A 53-year-old woman presented to the dermatology clinic complaining of a “bumpy itching, burning rash” of the left lateral neck and jawline. The patient stated that the rash began about 15 to 20 years ago and the lesions have progressively increased in both number and size. She reported occasional tenderness and pruritus, and stated that the bumps “burn” when it is cold outside.
During the consult, the patient discussed the social impact that these disfiguring bumps have had on her work and social life. She stated that she felt ostracized by friends and some family members. She also has not been hired for the customer service jobs she wanted because employers think her bumps look like sores or may be infectious.
On physical examination, more than 30 pink, erythematous nodules, ranging from 0.5 to 2 cm, were noted in clusters on the left neck and mandible. Nodules were firm and tender to palpation (Figure 1). Further questioning revealed a history of hysterectomy 20 years ago for painful uterine leiomyomas. A punch biopsy was performed from a representative lesion on the neck.
What is your diagnosis?
To learn the answer, go to page 2
{{pagebreak}}
Diagnosis: Multiple Cutaneous and Uterine Leiomyomatosis (Reed Syndrome)
Although solitary leiomyomas are often sporadic and the etiology remains mostly unknown, multiple studies have found that fumarate hydratase (FH) germline mutations are responsible for familial multiple cutaneous and uterine leiomyomatosis syndrome (MCUL).1-3 FH is an enzyme responsible for converting fumarate into malate as part of the Krebs cycle. FH is thought to be a tumor suppressor by regulating the transcription factors hypoxia inducible factor (HIF)-1a and HIF-2a elevated concentrations of these factors are associated with tumorigenesis and malignancy.4 This autosomal dominant disorder typically presents as benign, smooth muscle tumors of the skin and uterus, with a small subset of carriers who develop renal cell carcinoma (RCC).3 Most cases of hereditary leiomyomatosis and renal cell cancer (HLRCC) come from Eastern Europe, affecting only 180 families worldwide.4 Presently, 155 FH mutations resulting in MCUL/HLRCC have been identified, but no correlation between genotype and phenotype has been established.5,6
Clinical Presentations
Cutaneous leiomyomas may present as 3 distinct subtypes: vascular smooth muscle, angioleiomyomas; asymptomatic smooth muscle tumors in the groin, genital leiomyomas; and piloleiomyomas derived from arector pili muscle.7 Piloleiomyomas are the most common variant and may present as single nodules or multiple lesions.4,7 These lesions typically develop before age 40 as skin-colored or pink to brown, firm nodules, which are confined to the skin and move freely over deeper structures.4,7,8 These slow-growing nodules measure between 0.2 and 2 cm and most commonly present on the flexor surfaces of extremities in a linear, grouped, or dermatomal arrangement (Figure 1). The majority of leiomyomas elicit pain described as stabbing, burning, or pinching when triggered by pressure, cold, or emotion.
Most women who develop skin lesions will have a history of painful uterine fibroids before or after the cutaneous eruption.4,9 Women typically present with complaints of dysmenorrhea, pelvic pressure, and intense pain.10
Histology
The diagnosis of cutaneous leiomyomas is confirmed by biopsy. Hematoxylin and eosin staining of a representative lesion reveals fascicles of spindle cells with eiosinophilic cytoplasm with characteristic “cigar-shaped” nuclei.4,7
Imaging and Laboratory Evaluation
The presence of uterine fibroids is typically verified and monitored via ultrasound, but may also be detected by hysterography or hysteroscopy.11 Iron deficiency anemia may also be present in uterine leiomyomas due to chronic blood loss.10 Some studies suggest that those with a strong family history of MCUL should be referred to a geneticist for FH mutation screening because of the increased risk of RCC with poor prognosis.2,12 Papillary renal cancer is an aggressive malignancy, which is difficult to detect given its hypoechoic nature on ultrasound.7 Renal cancer is detected with computed tomography or magnetic resonance imaging.
Differential Diagnosis
A helpful mnemonic for painful dermal nodules/tumors is “LEND AN EGG”: leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomus tumor, and granular cell tumor.13 Leiomyomas will be discussed in further detail throughout this article. Eccrine spiradenoma are sweat gland tumors located in the dermis that typically present as a solitary shiny pink nodule on the head or neck.14,15 Neuromas may present after injury as nonpigmented, tender, firm nodules.13 Dermatofibromas are common firm, usually hyperpigmented fibrohistiocytic tumors that typically present on the lower extremities after trauma or a bug bite, but may be idiopathic.16,17 Cutaneous angiolipomas are well-circumscribed tumors composed of mature adipose tissue with a vascular component, which are often painful. Neurilemmomas, also known as schwannomas, are the most common tumor of peripheral nerves. They are commonly found incidentally on the flexor surfaces as a single nodule.18,19 Endometriomas are painful cysts of the endometrium that typically form in the ovary.11,20 Glomus tumors usually present as pink vascular tumors on the hands or feet and are associated with pain, tenderness, and cold sensitivity.21 Granular cell tumors often present as solitary, benign lesions with or without pigmentation on the skin, subcutaneous tissue, or oropharynx.22
Treatment
While treatment for uterine leiomyomas is well documented and can be achieved by medical management or definitively by myomectomy or hysterectomy,23 the appropriate management for cutaneous leiomyomas is less established. The management of these dermal nodules is dependent on the number and distribution of skin lesions.
The gold standard for treatment is surgical excision, but not all patients are surgical candidates due to the number of lesions present. Smaller lesions may be treated by cryotherapy, electrodesiccation, or carbon dioxide laser ablation, but all options carry the risk of scarring and recurrence.4 The symptoms of cutaneous leiomyomas may be treated medically with agents that affect smooth muscle contraction including calcium channel blockers, a-blockers, nitroglycerine, or botulinum toxin type A injections. Additionally, triamcinolone acetonide injections have been effective in treating the associated pain while decreasing the size of the tumors. Studies also suggest that gabapentin and topical lidocaine may be effective in treating temperature-induced tenderness.4,9,24 Full skin exams every 2 years are recommended to detect new lesions. Once the diagnosis of MCUL is made, the patient should follow-up with urology to rule out renal involvement and determine if further screening is necessary.4
Our Patient
Histological analysis of the pathology specimen revealed fascicles of intersecting spindle cells with “cigar-shaped” nuclei, consistent with leiomyomas (Figures 2A and B). The diagnosis of multiple cutaneous leiomyomas prompted further investigation into medical and familial history. Medical history was positive for painful uterine leiomyomas that required a hysterectomy approximately 20 years ago. Family history revealed that the patient’s mother and maternal aunt had similar cutaneous lesions and required hysterectomies for painful uterine fibroids, suggestive of an autosomal dominant mode of inheritance.
The extensive clusters of nodules on the face and neck complicate the management of this patient’s cutaneous lesions. A management plan is being finalized; this includes local injections of triamcinolone acetonide, a plastic surgery and genetics consult, and a urology referral, due to the predisposition to RCC that is associated with familial leiomyomatosis.
Conclusion
Cutaneous leiomyomas are sporadic or inherited benign smooth muscle tumors that may present asymptomatically or with associated tenderness. The solitary variants are sporadic, but multiple cutaneous leiomyomatosis with uterine leiomyomatosis is hereditary and may be associated with RCC, and thus warrants further consideration and diagnostic workup. This disorder is underrecognized, which may delay treatment in patients with associated RCC. The purpose of this case study is to address this uncommon disorder and emphasize the importance of a renal workup in patients with multiple lesions or with a history of uterine fibroids. Early detection of RCC may be beneficial to patients who would otherwise have a very poor prognosis.
Ms Thompson is a student at Western University of Health Sciences in Pomona, CA.
Dr Robles is dermatology director at Chaparral Medical Group in Upland, CA.
Dr Luo is a dermatopathologist at Dianon Pathology/A LabCorp Company in Los Angeles, CA.
Disclosure: The authors report no relevant financial relationships.
References
1. Tomlison IP, Alam NA, Rowan AJ, et al; Multiple Leiomyoma Consortium. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002;30(4):406-410.
2. Tolvanen J, Uimari O, Ryynänen M, Aaltonen LA, Vahteristo P. Strong family history of uterine leiomyomatosis warrants fumarate hydratase mutation screening. Hum Reprod. 2012;27(6):1865-1869.
3. Smit DL, Mensenkamp AR, Badeloe S, et al. Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Clin Genet. 2011;79(1):49-59.
4. Malik K, Patel P, Chen J, Khachemoune A. Leiomyoma cutis: a focused review on presentation, management, and association with malignancy. Am J Clin Dermatol. 2015;16(1):35-46.
5. Bayley JP, Launonen V, Tomlinson IP. The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase definciency. BMC Med Genet. 2008;9:20.
6. Chan I, Wong T, Martinez-Mir A, Christiano AM, McGrath JA. Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer. Clin Exp Dermatol. 2005;30(1):75-78.
7. Collgros H, Iglesias-Sancho M, Tribó-Boixareu MJ, Creus-vila L, Umbert-Millet P, Salleras-Redonnet M. Multiple cutaneous and uterine leiomyomatosis or reed syndrome: a retrospective study of 13 cases. Actas Dermosifiliogr. 2015;106(2): 117-125.
8. Holst VA, Junkins-Hopkins JM, Elenitsas R. Cutaneous smooth muscle neoplasms: clinical features, histologic findings, and treatment options. J Am Acad Dermatol. 2002;46(4):477-490; quiz, 491-494.
9. Henley ND, Tokarz VA. Multiple cutaneous and uterine leiomyomatosis in a 36-year-old female, and discussion of hereditary leiomyomatosis and renal cell carcinoma. Int J Dermatol. 2012;51(10):1213-1216.
10. Khan AT, Shehmar M, Gupta JK. Uterine fibroids: current perspectives. Int J Womens Health. 2014;29(6):95-114.
11. Van Holsbeke C, Van Calster B, Guerriero S, et al. Endometriomas: their ultrasound characteristics. Ultrasound Obstet Gynecol. 2010;35(6):730-740.
12. Alam NA, Olpin S, Leigh IM. Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer. Br J Dermatol. 2005;153(1):11-17.
13. Naverson DN, Trask DM, Watson FH, Burket JM. Painful tumors of the skin: “LEND AN EGG.” J Am Acad Dermatol. 1993;28(2 Pt 2):298-300.
14. Ben Brahim E, Sfia M, Tangour M, Makhlouf R, Cribier B, Chatti S. Malignant eccrine spiradenoma: a new case report. J Cutan Pathol. 2010;37(4):478-481.
15. Amoroso C, Grandi E, Carinci F. Eccrine spiradenoma of the ear: case report. Oral Maxillofac Surg. 2003;32(6):662-663.
16. Zelger B, Zelger BG, Burgdorf WH. Dermatofibroma-a critical evaluation. Int J Surg Pathol. 2004;2(4):333-344.
17. Jung KD, Lee DY, Lee JH, Yang JM, Lee ES. Subcutaneous dermatofibroma. Ann Dermatol. 2011;23(2):254-257.
18. Tiel R, Kline D. Peripheral nerve tumors: surgical principles, approaches, and techniques. Neurosurg Clin N Am. 2004;15(2):167-175.
19. Hilton DA, Hanemann CO. Schwannomas and their pathogenesis. Brain Pathol. 2014;24(3):205-220.
20. Asch E, Levine D. Variations in appearance of endometriomas. J Ultrasound Med. 2007;26(8):993-1002.
21. Gombos Z, Zhang PJ. Glomus tumor. Arch Pathol Lab Med. 2008;132(9):1448-1452.
22. Ayadi L, Khabir A, Fakhfakh I, Abdelmoula MH, Makni S, Sellami Boudawara T. Granular cell tumor. Rev Stomatol Chir Maxillofac. 2008;109(3):158-162.
23. Evans P, Brunsell S. Uterine fibroid tumors: diagnosis and treatment. Am Fam Physician. 2007;75(10):1503-1508.
24. Liu C, Tang ZH, Bei H, Zeng HY. Treatment of patient with multiple cutaneous piloleiomyoma-related pain with local injection of triamcinolone acetonide. Dermatology. 2013;227(1):52-54.
A 53-year-old woman presented to the dermatology clinic complaining of a “bumpy itching, burning rash” of the left lateral neck and jawline. The patient stated that the rash began about 15 to 20 years ago and the lesions have progressively increased in both number and size. She reported occasional tenderness and pruritus, and stated that the bumps “burn” when it is cold outside.
During the consult, the patient discussed the social impact that these disfiguring bumps have had on her work and social life. She stated that she felt ostracized by friends and some family members. She also has not been hired for the customer service jobs she wanted because employers think her bumps look like sores or may be infectious.
On physical examination, more than 30 pink, erythematous nodules, ranging from 0.5 to 2 cm, were noted in clusters on the left neck and mandible. Nodules were firm and tender to palpation (Figure 1). Further questioning revealed a history of hysterectomy 20 years ago for painful uterine leiomyomas. A punch biopsy was performed from a representative lesion on the neck.
What is your diagnosis?
Diagnosis: Multiple Cutaneous and Uterine Leiomyomatosis (Reed Syndrome)
Although solitary leiomyomas are often sporadic and the etiology remains mostly unknown, multiple studies have found that fumarate hydratase (FH) germline mutations are responsible for familial multiple cutaneous and uterine leiomyomatosis syndrome (MCUL).1-3 FH is an enzyme responsible for converting fumarate into malate as part of the Krebs cycle. FH is thought to be a tumor suppressor by regulating the transcription factors hypoxia inducible factor (HIF)-1a and HIF-2a elevated concentrations of these factors are associated with tumorigenesis and malignancy.4 This autosomal dominant disorder typically presents as benign, smooth muscle tumors of the skin and uterus, with a small subset of carriers who develop renal cell carcinoma (RCC).3 Most cases of hereditary leiomyomatosis and renal cell cancer (HLRCC) come from Eastern Europe, affecting only 180 families worldwide.4 Presently, 155 FH mutations resulting in MCUL/HLRCC have been identified, but no correlation between genotype and phenotype has been established.5,6
Clinical Presentations
Cutaneous leiomyomas may present as 3 distinct subtypes: vascular smooth muscle, angioleiomyomas; asymptomatic smooth muscle tumors in the groin, genital leiomyomas; and piloleiomyomas derived from arector pili muscle.7 Piloleiomyomas are the most common variant and may present as single nodules or multiple lesions.4,7 These lesions typically develop before age 40 as skin-colored or pink to brown, firm nodules, which are confined to the skin and move freely over deeper structures.4,7,8 These slow-growing nodules measure between 0.2 and 2 cm and most commonly present on the flexor surfaces of extremities in a linear, grouped, or dermatomal arrangement (Figure 1). The majority of leiomyomas elicit pain described as stabbing, burning, or pinching when triggered by pressure, cold, or emotion.
Most women who develop skin lesions will have a history of painful uterine fibroids before or after the cutaneous eruption.4,9 Women typically present with complaints of dysmenorrhea, pelvic pressure, and intense pain.10
Histology
The diagnosis of cutaneous leiomyomas is confirmed by biopsy. Hematoxylin and eosin staining of a representative lesion reveals fascicles of spindle cells with eiosinophilic cytoplasm with characteristic “cigar-shaped” nuclei.4,7
Imaging and Laboratory Evaluation
The presence of uterine fibroids is typically verified and monitored via ultrasound, but may also be detected by hysterography or hysteroscopy.11 Iron deficiency anemia may also be present in uterine leiomyomas due to chronic blood loss.10 Some studies suggest that those with a strong family history of MCUL should be referred to a geneticist for FH mutation screening because of the increased risk of RCC with poor prognosis.2,12 Papillary renal cancer is an aggressive malignancy, which is difficult to detect given its hypoechoic nature on ultrasound.7 Renal cancer is detected with computed tomography or magnetic resonance imaging.
Differential Diagnosis
A helpful mnemonic for painful dermal nodules/tumors is “LEND AN EGG”: leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomus tumor, and granular cell tumor.13 Leiomyomas will be discussed in further detail throughout this article. Eccrine spiradenoma are sweat gland tumors located in the dermis that typically present as a solitary shiny pink nodule on the head or neck.14,15 Neuromas may present after injury as nonpigmented, tender, firm nodules.13 Dermatofibromas are common firm, usually hyperpigmented fibrohistiocytic tumors that typically present on the lower extremities after trauma or a bug bite, but may be idiopathic.16,17 Cutaneous angiolipomas are well-circumscribed tumors composed of mature adipose tissue with a vascular component, which are often painful. Neurilemmomas, also known as schwannomas, are the most common tumor of peripheral nerves. They are commonly found incidentally on the flexor surfaces as a single nodule.18,19 Endometriomas are painful cysts of the endometrium that typically form in the ovary.11,20 Glomus tumors usually present as pink vascular tumors on the hands or feet and are associated with pain, tenderness, and cold sensitivity.21 Granular cell tumors often present as solitary, benign lesions with or without pigmentation on the skin, subcutaneous tissue, or oropharynx.22
Treatment
While treatment for uterine leiomyomas is well documented and can be achieved by medical management or definitively by myomectomy or hysterectomy,23 the appropriate management for cutaneous leiomyomas is less established. The management of these dermal nodules is dependent on the number and distribution of skin lesions.
The gold standard for treatment is surgical excision, but not all patients are surgical candidates due to the number of lesions present. Smaller lesions may be treated by cryotherapy, electrodesiccation, or carbon dioxide laser ablation, but all options carry the risk of scarring and recurrence.4 The symptoms of cutaneous leiomyomas may be treated medically with agents that affect smooth muscle contraction including calcium channel blockers, a-blockers, nitroglycerine, or botulinum toxin type A injections. Additionally, triamcinolone acetonide injections have been effective in treating the associated pain while decreasing the size of the tumors. Studies also suggest that gabapentin and topical lidocaine may be effective in treating temperature-induced tenderness.4,9,24 Full skin exams every 2 years are recommended to detect new lesions. Once the diagnosis of MCUL is made, the patient should follow-up with urology to rule out renal involvement and determine if further screening is necessary.4
Our Patient
Histological analysis of the pathology specimen revealed fascicles of intersecting spindle cells with “cigar-shaped” nuclei, consistent with leiomyomas (Figures 2A and B). The diagnosis of multiple cutaneous leiomyomas prompted further investigation into medical and familial history. Medical history was positive for painful uterine leiomyomas that required a hysterectomy approximately 20 years ago. Family history revealed that the patient’s mother and maternal aunt had similar cutaneous lesions and required hysterectomies for painful uterine fibroids, suggestive of an autosomal dominant mode of inheritance.
The extensive clusters of nodules on the face and neck complicate the management of this patient’s cutaneous lesions. A management plan is being finalized; this includes local injections of triamcinolone acetonide, a plastic surgery and genetics consult, and a urology referral, due to the predisposition to RCC that is associated with familial leiomyomatosis.
Conclusion
Cutaneous leiomyomas are sporadic or inherited benign smooth muscle tumors that may present asymptomatically or with associated tenderness. The solitary variants are sporadic, but multiple cutaneous leiomyomatosis with uterine leiomyomatosis is hereditary and may be associated with RCC, and thus warrants further consideration and diagnostic workup. This disorder is underrecognized, which may delay treatment in patients with associated RCC. The purpose of this case study is to address this uncommon disorder and emphasize the importance of a renal workup in patients with multiple lesions or with a history of uterine fibroids. Early detection of RCC may be beneficial to patients who would otherwise have a very poor prognosis.
Ms Thompson is a student at Western University of Health Sciences in Pomona, CA.
Dr Robles is dermatology director at Chaparral Medical Group in Upland, CA.
Dr Luo is a dermatopathologist at Dianon Pathology/A LabCorp Company in Los Angeles, CA.
Disclosure: The authors report no relevant financial relationships.
References
1. Tomlison IP, Alam NA, Rowan AJ, et al; Multiple Leiomyoma Consortium. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002;30(4):406-410.
2. Tolvanen J, Uimari O, Ryynänen M, Aaltonen LA, Vahteristo P. Strong family history of uterine leiomyomatosis warrants fumarate hydratase mutation screening. Hum Reprod. 2012;27(6):1865-1869.
3. Smit DL, Mensenkamp AR, Badeloe S, et al. Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Clin Genet. 2011;79(1):49-59.
4. Malik K, Patel P, Chen J, Khachemoune A. Leiomyoma cutis: a focused review on presentation, management, and association with malignancy. Am J Clin Dermatol. 2015;16(1):35-46.
5. Bayley JP, Launonen V, Tomlinson IP. The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase definciency. BMC Med Genet. 2008;9:20.
6. Chan I, Wong T, Martinez-Mir A, Christiano AM, McGrath JA. Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer. Clin Exp Dermatol. 2005;30(1):75-78.
7. Collgros H, Iglesias-Sancho M, Tribó-Boixareu MJ, Creus-vila L, Umbert-Millet P, Salleras-Redonnet M. Multiple cutaneous and uterine leiomyomatosis or reed syndrome: a retrospective study of 13 cases. Actas Dermosifiliogr. 2015;106(2): 117-125.
8. Holst VA, Junkins-Hopkins JM, Elenitsas R. Cutaneous smooth muscle neoplasms: clinical features, histologic findings, and treatment options. J Am Acad Dermatol. 2002;46(4):477-490; quiz, 491-494.
9. Henley ND, Tokarz VA. Multiple cutaneous and uterine leiomyomatosis in a 36-year-old female, and discussion of hereditary leiomyomatosis and renal cell carcinoma. Int J Dermatol. 2012;51(10):1213-1216.
10. Khan AT, Shehmar M, Gupta JK. Uterine fibroids: current perspectives. Int J Womens Health. 2014;29(6):95-114.
11. Van Holsbeke C, Van Calster B, Guerriero S, et al. Endometriomas: their ultrasound characteristics. Ultrasound Obstet Gynecol. 2010;35(6):730-740.
12. Alam NA, Olpin S, Leigh IM. Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer. Br J Dermatol. 2005;153(1):11-17.
13. Naverson DN, Trask DM, Watson FH, Burket JM. Painful tumors of the skin: “LEND AN EGG.” J Am Acad Dermatol. 1993;28(2 Pt 2):298-300.
14. Ben Brahim E, Sfia M, Tangour M, Makhlouf R, Cribier B, Chatti S. Malignant eccrine spiradenoma: a new case report. J Cutan Pathol. 2010;37(4):478-481.
15. Amoroso C, Grandi E, Carinci F. Eccrine spiradenoma of the ear: case report. Oral Maxillofac Surg. 2003;32(6):662-663.
16. Zelger B, Zelger BG, Burgdorf WH. Dermatofibroma-a critical evaluation. Int J Surg Pathol. 2004;2(4):333-344.
17. Jung KD, Lee DY, Lee JH, Yang JM, Lee ES. Subcutaneous dermatofibroma. Ann Dermatol. 2011;23(2):254-257.
18. Tiel R, Kline D. Peripheral nerve tumors: surgical principles, approaches, and techniques. Neurosurg Clin N Am. 2004;15(2):167-175.
19. Hilton DA, Hanemann CO. Schwannomas and their pathogenesis. Brain Pathol. 2014;24(3):205-220.
20. Asch E, Levine D. Variations in appearance of endometriomas. J Ultrasound Med. 2007;26(8):993-1002.
21. Gombos Z, Zhang PJ. Glomus tumor. Arch Pathol Lab Med. 2008;132(9):1448-1452.
22. Ayadi L, Khabir A, Fakhfakh I, Abdelmoula MH, Makni S, Sellami Boudawara T. Granular cell tumor. Rev Stomatol Chir Maxillofac. 2008;109(3):158-162.
23. Evans P, Brunsell S. Uterine fibroid tumors: diagnosis and treatment. Am Fam Physician. 2007;75(10):1503-1508.
24. Liu C, Tang ZH, Bei H, Zeng HY. Treatment of patient with multiple cutaneous piloleiomyoma-related pain with local injection of triamcinolone acetonide. Dermatology. 2013;227(1):52-54.
A 53-year-old woman presented to the dermatology clinic complaining of a “bumpy itching, burning rash” of the left lateral neck and jawline. The patient stated that the rash began about 15 to 20 years ago and the lesions have progressively increased in both number and size. She reported occasional tenderness and pruritus, and stated that the bumps “burn” when it is cold outside.
During the consult, the patient discussed the social impact that these disfiguring bumps have had on her work and social life. She stated that she felt ostracized by friends and some family members. She also has not been hired for the customer service jobs she wanted because employers think her bumps look like sores or may be infectious.
On physical examination, more than 30 pink, erythematous nodules, ranging from 0.5 to 2 cm, were noted in clusters on the left neck and mandible. Nodules were firm and tender to palpation (Figure 1). Further questioning revealed a history of hysterectomy 20 years ago for painful uterine leiomyomas. A punch biopsy was performed from a representative lesion on the neck.
What is your diagnosis?
,
A 53-year-old woman presented to the dermatology clinic complaining of a “bumpy itching, burning rash” of the left lateral neck and jawline. The patient stated that the rash began about 15 to 20 years ago and the lesions have progressively increased in both number and size. She reported occasional tenderness and pruritus, and stated that the bumps “burn” when it is cold outside.
During the consult, the patient discussed the social impact that these disfiguring bumps have had on her work and social life. She stated that she felt ostracized by friends and some family members. She also has not been hired for the customer service jobs she wanted because employers think her bumps look like sores or may be infectious.
On physical examination, more than 30 pink, erythematous nodules, ranging from 0.5 to 2 cm, were noted in clusters on the left neck and mandible. Nodules were firm and tender to palpation (Figure 1). Further questioning revealed a history of hysterectomy 20 years ago for painful uterine leiomyomas. A punch biopsy was performed from a representative lesion on the neck.
What is your diagnosis?
To learn the answer, go to page 2
{{pagebreak}}
Diagnosis: Multiple Cutaneous and Uterine Leiomyomatosis (Reed Syndrome)
Although solitary leiomyomas are often sporadic and the etiology remains mostly unknown, multiple studies have found that fumarate hydratase (FH) germline mutations are responsible for familial multiple cutaneous and uterine leiomyomatosis syndrome (MCUL).1-3 FH is an enzyme responsible for converting fumarate into malate as part of the Krebs cycle. FH is thought to be a tumor suppressor by regulating the transcription factors hypoxia inducible factor (HIF)-1a and HIF-2a elevated concentrations of these factors are associated with tumorigenesis and malignancy.4 This autosomal dominant disorder typically presents as benign, smooth muscle tumors of the skin and uterus, with a small subset of carriers who develop renal cell carcinoma (RCC).3 Most cases of hereditary leiomyomatosis and renal cell cancer (HLRCC) come from Eastern Europe, affecting only 180 families worldwide.4 Presently, 155 FH mutations resulting in MCUL/HLRCC have been identified, but no correlation between genotype and phenotype has been established.5,6
Clinical Presentations
Cutaneous leiomyomas may present as 3 distinct subtypes: vascular smooth muscle, angioleiomyomas; asymptomatic smooth muscle tumors in the groin, genital leiomyomas; and piloleiomyomas derived from arector pili muscle.7 Piloleiomyomas are the most common variant and may present as single nodules or multiple lesions.4,7 These lesions typically develop before age 40 as skin-colored or pink to brown, firm nodules, which are confined to the skin and move freely over deeper structures.4,7,8 These slow-growing nodules measure between 0.2 and 2 cm and most commonly present on the flexor surfaces of extremities in a linear, grouped, or dermatomal arrangement (Figure 1). The majority of leiomyomas elicit pain described as stabbing, burning, or pinching when triggered by pressure, cold, or emotion.
Most women who develop skin lesions will have a history of painful uterine fibroids before or after the cutaneous eruption.4,9 Women typically present with complaints of dysmenorrhea, pelvic pressure, and intense pain.10
Histology
The diagnosis of cutaneous leiomyomas is confirmed by biopsy. Hematoxylin and eosin staining of a representative lesion reveals fascicles of spindle cells with eiosinophilic cytoplasm with characteristic “cigar-shaped” nuclei.4,7
Imaging and Laboratory Evaluation
The presence of uterine fibroids is typically verified and monitored via ultrasound, but may also be detected by hysterography or hysteroscopy.11 Iron deficiency anemia may also be present in uterine leiomyomas due to chronic blood loss.10 Some studies suggest that those with a strong family history of MCUL should be referred to a geneticist for FH mutation screening because of the increased risk of RCC with poor prognosis.2,12 Papillary renal cancer is an aggressive malignancy, which is difficult to detect given its hypoechoic nature on ultrasound.7 Renal cancer is detected with computed tomography or magnetic resonance imaging.
Differential Diagnosis
A helpful mnemonic for painful dermal nodules/tumors is “LEND AN EGG”: leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomus tumor, and granular cell tumor.13 Leiomyomas will be discussed in further detail throughout this article. Eccrine spiradenoma are sweat gland tumors located in the dermis that typically present as a solitary shiny pink nodule on the head or neck.14,15 Neuromas may present after injury as nonpigmented, tender, firm nodules.13 Dermatofibromas are common firm, usually hyperpigmented fibrohistiocytic tumors that typically present on the lower extremities after trauma or a bug bite, but may be idiopathic.16,17 Cutaneous angiolipomas are well-circumscribed tumors composed of mature adipose tissue with a vascular component, which are often painful. Neurilemmomas, also known as schwannomas, are the most common tumor of peripheral nerves. They are commonly found incidentally on the flexor surfaces as a single nodule.18,19 Endometriomas are painful cysts of the endometrium that typically form in the ovary.11,20 Glomus tumors usually present as pink vascular tumors on the hands or feet and are associated with pain, tenderness, and cold sensitivity.21 Granular cell tumors often present as solitary, benign lesions with or without pigmentation on the skin, subcutaneous tissue, or oropharynx.22
Treatment
While treatment for uterine leiomyomas is well documented and can be achieved by medical management or definitively by myomectomy or hysterectomy,23 the appropriate management for cutaneous leiomyomas is less established. The management of these dermal nodules is dependent on the number and distribution of skin lesions.
The gold standard for treatment is surgical excision, but not all patients are surgical candidates due to the number of lesions present. Smaller lesions may be treated by cryotherapy, electrodesiccation, or carbon dioxide laser ablation, but all options carry the risk of scarring and recurrence.4 The symptoms of cutaneous leiomyomas may be treated medically with agents that affect smooth muscle contraction including calcium channel blockers, a-blockers, nitroglycerine, or botulinum toxin type A injections. Additionally, triamcinolone acetonide injections have been effective in treating the associated pain while decreasing the size of the tumors. Studies also suggest that gabapentin and topical lidocaine may be effective in treating temperature-induced tenderness.4,9,24 Full skin exams every 2 years are recommended to detect new lesions. Once the diagnosis of MCUL is made, the patient should follow-up with urology to rule out renal involvement and determine if further screening is necessary.4
Our Patient
Histological analysis of the pathology specimen revealed fascicles of intersecting spindle cells with “cigar-shaped” nuclei, consistent with leiomyomas (Figures 2A and B). The diagnosis of multiple cutaneous leiomyomas prompted further investigation into medical and familial history. Medical history was positive for painful uterine leiomyomas that required a hysterectomy approximately 20 years ago. Family history revealed that the patient’s mother and maternal aunt had similar cutaneous lesions and required hysterectomies for painful uterine fibroids, suggestive of an autosomal dominant mode of inheritance.
The extensive clusters of nodules on the face and neck complicate the management of this patient’s cutaneous lesions. A management plan is being finalized; this includes local injections of triamcinolone acetonide, a plastic surgery and genetics consult, and a urology referral, due to the predisposition to RCC that is associated with familial leiomyomatosis.
Conclusion
Cutaneous leiomyomas are sporadic or inherited benign smooth muscle tumors that may present asymptomatically or with associated tenderness. The solitary variants are sporadic, but multiple cutaneous leiomyomatosis with uterine leiomyomatosis is hereditary and may be associated with RCC, and thus warrants further consideration and diagnostic workup. This disorder is underrecognized, which may delay treatment in patients with associated RCC. The purpose of this case study is to address this uncommon disorder and emphasize the importance of a renal workup in patients with multiple lesions or with a history of uterine fibroids. Early detection of RCC may be beneficial to patients who would otherwise have a very poor prognosis.
Ms Thompson is a student at Western University of Health Sciences in Pomona, CA.
Dr Robles is dermatology director at Chaparral Medical Group in Upland, CA.
Dr Luo is a dermatopathologist at Dianon Pathology/A LabCorp Company in Los Angeles, CA.
Disclosure: The authors report no relevant financial relationships.
References
1. Tomlison IP, Alam NA, Rowan AJ, et al; Multiple Leiomyoma Consortium. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002;30(4):406-410.
2. Tolvanen J, Uimari O, Ryynänen M, Aaltonen LA, Vahteristo P. Strong family history of uterine leiomyomatosis warrants fumarate hydratase mutation screening. Hum Reprod. 2012;27(6):1865-1869.
3. Smit DL, Mensenkamp AR, Badeloe S, et al. Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Clin Genet. 2011;79(1):49-59.
4. Malik K, Patel P, Chen J, Khachemoune A. Leiomyoma cutis: a focused review on presentation, management, and association with malignancy. Am J Clin Dermatol. 2015;16(1):35-46.
5. Bayley JP, Launonen V, Tomlinson IP. The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase definciency. BMC Med Genet. 2008;9:20.
6. Chan I, Wong T, Martinez-Mir A, Christiano AM, McGrath JA. Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer. Clin Exp Dermatol. 2005;30(1):75-78.
7. Collgros H, Iglesias-Sancho M, Tribó-Boixareu MJ, Creus-vila L, Umbert-Millet P, Salleras-Redonnet M. Multiple cutaneous and uterine leiomyomatosis or reed syndrome: a retrospective study of 13 cases. Actas Dermosifiliogr. 2015;106(2): 117-125.
8. Holst VA, Junkins-Hopkins JM, Elenitsas R. Cutaneous smooth muscle neoplasms: clinical features, histologic findings, and treatment options. J Am Acad Dermatol. 2002;46(4):477-490; quiz, 491-494.
9. Henley ND, Tokarz VA. Multiple cutaneous and uterine leiomyomatosis in a 36-year-old female, and discussion of hereditary leiomyomatosis and renal cell carcinoma. Int J Dermatol. 2012;51(10):1213-1216.
10. Khan AT, Shehmar M, Gupta JK. Uterine fibroids: current perspectives. Int J Womens Health. 2014;29(6):95-114.
11. Van Holsbeke C, Van Calster B, Guerriero S, et al. Endometriomas: their ultrasound characteristics. Ultrasound Obstet Gynecol. 2010;35(6):730-740.
12. Alam NA, Olpin S, Leigh IM. Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer. Br J Dermatol. 2005;153(1):11-17.
13. Naverson DN, Trask DM, Watson FH, Burket JM. Painful tumors of the skin: “LEND AN EGG.” J Am Acad Dermatol. 1993;28(2 Pt 2):298-300.
14. Ben Brahim E, Sfia M, Tangour M, Makhlouf R, Cribier B, Chatti S. Malignant eccrine spiradenoma: a new case report. J Cutan Pathol. 2010;37(4):478-481.
15. Amoroso C, Grandi E, Carinci F. Eccrine spiradenoma of the ear: case report. Oral Maxillofac Surg. 2003;32(6):662-663.
16. Zelger B, Zelger BG, Burgdorf WH. Dermatofibroma-a critical evaluation. Int J Surg Pathol. 2004;2(4):333-344.
17. Jung KD, Lee DY, Lee JH, Yang JM, Lee ES. Subcutaneous dermatofibroma. Ann Dermatol. 2011;23(2):254-257.
18. Tiel R, Kline D. Peripheral nerve tumors: surgical principles, approaches, and techniques. Neurosurg Clin N Am. 2004;15(2):167-175.
19. Hilton DA, Hanemann CO. Schwannomas and their pathogenesis. Brain Pathol. 2014;24(3):205-220.
20. Asch E, Levine D. Variations in appearance of endometriomas. J Ultrasound Med. 2007;26(8):993-1002.
21. Gombos Z, Zhang PJ. Glomus tumor. Arch Pathol Lab Med. 2008;132(9):1448-1452.
22. Ayadi L, Khabir A, Fakhfakh I, Abdelmoula MH, Makni S, Sellami Boudawara T. Granular cell tumor. Rev Stomatol Chir Maxillofac. 2008;109(3):158-162.
23. Evans P, Brunsell S. Uterine fibroid tumors: diagnosis and treatment. Am Fam Physician. 2007;75(10):1503-1508.
24. Liu C, Tang ZH, Bei H, Zeng HY. Treatment of patient with multiple cutaneous piloleiomyoma-related pain with local injection of triamcinolone acetonide. Dermatology. 2013;227(1):52-54.
A 53-year-old woman presented to the dermatology clinic complaining of a “bumpy itching, burning rash” of the left lateral neck and jawline. The patient stated that the rash began about 15 to 20 years ago and the lesions have progressively increased in both number and size. She reported occasional tenderness and pruritus, and stated that the bumps “burn” when it is cold outside.
During the consult, the patient discussed the social impact that these disfiguring bumps have had on her work and social life. She stated that she felt ostracized by friends and some family members. She also has not been hired for the customer service jobs she wanted because employers think her bumps look like sores or may be infectious.
On physical examination, more than 30 pink, erythematous nodules, ranging from 0.5 to 2 cm, were noted in clusters on the left neck and mandible. Nodules were firm and tender to palpation (Figure 1). Further questioning revealed a history of hysterectomy 20 years ago for painful uterine leiomyomas. A punch biopsy was performed from a representative lesion on the neck.
What is your diagnosis?
Diagnosis: Multiple Cutaneous and Uterine Leiomyomatosis (Reed Syndrome)
Although solitary leiomyomas are often sporadic and the etiology remains mostly unknown, multiple studies have found that fumarate hydratase (FH) germline mutations are responsible for familial multiple cutaneous and uterine leiomyomatosis syndrome (MCUL).1-3 FH is an enzyme responsible for converting fumarate into malate as part of the Krebs cycle. FH is thought to be a tumor suppressor by regulating the transcription factors hypoxia inducible factor (HIF)-1a and HIF-2a elevated concentrations of these factors are associated with tumorigenesis and malignancy.4 This autosomal dominant disorder typically presents as benign, smooth muscle tumors of the skin and uterus, with a small subset of carriers who develop renal cell carcinoma (RCC).3 Most cases of hereditary leiomyomatosis and renal cell cancer (HLRCC) come from Eastern Europe, affecting only 180 families worldwide.4 Presently, 155 FH mutations resulting in MCUL/HLRCC have been identified, but no correlation between genotype and phenotype has been established.5,6
Clinical Presentations
Cutaneous leiomyomas may present as 3 distinct subtypes: vascular smooth muscle, angioleiomyomas; asymptomatic smooth muscle tumors in the groin, genital leiomyomas; and piloleiomyomas derived from arector pili muscle.7 Piloleiomyomas are the most common variant and may present as single nodules or multiple lesions.4,7 These lesions typically develop before age 40 as skin-colored or pink to brown, firm nodules, which are confined to the skin and move freely over deeper structures.4,7,8 These slow-growing nodules measure between 0.2 and 2 cm and most commonly present on the flexor surfaces of extremities in a linear, grouped, or dermatomal arrangement (Figure 1). The majority of leiomyomas elicit pain described as stabbing, burning, or pinching when triggered by pressure, cold, or emotion.
Most women who develop skin lesions will have a history of painful uterine fibroids before or after the cutaneous eruption.4,9 Women typically present with complaints of dysmenorrhea, pelvic pressure, and intense pain.10
Histology
The diagnosis of cutaneous leiomyomas is confirmed by biopsy. Hematoxylin and eosin staining of a representative lesion reveals fascicles of spindle cells with eiosinophilic cytoplasm with characteristic “cigar-shaped” nuclei.4,7
Imaging and Laboratory Evaluation
The presence of uterine fibroids is typically verified and monitored via ultrasound, but may also be detected by hysterography or hysteroscopy.11 Iron deficiency anemia may also be present in uterine leiomyomas due to chronic blood loss.10 Some studies suggest that those with a strong family history of MCUL should be referred to a geneticist for FH mutation screening because of the increased risk of RCC with poor prognosis.2,12 Papillary renal cancer is an aggressive malignancy, which is difficult to detect given its hypoechoic nature on ultrasound.7 Renal cancer is detected with computed tomography or magnetic resonance imaging.
Differential Diagnosis
A helpful mnemonic for painful dermal nodules/tumors is “LEND AN EGG”: leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomus tumor, and granular cell tumor.13 Leiomyomas will be discussed in further detail throughout this article. Eccrine spiradenoma are sweat gland tumors located in the dermis that typically present as a solitary shiny pink nodule on the head or neck.14,15 Neuromas may present after injury as nonpigmented, tender, firm nodules.13 Dermatofibromas are common firm, usually hyperpigmented fibrohistiocytic tumors that typically present on the lower extremities after trauma or a bug bite, but may be idiopathic.16,17 Cutaneous angiolipomas are well-circumscribed tumors composed of mature adipose tissue with a vascular component, which are often painful. Neurilemmomas, also known as schwannomas, are the most common tumor of peripheral nerves. They are commonly found incidentally on the flexor surfaces as a single nodule.18,19 Endometriomas are painful cysts of the endometrium that typically form in the ovary.11,20 Glomus tumors usually present as pink vascular tumors on the hands or feet and are associated with pain, tenderness, and cold sensitivity.21 Granular cell tumors often present as solitary, benign lesions with or without pigmentation on the skin, subcutaneous tissue, or oropharynx.22
Treatment
While treatment for uterine leiomyomas is well documented and can be achieved by medical management or definitively by myomectomy or hysterectomy,23 the appropriate management for cutaneous leiomyomas is less established. The management of these dermal nodules is dependent on the number and distribution of skin lesions.
The gold standard for treatment is surgical excision, but not all patients are surgical candidates due to the number of lesions present. Smaller lesions may be treated by cryotherapy, electrodesiccation, or carbon dioxide laser ablation, but all options carry the risk of scarring and recurrence.4 The symptoms of cutaneous leiomyomas may be treated medically with agents that affect smooth muscle contraction including calcium channel blockers, a-blockers, nitroglycerine, or botulinum toxin type A injections. Additionally, triamcinolone acetonide injections have been effective in treating the associated pain while decreasing the size of the tumors. Studies also suggest that gabapentin and topical lidocaine may be effective in treating temperature-induced tenderness.4,9,24 Full skin exams every 2 years are recommended to detect new lesions. Once the diagnosis of MCUL is made, the patient should follow-up with urology to rule out renal involvement and determine if further screening is necessary.4
Our Patient
Histological analysis of the pathology specimen revealed fascicles of intersecting spindle cells with “cigar-shaped” nuclei, consistent with leiomyomas (Figures 2A and B). The diagnosis of multiple cutaneous leiomyomas prompted further investigation into medical and familial history. Medical history was positive for painful uterine leiomyomas that required a hysterectomy approximately 20 years ago. Family history revealed that the patient’s mother and maternal aunt had similar cutaneous lesions and required hysterectomies for painful uterine fibroids, suggestive of an autosomal dominant mode of inheritance.
The extensive clusters of nodules on the face and neck complicate the management of this patient’s cutaneous lesions. A management plan is being finalized; this includes local injections of triamcinolone acetonide, a plastic surgery and genetics consult, and a urology referral, due to the predisposition to RCC that is associated with familial leiomyomatosis.
Conclusion
Cutaneous leiomyomas are sporadic or inherited benign smooth muscle tumors that may present asymptomatically or with associated tenderness. The solitary variants are sporadic, but multiple cutaneous leiomyomatosis with uterine leiomyomatosis is hereditary and may be associated with RCC, and thus warrants further consideration and diagnostic workup. This disorder is underrecognized, which may delay treatment in patients with associated RCC. The purpose of this case study is to address this uncommon disorder and emphasize the importance of a renal workup in patients with multiple lesions or with a history of uterine fibroids. Early detection of RCC may be beneficial to patients who would otherwise have a very poor prognosis.
Ms Thompson is a student at Western University of Health Sciences in Pomona, CA.
Dr Robles is dermatology director at Chaparral Medical Group in Upland, CA.
Dr Luo is a dermatopathologist at Dianon Pathology/A LabCorp Company in Los Angeles, CA.
Disclosure: The authors report no relevant financial relationships.
References
1. Tomlison IP, Alam NA, Rowan AJ, et al; Multiple Leiomyoma Consortium. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002;30(4):406-410.
2. Tolvanen J, Uimari O, Ryynänen M, Aaltonen LA, Vahteristo P. Strong family history of uterine leiomyomatosis warrants fumarate hydratase mutation screening. Hum Reprod. 2012;27(6):1865-1869.
3. Smit DL, Mensenkamp AR, Badeloe S, et al. Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Clin Genet. 2011;79(1):49-59.
4. Malik K, Patel P, Chen J, Khachemoune A. Leiomyoma cutis: a focused review on presentation, management, and association with malignancy. Am J Clin Dermatol. 2015;16(1):35-46.
5. Bayley JP, Launonen V, Tomlinson IP. The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase definciency. BMC Med Genet. 2008;9:20.
6. Chan I, Wong T, Martinez-Mir A, Christiano AM, McGrath JA. Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer. Clin Exp Dermatol. 2005;30(1):75-78.
7. Collgros H, Iglesias-Sancho M, Tribó-Boixareu MJ, Creus-vila L, Umbert-Millet P, Salleras-Redonnet M. Multiple cutaneous and uterine leiomyomatosis or reed syndrome: a retrospective study of 13 cases. Actas Dermosifiliogr. 2015;106(2): 117-125.
8. Holst VA, Junkins-Hopkins JM, Elenitsas R. Cutaneous smooth muscle neoplasms: clinical features, histologic findings, and treatment options. J Am Acad Dermatol. 2002;46(4):477-490; quiz, 491-494.
9. Henley ND, Tokarz VA. Multiple cutaneous and uterine leiomyomatosis in a 36-year-old female, and discussion of hereditary leiomyomatosis and renal cell carcinoma. Int J Dermatol. 2012;51(10):1213-1216.
10. Khan AT, Shehmar M, Gupta JK. Uterine fibroids: current perspectives. Int J Womens Health. 2014;29(6):95-114.
11. Van Holsbeke C, Van Calster B, Guerriero S, et al. Endometriomas: their ultrasound characteristics. Ultrasound Obstet Gynecol. 2010;35(6):730-740.
12. Alam NA, Olpin S, Leigh IM. Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer. Br J Dermatol. 2005;153(1):11-17.
13. Naverson DN, Trask DM, Watson FH, Burket JM. Painful tumors of the skin: “LEND AN EGG.” J Am Acad Dermatol. 1993;28(2 Pt 2):298-300.
14. Ben Brahim E, Sfia M, Tangour M, Makhlouf R, Cribier B, Chatti S. Malignant eccrine spiradenoma: a new case report. J Cutan Pathol. 2010;37(4):478-481.
15. Amoroso C, Grandi E, Carinci F. Eccrine spiradenoma of the ear: case report. Oral Maxillofac Surg. 2003;32(6):662-663.
16. Zelger B, Zelger BG, Burgdorf WH. Dermatofibroma-a critical evaluation. Int J Surg Pathol. 2004;2(4):333-344.
17. Jung KD, Lee DY, Lee JH, Yang JM, Lee ES. Subcutaneous dermatofibroma. Ann Dermatol. 2011;23(2):254-257.
18. Tiel R, Kline D. Peripheral nerve tumors: surgical principles, approaches, and techniques. Neurosurg Clin N Am. 2004;15(2):167-175.
19. Hilton DA, Hanemann CO. Schwannomas and their pathogenesis. Brain Pathol. 2014;24(3):205-220.
20. Asch E, Levine D. Variations in appearance of endometriomas. J Ultrasound Med. 2007;26(8):993-1002.
21. Gombos Z, Zhang PJ. Glomus tumor. Arch Pathol Lab Med. 2008;132(9):1448-1452.
22. Ayadi L, Khabir A, Fakhfakh I, Abdelmoula MH, Makni S, Sellami Boudawara T. Granular cell tumor. Rev Stomatol Chir Maxillofac. 2008;109(3):158-162.
23. Evans P, Brunsell S. Uterine fibroid tumors: diagnosis and treatment. Am Fam Physician. 2007;75(10):1503-1508.
24. Liu C, Tang ZH, Bei H, Zeng HY. Treatment of patient with multiple cutaneous piloleiomyoma-related pain with local injection of triamcinolone acetonide. Dermatology. 2013;227(1):52-54.
Diagnosis: Multiple Cutaneous and Uterine Leiomyomatosis (Reed Syndrome)
Although solitary leiomyomas are often sporadic and the etiology remains mostly unknown, multiple studies have found that fumarate hydratase (FH) germline mutations are responsible for familial multiple cutaneous and uterine leiomyomatosis syndrome (MCUL).1-3 FH is an enzyme responsible for converting fumarate into malate as part of the Krebs cycle. FH is thought to be a tumor suppressor by regulating the transcription factors hypoxia inducible factor (HIF)-1a and HIF-2a elevated concentrations of these factors are associated with tumorigenesis and malignancy.4 This autosomal dominant disorder typically presents as benign, smooth muscle tumors of the skin and uterus, with a small subset of carriers who develop renal cell carcinoma (RCC).3 Most cases of hereditary leiomyomatosis and renal cell cancer (HLRCC) come from Eastern Europe, affecting only 180 families worldwide.4 Presently, 155 FH mutations resulting in MCUL/HLRCC have been identified, but no correlation between genotype and phenotype has been established.5,6
Clinical Presentations
Cutaneous leiomyomas may present as 3 distinct subtypes: vascular smooth muscle, angioleiomyomas; asymptomatic smooth muscle tumors in the groin, genital leiomyomas; and piloleiomyomas derived from arector pili muscle.7 Piloleiomyomas are the most common variant and may present as single nodules or multiple lesions.4,7 These lesions typically develop before age 40 as skin-colored or pink to brown, firm nodules, which are confined to the skin and move freely over deeper structures.4,7,8 These slow-growing nodules measure between 0.2 and 2 cm and most commonly present on the flexor surfaces of extremities in a linear, grouped, or dermatomal arrangement (Figure 1). The majority of leiomyomas elicit pain described as stabbing, burning, or pinching when triggered by pressure, cold, or emotion.
Most women who develop skin lesions will have a history of painful uterine fibroids before or after the cutaneous eruption.4,9 Women typically present with complaints of dysmenorrhea, pelvic pressure, and intense pain.10
Histology
The diagnosis of cutaneous leiomyomas is confirmed by biopsy. Hematoxylin and eosin staining of a representative lesion reveals fascicles of spindle cells with eiosinophilic cytoplasm with characteristic “cigar-shaped” nuclei.4,7
Imaging and Laboratory Evaluation
The presence of uterine fibroids is typically verified and monitored via ultrasound, but may also be detected by hysterography or hysteroscopy.11 Iron deficiency anemia may also be present in uterine leiomyomas due to chronic blood loss.10 Some studies suggest that those with a strong family history of MCUL should be referred to a geneticist for FH mutation screening because of the increased risk of RCC with poor prognosis.2,12 Papillary renal cancer is an aggressive malignancy, which is difficult to detect given its hypoechoic nature on ultrasound.7 Renal cancer is detected with computed tomography or magnetic resonance imaging.
Differential Diagnosis
A helpful mnemonic for painful dermal nodules/tumors is “LEND AN EGG”: leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomus tumor, and granular cell tumor.13 Leiomyomas will be discussed in further detail throughout this article. Eccrine spiradenoma are sweat gland tumors located in the dermis that typically present as a solitary shiny pink nodule on the head or neck.14,15 Neuromas may present after injury as nonpigmented, tender, firm nodules.13 Dermatofibromas are common firm, usually hyperpigmented fibrohistiocytic tumors that typically present on the lower extremities after trauma or a bug bite, but may be idiopathic.16,17 Cutaneous angiolipomas are well-circumscribed tumors composed of mature adipose tissue with a vascular component, which are often painful. Neurilemmomas, also known as schwannomas, are the most common tumor of peripheral nerves. They are commonly found incidentally on the flexor surfaces as a single nodule.18,19 Endometriomas are painful cysts of the endometrium that typically form in the ovary.11,20 Glomus tumors usually present as pink vascular tumors on the hands or feet and are associated with pain, tenderness, and cold sensitivity.21 Granular cell tumors often present as solitary, benign lesions with or without pigmentation on the skin, subcutaneous tissue, or oropharynx.22
Treatment
While treatment for uterine leiomyomas is well documented and can be achieved by medical management or definitively by myomectomy or hysterectomy,23 the appropriate management for cutaneous leiomyomas is less established. The management of these dermal nodules is dependent on the number and distribution of skin lesions.
The gold standard for treatment is surgical excision, but not all patients are surgical candidates due to the number of lesions present. Smaller lesions may be treated by cryotherapy, electrodesiccation, or carbon dioxide laser ablation, but all options carry the risk of scarring and recurrence.4 The symptoms of cutaneous leiomyomas may be treated medically with agents that affect smooth muscle contraction including calcium channel blockers, a-blockers, nitroglycerine, or botulinum toxin type A injections. Additionally, triamcinolone acetonide injections have been effective in treating the associated pain while decreasing the size of the tumors. Studies also suggest that gabapentin and topical lidocaine may be effective in treating temperature-induced tenderness.4,9,24 Full skin exams every 2 years are recommended to detect new lesions. Once the diagnosis of MCUL is made, the patient should follow-up with urology to rule out renal involvement and determine if further screening is necessary.4
Our Patient
Histological analysis of the pathology specimen revealed fascicles of intersecting spindle cells with “cigar-shaped” nuclei, consistent with leiomyomas (Figures 2A and B). The diagnosis of multiple cutaneous leiomyomas prompted further investigation into medical and familial history. Medical history was positive for painful uterine leiomyomas that required a hysterectomy approximately 20 years ago. Family history revealed that the patient’s mother and maternal aunt had similar cutaneous lesions and required hysterectomies for painful uterine fibroids, suggestive of an autosomal dominant mode of inheritance.
The extensive clusters of nodules on the face and neck complicate the management of this patient’s cutaneous lesions. A management plan is being finalized; this includes local injections of triamcinolone acetonide, a plastic surgery and genetics consult, and a urology referral, due to the predisposition to RCC that is associated with familial leiomyomatosis.
Conclusion
Cutaneous leiomyomas are sporadic or inherited benign smooth muscle tumors that may present asymptomatically or with associated tenderness. The solitary variants are sporadic, but multiple cutaneous leiomyomatosis with uterine leiomyomatosis is hereditary and may be associated with RCC, and thus warrants further consideration and diagnostic workup. This disorder is underrecognized, which may delay treatment in patients with associated RCC. The purpose of this case study is to address this uncommon disorder and emphasize the importance of a renal workup in patients with multiple lesions or with a history of uterine fibroids. Early detection of RCC may be beneficial to patients who would otherwise have a very poor prognosis.
Ms Thompson is a student at Western University of Health Sciences in Pomona, CA.
Dr Robles is dermatology director at Chaparral Medical Group in Upland, CA.
Dr Luo is a dermatopathologist at Dianon Pathology/A LabCorp Company in Los Angeles, CA.
Disclosure: The authors report no relevant financial relationships.
References
1. Tomlison IP, Alam NA, Rowan AJ, et al; Multiple Leiomyoma Consortium. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002;30(4):406-410.
2. Tolvanen J, Uimari O, Ryynänen M, Aaltonen LA, Vahteristo P. Strong family history of uterine leiomyomatosis warrants fumarate hydratase mutation screening. Hum Reprod. 2012;27(6):1865-1869.
3. Smit DL, Mensenkamp AR, Badeloe S, et al. Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Clin Genet. 2011;79(1):49-59.
4. Malik K, Patel P, Chen J, Khachemoune A. Leiomyoma cutis: a focused review on presentation, management, and association with malignancy. Am J Clin Dermatol. 2015;16(1):35-46.
5. Bayley JP, Launonen V, Tomlinson IP. The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase definciency. BMC Med Genet. 2008;9:20.
6. Chan I, Wong T, Martinez-Mir A, Christiano AM, McGrath JA. Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer. Clin Exp Dermatol. 2005;30(1):75-78.
7. Collgros H, Iglesias-Sancho M, Tribó-Boixareu MJ, Creus-vila L, Umbert-Millet P, Salleras-Redonnet M. Multiple cutaneous and uterine leiomyomatosis or reed syndrome: a retrospective study of 13 cases. Actas Dermosifiliogr. 2015;106(2): 117-125.
8. Holst VA, Junkins-Hopkins JM, Elenitsas R. Cutaneous smooth muscle neoplasms: clinical features, histologic findings, and treatment options. J Am Acad Dermatol. 2002;46(4):477-490; quiz, 491-494.
9. Henley ND, Tokarz VA. Multiple cutaneous and uterine leiomyomatosis in a 36-year-old female, and discussion of hereditary leiomyomatosis and renal cell carcinoma. Int J Dermatol. 2012;51(10):1213-1216.
10. Khan AT, Shehmar M, Gupta JK. Uterine fibroids: current perspectives. Int J Womens Health. 2014;29(6):95-114.
11. Van Holsbeke C, Van Calster B, Guerriero S, et al. Endometriomas: their ultrasound characteristics. Ultrasound Obstet Gynecol. 2010;35(6):730-740.
12. Alam NA, Olpin S, Leigh IM. Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer. Br J Dermatol. 2005;153(1):11-17.
13. Naverson DN, Trask DM, Watson FH, Burket JM. Painful tumors of the skin: “LEND AN EGG.” J Am Acad Dermatol. 1993;28(2 Pt 2):298-300.
14. Ben Brahim E, Sfia M, Tangour M, Makhlouf R, Cribier B, Chatti S. Malignant eccrine spiradenoma: a new case report. J Cutan Pathol. 2010;37(4):478-481.
15. Amoroso C, Grandi E, Carinci F. Eccrine spiradenoma of the ear: case report. Oral Maxillofac Surg. 2003;32(6):662-663.
16. Zelger B, Zelger BG, Burgdorf WH. Dermatofibroma-a critical evaluation. Int J Surg Pathol. 2004;2(4):333-344.
17. Jung KD, Lee DY, Lee JH, Yang JM, Lee ES. Subcutaneous dermatofibroma. Ann Dermatol. 2011;23(2):254-257.
18. Tiel R, Kline D. Peripheral nerve tumors: surgical principles, approaches, and techniques. Neurosurg Clin N Am. 2004;15(2):167-175.
19. Hilton DA, Hanemann CO. Schwannomas and their pathogenesis. Brain Pathol. 2014;24(3):205-220.
20. Asch E, Levine D. Variations in appearance of endometriomas. J Ultrasound Med. 2007;26(8):993-1002.
21. Gombos Z, Zhang PJ. Glomus tumor. Arch Pathol Lab Med. 2008;132(9):1448-1452.
22. Ayadi L, Khabir A, Fakhfakh I, Abdelmoula MH, Makni S, Sellami Boudawara T. Granular cell tumor. Rev Stomatol Chir Maxillofac. 2008;109(3):158-162.
23. Evans P, Brunsell S. Uterine fibroid tumors: diagnosis and treatment. Am Fam Physician. 2007;75(10):1503-1508.
24. Liu C, Tang ZH, Bei H, Zeng HY. Treatment of patient with multiple cutaneous piloleiomyoma-related pain with local injection of triamcinolone acetonide. Dermatology. 2013;227(1):52-54.
