Pandey I*, Gupta AS**
(* Third Year Resident, ** Professor, Department of Obstetrics and Gynecology, Seth G.S. Medical College and K.E.M. Hospital, Mumbai, India)
Reed’s syndrome is an inherited disorder where unusual skin manifestations coexist with uterine leiomyomas (MCUL- multiple cutaneous and uterine leiomyomatosis). Leiomyomas are benign tumors, originated from smooth muscle cells. Cutaneous leiomyomas originate from the erector pili muscle of the hair follicle. These are uncommon, unrecognized and under- diagnosed tumors. Morphologically skin lesions are multiple, small, oval, reddish-brown tumors around hair follicles. Histopathological examination confirms the diagnosis. We report a case of an elderly woman who presented with symptomatic, recurrent uterine fibroid requiring surgical intervention, with multiple, occasionally painful skin lesions.
Reed’s syndrome is a condition known for the coexistence of benign smooth muscle tumor in the uterus and the skin. An autosomal dominant pattern of inheritance established by Reed et al in 1973.[2,3] Several synonyms have been used for this condition like multiple cutaneous and uterine leiomyomatosis (MCUL). This syndrome may be associated with papillary type 2 renal cell carcinoma, and termed as hereditary leiomyomatosis and renal cell cancer (HLRCC). Mutation in a disease predisposing gene "fumarate hydratase", an important gene of our mitochondrial cellular energy metabolism, has been identified. Our patient presented with menorrhagia and was detected to have multiple uterine fibroids. A supracervical hysterectomy was only possible due to dense adhesions of the cervix to the sigmoid colon. Multiple, small, reddish-brown, painful skin lesions were present around hair follicles; they were biopsied.
A 45 year old woman unsuccessfully treated for primary infertility presented to our department with complaints of menorrhagia and pelvic pain. Clinical examination, pelvic ultrasonography (USG), contrast-enhanced CT scan (CECT), and PET scan detected multiple uterine fibroids. She had similar complaints at the age of 28 years; subsequently she underwent myomectomy for uterine fibroid. She was on treatment for hypertension and diabetes mellitus; both were well controlled. CECT detected incidentally a benign adrenal adenoma. A PET scan confirmed the diagnosis. An endocrine evaluation with ACTH, basal cortisol, plasma free and urine free metanephrins, and 18-hydroxycortisol was done and all levels were within normal range. Her complete blood counts, liver and renal function test, chest X ray, and ECG were normal. On examination there were multiple groups of skin colored to red colored papules and nodules present on the back, thigh, and gluteal region. Mild tenderness was present over these lesions. She had these lesions since 15 years and they had increased in number. Dermatologic opinion was taken. A 6 mm deep biopsy of the nodules was taken and sent for histopathology examination. Histopathology showed smooth muscle cell proliferation, intermixed with collagen fibers and few lymphocytes suggestive of leiomyoma of skin. A total hysterectomy was planned; however only a supracervical hysterectomy was possible due to dense adhesions of the cervix to the sigmoid colon. These adhesions could not be released by the general surgeons also. Intraoperatively multiple fibroids with bosselation on the surface of uterus were seen. These multiple fibroids expanded the fundus and uterine body transversely. They extended from the right side broad ligament posteriorly, covering the bladder field anteriorly, and partly into the left side of the broad ligament. The anatomy of the uterus was distorted. Specimen was sent for histopathology, which showed multiple leiomyomata of uterus with one of them showing features of symplastic leiomyoma. The mitotic figure were less than 1/10 HPF. Uterus size was 13 x 12 x 9 cm, corpus was 8 cm and 3 cm of cervix. Largest fibroid measured 8 x 6 x 5 cm in size. Endometrial cavity was normal. No evidence of malignancy was found. No tumor necrosis was seen. On direct questioning, she said that her mother also underwent a hysterectomy for similar complaints but was never evaluated properly. Patient has been asked to follow up regularly.
Figure 1. Contrast enhanced CT scan. Yellow arrows have outlined the enlarged uterus with multiple fibroids.
Figure 2. Multiple, small, oval, reddish-brown papules and nodules in a group on the back.
Figure 3. Gross surgical specimen.
Reed’s syndrome is a rare hereditary neoplastic condition. It is associated with uterine leiomyomas and multiple cutaneous leiomyomas. In some cases it may be associated with type 2 papillary renal cell cancer and about 16% of patients may develop aggressive renal cell cancer. It has an autosomal dominant inheritance of mutation in the loss of function of fumarate hydratase enzyme. The gene for this enzyme is located on chromosome 1q42.3-q43, called MCUL 1 locus. Though the exact pathologic mechanism has not been understood, the cells which are deficient in function of fumarate hydratase enzyme have defective Kreb’s cycle. Hypoxic state created due to it may be responsible for cellular transformation and tumorigenesis. Fumarate hydratase enzyme gene may act as tumor suppressor gene, but its consequence is not yet identified. Mostly symptoms appear in young to middle age patients. Though approximately 80% of the patients have multiple or single cutaneous leiomyomas, a small proportion may present simply with uterine leiomyomas, may or may not be associated with an underlying renal cell carcinoma. Multiple uterine and cutaneous leiomyomatosis in our patient established the diagnosis of Reed Syndrome. Our patient did not have features of renal cell carcinoma even on PET scan. She had one symplastic leiomyoma wherein the mitotic figure were less than 1/10 HPF. Symplastic /bizarre leiomyoma contains multinucleated tumor cells with moderate to severe atypia. Usually these have a benign course. They are associated with the use of progesterone. Some patients may present with linear configuration of single cluster of cutaneous leimyomas along the Blaschko’s line due to genetic mosaicism. The lesions of this type may be misdiagnosed as herpes zoster infection. No specific diagnostic criteria has been established, and diagnosis is generally made by practical clinical criteria. The definite diagnosis of Reed syndrome can be established by identifying the fumarate hydratase enzyme gene mutation. Early detection and treatment of associated renal cell carcinoma is the most important aspect. One of the suggested screening programmes is first renal imaging at third decade of life, followed by biannual renal ultrasound and annual MRI.
Based on the size, number of uterine leiomyoma and the severity of symptoms, surgical management including hysterectomy are generally required.[15,16] Moreover, alternative treatment modality for uterine leiomyoma includes myomectomy, uterine artery embolization, or medical management with gonadotropin releasing hormone agonists. Skin lesions are usually benign. Solitary tumors may require surgical excision, cryoablation. Multiple painful tumors can be treated with nitroglycerol, calcium channel blockers, and alpha-adrenorecepter blockers to relieve pain. Genetic counseling may be recommended as the condition is inherited.
Reed’s syndrome mainly includes benign tumors of skin and uterus. Moreover, renal cell carcinomas that may be found in a subset of cases are very aggressive in clinical course. Hence, early diagnosis and appropriate surveillance is needed. Genetic analysis should be performed depending on the feasibility and affordability.
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Pandey I, Gupta AS. Reed’s Syndrome: Rare Tumor Disarray. JPGO 2015. Volume 3 No. 5. Available from: http://www.jpgo.org/2016/05/reeds-syndrome-rare-tumor-disarray.html