Hereditary leiomyomatosis and renal cell carcinoma syndrome: a case report

The simultaneous occurrence of multiple cutaneous leiomyomas, uterine leiomyomatosis, and renal cancer is described as a cancer syndrome with an autosomal dominant pattern of inheritance. We report a 79-year-old man who presented with multiple hyperkeratotic, erythematous nodules on his right leg with a histological diagnosis of pilar leiomyoma. In a review of systems, gross hematuria, weight loss, and bone pain were noted. His pathologic diagnosis was determined to be metastatic papillary renal cell carcinoma. A family history revealed that his sister had a hysterectomy for uterine leiomyomas. The findings in this case can be attributed to hereditary leiomyomatosis and renal cell carcinoma syndrome.     

Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer

Multiple cutaneous and uterine leiomyomas is an autosomal dominant condition that results in benign smooth muscle tumours of the skin and, in females, uterine fibroids. This syndrome overlaps with hereditary leiomyomatosis and renal cell cancer syndrome in which affected individuals may develop the rare type II papillary renal cell cancer, in addition to skin leiomyomas. Recently, heterozygous mutations in the gene encoding fumarate hydratase have been found to underlie both conditions. Fumarate hydratase is an enzyme that catalyses the conversion of fumarate to malate in the Kreb's cycle and may also function as a tumour suppressor gene. We report a family with multiple leiomyomas, uterine fibroids and papillary renal cell cancer. The proband is a 77-year-old Polish woman who developed multiple cutaneous leiomyomas on her right upper arm in her thirties and subsequently underwent a hysterectomy for uterine fibroids in her forties. She has four offspring: her eldest daughter also has skin and uterine leiomyomas with a similar onset; her son has multiple skin leiomyomas and in addition was diagnosed with metastatic papillary renal cell cancer at the age of 50 years; the two youngest daughters are unaffected. DNA sequencing in all the affected individuals disclosed a heterozygous G-->C substitution at nucleotide 173 of the fumarate hydratase gene, that converts an arginine residue (CGA) to proline (CCA). This missense mutation has not been reported previously and is designated R58P. Interestingly, the clinically asymptomatic 20-year-old son of the individual with renal cancer was also found to be heterozygous for R58P. It is likely that he will develop skin leiomyomas in the future but the risk of renal cancer is difficult to predict. Nevertheless, detection of this mutation has important implications for screening and genetic counselling in this and other family members.     

Cutaneous leiomyosarcoma with myxoid alteration arising in a setting of multiple cutaneous smooth muscle neoplasms

Background:  Cutaneous leiomyomas and leiomyosarcomas are rare tumors that originate from the arrector muscle of hair follicles or the smooth muscle of blood vessels.
Case report:  A 74-year-old male presented with a single, erythematous nodule on the left upper arm. This lesion developed within the excision scar of a piloleiomyoma that had been excised 3 years ago. Additionally, physical examination revealed a tender nodule on the right ear.
Results:  Histological examination showed a cutaneous leiomyosarcoma with myxoid alteration on the upper arm and an angioleiomyoma on the right ear.
Conclusion:  Myxoid leiomyosarcomas have exclusively been reported in the uterus and gastrointestinal tract, but not in the skin. Here, we describe a case of cutaneous leiomyosarcoma with myxoid alteration that developed in the excision scar of a piloleiomyoma and was accompanied by a cutaneous angioleiomyoma in a different location.     

Familial leiomyomatosis cutis et uteri

A 45-year-old woman presented with multiple, small, asymptomatic, hyperpigmented to skin-colored, smooth, dermal papules on the right temple as well as with uterine fibroids. She has a family history of uterine fibroids and cutaneous leiomyomas. An autosomal dominant disorder of multiple cutaneous leiomyomas and uterine fibroids (Reed syndrome) has been localized to a gene on chromosome 1q42.3-43. This gene encodes fumarate hydratase, which is an enzyme in the Kreb cycle, that acts as a tumor suppressor in this familial disorder. A subset of people may be at risk for papillary renal cell carcinoma.     

Multiple Cutaneous and Uterine Leiomyomas Associated with Gastric Gist

Background

There are a number of reports documenting familial cases of leiomyomatosis cutis associated with uterine leiomyomata. However, to our knowledge, the association of gastrointestinal stromal tumour (GIST) with this entity has not as yet been reported. We report an interesting case of cutaneous leiomyomatosis, metachronous uterine leiomyomata, and a gastric GIST in a 43-year-old woman.

Observation

The patient had previously undergone two separate uterine myomectomies at ages 25 and 26 years, respectively, followed by a hysterectomy at 27 years. At 36 years she underwent partial gastrectomy for excision of GIST and this was followed by the development of extensive, symptomatic cutaneous leiomyomata at 43 years. In the report, we have documented histological, immunohistochemical and clinical observations and furthermore report on the therapeutic measures undertaken.

Conclusion

We report an interesting association of cutaneous leiomyomatosis, uterine leiomyomas and GIST.     

Familial cutaneous and uterine leiomyomas: case report

Cutaneous leiomyomas are rare, benign tumors arising from the arrectores pilorum muscles of the skin, the tunica dartos of the scrotum, muscles of the areola of the nipple, and vulvar or vascular smooth muscles. Multiple cutaneous leiomyomas originate from the arrectores pilorum muscles of the skin (piloleiomyomata cutis). Occasionally, they seem hereditary and may be associated with uterine myomas. We present a family in which the mother and 4 of her 6 daughters had uterine myomas. All sisters had to undergo hysterectomy before the age of 40, and three of them had multiple cutaneous leiomyomas simultaneously. Our observations support the suggestion that this kind of leiomyomas is a disorder with autosomal dominant inheritance with incomplete gene penetration. Moreover, the data indicate the necessity of periodical examinations to rule out the presence of uterine myomas not only in cutaneous leiomyoma patients, but also in other women in a given family.     

Cutaneous sclerosing extramedullary hematopoietic tumor in chronic myelogenous leukemia

BACKGROUND: Extramedullary hematopoiesis is a well-documented manifestation of chronic myeloproliferative disorders, most commonly seen in chronic idiopathic myelofibrosis (agnogenic myeloid metaplasia), but rarely in chronic myelogenous leukemia. It typically occurs in the spleen and liver, but has also been described in skin. Microscopically, foci of extramedullary hematopoiesis consist of erythroid and myeloid precursors intermixed with megakaryocytes. The megakaryocytes may elaborate fibrogenic cytokines, which induce proliferation of fibroblasts. The term 'sclerosing extramedullary hematopoietic tumor' has been applied to this latter entity and its resemblance to a fibrohistiocytic neoplasm has been noted. METHODS: We report the case of a 66-year-old man, whose cutaneous sclerosing extramedullary hematopoietic tumor preceded the diagnosis of chronic myelogenous leukemia.     

Two cases of type 2 segmental manifestation in a family with cutaneous leiomyomatosis

Two types of segmental manifestation have been differentiated in autosomal dominant skin disorders. Type 1 reflects heterozygosity for the underlying mutation and the severity of lesions is similar to that observed in the nonmosaic phenotype. Type 2 reflects loss of heterozygosity and the segmental involvement is characterized by a more pronounced manifestation superimposed on the ordinary phenotype. We here describe an unusual familial occurrence of type 2 segmental manifestation of cutaneous leiomyomatosis. The proposita, a 37-year-old woman with a history of multiple uterine leiomyoma, showed multiple agminated firm, pale-red papules arranged in an 8 x 20 cm triangular area on her right chest. A few similar isolated lesions were found to be scattered all over her body. Her 70-year-old mother reported likewise a history of multiple uterine myoma and showed an accumulation of leiomyomas in a band-like area extending from her left chest to the extensor surface of her left forearm. Some isolated nonsegmental lesions were found in other areas of her body. In 1955, one lesion had been surgically removed and histopathological examination showed features of leiomyoma. Moreover, the family history revealed cutaneous leimyomatosis in the proposita's grandmother and in one aunt. Most likely, this familial occurrence of a segmental type 2 manifestation of cutaneous leiomyomatosis in two generations resulted from postzygotic loss of heterozygosity at an early developmental stage. We hypothesize that the underlying gene locus is particularly prone to mitotic recombination or other postzygotic mutational events resulting in loss of the corresponding wild-type allele.     

Piodermia gangrenosa asociada a leucemia linfocítica crónica

—Pyoderma gangrenosum is an ulcerative disease that often occurs in association with a systemic disease and hematologic neoplasms. Its association with chronic lymphocytic leukemia is unusual.We report the case of a 72-year-old man who presented with cutaneous ulcers on legs of four month duration, and afterwords was diagnosed of chronic lymphocytic leukemia. The patient was treated with cyclosporin, with total response of his cutaneous lesions.     

The syndrome of hereditary leiomyomatosis and renal cell cancer (HLRCC): The clinical features of an individual with a fumarate hydratase gene mutation

A 55-year-old woman presented with multiple cutaneous leiomyomas and multiple uterine leiomyomas (fibroids). The clinical diagnosis of the autosomal dominant hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome was confirmed by identification of a fumarate hydratase gene mutation. This case highlights the need to consider the possibility of renal and uterine cancer in members of cutaneous leiomyomatosis families.     

Treatment of three hereditary leiomyomatosis patients with cryotherapy

Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is an autosomal dominant disorder characterized by cutaneous leiomyomas (CLM), uterine leiomyomas, and the increased risk of renal cell carcinoma. Piloleiomyomas develop from the arrectorpili muscle and are usually painful. For 22% of the affected patients, the pain is reported to impair their life quality. Since there are few case reports about cryotherapy for cutaneous leiomyomas in the literature, we have decided to present three patients who had painful cutaneous leiomyomas treated with cryotherapy.     

Multiple cutaneous leiomyomas leading to discovery of novel splice mutation in the fumarate hydratase gene associated with HLRCC

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant condition, which manifests as cutaneous leiomyomas (CL), uterine fibroids and renal cell cancer (RCC). We describe the case of a 53‐year‐old woman who presented with multiple CL with a novel heterozygous canonical splice site mutation in intron 9 of the fumarate hydratase (FH) gene IVS 9–1 G>C ( NM_000143.3 :c 1391–1 G>C) that was not detected on initial screening of a mutation hotspot but was picked up on sequencing the remaining exons and splice site junctions. This report highlights the importance of clinical suspicion in the diagnosis of HLRCC in the absence of a family or personal history of cancer and despite initial genetic testing being negative.     

Imatinib-induced sweet syndrome in a patient with chronic myeloid leukemia

BACKGROUND: Imatinib mesylate has become one of the main chemotherapeutic agents currently used to treat patients with chronic myeloid leukemia (CML). Although cutaneous reactions to this drug have been documented before, this is the first time that Sweet syndrome has been reported with its use. OBSERVATIONS: We report a case of Sweet syndrome secondary to the administration of imatinib to treat CML. On 2 separate occasions, a 53-year-old African American woman with CML developed neutrophilic dermatosis consistent with Sweet syndrome after chemotherapy with imatinib. CONCLUSION: Greater awareness of the adverse effects of imatinib and the characterization of its cutaneous adverse effects will lead to improved surveillance for and treatment of those adverse effects.     

Atypical pilar leiomyomatosis: an unusual presentation of multiple atypical cutaneous leiomyomas

Cutaneous leiomyomas are relatively common benign smooth muscle tumors that may arise as solitary or multiple lesions. Rare forms with cytologic atypia, and features similar to symplastic leiomyomas of the uterus, have been described. We report a case of multiple cutaneous atypical leiomyomas occurring in a 43‐year‐old man with long history of lesions of the right lower leg and a family history of leiomyomatosis. Twenty of the lesions were excised due to pain and were examined histopathologically. All the lesions exhibited features described in atypical leiomyomas of the skin including increased cellularity, nuclear atypia and pleomorphism, and low mitotic activity. The biologic potential of cutaneous atypical leiomyomas is uncertain. Only a few case reports exist in the literature with the majority occurring as solitary lesions. Most of the reported atypical leiomyomas have behaved in a benign fashion. However, a rare account of transformation to leiomyosarcoma emphasizes the need for long‐term follow up of these patients. Herein, we describe a case of multiple atypical cutaneous leiomyomas arising in the setting of familial leiomyomatosis.     

Multiple cutaneous and uterine leiomyomatosis (Reed's syndrome)

A 51-year-old woman with a history of uterine fibroids status post myomectomy and hysterectomy presented for evaluation and treatment of intermittently painful papules of the left shoulder. Histopathologic examination showed a proliferation of smooth muscle fascicles consistent with the diagnosis of cutaneous leiomyomas. Genetic sequencing demonstrated a novel mutation in the fumarate hydratase gene that confirmed the diagnosis of Reed's syndrome. A subset of individuals with Reed's syndrome is predisposed to develop a papillary renal-cell carcinoma, so appropriate radiologic examinations should be performed. Treatment of the pain caused by cutaneous leiomyomas includes the use of nifedipine, nitroglycerine, phenoxybenzamine, surgical excision, and carbon dioxide laser ablation.     

Cutaneous xanthomas associated with chronic myelomonocytic leukemia

Monocytic leukemia may be associated with specific cutaneous changes in about a third of all cases, most characteristically the plum-colored nodule. Nonspecific cutaneous xanthomas have occasionally been reported with a variety of leukemias, mostly in the pediatric literature, but the first report (to our knowledge) of acute myelomonocytic leukemia presenting with specific cutaneous xanthomatous lesions appeared in 1982. Herein is reported a case of chronic myelomonocytic leukemia presenting with a papular histiocytic eruption, and later showing striking cutaneous xanthomas, together with autopsy findings. Physicians should be aware of this rare but important association.     

Actinic granuloma occurring in an unusual association with cutaneous B-cell chronic lymphocytic leukemia

Granulomatous cutaneous reactions are well described in association with T-cell non-Hodgkin lymphoma and Hodgkin lymphoma, but are rarely seen in association with B-cell non-Hodgkin lymphoma or leukemia. We report a case of a 65-year-old woman with B-cell chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who presented with multiple, tender, firm pink papules on the face, upper trunk and upper extremities 6 years after diagnosis of CLL. Biopsy revealed both palisading granulomatous dermatitis consistent with actinic granuloma and a dense perivascular lymphocytic infiltrate consistent with the patient's known history of leukemia. This is an unusual manifestation of cutaneous B-cell CLL that is rarely seen.     

Clinical features of multiple cutaneous and uterine leiomyomatosis: an underdiagnosed tumor syndrome

OBJECTIVE: To investigate the clinical features of the multiple cutaneous and uterine leiomyomatosis (MCUL) syndrome, including the hereditary leiomyomatosis and renal cell cancer syndrome. DESIGN: A case series of patients with multiple skin leiomyomas solicited via a circular letter to dermatologists. SETTING: Research institute. PATIENTS: A total of 108 affected individuals, including 46 probands and 62 affected relatives. MAIN OUTCOME MEASURES: The proportion of probands with underlying fumarate hydratase (FH) mutations, the penetrance of FH mutations, and clinicopathologic features of MCUL. RESULTS: Forty-one (89%) of 46 probands with multiple skin leiomyomas had evidence of germline FH mutations, which were highly penetrant. All 26 male mutation carriers had skin leiomyomas. Of 67 women with FH mutations, 46 (69%) had both skin and uterine leiomyomas; 10 (15%) had only skin leiomyomas; 5 (7%) had only uterine leiomyomas; and 6 (9%) were clinically unaffected. Patients presented with skin leiomyomas at a mean age of 24 years and had a mean of 25 lesions. Forty-one individuals (89%) reported painful lesions, particularly in response to cold or trauma. Fibroids were histologically unremarkable, highly symptomatic, and associated with a high risk of early hysterectomy. One individual had a very aggressive collecting duct renal cancer. The G354R FH mutation predisposed patients to uterine fibroids without skin leiomyomas (P = .03). Many patients with skin leiomyomas had not previously presented for medical attention. Fibroids were rarely recognized as cases of MCUL. CONCLUSIONS: Highly penetrant FH mutations underlie MCUL. Increased clinical awareness is important because of the associated risk of severe uterine fibroids and, in some cases, aggressive renal cancer.     

Extramedullary acute leukemia developing in a pre‐existing osteoma cutis

Primary osteoma cutis (cutaneous ossification) is an uncommon disease in which there is bone formation within the skin in the absence of a demonstrable pre‐existing condition. Osteoma cutis is a chronic and benign condition. We report a case of a 45‐year‐old man who developed extramedullary acute leukemia with a myeloid immunophenotype (myeloid sarcoma) with its initial presentation within an isolated pre‐existing osteoma cutis in the post‐auricular scalp without evidence of systemic acute leukemia or chronic myeloid stem cell disorders. The tumor was surgically excised without complications. Four months later, acute leukemia recurred in the contralateral posterior mandible and showed an immunophenotype consistent with acute lymphoblastic leukemia/lymphoma. The patient now has been treated by standard protocols for acute leukemia. The diagnosis of an extramedullary acute leukemia is challenging because of its inconsistent clinical and histopathologic presentations. Extramedullary acute leukemia developing in a pre‐existing osteoma cutis is very unusual and has not been previously reported in the literature.