Images in Gynecology
www.AJOG .org
Something to Reed about Fibroids, cutaneous leiomyomas, and renal cell carcinoma Meredith L. Orseth, BS; Dana Redick, MD; Joel Pinczewski, MD, PhD; Barbara B. Wilson, MD; Smitha S. Kuppalli, MD
O
n annual examination, a 48 year old perimenopausal G0 diagnosed with uterine fibroids nearly a decade previously mentioned noticing several asymptomatic, unchanging pink bumps on her arms, torso, and legs 2 months previously. She was otherwise healthy and on oral contraceptive pills. Her mother and sister had uterine fibroids diagnosed at age 30 years. Examination revealed 8 light pink 3-5 mm firm, oval, discrete dermal papules on her dorsal forearms, left flank, and anterior thighs (Figure 1, A). The remainder of the physical examination was unremarkable. A dermatologist performed a biopsy, which revealed cutaneous leiomyoma (Figure 1, B and C).
Comment Given her rare dermatological diagnosis and uterine fibroids, a genetic evaluation was done on the patient, which revealed a pathogenic missense mutation in fumarate hydratase leading to the diagnosis of hereditary leiomyomatosis and renal cell cancer (HLRCC). Two years after the diagnosis, she underwent a hysterectomy because of increased fibroid size (Figure 2). Surgical pathology demonstrated multiple benign leiomyomas. Hereditary leiomyomatosis and renal cell cancer (HLRCC; OMIM 150800), also called Reed’s syndrome and multiple cutaneous and uterine leiomyomatosis (MCUL), is characterized by uterine leiomyomas, cutaneous leiomyomas, and, less commonly, papillary renal cell carcinoma. This autosomal dominant disorder is caused by a defect in fumarate hydratase, an enzyme in the tricarboxylic acid (Krebs) cycle that acts as a tumor suppressor.1-3 From the Department of Obstetrics and Gynecology (Dr Redick), Department of Pathology (Dr Pinczewski), Department of Dermatology (Drs Wilson and Kuppalli), and School of Medicine (Ms Orseth), University of Virginia, Charlottesville, VA. Received Feb. 22, 2014; revised March 3, 2014; accepted March 4, 2014. Written permission from the patient on whom this report is based has been obtained. The authors report no conflict of interest. Cite this article as: Orseth ML, Redick D, Pinczewski J, et al. Something to Reed about: fibroids, cutaneous leiomyomas, and renal cell carcinoma. Am J Obstet Gynecol 2014;210:X. Reprints: Smitha S. Kuppalli, MD, 1221 Lee St., Charlottesville, VA 22908. [email protected]. 0002-9378/$36.00 ª 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2014.03.008
A 48 year-old woman with a history of fibroids presents with asymptomatic skin lesions. Biopsy reveals cutaneous leiomyomas and subsequent genetic evaluation confirms the diagnosis of hereditary leiomyomatosis and renal cell cancer. In this report, we review the typical presentation of the syndrome as well as recommendations for surveillance. Key words: early-onset leiomyomas, fibroids, hereditary leiomyomatosis and renal cell cancer, multiple cutaneous and uterine leiomyomatosis, Reed’s syndrome
The presentation of HLRCC is variable. In women, symptomatic uterine leiomyomas present at a young age. Typically, cutaneous leiomyomas appear at 20-40 years of age as firm, smooth, skin-colored to brownish red dermal papules or nodules measuring 0.2-2 cm in size.1,4 Unlike our patient, 90% of individuals with cutaneous leiomyomas have associated pain characteristically precipitated by cold or trauma.4 Screening is of utmost importance for individuals with HLRCC because approximately 15% have renal tumors on imaging following presentation.5 Although rare, both uterine and cutaneous leiomyomas can transform into leiomyosarcomas.2,5 Whereas no official screening guidelines exist, recommendations include annual gynecologist examinations and full skin examinations and abdominal imaging to identify renal lesions every 1-2 years.2 Given the autosomal dominant inheritance pattern, it is appropriate to discuss the implications for at-risk family members and offer genetic counseling. REFERENCES 1. Tomlinson IP, Alam NA, Rowan AJ, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002;30:406-10. 2. Pithukpakorn M, Toro JR. Hereditary leiomyomatosis and renal cell cancer. Seattle, WA: National Institutes of Health. Available at: http://www. ncbi.nlm.nih.gov/pubmed/20301430. Accessed July 31, 2006. 3. Pithukpakorn M, Wei MH, Toure O, et al. Fumarate hydratase enzyme activity in lymphoblastoid cells and fibroblasts of individuals in families with hereditary leiomyomatosis and renal cell cancer. J Med Genet 2006;43: 755-62. 4. Alam NA, Barclay E, Rowan AJ, et al. Clinical features of multiple cutaneous and uterine leiomyomatosis: an underdiagnosed tumor syndrome. Arch Dermatol 2005;141:199-206. 5. Toro JR, Nickerson ML, Wei MH, et al. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 2003;73:95-106.
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2014 American Journal of Obstetrics & Gynecology
1.e1
Images in Gynecology
www.AJOG.org
FIGURE 1
FIGURE 2
Transvaginal ultrasound imaging of uterus was performed. This is a sagittal image of uterus demonstrating 1 of the multiple fibroids. At least 6 fibroids were identified (the largest shown here measures 5.1 4.0 4.5 cm). The uterus measures 12.2 8.7 9.5 cm. The endometrial strip is seen throughout its course and measures 5 mm, which is normal. Orseth. Something to Reed about. Am J Obstet Gynecol 2014.
A, Firm, painless pink papule on the left flank. B, At low power (hematoxylin and eosin staining, 40), the skin shave biopsy shows dermal proliferation of haphazardly arranged spindled cells forming disorganized thick ropy fibers. C, The proliferating spindled cells stain strongly with smooth muscle actin (smooth muscle actin stain, 40), confirming that this lesion is a leiomyoma. Orseth. Something to Reed about. Am J Obstet Gynecol 2014.
1.e2 American Journal of Obstetrics & Gynecology
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2014
www.AJOG .org
Something to Reed about Fibroids, cutaneous leiomyomas, and renal cell carcinoma Meredith L. Orseth, BS; Dana Redick, MD; Joel Pinczewski, MD, PhD; Barbara B. Wilson, MD; Smitha S. Kuppalli, MD
O
n annual examination, a 48 year old perimenopausal G0 diagnosed with uterine fibroids nearly a decade previously mentioned noticing several asymptomatic, unchanging pink bumps on her arms, torso, and legs 2 months previously. She was otherwise healthy and on oral contraceptive pills. Her mother and sister had uterine fibroids diagnosed at age 30 years. Examination revealed 8 light pink 3-5 mm firm, oval, discrete dermal papules on her dorsal forearms, left flank, and anterior thighs (Figure 1, A). The remainder of the physical examination was unremarkable. A dermatologist performed a biopsy, which revealed cutaneous leiomyoma (Figure 1, B and C).
Comment Given her rare dermatological diagnosis and uterine fibroids, a genetic evaluation was done on the patient, which revealed a pathogenic missense mutation in fumarate hydratase leading to the diagnosis of hereditary leiomyomatosis and renal cell cancer (HLRCC). Two years after the diagnosis, she underwent a hysterectomy because of increased fibroid size (Figure 2). Surgical pathology demonstrated multiple benign leiomyomas. Hereditary leiomyomatosis and renal cell cancer (HLRCC; OMIM 150800), also called Reed’s syndrome and multiple cutaneous and uterine leiomyomatosis (MCUL), is characterized by uterine leiomyomas, cutaneous leiomyomas, and, less commonly, papillary renal cell carcinoma. This autosomal dominant disorder is caused by a defect in fumarate hydratase, an enzyme in the tricarboxylic acid (Krebs) cycle that acts as a tumor suppressor.1-3 From the Department of Obstetrics and Gynecology (Dr Redick), Department of Pathology (Dr Pinczewski), Department of Dermatology (Drs Wilson and Kuppalli), and School of Medicine (Ms Orseth), University of Virginia, Charlottesville, VA. Received Feb. 22, 2014; revised March 3, 2014; accepted March 4, 2014. Written permission from the patient on whom this report is based has been obtained. The authors report no conflict of interest. Cite this article as: Orseth ML, Redick D, Pinczewski J, et al. Something to Reed about: fibroids, cutaneous leiomyomas, and renal cell carcinoma. Am J Obstet Gynecol 2014;210:X. Reprints: Smitha S. Kuppalli, MD, 1221 Lee St., Charlottesville, VA 22908. [email protected]. 0002-9378/$36.00 ª 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2014.03.008
A 48 year-old woman with a history of fibroids presents with asymptomatic skin lesions. Biopsy reveals cutaneous leiomyomas and subsequent genetic evaluation confirms the diagnosis of hereditary leiomyomatosis and renal cell cancer. In this report, we review the typical presentation of the syndrome as well as recommendations for surveillance. Key words: early-onset leiomyomas, fibroids, hereditary leiomyomatosis and renal cell cancer, multiple cutaneous and uterine leiomyomatosis, Reed’s syndrome
The presentation of HLRCC is variable. In women, symptomatic uterine leiomyomas present at a young age. Typically, cutaneous leiomyomas appear at 20-40 years of age as firm, smooth, skin-colored to brownish red dermal papules or nodules measuring 0.2-2 cm in size.1,4 Unlike our patient, 90% of individuals with cutaneous leiomyomas have associated pain characteristically precipitated by cold or trauma.4 Screening is of utmost importance for individuals with HLRCC because approximately 15% have renal tumors on imaging following presentation.5 Although rare, both uterine and cutaneous leiomyomas can transform into leiomyosarcomas.2,5 Whereas no official screening guidelines exist, recommendations include annual gynecologist examinations and full skin examinations and abdominal imaging to identify renal lesions every 1-2 years.2 Given the autosomal dominant inheritance pattern, it is appropriate to discuss the implications for at-risk family members and offer genetic counseling. REFERENCES 1. Tomlinson IP, Alam NA, Rowan AJ, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002;30:406-10. 2. Pithukpakorn M, Toro JR. Hereditary leiomyomatosis and renal cell cancer. Seattle, WA: National Institutes of Health. Available at: http://www. ncbi.nlm.nih.gov/pubmed/20301430. Accessed July 31, 2006. 3. Pithukpakorn M, Wei MH, Toure O, et al. Fumarate hydratase enzyme activity in lymphoblastoid cells and fibroblasts of individuals in families with hereditary leiomyomatosis and renal cell cancer. J Med Genet 2006;43: 755-62. 4. Alam NA, Barclay E, Rowan AJ, et al. Clinical features of multiple cutaneous and uterine leiomyomatosis: an underdiagnosed tumor syndrome. Arch Dermatol 2005;141:199-206. 5. Toro JR, Nickerson ML, Wei MH, et al. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 2003;73:95-106.
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2014 American Journal of Obstetrics & Gynecology
1.e1
Images in Gynecology
www.AJOG.org
FIGURE 1
FIGURE 2
Transvaginal ultrasound imaging of uterus was performed. This is a sagittal image of uterus demonstrating 1 of the multiple fibroids. At least 6 fibroids were identified (the largest shown here measures 5.1 4.0 4.5 cm). The uterus measures 12.2 8.7 9.5 cm. The endometrial strip is seen throughout its course and measures 5 mm, which is normal. Orseth. Something to Reed about. Am J Obstet Gynecol 2014.
A, Firm, painless pink papule on the left flank. B, At low power (hematoxylin and eosin staining, 40), the skin shave biopsy shows dermal proliferation of haphazardly arranged spindled cells forming disorganized thick ropy fibers. C, The proliferating spindled cells stain strongly with smooth muscle actin (smooth muscle actin stain, 40), confirming that this lesion is a leiomyoma. Orseth. Something to Reed about. Am J Obstet Gynecol 2014.
1.e2 American Journal of Obstetrics & Gynecology
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