A High-Grade Primary Leiomyosarcoma of the Bladder in a Survivor of Retinoblastoma.
Retinoblastoma Retinoblastoma Definition
Retinoblastoma is a malignant tumor of the retina that occurs predominantly in young children.
The eye has three layers, the sclera, the choroid, and the retina. is a rare childhood tumor with an incidence of 1 per 20 000 live births. It may be familial or sporadic in origin. Familial cases show an autosomal dominant inheritance Autosomal dominant inheritance
A pattern of inheritance in which a trait will be expressed if the gene is inherited from either parent.
Mentioned in: Creutzfeldt-Jakob Disease pattern and are usually bilateral and multifocal multifocal /mul·ti·fo·cal/ (mul?te-fo´k'l) arising from or pertaining to many foci.
Relating to or arising from many foci. . 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 Rb1 gene located at chromosome 13q14. Study of the Rb1 gene shows mutation at both alleles. 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 her·i·ta·ble
1. Capable of being passed from one generation to the next; hereditary.
2. Capable of inheriting or taking by inheritance. 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. Osteosarcoma osteosarcoma /os·teo·sar·co·ma/ (os?te-o-sahr-ko´mah) a malignant primary neoplasm of bone composed of a malignant connective tissue stroma with evidence of malignant osteoid, bone, or cartilage formation; it is subclassified as 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 maxilla /max·il·la/ (mak-sil´ah) pl. maxil´las, maxil´lae [L.] the irregularly shaped bone that with its fellow forms the upper jaw. max´illary
n. pl. . Only 2 visceral leiomyosarcomas have been described, one each in the liver and bladder. 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 enucleation /enu·cle·a·tion/ (e-noo?kle-a´shun) removal of an organ or other mass intact from its supporting tissues, as of the eyeball from the orbit.
Surgical removal of the eyeball. , 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.
REPORT OF A CASE
A 49-year-old woman presented with a 1-week history of left flank pain and hematuria hematuria
Blood in the urine. It usually indicates injury or disease of the kidney or another structure of the urinary system or possibly, in males, the reproductive system. It may result from infection, inflammation, tumours, kidney stones, or other disorders. . Initial evaluation with a non-contrast-enhanced abdominal computed tomography scan Computed tomography scan (CT scan)
A specialized type of x-ray imaging that uses highly focused and relatively low energy radiation to produce detailed two-dimensional images of soft tissue structures, particularly the brain. 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 syncope
Effect of temporary impairment of blood circulation to a part of the body. It is often used as a synonym for fainting, which is loss of consciousness due to inadequate blood flow to the brain. 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 pedunculated (pdung´ky bladder tumor arising from the left side of the bladder near the dome was seen on flexible cystoscopy Cystoscopy Definition
Cystoscopy (cystourethroscopy) is a diagnostic procedure that is used to look at the bladder (lower urinary tract), collect urine samples, and examine the prostate gland. . A biopsy of the tumor revealed a high-grade leiomyosarcoma. The patients 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 exenteration /ex·en·ter·a·tion/ (ek-sen?ter-a´shun)
1. surgical removal of the inner organs; evisceration.
2. in ophthalmology, removal of the entire contents of the orbit. (radical cystectomy, hysterectomy, and bilateral salpingo-oophorectomy) and ileal ileal /il·e·al/ (il´e-ahl) pertaining to the ileum.
Of or relating to the ileum.
pertaining to the ileum. 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.
MATERIALS AND METHODS
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 [micro]m 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 D1 (Novocastra Laboratories Ltd, Newcastle upon Tyne Newcastle upon Tyne, city (1991 pop. 199,064) and metropolitan district, NE England, on the Tyne River. The city is an important shipping and trade center. The famous coal-shipping industry began in the 13th cent. , UK), smooth muscle actin, and desmin (Dako) were used. Immunostaining was done with the avidin-biotin-peroxidase kit (Ventana Medical Systems, Tucson, Ariz), according to the manufacturer's specifications. The slides were counterstained with hematoxylin hematoxylin /he·ma·tox·y·lin/ (he?mah-tok´si-lin) an acid coloring matter from the heartwood of Haematoxylon campechianum; used as a histologic stain and also as an indicator. . 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 neoplastic /neo·plas·tic/ (ne?o-plas´tik)
1. pertaining to a neoplasm.
2. pertaining to neoplasia.
pertaining to neoplasia or a neoplasm. 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.
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 whorled
Having, arranged in, or forming whorls or a whorl. 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 myometrium /myo·me·tri·um/ (-me´tre-um) the tunica muscularis of the uterus.myome´trial
The muscular wall of the uterus. , 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.
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 fascicular /fas·cic·u·lar/ (fah-sik´u-lar)
1. pertaining to a fasciculus.
fas·cic·u·lar or fas·cic·u·late or fas·cic·u·lat·ed
adj. growth pattern (Figure 2, A). The tumor cells had elongated blunt-ended nuclei and acidophilic acidophilic /ac·i·do·phil·ic/ (as?i-do-fil´ik)
1. easily stained with acid dyes.
2. growing best on acid media. fibrillary fi·bril
1. A small slender fiber or filament.
2. Anatomy Any threadlike fiber or filament, such as a myofibril or neurofibril, that is a constituent of a cell or larger structure. cytoplasm. There was marked nuclear pleomorphism pleomorphism /pleo·mor·phism/ (-mor´fizm) the occurrence of various distinct forms by a single organism or within a species.pleomor´phicpleomor´phous
1. 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 overlying
suffocation of piglets by the sow. The piglets may be weak from illness or malnutrition, the sow may be clumsy or ill, the pen may be inadequate in size or poorly designed so that piglets cannot escape. normal urothelial cells were positive for pRb (Figure 2, D, insert). The results of staining for p53 and cyclin D1 were negative (data not shown).
No tumor was detected in the right and left obturator obturator /ob·tu·ra·tor/ (ob´tu-rat?er) a disk or plate, natural or artificial, that closes an opening.
1. 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. 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 cyclophosphamide /cy·clo·phos·pha·mide/ (-fos´fah-mid) a cytotoxic alkylating agent of the nitrogen mustard group; used as an antineoplastic, as an immunosuppressant to prevent transplant rejection, and to treat some diseases treatment, supporting the theory that a mutation of the second Rb1 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 al 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 acrolein /acro·le·in/ (ak-ro´le-in) a volatile, highly toxic liquid, produced industrially and also one of the degradation products of cyclophosphamide. , 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 vesical /ves·i·cal/ (ves´i-k'l) pertaining to the urinary bladder. Cf. cystic.
pertaining to or emanating from the urinary bladder. 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.[9,10]
The p53 gene is a tumor suppressor gene tumor suppressor gene
A gene that suppresses cellular proliferation. When inherited in a mutated state, it is associated with the development of various cancers, including most familial cancers. Also called antioncogene. encoding a 53-kd nuclear phosphoprotein phosphoprotein /phos·pho·pro·tein/ (-pro´ten) a conjugated protein in which phosphoric acid is esterified with a hydroxy amino acid.
n. . 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, 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 110-kd 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 phosphorylation, chemical process in which a phosphate group is added to an organic molecule. In living cells phosphorylation is associated with respiration, which takes place in the cell's mitochondria, and photosynthesis, which takes place in the chloroplasts. of pRb by the cyclincyclin-dependent kinase complex relieves the block on E2F proteins, which are then able to transactivate trans·ac·ti·vate
tr.v. trans·ac·ti·vat·ed, trans·ac·ti·vat·ing, trans·ac·ti·vates
To stimulate (a host cell) to replicate the genetic components of a virus. Used of a viral protein. 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 A cyclin-dependent kinase complex (abbreviated cdkc, also called cyclin-CDK) is a protein complex formed by the association of cyclin with cyclin-dependent kinase. These complexes are able to phosphorylate other compounds under consumption of ATP, and are thereby involved in , 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 and sarcomas, In one study, as many as 90% of leiomyosarcoma had abnormalities of pRb and p16 expression. 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 cohen
(Hebrew: “priest”) Jewish priest descended from Zadok (a descendant of Aaron), priest at the First Temple of Jerusalem. The biblical priesthood was hereditary and male. et al. 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 UMMS is ranked fourth in primary care education among the nation’s 125 medical schools in the 2006 U.S.News & World Report annual guide, “America’s Best Graduate Schools”. UMMS is also a major center for research. , Worcester, Mass. We thank Mr Lou Savas (Department of Pathology, University of Massachusetts Medical School) for his assistance with immunohistochemistry and photo image preparation.
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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: email@example.com).