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Active chemotherapy for collecting duct carcinoma of the kidney
A case report and review of the literature
Article first published online: 28 DEC 2001
Copyright © 2002 American Cancer Society
Volume 94, Issue 1, pages 111–116, 1 January 2002
How to Cite
Milowsky, M. I., Rosmarin, A., Tickoo, S. K., Papanicolaou, N. and Nanus, D. M. (2002), Active chemotherapy for collecting duct carcinoma of the kidney. Cancer, 94: 111–116. doi: 10.1002/cncr.10204
- Issue published online: 28 DEC 2001
- Article first published online: 28 DEC 2001
- Manuscript Accepted: 12 SEP 2001
- Manuscript Received: 25 JUN 2001
- National Institutes of Health. Grant Number: K24 CA85609
- Turobiner Kidney Cancer Research Fund
- collecting duct carcinoma (CDC);
- kidney carcinoma;
- transitional cell carcinoma (TCC)
Collecting (Bellini) duct carcinoma (CDC) of the kidney is associated with an aggressive course and an extremely poor prognosis. To the authors' knowledge, there are no standard treatment regimens and neither immunotherapy nor chemotherapy have been found to be effective.
In the current study, the authors report a 49-year-old man who presented with a 7.0 cm × 6.0 cm renal mass with extensive regional, paraaortic, and left supraclavicular lymphadenopathy. Radical nephrectomy revealed a CDC. The patient was treated with doxorubicin, 50 mg/m2 (Day 1), and gemcitabine, 2000 mg/m2 (Day 1), (AG) every 2 weeks with granulocyte–colony-stimulating factor (GCSF) support.
The left supraclavicular lymphadenopathy significantly decreased in size after the first cycle. Computed tomography (CT) scan after the third cycle revealed a significant (68%) reduction in the tumor volume. Toxicity was comprised of only CTC version 2.0, 1998; Grade 1 nausea and fatigue. After Cycle 6, a repeat CT scan demonstrated minimal disease progression. Based on recent Phase II data of an active regimen comprised of AG alternating with ifosfamide, paclitaxel, and cisplatin (ITP) in patients with transitional cell carcinoma, the patient was treated with ifosfamide, 1500 mg/m2 (Days 1–3); paclitaxel, 175 mg/m2 (Day 1); and cisplatin, 35 mg/m2 (Days 1 and 2), every 4 weeks with GCSF support. After two cycles of ITP, the patient developed disease progression in bone and received palliative radiation therapy. Follow-up CT scan demonstrated new liver metastases. The patient received palliative care without further chemotherapy and died approximately 10 months after the initial diagnosis of CDC.
Immunohistologic and molecular analyses indicate that CDC more closely resembles transitional cell carcinoma than renal cell carcinoma. Chemotherapy regimens used to treat advanced transitional cell carcinoma such as AG should be evaluated as first-line therapy for CDC. Cancer 2002;94:111–6. © 2002 American Cancer Society.
Collecting or Bellini duct carcinoma (CDC) is a rare variant of kidney carcinoma that is associated with an aggressive course and an extremely poor prognosis. CDC accounts for approximately 1–3% of all renal neoplasms and tends to occur in younger (median age at diagnosis of 43 years), male (male-to-female ratio of 2:1), and white patients.1, 2 Both CDC and clear cell renal cell carcinoma (RCC) typically present with a renal mass, macroscopic hematuria, and associated flank pain; however, the majority of patients with CDC have evidence of metastatic disease at the time of presentation. The most common site of metastatic disease is the lymph nodes, including involvement of cervical or supraclavicular lymph nodes.2–4 In contrast to RCC, blastic bone metastases occur more frequently than lytic bone metastases in CDC.2 Radiographically, CDC typically appears as a centrally arising mass with preservation of the contour of the kidney and minimal contrast enhancement.5 Immunotherapy does not appear to be effective and to our knowledge there are no standard treatment regimens for CDC. In the current study, we report a patient with CDC who achieved a major response to combination chemotherapy with doxorubicin and gemcitabine.
A 49 year-old man of Japanese and African-American descent with no significant past medical history presented to his internist reporting left flank pain, a single episode of hematuria, and left arm paresthesia. Physical examination revealed a palpable left flank mass and fixed, nontender, left supraclavicular lymphadenopathy. Computed tomography (CT) and magnetic resonance imaging (MRI) scans of the abdomen revealed a left renal mass measuring 7.0 cm × 6.0 cm with extensive regional and paraaortic retroperitoneal lymphadenopathy. A left radical nephrectomy was performed and the pathology revealed a high-grade carcinoma of the kidney with involvement of regional lymph nodes and the left adrenal gland. The morphologic features including multinodularity, extensive inflammatory infiltrate (predominantly neutrophilic) admixed with tumor, solid and tubulopapillary growth patterns with a high-grade cytology, focal intracellular mucin, and tubal dysplasia in the surrounding kidney were consistent with CDC (Fig. 1).1 The patient was referred to our institution for further disease management. A repeat CT scan of the chest, abdomen, and pelvis showed significant lymphadenopathy in the left supraclavicular and base of neck regions (3.0 cm × 1.8 cm), as well as extensive paraaortic (4.8 cm × 3.0 cm) and aortocaval (2.1 cm × 2.2 cm) lymphadenopathy (Figs 2A and 3A). There was no evidence of lung parenchymal involvement. Laboratory studies were unremarkable. Based on similarities between CDC and urothelial carcinoma (Table 1), we chose a previously reported chemotherapy regimen that is reported to be highly active in transitional cell carcinoma (TCC) of the bladder. The patient received a dose-intense regimen of doxorubicin, 50 mg/m2 (Day 1), and gemcitabine, 2000 mg/m2 (Day 1), (AG) every other week with granulocyte–colony-stimulating factor (GCSF) support.6 After the first cycle of chemotherapy, the left supraclaviclular and base of neck lymphadenopathy were found to have significantly decreased in size on physical examination and the patient's left arm paresthesias resolved. A CT scan performed after 3 cycles of AG demonstrated a 67% decrease in the size of the left supraclavicular (from 3.0 cm × 1.8 cm to 1.8 cm × 1.0 cm) and paraaortic lymphadenopathy (from 4.8 cm × 3.0 cm to 2.4 cm × 2.0 cm), and a 74% decrease in the size of the aortocaval lymphadenopathy (from 2.1 cm × 2.2 cm to 1.2 cm × 1.0 cm) compared with pretreatment measurements (total reduction in tumor volume of 68%) (Figs 2B and 3B). Toxicity was comprised only of CTC version 2.0, 1998; Grade 1 nausea and fatigue. After completing 6 cycles of AG, the patient continued to feel well; however, he noted an approximately 1-cm increase in the size of his left neck mass. Repeat tests including laboratory studies, a radionuclide scan to evaluate cardiac function, and a CT of the chest, abdomen, and pelvis were performed. The laboratory studies were unremarkable and the cardiac ejection fraction was normal. CT scan demonstrated evidence of disease progression with a slight increase in the size of the supraclavicular and base of neck lymphadenopathy (from 1.2 cm × 1.0 cm to 2.0 cm × 1.2 cm) and an increase in the size of the paraaortic (from 2.4 cm × 2.0 cm to 3.0 cm × 3.1 cm) and aortocaval (from 1.2 cm × 1.0 cm to 1.8 cm × 1.2 cm) lymphadenopathy. Based on recent data using an active regimen comprised of AG alternating with ifosfamide, paclitaxel, and cisplatin (ITP) in patients with TCC, we elected to treat our patient with ifosfamide, 1500 mg/m2 (Days 1–3); paclitaxel, 175 mg/m2 (Day 1); and cisplatin, 35 mg/m2 (Days 1–2), every 4 weeks with GCSF support.6 The patient received two cycles of ITP and developed lower back and left hip pain. An MRI of the spine did not demonstrate evidence of spinal cord compression, although a bone scan did demonstrate evidence of osseous metastases involving the upper thoracic spine, several ribs, the right femur, and left inferior pubic ramus. The patient received palliative radiation therapy to his lumbar spine with symptomatic improvement. Approximately 1 month after the completion of radiation therapy, a repeat CT scan of the chest, abdomen, and pelvis demonstrated new low attenuation areas in the liver that were consistent with metastatic disease. Based on disease progression and the patient's worsening performance status, a decision was made to provide palliative care without further chemotherapy. The patient died approximately 10 months after the initial diagnosis of CDC.
|CDC||Urothelial (TCC)||Conventional (Clear Cell) RCC|
|Macroscopic||Centered on renal medulla, usually infiltrative||Centered on pelvicalyceal system||Usually cortical|
|architecture||Tubulopapillary or papillary, usually multinodular, with extensive desmoplasia, often with admixed neutrophils||Usually papillary, or solid||Solid alveolar/sheet-like with intricate vascularity|
|Cytology||Usually eosinophilic cytoplasm, high-grade nuclei.||Amphophilic or eosinophilic cytoplasm, nuclear grade variable||Clear or eosinophilic cytoplasm, nuclear grade variable|
|Mucin stains||Often positive||Focal positivity in up to 40%, more common in high-grade tumors||Absent|
|Tubular dysplasia||Present||Tumor extension along tubules, resembling tubular dysplasia||Absent|
|Urothelial carcinoma in situ||Absent||Present||Absent|
|Molecular genetics||Monosomies 1, 6, 14, 15, and 22 LOH of 1q, 8p, 9p, and 13q c-erb B-2 amplification||LOH 8p, 9 p53, Rb mutations c-erb B-2 amplification||Chromosome 3p abnormalities (e.g., losses, von Hippel–Lindau gene mutations etc.)|
DISCUSSION AND REVIEW OF THE LITERATURE
Much of the literature concerning CDC has focused on pathologic and immunohistochemical characteristics. Pierre Mason provided one of the initial descriptions of this tumor in 1955.3, 7 Because the cyst lining resembled the ducts of Bellini (collecting ducts), Mason referred to the tumor as “Bellinian epithelioma.” In 1976, Mancilla-Jimenez et al. reported on 34 cases of papillary RCC and postulated a collecting duct origin for 3 of these tumors based on the finding of atypical hyperplastic changes in adjacent collecting tubules.8 Subsequently, Fleming and Lewi created diagnostic criteria when they described the clinical and pathologic findings of six cases of CDC.1 These tumors had a tubulopapillary architecture, arose in the renal medulla (and later invaded the renal cortex), and demonstrated infiltrating tubules with an associated desmoplastic reaction. Five of the six tumors also had atypical hyperplastic changes in adjacent collecting tubules. Immunohistochemical studies, specifically staining for high molecular weight cytokeratins, provided further evidence for a collecting duct origin. Additional studies have confirmed these observations and further characterized these tumors with respect to immunohistochemistry (Table 1).3 Several cytogenetic abnormalities have been described in CDC including monosomies 1, 6, 14, 15, and 22, loss of heterozygosity (LOH) of 8p (which also occurs in 23% of cases of TCC), LOH of 13q (reported to occur in 50% of cases), LOH of 1q (reported to occur in approximately 60% of cases), and LOH of 9p (reported to occur in 50% of cases).9, 10–13 CDC is characterized further by a high incidence of c-erb B-2 oncogene amplification.14
Both immunotherapy and chemotherapy have been used to treat patients with CDC; however, many physicians have favored using chemotherapy based on the aggressive disease course. Single case reports have provided much of the information regarding the systemic treatment of CDC. To our knowledge, the largest series reported to date is a retrospective review of 12 patients from the M. D. Anderson Cancer Center.2 Seven of eight patients who presented with metastatic disease were treated with various combinations of chemotherapy, most commonly methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). Only one patient achieved a minor response that lasted 5 months. Additional case reports using chemotherapy that included other cisplatin-containing regimens have been disappointing.4 One patient treated with a combination of 5-fluorouracil, interferon-α (IFN-α), and mitomycin-C achieved objective disease stabilization for 16 months. The four patients without metastatic disease at the time of diagnosis underwent radical nephrectomy and hilar lymphadenectomy. In all cases, the tumor recurred within 1 year. Radiation therapy in two patients with locally recurrent disease resulted in only a transient minor response. Six patients were treated with a combination of interleukin-2 and IFN-α with only a 24-year-old male who presented with extensive involvement of the lymph nodes achieving a dramatic response. This patient subsequently underwent a nephrectomy and abdominal lymph node dissection and remained free of disease for 30 months. Two other patients achieved objective disease stabilization that lasted for 10 months and 15 months, respectively.
The pathologic and immunohistochemical description as well as the cytogenetic abnormalities support the belief that CDC is more similar to urothelial carcinoma than to clear cell RCC (Table 1). Although MVAC combination chemotherapy, which has been the standard therapy for TCC for over a decade, has not been reported to be active in the treatment of CDC, newer regimens used in the treatment of TCC should be investigated. In the recent literature, there are several new approaches to the treatment of advanced and metastatic bladder carcinoma using chemotherapy combinations incorporating drugs such as ifosfamide, the taxanes, and gemcitabine.15 Phase I data suggest that regimens combining doxorubicin and gemcitabine (AG) and those combining ifos- famide, paclitaxel, and cisplatin (ITP) are well tolerated, active regimens.6 A recent Phase II trial of 21 patients with TCC who were treated with sequential AG followed by ITP reported that a major response (either complete response or partial response) was achieved in 18 patients (86%).16 A large, randomized, multinational, multicenter Phase III trial of gemcitabine and cisplatin (GC) versus MVAC in patients with advanced or metastatic bladder carcinoma demonstrated a similar survival advantage with GC found to have a better safety profile and tolerability.15 These recently developed chemotherapy regimens have significant activity and a favorable toxicity profile in the treatment of TCC patients, and should be evaluated in the treatment of patients with CDC of the kidney. Based on the similarities between CDC and urothelial carcinoma, we believe that chemotherapy should be the first-line treatment of CDC, not immunotherapy.
- 7Tumeurs humaines: human tumors, histology, diagnosis and technique. 2nd edition. Detroit: Wayne State University Press, 1955.. In: Kobernick S, translator.
- 13Deletion mapping implicates two tumor suppressor genes on chromosome 8p in the development of bladder cancer. Oncogene 1996; 12: 1087., .
- 16Sequential doxorubicin/gemcitabine and ifosfamide, paclitaxel, and cisplatin chemotherapy in patients with metastatic or locally advanced transitional cell carcinoma of the urothelium. Proc ASCO 2000: 19: 3422., , , , , , et al.