surgery usually appropriate [60]. However, RCC in HLRCC is thought to differ from sporadic RCCs because they are often metastatic at presentation even if the size of tumor is less than 1 cm. Therefore, tumors in HLRCC are recommended to be excised with radical surgery immediately [15, 59, 60]. Sorafenib and sunitinib, which are inhibitors of receptor tyrosine kinases activated by HIF1 targets such as VEGF, PDGF and TNF-α, have been used in the treatment of sporadic papillary RCC with varying success. These treatments are specific targeted pharmaceutical approaches. However, Information regarding the specific response of HLRCC associated tumors to these molecules is not available.
4. Conclusion
MCUL/HLRCC is a syndrome predisposing the
References
- 1.
Garcia Muret MP Pujol RM, Alomer A et al. Familial leiomyomatosis cutis et uteri (Reed’s syndrome). Arch Dermatol Res1988 S29 32 - 2.
Localization of a gene (MCUL1) for multiple cutaneous leiomyomata and uterine fibroids to chromosome 1q42.3-q43. Am J Hum GenetAlam N. A Bevan S Churchman M et al 2001 68 1264 1269 - 3.
Reed W. B Walker R Horowitz R Cutaneous leiomyomata with uterine leiomyomata. Acta Derm Venereol1973 53 409 416 - 4.
Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology. Am J PatholKiuru M Launonen V Hietala M et al 2001 159 825 829 - 5.
Launonen V Vierimaa O Kiuru M et al 2001 Inherited susceptibility to uterine leiomyomas and renal cell cancer Proc Natl Acad Sci USA98 3387 3392 - 6.
Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat GenetTomlinson I. P Alam N. A Rowan A. J et al 2002 30 406 410 - 7.
Absence of fumarate hydratase mutation in a family with cutaneous leiomyosarcoma and renal cancer. Int J DermatolBadeloe S Van Geest A. J Van Marion A. M et al 2008 Suppl 1): 18-20 - 8.
Type 2 segmental manifestation of cutaneous leiomyomatosis in four unrelated women with additional uterine leiomyomas (Reed’s syndrome). DermatologyRitzmann S Hanneken S Neumann N. J et al 2006 212 84 87 - 9.
Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum GenetToro J. R Nickerson M. L Wei M. H et al 2003 73 95 106 - 10.
Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer. J Med GenetWei M. H Toure O Glenn G. M et al 2006 43 18 27 - 11.
Kilpatrick S. E Mentzel T Fletcher C. D Leiomyoma of deep soft tissue. Clinicopathologic analysis of a series. Am J Surg Pathol1994 18 576 582 - 12.
Mcginley K. M Bryant S Kattine A. A et al Cutaneous leiomyomas lack estrogen and progesterone receptor immunoreactivity. J Cutan Pathol1997 24 241 245 - 13.
Clinical features of multiple cutaneous and uterine leiomyomatosis: an underdiagnosed tumor syndrome. Arch DermatolAlam N. A Barclay E Rowan A. J et al 2005 141 199 206 - 14.
J. Uterine sarcomas: a review. Gynecol OncolD Angelo E Prat 2010 116 131 139 - 15.
Renal-cell carcinoma. N Engl J MedCohen H. T Mcgovern F. J 2005 353 2477 2490 - 16.
Sesterhenn IA (ed.) World Health Organization classification of tumours: pathology & genetics of tumours of the urinary system and male genital organs. Lyon: IARC Press;Eble J. N Sauter G Epstein J. I 2004 - 17.
Delahunt B Eble J. N Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors. Mod Pathol1997 10 537 544 - 18.
Lehtonen H. J Molecular and clinical characteristics of tricarboxylic acid cycle-associated tumors Dissertation: University of Helsinki;2008 - 19.
The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Am J Surg PatholMerino M. J Torres-cabala C Pinto P et al 2007 31 1578 1585 - 20.
Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum Mol GenetAlam N. A Rowan A. J Wortham N. C et al 2003 12 1241 1252 - 21.
Increased risk of cancer in patients with fumarate hydratase germline mutation. J Med GenetLehtonen H. J Kiuru M Ylisaukko-oja S. K et al 2006 43 523 526 - 22.
Bayley J. P Launonen V Tomlinson I. P The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency BMC Med Genet2008 - 23.
Koski T. A Molecular genetic background of tumours in hereditary leiomyomatosis and renal cell cancer syndrome Dissertation: University of Helsinki;2010 - 24.
Hereditary leiomyomatosis and renal cell carcinoma: very early diagnosis of renal cancer in a paediatric patient. Fam CancerAlrashdi I Levine S Paterson J et al 2010 9 239 243 - 25.
rd, Franks ME, Toro J et al. Hereditary leiomyomatosis and renal cell cancer: a syndrome associated with an aggressive form of inherited renal cancer. J UrolGrubb R. L 2007 177 2074 2079 - 26.
Targeted inactivation of fh1 causes proliferative renal cyst development and activation of the hypoxia pathway. Cancer CellPollard P. J Spencer-dene B Shukla D et al 2007 11 311 319 - 27.
HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer CellMandriota S. J Turner K. J Davies D. R et al 2002 1 459 468 - 28.
Kinsella B. T Doonan S Nucleotide sequence of a cDNA coding for mitochondrial fumarase from human liver. Biosci Rep1986 6 921 929 - 29.
Tolley E Craig I Presence of two forms of fumarase (Fumarate Hydratase E.C. 4.2.1.2) in mammalian cells: immunological characterization and genetic analysis in somatic cell hybrids. Confirmation of the assignment of a gene necessary for the enzyme expression to human chromosome 1. Biochem Genet1975 13 867 883 - 30.
Weaver T. M Levitt D. G Donnelly M. I et al The multisubunit active site of fumarase C from Escherichia coli. Nat Struct Biol1995 2 654 662 - 31.
Sass E Karniely S Pines O Folding of fumarase during mitochondrial import determines its dual targeting in yeast. J Biol Chem2003 278 45109 45116 - 32.
Diffuse and segmental variants of cutaneous leiomyomatosis: novel mutations in the fumarate hydratase gene and review of the literature. Exp DermatolBadeloe S Van Geel M Van Steensel M. A et al 2006 15 735 741 - 33.
Alam N. A Olpin S Rowan A et al Missense mutation in Fumarate Hydratase in Multiple Cutaneous and Uterine Leiomyomatosis and Renal Cell Cancer. J Mol Diagn2005 7 437 443 - 34.
Lorenzato A Olivero M Perro M et al A cancer-predisposing “hot spot” mutation of the fumarase gene creates a dominant negative protein Int J Cancer2008 122 947 951 - 35.
Hereditary leiomyomatosis associated with bilateral, massive, macronodular adrenocortical disease and atypical Cushing syndrome: a clinical and molecular genetic investigation. J Clin Endocrinol MetabMatyakhina L Freedman R. J Bourdeau I et al 2005 90 3773 3779 - 36.
Adult leydig cell tumors of the testis caused by germline fumarate hydratase mutations. J Clin Endocrinol MetabCarvajal-carmona L. G Alam N. A Pollard P. J et al 2006 91 3071 3075 - 37.
Zinn A. B Kerr D. S Hoppel C. L Fumarase deficiency: a new cause of mitochondrial encephalomyopathy. N Engl J Med1986 315 469 475 - 38.
Molecular and biochemical investigations in fumarase deficiency. Mol Genet MetabDeschauer M Gizatullina Z Schulze A et al 2006 88 146 152 - 39.
Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families. Cancer ResKiuru M Lehtonen R Arola J et al 2002 62 4554 4557 - 40.
Oxygen homeostasis. Wiley Interdiscip Rev Syst Biol MedSemenza G. L 2010 2 336 361 - 41.
Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol GenetPollard P. J Briere J. J Alam N. A et al 2005 14 2231 2239 - 42.
HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer CellIsaacs J. S Jung Y. J Mole D. R et al 2005 8 143 153 - 43.
MacKenzie ED Selak MA, Tennant DA et al. Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells. Mol Cell Biol2007 27 3282 3289 - 44.
Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro. Mol Cell BiolPan Y Mansfield K. D Bertozzi C. C et al 2007 27 912 925 - 45.
J et al. Expression profiling in progressive stages of fumarate-hydratase deficiency: the contribution of metabolic changes to tumorigenesis. Cancer ResAshrafian H O Flaherty L Adam 2010 70 9153 9165 - 46.
Glutamine: pleiotropic roles in tumor growth and stress resistance. J Mol Med (Berl)Shanware N. P Mullen A. R Deberardinis R. J et al 2011 89 229 236 - 47.
s next: the diverse functions of glutamine in metabolism, cell biology and cancer.Deberardinis R. J Cheng T. Q 2010 29 313 324 - 48.
Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability. Proc. Natl. Acad. Sci. U.S.A.Wise D. R Ward P. S Shay J. E et al 2011 108 19611 19616 - 49.
Reductive carboxylation supports growth in tumour cells with defective mitochondria. NatureMullen A. R Wheaton W. W Jin E. S et al 2012 481 385 388 - 50.
Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. NatureMetallo C. M Gameiro P. A Bell E. L et al 2012 481 380 384 - 51.
Comparative metabolic flux profiling of melanoma cell lines: beyond the Warburg effect. J Biol ChemScott D. A Richardson A. D Filipp F. V et al 2011 286 42626 42634 - 52.
S-(2-Succinyl) cysteine: a novel chemical modification of tissue proteins by a Krebs cycle intermediate. Arch Biochem BiophysAlderson N. L Wang Y Blatnik M et al 2006 450 1 8 - 53.
An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer CellOoi A Wong J. C Petillo D et al 2011 20 511 523 - 54.
L et al. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer CellAdam J Hatipoglu E O Flaherty 2011 20 524 537 - 55.
Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status. J Pathol El-Bardella C Bahrawy M Frizzell N et al 2011 225 4 11 - 56.
Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Clin GenetSmit D. L Mensenkamp A. R Badeloe S et al 2011 79 49 59 - 57.
Association of germline mutations in the fumarate hydratase gene and uterine fibroids in women with hereditary leiomyomatosis and renal cell cancer. Arch DermatolStewart L Glenn G. M Stratton P et al 2008 144 1584 1592 - 58.
Mutation screening of fumarate hydratase by multiplex ligation-dependent probe amplification: detection of exonic deletion in a patient with leiomyomatosis and renal cell cancer. Cancer Genet CytogenetAhvenainen T Lehtonen H. J Lehtonen R et al 2008 183 83 88 - 59.
Pavlovich C. P Schmidt L. S Searching for the hereditary causes of renal-cell carcinoma. Nat Rev Cancer2004 4 381 393 - 60.
Oncological outcomes of partial nephrectomy for multifocal renal cell carcinoma greater than 4 Cm. J UrolGupta G. N Peterson J Thakore K. N et al 2010 184 59 63