Case 6-2006 — A 71-Year-Old Woman with Urinary Incontinence and a Mass in the Bladder
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《新英格兰医药杂志》
Presentation of Case
Dr. Donald S. Kaufman: A 71-year-old woman was referred to this hospital for a second opinion on the management of a malignant tumor of the urinary bladder. Urinary incontinence had developed suddenly, six months earlier. One month after the onset of incontinence, the patient saw her primary care physician, who referred her to an incontinence clinic. An ultrasonographic study of the pelvis was obtained at another hospital, and the patient was told to see her gynecologist. On pelvic examination, the cervix was normal; there was marked thickening along the anterior wall of the vagina and bladder. No discrete pelvic mass was detected. The rectovaginal septum was smooth, and the stool was guaiac-negative. A Papanicolaou smear, an endometrial biopsy, and cytologic examination of the endometrial fluid revealed no abnormalities.
Computed tomographic (CT) scanning of the abdomen and pelvis at the other hospital showed bilateral hydronephrosis and bilateral solid ovarian masses; the mass in the right ovary measured 4.4 cm by 2.5 cm, and the mass in the left ovary measured 5.6 cm by 4.5 cm. In addition, there was an enlarged aortocaval lymph node, 1.4 cm in diameter. The bladder wall was asymmetrically thickened on the anterior, posterior, and left lateral aspects. A repeated pelvic ultrasonographic study showed a heterogeneous myometrium, with a possible fibroid on the left side and solid bilateral adnexal masses.
Cystoscopy with transurethral resection of the tumor in the bladder was performed at the other hospital two weeks before the patient's evaluation at this hospital. The posterior bladder mucosa was thickened and friable. The muscular wall was distorted and effaced by a rigid, infiltrating mass. The ureters were narrowed, and stents were placed during the cystoscopy. An examination of specimens obtained from the resected tumor revealed invasive transitional-cell carcinoma, grade 3 out of 3, with invasion of the muscularis propria.
A radical cystectomy was advised. However, on consultation with a medical oncologist for consideration of preoperative chemotherapy, it was recommended that the primary treatment should be chemotherapy, since the disease was metastatic to the ovaries and possibly to a lymph node. The patient requested a second opinion and was referred to this hospital.
The patient had had breast cancer 22 years earlier; a radical mastectomy had been performed, and four positive lymph nodes were found. She had received chemotherapy with cyclophosphamide, methotrexate, and fluorouracil for one year. There had been no evidence of recurrent disease. A mammogram performed three months before the referral visit to this hospital showed no abnormalities. Three years before this referral visit, the patient's sister had had breast cancer, followed by ovarian cancer six months later. Her mother had had lung cancer, two maternal uncles pancreatic cancer, a maternal aunt myeloma, and her maternal grandmother uterine cancer. The patient and her sister each had two daughters, who were well. Genetic testing of the patient's sister at the time of the sister's diagnosis of ovarian cancer showed that the BRCA2 gene was normal. The BRCA1 gene contained a missense mutation; the testing laboratory noted that this mutation had been seen in two other patients who also had additional, clearly deleterious mutations in the BRCA1 gene. The patient under discussion also had genetic testing when her sister received the diagnosis of ovarian cancer, which revealed the same missense mutation as was identified in her sister.
On physical examination, the patient appeared well, and her vital signs were normal. There was no lymphadenopathy. The left breast was normal, and the right chest wall contained a prosthetic breast implant. The lungs were clear, the heart sounds were normal, and the abdomen was soft, with no masses and no tenderness. There was no edema of the legs. The results of a complete blood count and the levels of electrolytes, calcium, creatinine, urea nitrogen, protein, albumin, globulin, and bilirubin were normal. Magnetic resonance imaging (MRI) of the pelvis showed a solid left adnexal mass, 4.2 cm by 4.8 cm, with invasion into the uterus. The left side of the uterine fundus was infiltrated, and there was a smaller but similarly enhancing right adnexal mass that did not invade the uterus. There was thickening of the wall of the urinary bladder that was most prominent in the dome and along the left lateral wall. CT scanning of the chest showed no abnormalities, and a bone scan showed no evidence of metastasis.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Paula D. Ryan: May we see the radiographic images?
Dr. Mukesh Harisinghani: A CT examination of the abdomen and pelvis (Figure 1A and 1B) showed an aortocaval lymph node, 1.4 cm in diameter, and bilateral hydronephrosis. Within the pelvis, bilateral adnexal masses were seen in the expected location for the ovaries. On referral to this hospital, an MRI examination of the pelvis (Figure 1C) was performed, which showed thickening of the bladder wall and bilateral adnexal masses with areas of mixed signal intensity. On an image obtained after the administration of gadolinium (Figure 1D), the anatomical plane between the uterus and the left adnexal mass was not well delineated, suggesting myometrial invasion by the left adnexal mass.
Figure 1. Radiographic Images of the Abdomen and Pelvis.
Axial CT images of the abdomen obtained after the intravenous administration of contrast material (Panels A and B) show hydronephrosis (Panel A, arrow) and bilateral solid ovarian masses (Panel B, arrows). An axial T2-weighted MRI examination of the pelvis (Panel C) shows left lateral and posterior thickening of the bladder (large arrow); ureteric stents are visible in the bladder (small arrow). An axial image obtained after the administration of gadolinium (Panel D) shows bilateral adnexal masses (arrows); lack of an anatomic plane between the left adnexal mass and uterus indicates invasion of the uterus.
Dr. Ryan: Did you see any disease on the omentum?
Dr. Harisinghani: We saw no omental or hepatic surface implants.
Dr. Ryan: This 71-year-old woman with a history of breast cancer that was lymph-node–positive and that had been treated with a radical mastectomy and chemotherapy had been disease-free for 22 years. She presented with an acute onset of urinary incontinence and was found to have bilateral, solid ovarian masses with possible uterine involvement, bilateral hydronephrosis, a thickened bladder wall, and an enlarged aortocaval lymph node. The findings on examination of a bladder-biopsy specimen were interpreted as showing an invasive transitional-cell carcinoma. Her sister had received diagnoses of both breast and ovarian cancer and was found to have a missense mutation in BRCA1, a mutation that this patient also had.
The main issue of concern in this case is the origin of the carcinoma in this patient. The possible primary sites include the bladder, the cervix or the endometrium, the ovaries, or the breast. The likelihood that this neoplasm originated in the cervix or the endometrium is extremely low, because the cervix appeared normal on pelvic examination, a Papanicolaou smear was normal, and an endometrial biopsy and cytologic examination of endometrial fluid revealed no abnormalities. The patient presented with symptoms referable to the bladder, and a tumor involving the bladder mucosa was discovered at cystoscopy, leading to the obvious suspicion of a primary bladder cancer, which was supported by the pathological interpretation of the biopsy specimen. Is this a likely diagnosis in this case? The greatest risk factor for bladder cancer is smoking.1 Occupational exposure to aromatic amines, such as benzidine and beta-naphthylamine, in the rubber, paint, and dye industries; drugs, including phenacetin-containing analgesics and cyclophosphamide; and chronic urinary tract inflammation also increase the risk of the development of bladder cancer. This patient had none of these risk factors, except for the cyclophosphamide treatment she received for her breast cancer many years earlier. The risk associated with cyclophosphamide is dose-dependent, with an elevated risk occurring at doses of 20 g or more.2 Although gross, painless hematuria is the presenting sign of bladder cancer in 80 to 90 percent of cases, it may occasionally present with urinary urgency, frequency, and dysuria. Of newly diagnosed cases of bladder cancer, approximately 75 percent are superficial; however, at the time of the diagnosis, invasive bladder cancer (20 percent of the cases) or metastatic disease (5 percent) may be found.3 This patient presented with urinary incontinence, which would be a rather unusual initial presenting symptom for bladder cancer.4 This symptom suggests that there is obstruction resulting in overflow incontinence, which is possible, given the presence on imaging of a mass infiltrating the wall of the bladder.
Cystoscopic evaluation in a patient in whom a urothelial tumor is suspected provides diagnostic and staging information, and when hydronephrosis is present, as in this patient, such an evaluation can provide a therapeutic benefit by the placement of stents to relieve the obstruction and to prevent loss of renal function. Biopsy specimens of a suspected urothelial tumor must include samples from the bladder wall so it can be determined whether there is invasion of muscle by the overlying carcinoma.
Despite the interpretation of the bladder-biopsy specimen as indicating transitional-cell carcinoma, the patient's clinical presentation is distinctly unusual for metastatic bladder cancer and, therefore, I am not immediately prepared to accept that conclusion.
The family history is an important consideration in a patient such as this one, who has a personal history of breast cancer and now bilateral ovarian masses. For carriers of both BRCA1 and BRCA2 germ-line mutations, there is an elevated lifetime risk of breast cancer, ovarian cancer, or both.5 The patient and her sister, both of whom had had breast cancer, had the same missense mutation in BRCA1. Although most mutations that cause cancer are nonsense mutations, a missense change may also be deleterious. Various types of evidence may assist one in classifying such variants as deleterious or neutral.6 Because the testing laboratory noted that the mutation had been seen twice in patients who had clearly deleterious mutations in BRCA1, it is less probable that this missense mutation is of functional importance than if it had been seen in isolation in patients with cancer. This observation suggests that the patient and her sister share this missense alteration as a result of their close genetic relationship. Although I believe it is unlikely that the patient had a hereditary risk of ovarian cancer on the basis of the results of her genetic testing, the bilateral adnexal masses require explanation. The radiologic findings suggest that the masses are malignant. It would be rare for bladder cancer to metastasize to the ovaries. The clinical presentation is also somewhat unusual for advanced ovarian cancer, which frequently presents with ascites or peritoneal implants outside the pelvis or with spread to the liver or the pleura. A biopsy of the adnexal mass would be required to document metastatic disease outside the bladder and to determine whether there is a second primary cancer.
Despite this patient's long disease-free interval after the diagnosis of breast cancer 22 years ago, metastatic breast cancer should always be included in the differential diagnosis of a patient with a history of invasive breast cancer, given the persistent natural history of this disease and its heterogeneity among patients. The time course to the appearance of clinically detected metastatic disease can be extremely protracted. The average hazard rate for breast-cancer recurrence between 5 and 12 years after primary therapy, for example, has been calculated at 4.3 percent per year.7 Although the bones, lungs, and liver are the most common sites of spread of distant disease, metastases from breast cancer can be seen in many organs, including the bladder8,9 and the ovaries. Ureteral obstruction caused by breast cancer has been described,10 and in one study, breast cancer was the most common nonpelvic tumor causing ureteral obstruction.10 My interpretation of the clinical presentation in combination with the radiologic findings in this case is that this patient's breast cancer metastasized to both ovaries, as well as to the bladder, the ureters, and the aortocaval lymph nodes.
I would recommend as the first diagnostic procedure a review of the pathological specimen from the transurethral resection performed at the other hospital to determine whether there is agreement on the diagnosis of transitional-cell carcinoma. A critically important diagnostic aid in this type of situation is comparison of the tissue from the original breast cancer, if available, with the biopsy specimen from the metastatic site. However, it is unlikely that tissue obtained from this patient's breast cancer 22 years ago was available. I would also recommend biopsy of one of the adnexal masses; a sample of tissue from an adnexal mass and the bladder specimen should be stained for the estrogen receptor, progesterone receptor, and the HER2/neu protein, since these would assist in the diagnosis and guide medical management.
Dr. Kaufman: When I saw this patient in consultation, my thinking was very similar to that of Dr. Ryan; I believed that this clinical presentation was extremely unusual for a primary bladder cancer and requested the slides from the other hospital for review by the pathology department.
Clinical Diagnosis
Metastatic breast cancer.
Dr. Paula D. Ryan's Diagnosis
Metastatic breast cancer.
Pathological Discussion
Dr. Melinda F. Lerwill: The slides from the other institution of the patient's bladder tumor were reviewed. All of the tissue fragments showed a diffusely infiltrating carcinoma with invasion of the muscularis propria (Figure 2A) and a prominent, sheet-like growth pattern (Figure 2B). Cases of primary transitional-cell carcinoma of the bladder occasionally demonstrate a similar diffuse growth pattern but more typically show nesting or clustering of the tumor cells. The tumor cells in the biopsy specimen from this patient also frequently aligned themselves in linear cords (Figure 2C), a morphologic feature highly characteristic of invasive lobular carcinoma of the breast, but only rarely seen in transitional-cell carcinoma.11 The tumor was composed of a relatively homogeneous population of small round cells with eosinophilic cytoplasm, moderate nuclear atypia, and occasional mitotic figures (Figure 2D). The overlying urothelium was completely benign, without dysplasia or carcinoma in situ. The absence of preinvasive neoplasia coupled with the morphologic features of the tumor was more consistent with a metastatic lesion than with transitional-cell carcinoma. The features were not typical of a tumor of ovarian origin. A diagnosis of metastatic breast carcinoma was made on the basis of the patient's history and the histomorphologic features of the tumor. Slides of the patient's earlier breast carcinoma were not available for comparison, but it was reported to have been an invasive lobular carcinoma.
Figure 2. Biopsy Specimen of the Bladder.
Carcinoma cells diffusely infiltrate the tissue and invade the large smooth-muscle bundles of the muscularis propria (Panel A). The tumor has a sheet-like growth pattern (Panel B) that is unusual for bladder cancer. The tumor cells form linear cords (Panel C), a pattern highly unusual for transitional-cell carcinoma, but characteristic of invasive lobular carcinoma of the breast. The tumor is composed of a relatively homogeneous population of small, round cells with moderate nuclear atypia and occasional mitotic figures (Panel D). The tumor cells show nuclear staining for estrogen-receptor protein (Panel D, inset) (Panels A through D, hematoxylin and eosin; inset, Panel D, immunoperoxidase stain for estrogen receptor).
A panel of immunohistochemical stains was used to confirm the diagnosis. The tumor cells were positive for cytokeratin 7, negative for cytokeratin 20, and positive for estrogen receptor (Figure 2D, inset); they were negative for progesterone receptor and for HER2/neu protein. Although a minority of cases of transitional-cell carcinoma may show a similar staining pattern,12,13 this profile is much more characteristic of tumors of breast origin.12,14 The tumor cells were negative for gross cystic disease fluid protein-15, which in this context would be a fairly specific marker for a tumor of breast origin; however, only approximately 60 percent of breast tumors express this antigen, and a negative result does not rule out a diagnosis of breast carcinoma.15 The immunohistochemical findings were therefore consistent with a diagnosis of metastatic breast carcinoma. A subsequent biopsy of the left ovarian mass also demonstrated metastatic breast carcinoma.
Secondary neoplasms of the bladder account for 2 to 14 percent of all malignant bladder tumors.16 Tumors spread to the bladder most commonly by direct regional spread from local organs, such as the colon, prostate, rectum, and cervix, or as metastases from distant sites, of which stomach, skin (melanoma), lung, and breast are the most common.17 Breast carcinoma metastatic to the bladder is, overall, rare, and it accounts for about 3 percent of secondary bladder neoplasms, usually occurring in association with widespread metastatic disease.17,18 The reported interval from the initial diagnosis to the development of bladder metastases ranges from 7 months to 30 years, with a mean interval of 7.5 years.18 Lobular carcinomas appear to have a stronger association with bladder metastases than the more common ductal subtype of breast carcinoma.18 Lobular carcinomas have a propensity to metastasize to serosal surfaces, the gynecologic tract, and the gastrointestinal tract,19 and perhaps spreading from these adjacent sites accounts for the greater frequency of bladder involvement. Metastatic lobular carcinoma also often occurs as a diffuse thickening of an affected organ, as seen in this case, rather than as discrete tumor nodules.19 The development of bladder metastases has generally been a poor prognostic feature, and most patients die of the disease within two years.18
Dr. Kaufman: The remote breast-cancer history was not prominently discussed by the patient when she came to us for a second opinion on the management of the bladder tumor, and therefore, this diagnosis was apparently not known to the pathologist at the other hospital. Dr. Young's initial review of the pathological slides alerted those of us responsible for her care to the possibility that the patient had metastatic disease involving the urinary bladder from a primary tumor in the breast. This case underscores the importance of our policy of asking for a review of the slides of every patient referred to us for care.
Dr. Robert H. Young (Pathology): The pattern of growth that Dr. Lerwill pointed out in the bladder specimen is so characteristic of breast carcinoma that I immediately thought of a metastatic process. The presence of ovarian masses is an important clinical clue, because breast cancer often spreads to the ovary, whereas bladder cancer rarely does. Understanding the typical patterns of spread of tumors can be as important for the pathologist in making the diagnosis as it is for the clinician in management.
Dr. Kaufman: Dr. McDougal, would the severe urinary incontinence have made you suspect diseases other than bladder cancer?
Dr. W. Scott McDougal (Urology): I think that a presentation such as this would be unusual for a patient with primary bladder cancer. Incontinence would be extremely unusual as an initial presenting symptom. A second reason for suspicion is the observation that the tumor was predominantly submucosal, which would be highly unlikely for a primary transitional-cell carcinoma in the presence of this extensive extravesical spread.
Dr. Kaufman: Because the patient's tumor tested positive for estrogen-receptor protein, treatment with tamoxifen (20 mg daily) was begun three weeks after her initial consultation. Three months later, she reported an improvement in her bladder capacity, with the disappearance of urgency and incontinence and a decrease in nocturia. Abdominal and pelvic CT scans obtained at that time showed marked shrinkage of the pelvic masses. After six months of taking tamoxifen, she reported the complete disappearance of urinary symptoms. CT scans obtained then, however, were unchanged from the earlier studies. Six months after beginning tamoxifen treatment, the patient began chemotherapy with doxorubicin and cyclophosphamide, given every 21 days, for a total of six cycles, followed by single-agent docetaxel for three monthly cycles. She then started taking anastrozole and continues with that to date. Repeated abdominal, pelvic, and thoracic CT scans have shown stable disease without progression, slightly more than three years after the beginning of treatment. Dr. Ryan, what do you think about that treatment plan?
Dr. Ryan: A common strategy for treating symptomatic patients with estrogen-receptor–positive disease is to initiate chemotherapy until the disease is stabilized, then switch to hormonal treatment for maintenance. This decision is based on many factors, including the patient's age and performance status (how the disease affects the patient's ability to perform acts of daily living) and the exact nature of the symptoms from metastatic disease. Because this patient had never received any endocrine therapy and she did not have life-threatening visceral disease, the initiation of antiestrogen therapy is a reasonable plan, and it is the strategy I generally use. If there is progression of the disease or worrisome symptoms, chemotherapy may need to be considered in the course of treatment for metastatic breast cancer.
Anatomical Diagnosis
Infiltrating lobular carcinoma of the breast, metastatic to the urinary bladder and ovaries.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Departments of Medical Oncology (P.D.R., D.S.K.), Radiology (M.H.), and Pathology (M.F.L.), Massachusetts General Hospital; and the Departments of Medicine (P.D.R., D.S.K.), Radiology (M.H.), and Pathology (M.F.L.), Harvard Medical School — both in Boston.
References
Cancer facts and figures 2004. Atlanta: American Cancer Society, 2004.
Travis LB, Curtis RE, Glimelius B, et al. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin's lymphoma. J Natl Cancer Inst 1995;87:524-530.
Herr HW, Shipley WU, Bajorin DF. Cancer of the bladder. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2001:1396-418.
Messing EM. Urothelial tumors of the urinary tract. In: Walsh PC, Retick AB, Vaughan ED, et al., eds. Campbell's urology. 8th ed. Philadelphia: Saunders, 2002:2732-72.
Struewing JP, Hartge P, Wacholder S, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 1997;336:1401-1408.
Goldgar DE, Easton DF, Deffenbaugh AM, et al. Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2. Am J Hum Genet 2004;75:535-544.
Saphner T, Tormey DC, Gray R. Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 1996;14:2738-2746.
Feun LG, Drelichman A, Singhakowinta A, Vaitkevicius VK. Ureteral obstruction secondary to metastatic breast cancer. Cancer 1979;44:1164-1171.
Recloux P, Weiser M, Piccart M, Sculier JP. Ureteral obstruction in patients with breast cancer. Cancer 1988;61:1904-1907.
Zadra JA, Jewett MA, Keresteci AG. Nonoperative urinary diversion for malignant ureteral obstruction. Cancer 1987;60:1353-1357.
Baldwin L, Lee AHS, Al-Talib RK, Theaker JM. Transitional cell carcinoma of the bladder mimicking lobular carcinoma of the breast: a discohesive variant of urothelial carcinoma. Histopathology 2005;46:50-56.
Wang NP, Zee S, Zarbo RJ, Bacchi CE, Gown AM. Coordinate expression of cytokeratins 7 and 20 defines unique subsets of carcinomas. Appl Immunohistochem 1995;3:99-107.
Kaufmann O, Baume H, Dietel M. Detection of oestrogen receptors in non-invasive and invasive transitional cell carcinomas of the urinary bladder using both conventional immunohistochemistry and the tyramide staining amplification (TSA) technique. J Pathol 1998;186:165-168.
Tavassoli FA, Devilee P, eds. Pathology and genetics of tumours of the breast and female genital organs. Vol. 5 of World Health Organization classification of tumours. Lyon, France: IARC Press, 2003.
Lerwill MF. Current practical applications of diagnostic immunohistochemistry in breast pathology. Am J Surg Pathol 2004;28:1076-1091.
Bates AW, Baithun SI. The differential diagnosis of secondary and unusual primary tumours of the bladder. Curr Diagn Pathol 1998;5:188-97.
Bates AW, Baithun SI. Secondary neoplasms of the bladder are histological mimics of nontransitional cell primary tumours: clinicopathological and histological features of 282 cases. Histopathology 2000;36:32-40.
Feldman PA, Madeb R, Naroditsky I, Halachmi S, Nativ O. Metastatic breast cancer to the bladder: a diagnostic challenge and review of the literature. Urology 2002;59:138-138.
Harris M, Howell A, Chrissohou M, Swindell RI, Hudson M, Sellwood RA. A comparison of the metastatic pattern of infiltrating lobular carcinoma and infiltrating duct carcinoma of the breast. Br J Cancer 1984;50:23-30.(Paula D. Ryan, M.D., Ph.D)
Dr. Donald S. Kaufman: A 71-year-old woman was referred to this hospital for a second opinion on the management of a malignant tumor of the urinary bladder. Urinary incontinence had developed suddenly, six months earlier. One month after the onset of incontinence, the patient saw her primary care physician, who referred her to an incontinence clinic. An ultrasonographic study of the pelvis was obtained at another hospital, and the patient was told to see her gynecologist. On pelvic examination, the cervix was normal; there was marked thickening along the anterior wall of the vagina and bladder. No discrete pelvic mass was detected. The rectovaginal septum was smooth, and the stool was guaiac-negative. A Papanicolaou smear, an endometrial biopsy, and cytologic examination of the endometrial fluid revealed no abnormalities.
Computed tomographic (CT) scanning of the abdomen and pelvis at the other hospital showed bilateral hydronephrosis and bilateral solid ovarian masses; the mass in the right ovary measured 4.4 cm by 2.5 cm, and the mass in the left ovary measured 5.6 cm by 4.5 cm. In addition, there was an enlarged aortocaval lymph node, 1.4 cm in diameter. The bladder wall was asymmetrically thickened on the anterior, posterior, and left lateral aspects. A repeated pelvic ultrasonographic study showed a heterogeneous myometrium, with a possible fibroid on the left side and solid bilateral adnexal masses.
Cystoscopy with transurethral resection of the tumor in the bladder was performed at the other hospital two weeks before the patient's evaluation at this hospital. The posterior bladder mucosa was thickened and friable. The muscular wall was distorted and effaced by a rigid, infiltrating mass. The ureters were narrowed, and stents were placed during the cystoscopy. An examination of specimens obtained from the resected tumor revealed invasive transitional-cell carcinoma, grade 3 out of 3, with invasion of the muscularis propria.
A radical cystectomy was advised. However, on consultation with a medical oncologist for consideration of preoperative chemotherapy, it was recommended that the primary treatment should be chemotherapy, since the disease was metastatic to the ovaries and possibly to a lymph node. The patient requested a second opinion and was referred to this hospital.
The patient had had breast cancer 22 years earlier; a radical mastectomy had been performed, and four positive lymph nodes were found. She had received chemotherapy with cyclophosphamide, methotrexate, and fluorouracil for one year. There had been no evidence of recurrent disease. A mammogram performed three months before the referral visit to this hospital showed no abnormalities. Three years before this referral visit, the patient's sister had had breast cancer, followed by ovarian cancer six months later. Her mother had had lung cancer, two maternal uncles pancreatic cancer, a maternal aunt myeloma, and her maternal grandmother uterine cancer. The patient and her sister each had two daughters, who were well. Genetic testing of the patient's sister at the time of the sister's diagnosis of ovarian cancer showed that the BRCA2 gene was normal. The BRCA1 gene contained a missense mutation; the testing laboratory noted that this mutation had been seen in two other patients who also had additional, clearly deleterious mutations in the BRCA1 gene. The patient under discussion also had genetic testing when her sister received the diagnosis of ovarian cancer, which revealed the same missense mutation as was identified in her sister.
On physical examination, the patient appeared well, and her vital signs were normal. There was no lymphadenopathy. The left breast was normal, and the right chest wall contained a prosthetic breast implant. The lungs were clear, the heart sounds were normal, and the abdomen was soft, with no masses and no tenderness. There was no edema of the legs. The results of a complete blood count and the levels of electrolytes, calcium, creatinine, urea nitrogen, protein, albumin, globulin, and bilirubin were normal. Magnetic resonance imaging (MRI) of the pelvis showed a solid left adnexal mass, 4.2 cm by 4.8 cm, with invasion into the uterus. The left side of the uterine fundus was infiltrated, and there was a smaller but similarly enhancing right adnexal mass that did not invade the uterus. There was thickening of the wall of the urinary bladder that was most prominent in the dome and along the left lateral wall. CT scanning of the chest showed no abnormalities, and a bone scan showed no evidence of metastasis.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Paula D. Ryan: May we see the radiographic images?
Dr. Mukesh Harisinghani: A CT examination of the abdomen and pelvis (Figure 1A and 1B) showed an aortocaval lymph node, 1.4 cm in diameter, and bilateral hydronephrosis. Within the pelvis, bilateral adnexal masses were seen in the expected location for the ovaries. On referral to this hospital, an MRI examination of the pelvis (Figure 1C) was performed, which showed thickening of the bladder wall and bilateral adnexal masses with areas of mixed signal intensity. On an image obtained after the administration of gadolinium (Figure 1D), the anatomical plane between the uterus and the left adnexal mass was not well delineated, suggesting myometrial invasion by the left adnexal mass.
Figure 1. Radiographic Images of the Abdomen and Pelvis.
Axial CT images of the abdomen obtained after the intravenous administration of contrast material (Panels A and B) show hydronephrosis (Panel A, arrow) and bilateral solid ovarian masses (Panel B, arrows). An axial T2-weighted MRI examination of the pelvis (Panel C) shows left lateral and posterior thickening of the bladder (large arrow); ureteric stents are visible in the bladder (small arrow). An axial image obtained after the administration of gadolinium (Panel D) shows bilateral adnexal masses (arrows); lack of an anatomic plane between the left adnexal mass and uterus indicates invasion of the uterus.
Dr. Ryan: Did you see any disease on the omentum?
Dr. Harisinghani: We saw no omental or hepatic surface implants.
Dr. Ryan: This 71-year-old woman with a history of breast cancer that was lymph-node–positive and that had been treated with a radical mastectomy and chemotherapy had been disease-free for 22 years. She presented with an acute onset of urinary incontinence and was found to have bilateral, solid ovarian masses with possible uterine involvement, bilateral hydronephrosis, a thickened bladder wall, and an enlarged aortocaval lymph node. The findings on examination of a bladder-biopsy specimen were interpreted as showing an invasive transitional-cell carcinoma. Her sister had received diagnoses of both breast and ovarian cancer and was found to have a missense mutation in BRCA1, a mutation that this patient also had.
The main issue of concern in this case is the origin of the carcinoma in this patient. The possible primary sites include the bladder, the cervix or the endometrium, the ovaries, or the breast. The likelihood that this neoplasm originated in the cervix or the endometrium is extremely low, because the cervix appeared normal on pelvic examination, a Papanicolaou smear was normal, and an endometrial biopsy and cytologic examination of endometrial fluid revealed no abnormalities. The patient presented with symptoms referable to the bladder, and a tumor involving the bladder mucosa was discovered at cystoscopy, leading to the obvious suspicion of a primary bladder cancer, which was supported by the pathological interpretation of the biopsy specimen. Is this a likely diagnosis in this case? The greatest risk factor for bladder cancer is smoking.1 Occupational exposure to aromatic amines, such as benzidine and beta-naphthylamine, in the rubber, paint, and dye industries; drugs, including phenacetin-containing analgesics and cyclophosphamide; and chronic urinary tract inflammation also increase the risk of the development of bladder cancer. This patient had none of these risk factors, except for the cyclophosphamide treatment she received for her breast cancer many years earlier. The risk associated with cyclophosphamide is dose-dependent, with an elevated risk occurring at doses of 20 g or more.2 Although gross, painless hematuria is the presenting sign of bladder cancer in 80 to 90 percent of cases, it may occasionally present with urinary urgency, frequency, and dysuria. Of newly diagnosed cases of bladder cancer, approximately 75 percent are superficial; however, at the time of the diagnosis, invasive bladder cancer (20 percent of the cases) or metastatic disease (5 percent) may be found.3 This patient presented with urinary incontinence, which would be a rather unusual initial presenting symptom for bladder cancer.4 This symptom suggests that there is obstruction resulting in overflow incontinence, which is possible, given the presence on imaging of a mass infiltrating the wall of the bladder.
Cystoscopic evaluation in a patient in whom a urothelial tumor is suspected provides diagnostic and staging information, and when hydronephrosis is present, as in this patient, such an evaluation can provide a therapeutic benefit by the placement of stents to relieve the obstruction and to prevent loss of renal function. Biopsy specimens of a suspected urothelial tumor must include samples from the bladder wall so it can be determined whether there is invasion of muscle by the overlying carcinoma.
Despite the interpretation of the bladder-biopsy specimen as indicating transitional-cell carcinoma, the patient's clinical presentation is distinctly unusual for metastatic bladder cancer and, therefore, I am not immediately prepared to accept that conclusion.
The family history is an important consideration in a patient such as this one, who has a personal history of breast cancer and now bilateral ovarian masses. For carriers of both BRCA1 and BRCA2 germ-line mutations, there is an elevated lifetime risk of breast cancer, ovarian cancer, or both.5 The patient and her sister, both of whom had had breast cancer, had the same missense mutation in BRCA1. Although most mutations that cause cancer are nonsense mutations, a missense change may also be deleterious. Various types of evidence may assist one in classifying such variants as deleterious or neutral.6 Because the testing laboratory noted that the mutation had been seen twice in patients who had clearly deleterious mutations in BRCA1, it is less probable that this missense mutation is of functional importance than if it had been seen in isolation in patients with cancer. This observation suggests that the patient and her sister share this missense alteration as a result of their close genetic relationship. Although I believe it is unlikely that the patient had a hereditary risk of ovarian cancer on the basis of the results of her genetic testing, the bilateral adnexal masses require explanation. The radiologic findings suggest that the masses are malignant. It would be rare for bladder cancer to metastasize to the ovaries. The clinical presentation is also somewhat unusual for advanced ovarian cancer, which frequently presents with ascites or peritoneal implants outside the pelvis or with spread to the liver or the pleura. A biopsy of the adnexal mass would be required to document metastatic disease outside the bladder and to determine whether there is a second primary cancer.
Despite this patient's long disease-free interval after the diagnosis of breast cancer 22 years ago, metastatic breast cancer should always be included in the differential diagnosis of a patient with a history of invasive breast cancer, given the persistent natural history of this disease and its heterogeneity among patients. The time course to the appearance of clinically detected metastatic disease can be extremely protracted. The average hazard rate for breast-cancer recurrence between 5 and 12 years after primary therapy, for example, has been calculated at 4.3 percent per year.7 Although the bones, lungs, and liver are the most common sites of spread of distant disease, metastases from breast cancer can be seen in many organs, including the bladder8,9 and the ovaries. Ureteral obstruction caused by breast cancer has been described,10 and in one study, breast cancer was the most common nonpelvic tumor causing ureteral obstruction.10 My interpretation of the clinical presentation in combination with the radiologic findings in this case is that this patient's breast cancer metastasized to both ovaries, as well as to the bladder, the ureters, and the aortocaval lymph nodes.
I would recommend as the first diagnostic procedure a review of the pathological specimen from the transurethral resection performed at the other hospital to determine whether there is agreement on the diagnosis of transitional-cell carcinoma. A critically important diagnostic aid in this type of situation is comparison of the tissue from the original breast cancer, if available, with the biopsy specimen from the metastatic site. However, it is unlikely that tissue obtained from this patient's breast cancer 22 years ago was available. I would also recommend biopsy of one of the adnexal masses; a sample of tissue from an adnexal mass and the bladder specimen should be stained for the estrogen receptor, progesterone receptor, and the HER2/neu protein, since these would assist in the diagnosis and guide medical management.
Dr. Kaufman: When I saw this patient in consultation, my thinking was very similar to that of Dr. Ryan; I believed that this clinical presentation was extremely unusual for a primary bladder cancer and requested the slides from the other hospital for review by the pathology department.
Clinical Diagnosis
Metastatic breast cancer.
Dr. Paula D. Ryan's Diagnosis
Metastatic breast cancer.
Pathological Discussion
Dr. Melinda F. Lerwill: The slides from the other institution of the patient's bladder tumor were reviewed. All of the tissue fragments showed a diffusely infiltrating carcinoma with invasion of the muscularis propria (Figure 2A) and a prominent, sheet-like growth pattern (Figure 2B). Cases of primary transitional-cell carcinoma of the bladder occasionally demonstrate a similar diffuse growth pattern but more typically show nesting or clustering of the tumor cells. The tumor cells in the biopsy specimen from this patient also frequently aligned themselves in linear cords (Figure 2C), a morphologic feature highly characteristic of invasive lobular carcinoma of the breast, but only rarely seen in transitional-cell carcinoma.11 The tumor was composed of a relatively homogeneous population of small round cells with eosinophilic cytoplasm, moderate nuclear atypia, and occasional mitotic figures (Figure 2D). The overlying urothelium was completely benign, without dysplasia or carcinoma in situ. The absence of preinvasive neoplasia coupled with the morphologic features of the tumor was more consistent with a metastatic lesion than with transitional-cell carcinoma. The features were not typical of a tumor of ovarian origin. A diagnosis of metastatic breast carcinoma was made on the basis of the patient's history and the histomorphologic features of the tumor. Slides of the patient's earlier breast carcinoma were not available for comparison, but it was reported to have been an invasive lobular carcinoma.
Figure 2. Biopsy Specimen of the Bladder.
Carcinoma cells diffusely infiltrate the tissue and invade the large smooth-muscle bundles of the muscularis propria (Panel A). The tumor has a sheet-like growth pattern (Panel B) that is unusual for bladder cancer. The tumor cells form linear cords (Panel C), a pattern highly unusual for transitional-cell carcinoma, but characteristic of invasive lobular carcinoma of the breast. The tumor is composed of a relatively homogeneous population of small, round cells with moderate nuclear atypia and occasional mitotic figures (Panel D). The tumor cells show nuclear staining for estrogen-receptor protein (Panel D, inset) (Panels A through D, hematoxylin and eosin; inset, Panel D, immunoperoxidase stain for estrogen receptor).
A panel of immunohistochemical stains was used to confirm the diagnosis. The tumor cells were positive for cytokeratin 7, negative for cytokeratin 20, and positive for estrogen receptor (Figure 2D, inset); they were negative for progesterone receptor and for HER2/neu protein. Although a minority of cases of transitional-cell carcinoma may show a similar staining pattern,12,13 this profile is much more characteristic of tumors of breast origin.12,14 The tumor cells were negative for gross cystic disease fluid protein-15, which in this context would be a fairly specific marker for a tumor of breast origin; however, only approximately 60 percent of breast tumors express this antigen, and a negative result does not rule out a diagnosis of breast carcinoma.15 The immunohistochemical findings were therefore consistent with a diagnosis of metastatic breast carcinoma. A subsequent biopsy of the left ovarian mass also demonstrated metastatic breast carcinoma.
Secondary neoplasms of the bladder account for 2 to 14 percent of all malignant bladder tumors.16 Tumors spread to the bladder most commonly by direct regional spread from local organs, such as the colon, prostate, rectum, and cervix, or as metastases from distant sites, of which stomach, skin (melanoma), lung, and breast are the most common.17 Breast carcinoma metastatic to the bladder is, overall, rare, and it accounts for about 3 percent of secondary bladder neoplasms, usually occurring in association with widespread metastatic disease.17,18 The reported interval from the initial diagnosis to the development of bladder metastases ranges from 7 months to 30 years, with a mean interval of 7.5 years.18 Lobular carcinomas appear to have a stronger association with bladder metastases than the more common ductal subtype of breast carcinoma.18 Lobular carcinomas have a propensity to metastasize to serosal surfaces, the gynecologic tract, and the gastrointestinal tract,19 and perhaps spreading from these adjacent sites accounts for the greater frequency of bladder involvement. Metastatic lobular carcinoma also often occurs as a diffuse thickening of an affected organ, as seen in this case, rather than as discrete tumor nodules.19 The development of bladder metastases has generally been a poor prognostic feature, and most patients die of the disease within two years.18
Dr. Kaufman: The remote breast-cancer history was not prominently discussed by the patient when she came to us for a second opinion on the management of the bladder tumor, and therefore, this diagnosis was apparently not known to the pathologist at the other hospital. Dr. Young's initial review of the pathological slides alerted those of us responsible for her care to the possibility that the patient had metastatic disease involving the urinary bladder from a primary tumor in the breast. This case underscores the importance of our policy of asking for a review of the slides of every patient referred to us for care.
Dr. Robert H. Young (Pathology): The pattern of growth that Dr. Lerwill pointed out in the bladder specimen is so characteristic of breast carcinoma that I immediately thought of a metastatic process. The presence of ovarian masses is an important clinical clue, because breast cancer often spreads to the ovary, whereas bladder cancer rarely does. Understanding the typical patterns of spread of tumors can be as important for the pathologist in making the diagnosis as it is for the clinician in management.
Dr. Kaufman: Dr. McDougal, would the severe urinary incontinence have made you suspect diseases other than bladder cancer?
Dr. W. Scott McDougal (Urology): I think that a presentation such as this would be unusual for a patient with primary bladder cancer. Incontinence would be extremely unusual as an initial presenting symptom. A second reason for suspicion is the observation that the tumor was predominantly submucosal, which would be highly unlikely for a primary transitional-cell carcinoma in the presence of this extensive extravesical spread.
Dr. Kaufman: Because the patient's tumor tested positive for estrogen-receptor protein, treatment with tamoxifen (20 mg daily) was begun three weeks after her initial consultation. Three months later, she reported an improvement in her bladder capacity, with the disappearance of urgency and incontinence and a decrease in nocturia. Abdominal and pelvic CT scans obtained at that time showed marked shrinkage of the pelvic masses. After six months of taking tamoxifen, she reported the complete disappearance of urinary symptoms. CT scans obtained then, however, were unchanged from the earlier studies. Six months after beginning tamoxifen treatment, the patient began chemotherapy with doxorubicin and cyclophosphamide, given every 21 days, for a total of six cycles, followed by single-agent docetaxel for three monthly cycles. She then started taking anastrozole and continues with that to date. Repeated abdominal, pelvic, and thoracic CT scans have shown stable disease without progression, slightly more than three years after the beginning of treatment. Dr. Ryan, what do you think about that treatment plan?
Dr. Ryan: A common strategy for treating symptomatic patients with estrogen-receptor–positive disease is to initiate chemotherapy until the disease is stabilized, then switch to hormonal treatment for maintenance. This decision is based on many factors, including the patient's age and performance status (how the disease affects the patient's ability to perform acts of daily living) and the exact nature of the symptoms from metastatic disease. Because this patient had never received any endocrine therapy and she did not have life-threatening visceral disease, the initiation of antiestrogen therapy is a reasonable plan, and it is the strategy I generally use. If there is progression of the disease or worrisome symptoms, chemotherapy may need to be considered in the course of treatment for metastatic breast cancer.
Anatomical Diagnosis
Infiltrating lobular carcinoma of the breast, metastatic to the urinary bladder and ovaries.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Departments of Medical Oncology (P.D.R., D.S.K.), Radiology (M.H.), and Pathology (M.F.L.), Massachusetts General Hospital; and the Departments of Medicine (P.D.R., D.S.K.), Radiology (M.H.), and Pathology (M.F.L.), Harvard Medical School — both in Boston.
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