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Retinoblastoma is a cancer of the retina. It is caused by a mutation in the Rb-1 protein. It occurs mostly in younger children and accounts for about 3% of the cancers occurring in children younger than 15 years. The estimated annual incidence is approximately 4 per million children . more...

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The tumor may begin in one or both eyes. Retinoblastoma is usually confined to the eye but can spread to the brain via the optic nerve.


Retinoblastoma may be hereditary (genetically inherited) or nonhereditary. The hereditary form may be in one or both eyes, and generally affects younger children. Retinoblastoma occurring in only one eye is often not hereditary and is more prevalent in older children. When the disease occurs in both eyes, it is always hereditary. Because of the hereditary factor, patients and their brothers and sisters should have periodic examinations, including genetic counseling, to determine their risk for developing the disease.

A statistical study by Dr Alfred G. Knudson in 1971 led to a hypothesis (later known as the Knudson hypothesis) about why some retinablastomas are hereditary and others occur by chance. This hypothesis led to the first identification of a tumor suppressor gene by a team led by Dr Thaddeus P. Dryja in 1986. Knudson won the 1998 Albert Lasker Medical Research Award for this work.

Hereditary retinoblastoma is caused by an inherited mutation in a single copy of the Rb1 gene. The remaining functional copy prevents most retinal cells from becoming cancerous. However, one or more cells in the retina are likely to undergo a spontaneous loss of this functional copy, causing those cells to transform into cancer. This loss of the second copy of Rb1 is termed loss of heterozygosity, a frequent event in cancer for which retinoblastoma is the canonical example.


The patient's choice of treatment depends on the extent of the disease within and beyond the eye. Smaller tumors can be removed with laser surgery, thermo-, or cryotherapy. Larger tumors may require enucleation.

Genetic testing can identify the mutation that lead to the development of retinoblastoma. Testing in unilateral cases can identify the 15% of unilateral cases with a germline mutation, indicating risk in future children. Testing amniotic cells in an at-risk pregnancy can identify a fetus with the mutation, which can then be delivered early before retinal cells have fully developed and before tumors arise. This early treatment can lead to a fully sighted bilaterally affected patient.


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A high-grade primary leiomyosarcoma of the bladder in a survivor of retinoblastoma
From Archives of Pathology & Laboratory Medicine, 9/1/01 by Liang, Sharon X

Second nonocular malignancies develop with increased incidence in patients with hereditary retinoblastoma. Osteosarcoma is by far the most common type with an incidence of up to 50%, followed by soft tissue sarcomas. Visceral leiomyosarcoma is extremely rare and only 2 cases have been reported in the past 2 decades, one in the liver and another one in the urinary bladder, both of which developed after cyclophosphamide therapy. Here we report a case of vesical leiomyosarcoma that was diagnosed in a 49-year-old woman 47 years after the diagnosis of a hereditary retinoblastoma. The patient's retinoblastoma was treated with unilateral enucleation without adjuvant radiation or chemotherapy. We believe that this is the first report of vesical leiomyosarcoma occurring in a patient with retinoblastoma without a prior history of radiation or chemotherapy. This report is significant not only because of the rarity of vesical leiomyosarcoma as a second nonocular tumor in retinoblastoma patients, but also because of the infrequency of vesical leiomyosarcoma in general. We also investigated the potential molecular pathogenesis of the leiomyosarcoma.

(Arch Pathol Lab Med. 2001;125:1231-1234)

Retinoblastoma is a rare childhood tumor with an incidence of 1 per 20 000 live births.1 It may be familial or sporadic in origin. Familial cases show an autosomal dominant inheritance pattern and are usually bilateral and multifocal. The majority of retinoblastomas, however, are sporadic and are almost exclusively unilateral and unifocal. The occurrence of the tumor, in its familial and sporadic form, is attributable to mutation of the Rbl gene located at chromosome 13q14.2 Study of the Rbl gene shows mutation at both alleles.3 The familial form is associated with a germ line mutation of Rb1. During the development of the retinoblastoma, a second somatic mutation occurs. In the sporadic form, both copies of Rb1 undergo somatic mutation.

The propensity for survivors of heritable retinoblastoma to develop second nonocular malignancies is well known.4,5 It was initially reported that second tumors occur within the field of irradiation. Subsequently, it was demonstrated that second tumors could also develop outside the field of radiation or after chemotherapy. The major controversy, however, is the actual magnitude of the risk of second tumors among survivors of retinoblastoma.

A wide variety of second malignancies have been reported.6 Osteosarcoma is most commonly reported, with an incidence of up to 50%. Fibrosarcomas account for about 20%. Leiomyosarcomas have rarely been reported. They have been described in soft tissues adjacent to the orbit, femur, and maxilla. Only 2 visceral leiomyosarcomas have been described, one each in the liver and bladder.8 The leiomyosarcomas occurred in patients with history of radiation and/or chemotherapy as primary or adjuvant therapy for their retinoblastoma. However, there have been no reported cases of leiomyosarcoma of the urinary bladder in a survivor of retinoblastoma who had no history of radiation or chemotherapy. We report the case of a 49-year-old woman with a family history of retinoblastoma who developed a unilateral retinoblastoma at age 2 and was treated with enucleation, without adjuvant radiation or chemotherapy. We believe that this is the first occurrence of a visceral leiomyosarcoma in a patient with retinoblastoma treated without any adjuvant therapy and is only the second case of a bladder leiomyosarcoma reported in a patient with retinoblastoma.


A 49-year-old woman presented with a 1-week history of left flank pain and hematuria. Initial evaluation with a non-contrastenhanced abdominal computed tomography scan showed a stone measuring 2 to 3 mm in diameter in the central portion of the left kidney and a second stone at the left ureterovesical junction. Over the next few days, the woman passed a stone and improved with oral pain medication. Two to 3 weeks later, gross hematuria recurred, with clots, and the patient suffered an episode of syncope because of a low hematocrit (0.20 [20%]). Repeated abdominal computed tomography scan with contrast enhancement revealed a large filling defect in the lumen of the bladder (Figure 1, arrowhead). A large pedunculated bladder tumor arising from the left side of the bladder near the dome was seen on flexible cystoscopy. A biopsy of the tumor revealed a high-grade leiomyosarcoma. The patient's past history revealed that she had developed a unilateral retinoblastoma that was treated with enucleation without adjuvant therapy at age 2. Her family history was significant for retinoblastoma in one sibling.

The results of a bone scan for metastases were negative. The patient then underwent anterior exenteration (radical cystectomy, hysterectomy, and bilateral salpingo-oophorectomy) and deal loop urinary diversion. She was followed postoperatively without any adjuvant therapy. Unfortunately, 18 months after the initial diagnosis of leiomyosarcoma of the bladder, she developed multiple lung metastases. She is currently receiving combination chemotherapy with cisplatinum and doxorubicin.


A resection specimen from the radical cystectomy, hysterectomy, and bilateral salpingo-oophorectomy was received in the Pathology Department. The lumen of the bladder was inflated with 10% buffered formalin, and the entire specimen was fixed before dissection. Tissue sections were embedded in paraffin and stained with hematoxylin-eosin. For immunohistochemical staining, formalin-fixed, paraffin-embedded tissue sections were cut at 5 wm and treated with 0.1 mol/L citrate, pH 6.0, in an 800-W microwave oven for 15 minutes for antigen retrieval before immunostaining. Primary antibodies to pRb (Dako, Carpinteria, Calif), p53 (Oncogene Research Products, Cambridge, Mass: a mixture of Ab-2 and Ab-6), cyclin Dl (Novocastra Laboratories Ltd, Newcastle upon Tyne, UK), smooth muscle actin, and desmin (Dako) were used. Immunostaining was done with the avidinbiotin-peroxidase kit (Ventana Medical Systems, Tucson, Ariz), according to the manufacturer's specifications. The slides were counterstained with hematoxylin. The negative controls were the same tissue sections processed identically for immunostaining process except for the omission of the primary antibody. The positive controls for p53 and pRb were a cancer and a normal epithelium that were known to contain a p53 mutation and normal pRb, respectively.

Immunoreactivity for p53 and pRb was determined by positive nuclear staining. The final evaluation of staining was based on published criteria.9,10 For p53, negative staining was defined as an absence of staining in all nuclei. For pRb, normal staining was defined as staining of neoplastic nuclei throughout the tumor, whereas abnormal staining was defined as absent staining or staining in a scattered, or focal distribution in the tumor. The staining was defined as inconclusive if both neoplastic and normal urothelial nuclei did not stain or stained only weakly.


Gross Description

The resection specimen consisted of a bladder, a uterus with cervix, bilateral ovaries, and bilateral fallopian tubes. A tan-yellow firm mass measuring 9.0 x 6.5 X 6.0 cm was present in the left lower anterior wall of the bladder, near the dome. The tumor was exophytic, polypoid, and pedunculated, with a 1.5-cm stalk. The cut surface of the tumor was tan-white and fleshy with a whorled appearance. Foci of hemorrhage and necrosis were present. The bladder mucosa was unremarkable.

Dissection of the uterus, cervix, ovaries, and fallopian tubes showed multiple well-circumscribed, tan-pink, firm leiomyomas in the myometrium, ranging in size from 0.7 cm to 2.0 cm in greatest dimension. The remaining uterus, cervix, ovaries, and fallopian tubes were otherwise unremarkable.

Microscopic Description

Sections of the bladder showed that the tumor originated in the muscularis propria and penetrated the bladder wall in the area of the stalk. The tumor exhibited a fascicular growth pattern (Figure 2, A). The tumor cells had elongated blunt-ended nuclei and acidophilic fibrillary cytoplasm. There was marked nuclear pleomorphism with atypia (Figure 2, B) and a high mitotic rate (more than 22 mitotic figures per 10 high-power field). Focal necrosis was present, and vascular invasion was not seen. Immunohistochemical studies showed that the cells expressed the smooth muscle actin (Figure 2, C) and desmin (data not shown) characteristic of leiomyosarcoma. Most of tumor cells were negative for pRb with scattered weak nuclear staining (Figure 2, D). Overlying normal urothelial cells were positive for pRb (Figure 2, D, insert). The results of staining for p53 and cyclin Dl were negative (data not shown).

No tumor was detected in the right and left obturator lymph nodes. Only leiomyoma was found in the myometrium of the uterus. No atypia or mitosis was noted.


Second nonocular primary tumors are known to develop in survivors of hereditary retinoblastoma .1 The incidence increases with time, and the development of these tumors is related to the loss of tumor suppressor activity resulting from alterations in the Rb1 gene because of radiation, hereditary mutations, or other causes.

Leiomyosarcoma as a second tumor has rarely been described in survivors of retinoblastoma. Most of these cases have had a soft tissue origin. Liver and bladder are the only 2 visceral organs in which leiomyosarcoma has developed in patients with retinoblastoma.7,8 Furthermore, all of the reported cases have been associated with radiation or cyclophosphamide treatment, supporting the theory that a mutation of the second Rbl locus is enhanced by radiation or chemotherapy.

Leiomyosarcoma of the bladder is a rare tumor, accounting for less than 0.5% of all primary bladder malignancies, and is associated with cyclophosphamide treatment. The latency between the therapy and onset of the leiomyosarcoma varies in different reports. Thrasher et all reported 2 cases of leiomyosarcoma occurring 7 and 11 years after cyclophosphamide treatment for lupus nephritis. There are also reports of leiomyosarcoma developing 7 and 13 years after cyclophosphamide therapy for Hodgkin disease and Wegener granulomatosis. The first reported case of bladder leiomyosarcoma in a patient with retinoblastoma occurred in an 18-year-old adolescent who had been treated with cyclophosphamide therapy over a period of 6 years for retinoblastoma diagnosed 50 days after birth. It is hypothesized that accumulation of acrolein, a metabolite of cyclophosphamide, in the bladder causes hemorrhagic cystitis and increases the risk of bladder cancers, including epithelial and the rare nonepithelial cancers.

To the best of our knowledge, the present report is the first case of primary leiomyosarcoma of the bladder reported in a patient with retinoblastoma who had no history of radiation or chemotherapy. The latency of the onset of the tumor was 47 years. Although the patient had unilateral retinoblastoma, her positive family history makes it highly unlikely that she had sporadic retinoblastoma.

It is not likely that the leiomyosarcoma of the bladder was secondary to a metastasis from a uterine leiomyoma because the uterine tumor was very small and had a bland microscopic appearance and a lack of necrosis and mitosis, whereas the vesical tumor was a large, high-grade lesion with marked pleomorphism and necrosis and numerous mitotic figures.

There is limited information about the molecular pathogenesis of leiomyosarcoma. Several reports have demonstrated abnormalities in the p53 pathway as well as in the Rb-cyclin D pathway in leiomyosarcoma.9,111

The p53 gene is a tumor suppressor gene encoding a 53-kd nuclear phosphoprotein. The phosphoprotein acts as a transcription factor; recognizes specific DNA sequences located adjacent to several different genes; and is intimately involved in the regulation of transcription, DNA repair, and apoptosis. Mutation of p53 leads to accumulation of an abnormal p53 protein that is more resistant to degradation than the wild type protein. Several reports in recent years have described alterations in the p53 gene and/or protein in about 20% of leiomyosarcoma of soft tissue origins.9 However, analysis of p53 protein demonstrated no abnormality in our case, suggesting that the p53 pathway is not a preferred target for molecular abnormalities.

The Rb gene is a tumor suppressor gene encoding a 110kd nuclear phosphoprotein. It is involved in cell cycle control, as it prevents the cell from entering the S phase of the cell cycle by sequestering the E2F family of transcription factors. The phosphorylation of pRb by the cyclin-- cyclin-dependent kinase complex relieves the block on E2F proteins, which are then able to transactivate those genes involved in DNA replication. Recently, p16, the product of the CDKN2/MTS1 gene, has been shown to inhibit the cyclin-dependent kinase complex, thereby mimicking the tumor-suppressing function of pRb. Abnormalities in the p16-cyclin D-Rb pathway, including mutations and deletions of the genes, are very common in human carcinomas 12 and sarcomas.10 In one study, as many as 90% of leiomyosarcoma had abnormalities of pRb and p16 expression.10 In our study, expression of pRb was aberrant in leiomyosarcoma cells but normal in the overlying urothelial cells. This finding is similar to that of Cohen et al.10 Unfortunately, assessment of p16 status in our case was not possible because of a lack of antibody resources for paraffin-embedded tissue sections.

In summary, we have reported a case of primary vesical leiomyosarcoma in a 49-year-old woman with a history of hereditary retinoblastoma. This report illustrates that a prior history of radiation or chemotherapy is not always an identifiable contributing factor in the development of rare visceral leiomyosarcomas as second malignancies in patients with hereditary retinoblastoma. Loss of pRb expression may have played an important role in the pathogenesis of this case.

Financial support of this work was provided by the Department of Pathology, University of Massachusetts Medical School, Worcester, Mass. We thank Mr Lou Savas (Department of Pathology, University of Massachusetts Medical School) for his assistance with immunohistochemistry and photo image preparation.


1. Lueder GT, Smith ME. Retinoblastoma. Semin Diagn Pathol. 1994; 11:104-- 106.

2. Friend SH, Bernards R, Rogelj S, et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986;323:643-646.

3. Knudson AG, Hethcote HkA Brown BW. Mutation and childhood cancer: a probabilistic model for the incidence of retinoblastoma. Proc Natl Acad Sci U S A. 1975;72:5116-5120.

4. Draper GJ, Sanders BM, Kingston JE. Second primary neoplasms in patients with retinoblastoma. Br J Cancer. 1986;53:661-671.

5. Moll AC, Imhof SM, Bouter LM, Tan KE. Second primary tumors in patients with retinoblastoma. A review of the literature. Ophthalmic Genet. 1997;18:2734.

6. Moll AC, Imhof SM, Bouter LM, et al. Second primary tumors in patients with hereditary retinoblastoma: register-based follow-up study, 1945-1994. Int/ Cancer. 1996;67:515-519.

7. Abdelli N, Thiefin G, Diebold MD, Bouche O, Aucouturier IP, Zeitoun P. Primary leiomyosarcoma of the liver 37 years after successful treatment of retinoblastoma. Gastroenterol Clin Biol. 1996;20:502-505.

8. Kawamura J, Sakurai M, Tsukamoto K, Tochigi H. Leiomyosarcoma of the bladder eighteen years after cyclophosphamide therapy for retinoblastoma. Urol Int. 1993;51:49-53.

9. Konomoto T, Fukuda T, Hayashi K, Kumazawa 1, Tsuneyoshi M. Leiomyosarcoma in soft tissue: examination of p53 status and cell proliferating factors in different locations. Hum Pathol. 1998;29:74-81.

10. Cohen JA, Geradts J. Loss of RB and MTSI/CDKN2 (p16) expression in human sarcomas. Hum Pathol. 1997;28:893-898.

11. Thrasher JB, Miller GJ, Wettlaufer JN. Bladder leiomyosarcoma following cyclophosphamide therapy for lupus nephritis. J Urol. 1990;143:119-121.

12. Geradts J, Kratzke RA, Niehans GA, Lincoln CE. Immunohistochemical detection of the cyclin-dependent kinase inhibitor 2/multiple tumor suppressor gene 1 (CDKN2/MTS1) product p161NK4A in archival human solid tumors: correlation with retinoblastoma protein expression. Cancer Res. 1995;55:60066011.

Sharon X. Liang, MD, PhD; Yegappan Lakshmanan, MD; Bruce A. Woda, MD; Zhong Jiang, MD

Accepted for publication March 12, 2001.

From the Department of Pathology (Drs Liang, Woda, and Jiang) and Division of Urology, Department of Surgery (Dr Lakshmanan), University of Massachusetts Medical School, Worcester, Mass.

Reprints: Zhong Jiang, MD, Department of Pathology, University of Massachusetts Medical School, 55 Lake Ave N, Worcester, MA 01655 (e-mail:

Copyright College of American Pathologists Sep 2001
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