- Email: [email protected]
Outcomes Following Radical Cystectomy for Plasmacytoid Urothelial Carcinoma: Defining the Need for Improved Local Cancer Control
Accepted Manuscript Title: Outcomes Following Radical Cystectomy for Plasmacytoid Urothelial Carcinoma: Defining the Need for Improved Local Cancer Control Author: Patrick A. Cockerill, John C. Cheville, Stephen A. Boorjian, Andrew Blackburne, Prabin Thapa, Robert F. Tarrell, Igor Frank PII: DOI: Reference:
S0090-4295(16)30793-2 http://dx.doi.org/doi: 10.1016/j.urology.2016.09.053 URL 20113
To appear in:
Urology
Received date: Accepted date:
20-6-2016 3-9-2016
Please cite this article as: Patrick A. Cockerill, John C. Cheville, Stephen A. Boorjian, Andrew Blackburne, Prabin Thapa, Robert F. Tarrell, Igor Frank, Outcomes Following Radical Cystectomy for Plasmacytoid Urothelial Carcinoma: Defining the Need for Improved Local Cancer Control, Urology (2016), http://dx.doi.org/doi: 10.1016/j.urology.2016.09.053. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Outcomes Following Radical Cystectomy for Plasmacytoid Urothelial Carcinoma: Defining the Need for Improved Local Cancer Control Patrick A. Cockerill, John C. Cheville, Stephen A. Boorjian, Andrew Blackburne, Prabin Thapa, Robert F. Tarrell, Igor Frank Department of Urology, Mayo Clinic, Rochester, Minnesota
Correspondence:
Igor Frank, MD Mayo Clinic Department of Urology Mayo Clinic 200 First Street Southwest Rochester, Minnesota 55905 E-mail: [email protected] Telephone: 507-266-0191 Fax: (507) 284-4951
Word count of text: 1718 Word count of abstract: 242 Key words: Plasmacytoid urothelial cancer Conflict of Interest: Drs. Cockerill, Cheville, Boorjian, Blackburne and Frank, and Mr. Thapa and Mr. Tarrell, have nothing to disclose.
Page 1 of 19
2 ABSTRACT Objective: To evaluate oncologic outcomes after radical cystectomy (RC) in patients with plasmacytoid urothelial carcinoma (UC), and compared survival to that in patients with pure UC of the bladder. Methods: We identified 46 patients with plasmacytoid UC and 972 with pure UC who were treated with RC between 1980 and 2009. All pathologic specimens were re-reviewed by a single GU pathologist. Patients were matched 1:2 by age, gender, ECOG performance status, pathological tumor stage and nodal status to patients with pure UC. Survival was estimated using the Kaplan-Meier method and compared with the log rank test. Results: Patients with plasmacytoid UC were more likely to have extravesical disease (≥pT3) (83% versus 43%, p<0.0001) and positive margins (31% versus 2.1%, p<0.0001), than patients with pure UC. Plasmacytoid UC was associated with decreased overall survival (27% v 45% at 5 years, RR 1.4, p=0.04), cancer specific survival (36% v 57% at 5 years, RR 1.7, p=0.01), and local recurrence free survival (63% v 81% at 5 years, RR 2, p=0.01). When patients with plasmacytoid UC were matched to those with pure UC, there were no significant differences in 5-year overall, cancer specific, local or distant recurrence free survival. Conclusion: Plasmacytoid UC is associated with a high rate of locally advanced disease and positive margins at RC, as well as increased local recurrence rates. Further research is necessary to delineate adjuvant or neoadjuvant treatment strategies to improve local cancer control this rare subtype of UC. INTRODUCTION Plasmacytoid carcinoma is a rare but increasingly recognized pathologic subtype of bladder cancer. It was first recognized in 1991 separately by Sahin et al1 and Zukerberg2. Sahin described a patient with metastatic bladder cancer presenting as multiple lytic bone lesions, which on biopsy was noted to resemble plasma cells. Zukerberg reported two cases of locally advanced urothelial carcinoma that
Page 2 of 19
3 resembled lymphoma and plasmacytoma. In 2004, the WHO recognized plasmacytoid variants, describing the malignant cells as resembling lymphocytes, monocytes and plasma cells.
Since the WHO recognition, there have been further case series that have included 4 to 31 patients.4-13 These case series identified plasmacytoid carcinoma as locally aggressive, infiltrative, and associated with poor outcomes. The optimal treatment strategy has not been elucidated secondary to the small number of patients, however at least some tumors are chemosensitive to standard urothelial cancer regimens, including Methotrexate/Vinblastine/Adriamycin/Cisplatin (MVAC) and Gemcitabine/Cisplatin (GC).
In this study, we describe our experience with plasmacytoid carcinoma treated by radical cystectomy. Specifically, we report clinical outcomes of these patients and compare their outcome with patients with typical urothelial carcinoma.
Page 3 of 19
4 MATERIALS AND METHODS With institutional review board approval, we retrospectively reviewed the cystectomy registry at our institution. From 1980 to 2009, 3186 radical cystectomies were performed by various surgeons. Of these, 46 patients (1%) had plasmacytoid carcinoma. All pathologic specimens were re-reviewed by a urologic pathologist (JC). Clinico-pathologic features evaluated included age, gender, ECOG performance status, presence of lymphovascular invasion, surgical margin status, and receipt of chemotherapy, whether adjuvant or neoadjuvant. Tumors were staged according to the 2010 American Join Committee on Cancer/UICC TNM classification.
Follow up after radical cystectomy at our institution has evolved over the past 3 decades, however, in general, is performed every 3 months for 2 years, then every six months for 3 years, then annually thereafter assuming there is no recurrence. Oncologic surveillance includes history and physical exam, urine cytology, computed tomography of the abdomen and pelvis, and either computed tomography or X-ray of the chest.
Local recurrence was defined as recurrence within the surgical bed or within the lymph node dissection template. Distant metastasis included lymph nodes outside the surgical dissection template, viscera, or bone. Survival status was accumulated from death certificates, or from patient/physician correspondence if the patient was treated elsewhere following cystectomy. We evaluated the clinicopathologic characteristics of patients with plasmacytoid carcinoma and compared them to patients with urothelial carcinoma. If the pathologic specimen had any other variant histology present, it was excluded. Patients with plasmacytoid carcinoma were matched for age, gender, ECOG performance status, tumor stage, nodal stage, 1:2 with a cohort of typical UC Survival outcomes evaluated included
Page 4 of 19
5 overall survival, cancer specific survival, local recurrence free survival and distant metastasis free survival.
Comparison of clinicopathologic features was done using conditional logistic regression analysis. Survival was estimated as time from RC to death, cancer death, or recurrence using the Kaplan-Meier method and compared with the log rank test. SAS software was used for analysis.
Page 5 of 19
6 RESULTS Pathology Plasmacytoid carcinoma exhibited an infiltrative growth pattern, diffusely involving the bladder with a minimal desmoplastic reaction (Figure 1). The cells were small and resembled lymphocytes, monocytes and plasma cells. In addition, some cells contained clear vacuoles with eccentric nuclei but lacked intracellular mucin in contrast to signet ring cell adenocarcinoma (Figure 1). Additionally, cells exhibited single filing similar to lobular carcinoma of the breast (Supplementary Figure 4). Clinicopathologic Features The clinicopathologic features of the cohorts are presented in Table 1. There were 46 patients with plasmacytoid carcinoma and 972 patients with urothelial carcinoma. Median age, gender, and ECOG performance status were similar between the cohorts. Patients with plasmacytoid carcinoma were more likely to have a locally advanced tumor; 37% of patients had pT4 disease compared to 6% of patients with UC (p<0.0001). These patients were also more likely to receive adjuvant chemotherapy (37% v 11%, p<0.0001), a reflection of their advanced stage at cystectomy. Patients with plasmacytoid carcinoma were more likely to have a positive peripheral perivesical surgical margins as a result of locally advanced stage and minimal desmoplastic reaction (14 [30%] v 18 [2%], p<0.0001). There was no difference in the rate of lymph node metastasis or receipt of neoadjuvant chemotherapy. Additionally, 5 (11%) of the plasmacytoid carcinoma patients had a positive final ureteral margin for invasive carcinoma. Survival Analysis Of the 46 patients with plasmacytoid carcinoma, 27 (59%) died of bladder cancer with a median survival of 1.7 years, and 10 patients died of other causes with a median follow-up of 2.2 years. Of the 9
Page 6 of 19
7 surviving patients, median follow-up is 10.3 years. Additionally, 13 (29%), 21 (46%), and 2 (4%) patients had local, distant, and upper tract recurrence, respectively. Patients with plasmacytoid carcinoma were significantly more likely to experience cancer specific and overall death with locally advanced disease (T3N0 and T4N0) versus organ confined disease (T1N0 and T2N0). At 5 years, cancer specific and overall survival were 86% and 75% for T1/T2 versus 30% and 25% for T3/T4 (p<0.05) (Figure 2). When patients with plasmacytoid carcinoma were compared to all patients with urothelial carcinoma, five-year overall survival was significantly decreased in the patients with plasmacytoid carcinoma, 27% versus 45% (RR 1.4, p=0.04) (Table 2). Cancer specific survival (36% v 57%, RR 1.7, p=0.01) and local recurrence free survival (63% v 81%, RR 2.0, p=0.01) were also significantly decreased in the patients with plasmacytoid carcinoma. There was a non-significant trend toward decreased distant metastasis free survival (p=0.07). When patients with plasmacytoid carcinoma were matched 1:2 with a cohort of patients with typical urothelial carcinoma for age, gender, ECOG performance status, and pathologic tumor stage, only peripheral tumor margin positivity remained significantly different between the two cohorts (30% positive margins with plasmacytoid carcinoma versus 5% with of urothelial carcinoma. Additionally, although there was a difference in overall, cancer specific, local recurrence free, and distant metastasis free survival, this did not reach statistical significance (Table 2) (Supplementary Figures 1-3).
Page 7 of 19
8 DISCUSSION Plasmacytoid carcinoma of the urinary bladder is a rare variant of bladder cancer, accounting for only 1% of cancers in our cystectomy registry. In our experience, patients with plasmacytoid carcinoma treated by radical cystectomy presented with locally advanced disease, with 83% of patients presenting with extravesical spread (pT3 or pT4). As a result, patients are much more likely to have positive radial surgical margins compared to patients with typical urothelial carcinoma. Another important contributor to the high rate of margin positivity is the pattern of spread and the lack of desmoplastic reaction characteristic of these tumors, such that the plane between tumor and normal tissue is difficult to discern surgically. Not surprisingly, we noted an increased rate of local recurrence in these patients, with 28% experiencing local recurrence compared to 16% of UC patients, likely related to the high rate of positive margins. It is critical that plasmacytoid carcinoma is recognized by the pathologist preoperatively such that care can be given to obtaining negative surgical margins at cystectomy. Other studies have also reported a high rate of surgical margin positivity ranging from 11 to 60% (Supplementary Figure 5).4-6 In addition, Kaimakliotis et al noted a high rate of invasive tumor at the ureteral margin with 32% of patients with plasmacytoid carcinoma having a positive ureteral margin compared to less than 4% for patients with urothelial carcinoma.6 In our cohort, 5 patients (11%) had a positive final ureteral margin for invasive carcinoma.
Our experience with outcome is similar to previous reports. Patients with plasmacytoid carcinoma had worse cancer specific outcomes compared to patients with urothelial carcinoma. The difference in outcome was evident even when patients with plasmacytoid carcinoma were matched for prognostic features with patients with urothelial carcinoma (36% 5-year cancer specific survival for patients with plasmacytoid carcinoma compared to 51% with patients with urothelial carcinoma) although this did not
Page 8 of 19
9 reach statistical significance likely due to the small number of patients with plasmacytoid carcinoma. This finding is in contrast to our previous reports of variant histologies such as squamous and glandular differentiation, nested variant, and micropapillary carcinoma that showed matched patients had similar outcomes.14-16 However, the high rate of locally advanced disease in the plasmacytoid variant is similar to our findings regarding squamous and glandular differentiation, nested variant, and micropapillary urothelial carcinoma.14-16 Finally, we found a significant increase in cancer specific and overall mortality in plasmacytoid carcinoma patients when the final pathology from cystectomy was locally advanced versus organ confined (T3/T4 versus T1/T2). Thus, early detection and aggressive treatment is critical to the outcome in these patients.
The rarity of plasmacytoid carcinoma makes it difficult to define the optimal treatment strategy. Non muscle invasive tumors have successfully been managed with resection and intravesical BCG therapy.5 Caution must be taken, however, as the concern in these instances is under-staging, as clinical staging based on imaging may not be indicative of pathologic staging secondary to the discohesive nature of spread of tumor cells and the lack of desmoplastic reaction. The role of chemotherapy in the neoadjuvant or adjuvant setting continues to be defined. Dayyani reported on 31 patients with plasmacytoid carcinoma, 16 with localized disease at presentation.4 Five patients received neoadjuvant chemotherapy with cisplatin based regimens (MVAC or GC), with four patients exhibiting pathologic downstaging, and a complete response (ypT0N0) in three patients. Adjuvant chemotherapy was given in an additional 7 patients. Combining their localized and metastatic patients (15 patients), they noted that plasmacytoid carcinomas chemosensitive in general, however recurrence was common, and survival outcomes inferior to urothelial carcinoma. Keck reported on 32 patients with plasmacytoid
Page 9 of 19
10 carcinoma, 16 of who received adjuvant chemotherapy and noted an overall survival of 23 months, which was significantly worse than a comparable group of patients with urothelial carcinoma.7
Unfortunately, genomic markers were unable to be obtained from our specimens. A recent study by AlAhmadie et al, demonstrated nonsense mutations in CDH1 with loss of E-cadherin expression in patients with plasmacytoid variant bladder cancer.17
CONCLUSION Plasmacytoid carcinoma of the urinary bladder is an aggressive histologic variant so that early detection, and accurate pathologic recognition and clinical staging are critical to improving patient survival. This histologic variant is associated with locally advanced disease at radical cystectomy resulting in a high rate of surgical margin positivity. The optimal treatment modality continues to be defined, however aggressive resection to obtain a negative margins, and systemic chemotherapy in the adjuvant or neoadjuvant setting have shown promise.
Page 10 of 19
11 REFERENCES 1. 2. 3. 4.
5. 6. 7.
8. 9.
10.
11. 12. 13.
Sahin AA, Myhre M, Ro JY, et al: Plasmacytoid transitional cell carcinoma. Report of a case with initial presentation mimicking multiple myeloma. Acta cytologica. 35: 277-80, 1991. Zukerberg LR, Harris NL and Young RH: Carcinomas of the urinary bladder simulating malignant lymphoma. A report of five cases. The American journal of surgical pathology. 15: 569-76, 1991. Eble JN SG, Epstein JI: Pathology and genetics: tumours of the urinary system and male genital organs. WHO Classification of Tumours. Lyon: IARC press, 2004. Dayyani F, Czerniak BA, Sircar K, et al. Plasmacytoid urothelial carcinoma, a chemosensitive cancer with poor prognosis, and peritoneal carcinomatosis. The Journal of urology. 189: 165661, 2013. Fritsche HM, Burger M, Denzinger S, et al. Plasmacytoid urothelial carcinoma of the bladder: histological and clinical features of 5 cases. The Journal of urology. 180: 1923-7, 2008. Kaimakliotis HZ, Monn MF, Cheng L, et al: Plasmacytoid bladder cancer: variant histology with aggressive behavior and a new mode of invasion along fascial planes. Urology. 83: 1112-6, 2014. Keck B, Wach S, Stoehr R, et al: Plasmacytoid variant of bladder cancer defines patients with poor prognosis if treated with cystectomy and adjuvant cisplatin-based chemotherapy. BMC cancer. 13: 71, 2013. Lopez-Beltran A, Requena MJ, Montironi R, et al: Plasmacytoid urothelial carcinoma of the bladder. Human pathology. 40: 1023-8, 2009. Raspollini MR, Sardi I, Giunti L, et al: Plasmacytoid urothelial carcinoma of the urinary bladder: clinicopathologic, immunohistochemical, ultrastructural, and molecular analysis of a case series. Human pathology. 42: 1149-58, 2011. Ricardo-Gonzalez RR, Nguyen M, Gokden N, et al: Plasmacytoid carcinoma of the bladder: a urothelial carcinoma variant with a predilection for intraperitoneal spread. The Journal of urology. 187: 852-5, 2012. Ro JY, Shen SS, Lee HI, et al: Plasmacytoid transitional cell carcinoma of urinary bladder: a clinicopathologic study of 9 cases. The American journal of surgical pathology. 32: 752-7, 2008. Mai KT, Park PC, Yazdi HM, et al: Plasmacytoid urothelial carcinoma of the urinary bladder report of seven new cases. European urology. 50: 1111-4, 2006. Aldousari S, Sircar K and Kassouf W: Plasmacytoid urothelial carcinoma of the bladder: a case report. Cases journal. 2: 6647, 2009.
14.
Kim SP, Frank I, Cheville JC, et al: The impact of squamous and glandular differentiation on survival after radical cystectomy for urothelial carcinoma. The Journal of Urology. 188: 405-9, 2012.
15.
Linder BJ, Frank I, Cheville JC, et al: Outcomes following radical cystectomy for nested variant of urothelial carcinoma: A matched cohort analysis. The Journal of Urology. 189: 1670-5, 2013.
16.
Wang JK, Boorjian SA, Cheville JC, et al: Outcomes following radical cystectomy for micropapillary bladder cancer versus pure urothelial carcinoma: a matched cohort analysis. World Journal of Urology. 30: 801-6, 2012.
17.
Al-Ahmadie HA, Iyer G, Lee BH, et al: Frequent somatic CDH1 loss-of-function mutations in plasmacytoid variant bladder cancer. 48: 356-8, 2016.
Page 11 of 19
12
Figure 1 a) Cystectomy specimen showing diffusely thickened rigid bladder wall with lack of intraluminal mass. b) Plasmacytoid carcinoma is characterized by non-cohesive cells resembling lymphocytes, plasma cells and monocytes. Scattered cells show intraluminal vacuoles with eccentric nuclei resembling signet ring cells but lacking intracellular mucin.
Page 12 of 19
13
Figure 2 Plasmacytoid carcinoma cancer specific survival by stage
Supplementary Figure 1 Matched overall survival Supplementary Figure 2 Matched cancer specific survival. Supplementary Figure 3
Page 13 of 19
14
Matched local recurrence free survival Supplementary Figure 4 The infiltrating tumor lacks an associated stromal reaction, and the pattern of spread resembles lobular carcinoma of the breast. Supplementary Figure 5 Literature Summary
Page 14 of 19
15
Table 1. Clinico-pathologic features of patients with plasmacytoid carcinoma and typical urothelial carcinoma
Number of patients Age at surgery (yrs) median (IQR) Male Gender
Plasmacytoid carcinoma 46 68 (60, 73) 36 (78%)
Urothelial carcinoma 972 68 (62, 75) 805 (83%)
ECOG performance status
p value
0.2 0.4 0.6
0
32 (74%)
772 (81%)
1
8 (19%)
138 (14%)
2+
3 (7%)
49 (5%)
Neoadjuvant chemotherapy
4 (9%)
60 (6.2%)
0.5
17 (37%)
111 (11%)
<0.0001
Adjuvant chemotherapy Pathologic Tumor Stage
<0.0001
≤T1
1 (2%)
286 (29%)
T2
7 (15%)
274 (28%)
T3
21 (46%)
358 (37%)
T4
17 (37%)
54 (6%)
pN+
13 (29%)
183 (19%)
0.1
Positive Tumor Margin
14 (30%)
18 (2%)
<0.0001
Page 15 of 19
16
Table 2 Survival Outcomes
5 yr OS 5 yr CSS 5 yr Local RFS 5 yr Distant Metastasis FS 5 yr OS 5 yr CSS 5 yr Local RFS 5 yr Distant Metastasis FS
Pure UC 45% 57% 81%
Unmatched Plasmactyoid RR UC 27% 1.4 36% 1.6 63% 2.7
p value 0.04 0.01 0.01
62%
45%
1.6
0.07
38% 51% 69%
Matched 27% 1.2 36% 1.4 63% 1.2
0.5 0.2 0.6
60%
44%
0.4
1.3
Page 16 of 19
17 EDITORIAL COMMENT Byron H. Lee, MD, PhD (corresponding author) Department of Urology Glickman Urological and Kidney Institute Cleveland Clinic 9500 Euclid Ave., Q10-1 Cleveland, OH 44195 Tel: (216) 444-0526 Fax: (216) 636-4492 Email: [email protected] Gopa Iyer, MD Genitourinary Oncology Service Department of Medicine Memorial Sloan Kettering Cancer Center Hikmat A. Al-Ahmadie, MD Department of Pathology Memorial Sloan Kettering Cancer Center
Bladder cancer is the fifth most common cancer diagnosed in the United States and can display a diverse array of histologic variants. Plasmacytoid urothelial carcinoma (PUC) is a rare histologic variant that is characterized by malignant cells growing in an infiltrating discohesive pattern with minimal stromal reaction. Clinically, PUC is associated with upstaging at cystectomy, high rates of surgical margin positivity and lymph node involvement, predilection for peritoneal recurrence, and poor outcomes when compared with urothelial carcinoma, not otherwise specified (UC, NOS) 1-5.
In this study, the authors performed a retrospective review of 46 patients with PUC identified between 1980 to 2009 at a single institution and compared oncologic outcomes with patients who had UC, NOS. Of note, 4/46 (9%) of patients received neoadjuvant chemotherapy and 17/46 (37%) of patients received adjuvant chemotherapy. The authors found that PUC is associated with increased pathologic stage and positive surgical margins at cystectomy as well as inferior recurrence free survival, cancer
Page 17 of 19
18 specific survival, and overall survival. Given the rarity of PUC, this series represents one of the largest in the published literature and corroborates the experiences at other institutions.
Nonetheless, the optimal care strategy for patients with PUC remains to be determined. Since understaging is common, many authors support early cystectomy for these patients. However, the role of perioperative systemic therapy needs to be better defined. Some studies report sensitivity to cisplatin-based chemotherapy but with early relapse while others showed no benefit for patients receiving chemotherapy. Data for response to chemotherapy across studies is limited by factors that are difficult to overcome for a rare tumor such as retrospective design, differences in chemotherapeutic regimen and setting (neoadjuvant, adjuvant, or definitive), and inclusion/exclusion criteria for percent variant histology. Molecular characterization revealed somatic CDH1 alterations in 84% of PUC; however, there are currently no therapies that can be used to target this pathway. Nonetheless, the presence of other actionable mutations was identified and these patients may potentially benefit from targeted therapies. Additionally, ERCC2 mutations predict for sensitivity to platinum-based chemotherapy in patients with UC, NOS 6, 7, and a similar study can be performed to determine whether ERCC2 mutations also predict for response in patients with PUC. Ultimately, innovative clinical trial methods will be needed to identify novel therapies for patients with PUC.
Page 18 of 19
19 References 1.
2.
3. 4.
5. 6. 7.
Dayyani F, Czerniak BA, Sircar K, et al. Plasmacytoid urothelial carcinoma, a chemosensitive cancer with poor prognosis, and peritoneal carcinomatosis. The Journal of urology. 2013;189:1656-1661. Keck B, Wach S, Stoehr R, et al. Plasmacytoid variant of bladder cancer defines patients with poor prognosis if treated with cystectomy and adjuvant cisplatin-based chemotherapy. BMC cancer. 2013;13:71. Kaimakliotis HZ, Monn MF, Cary KC, et al. Plasmacytoid variant urothelial bladder cancer: is it time to update the treatment paradigm? Urologic oncology. 2014;32:833-838. Kaimakliotis HZ, Monn MF, Cheng L, et al. Plasmacytoid bladder cancer: variant histology with aggressive behavior and a new mode of invasion along fascial planes. Urology. 2014;83:11121116. Al-Ahmadie HA, Iyer G, Lee BH, et al. Frequent somatic CDH1 loss-of-function mutations in plasmacytoid variant bladder cancer. Nature genetics. 2016;48:356-358. Van Allen EM, Mouw KW, Kim P, et al. Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer discovery. 2014;4:1140-1153. Liu D, Plimack ER, Hoffman-Censits J, et al. Clinical Validation of Chemotherapy Response Biomarker ERCC2 in Muscle-Invasive Urothelial Bladder Carcinoma. JAMA oncology. 2016;2:1094-1096.
Page 19 of 19
S0090-4295(16)30793-2 http://dx.doi.org/doi: 10.1016/j.urology.2016.09.053 URL 20113
To appear in:
Urology
Received date: Accepted date:
20-6-2016 3-9-2016
Please cite this article as: Patrick A. Cockerill, John C. Cheville, Stephen A. Boorjian, Andrew Blackburne, Prabin Thapa, Robert F. Tarrell, Igor Frank, Outcomes Following Radical Cystectomy for Plasmacytoid Urothelial Carcinoma: Defining the Need for Improved Local Cancer Control, Urology (2016), http://dx.doi.org/doi: 10.1016/j.urology.2016.09.053. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Outcomes Following Radical Cystectomy for Plasmacytoid Urothelial Carcinoma: Defining the Need for Improved Local Cancer Control Patrick A. Cockerill, John C. Cheville, Stephen A. Boorjian, Andrew Blackburne, Prabin Thapa, Robert F. Tarrell, Igor Frank Department of Urology, Mayo Clinic, Rochester, Minnesota
Correspondence:
Igor Frank, MD Mayo Clinic Department of Urology Mayo Clinic 200 First Street Southwest Rochester, Minnesota 55905 E-mail: [email protected] Telephone: 507-266-0191 Fax: (507) 284-4951
Word count of text: 1718 Word count of abstract: 242 Key words: Plasmacytoid urothelial cancer Conflict of Interest: Drs. Cockerill, Cheville, Boorjian, Blackburne and Frank, and Mr. Thapa and Mr. Tarrell, have nothing to disclose.
Page 1 of 19
2 ABSTRACT Objective: To evaluate oncologic outcomes after radical cystectomy (RC) in patients with plasmacytoid urothelial carcinoma (UC), and compared survival to that in patients with pure UC of the bladder. Methods: We identified 46 patients with plasmacytoid UC and 972 with pure UC who were treated with RC between 1980 and 2009. All pathologic specimens were re-reviewed by a single GU pathologist. Patients were matched 1:2 by age, gender, ECOG performance status, pathological tumor stage and nodal status to patients with pure UC. Survival was estimated using the Kaplan-Meier method and compared with the log rank test. Results: Patients with plasmacytoid UC were more likely to have extravesical disease (≥pT3) (83% versus 43%, p<0.0001) and positive margins (31% versus 2.1%, p<0.0001), than patients with pure UC. Plasmacytoid UC was associated with decreased overall survival (27% v 45% at 5 years, RR 1.4, p=0.04), cancer specific survival (36% v 57% at 5 years, RR 1.7, p=0.01), and local recurrence free survival (63% v 81% at 5 years, RR 2, p=0.01). When patients with plasmacytoid UC were matched to those with pure UC, there were no significant differences in 5-year overall, cancer specific, local or distant recurrence free survival. Conclusion: Plasmacytoid UC is associated with a high rate of locally advanced disease and positive margins at RC, as well as increased local recurrence rates. Further research is necessary to delineate adjuvant or neoadjuvant treatment strategies to improve local cancer control this rare subtype of UC. INTRODUCTION Plasmacytoid carcinoma is a rare but increasingly recognized pathologic subtype of bladder cancer. It was first recognized in 1991 separately by Sahin et al1 and Zukerberg2. Sahin described a patient with metastatic bladder cancer presenting as multiple lytic bone lesions, which on biopsy was noted to resemble plasma cells. Zukerberg reported two cases of locally advanced urothelial carcinoma that
Page 2 of 19
3 resembled lymphoma and plasmacytoma. In 2004, the WHO recognized plasmacytoid variants, describing the malignant cells as resembling lymphocytes, monocytes and plasma cells.
Since the WHO recognition, there have been further case series that have included 4 to 31 patients.4-13 These case series identified plasmacytoid carcinoma as locally aggressive, infiltrative, and associated with poor outcomes. The optimal treatment strategy has not been elucidated secondary to the small number of patients, however at least some tumors are chemosensitive to standard urothelial cancer regimens, including Methotrexate/Vinblastine/Adriamycin/Cisplatin (MVAC) and Gemcitabine/Cisplatin (GC).
In this study, we describe our experience with plasmacytoid carcinoma treated by radical cystectomy. Specifically, we report clinical outcomes of these patients and compare their outcome with patients with typical urothelial carcinoma.
Page 3 of 19
4 MATERIALS AND METHODS With institutional review board approval, we retrospectively reviewed the cystectomy registry at our institution. From 1980 to 2009, 3186 radical cystectomies were performed by various surgeons. Of these, 46 patients (1%) had plasmacytoid carcinoma. All pathologic specimens were re-reviewed by a urologic pathologist (JC). Clinico-pathologic features evaluated included age, gender, ECOG performance status, presence of lymphovascular invasion, surgical margin status, and receipt of chemotherapy, whether adjuvant or neoadjuvant. Tumors were staged according to the 2010 American Join Committee on Cancer/UICC TNM classification.
Follow up after radical cystectomy at our institution has evolved over the past 3 decades, however, in general, is performed every 3 months for 2 years, then every six months for 3 years, then annually thereafter assuming there is no recurrence. Oncologic surveillance includes history and physical exam, urine cytology, computed tomography of the abdomen and pelvis, and either computed tomography or X-ray of the chest.
Local recurrence was defined as recurrence within the surgical bed or within the lymph node dissection template. Distant metastasis included lymph nodes outside the surgical dissection template, viscera, or bone. Survival status was accumulated from death certificates, or from patient/physician correspondence if the patient was treated elsewhere following cystectomy. We evaluated the clinicopathologic characteristics of patients with plasmacytoid carcinoma and compared them to patients with urothelial carcinoma. If the pathologic specimen had any other variant histology present, it was excluded. Patients with plasmacytoid carcinoma were matched for age, gender, ECOG performance status, tumor stage, nodal stage, 1:2 with a cohort of typical UC Survival outcomes evaluated included
Page 4 of 19
5 overall survival, cancer specific survival, local recurrence free survival and distant metastasis free survival.
Comparison of clinicopathologic features was done using conditional logistic regression analysis. Survival was estimated as time from RC to death, cancer death, or recurrence using the Kaplan-Meier method and compared with the log rank test. SAS software was used for analysis.
Page 5 of 19
6 RESULTS Pathology Plasmacytoid carcinoma exhibited an infiltrative growth pattern, diffusely involving the bladder with a minimal desmoplastic reaction (Figure 1). The cells were small and resembled lymphocytes, monocytes and plasma cells. In addition, some cells contained clear vacuoles with eccentric nuclei but lacked intracellular mucin in contrast to signet ring cell adenocarcinoma (Figure 1). Additionally, cells exhibited single filing similar to lobular carcinoma of the breast (Supplementary Figure 4). Clinicopathologic Features The clinicopathologic features of the cohorts are presented in Table 1. There were 46 patients with plasmacytoid carcinoma and 972 patients with urothelial carcinoma. Median age, gender, and ECOG performance status were similar between the cohorts. Patients with plasmacytoid carcinoma were more likely to have a locally advanced tumor; 37% of patients had pT4 disease compared to 6% of patients with UC (p<0.0001). These patients were also more likely to receive adjuvant chemotherapy (37% v 11%, p<0.0001), a reflection of their advanced stage at cystectomy. Patients with plasmacytoid carcinoma were more likely to have a positive peripheral perivesical surgical margins as a result of locally advanced stage and minimal desmoplastic reaction (14 [30%] v 18 [2%], p<0.0001). There was no difference in the rate of lymph node metastasis or receipt of neoadjuvant chemotherapy. Additionally, 5 (11%) of the plasmacytoid carcinoma patients had a positive final ureteral margin for invasive carcinoma. Survival Analysis Of the 46 patients with plasmacytoid carcinoma, 27 (59%) died of bladder cancer with a median survival of 1.7 years, and 10 patients died of other causes with a median follow-up of 2.2 years. Of the 9
Page 6 of 19
7 surviving patients, median follow-up is 10.3 years. Additionally, 13 (29%), 21 (46%), and 2 (4%) patients had local, distant, and upper tract recurrence, respectively. Patients with plasmacytoid carcinoma were significantly more likely to experience cancer specific and overall death with locally advanced disease (T3N0 and T4N0) versus organ confined disease (T1N0 and T2N0). At 5 years, cancer specific and overall survival were 86% and 75% for T1/T2 versus 30% and 25% for T3/T4 (p<0.05) (Figure 2). When patients with plasmacytoid carcinoma were compared to all patients with urothelial carcinoma, five-year overall survival was significantly decreased in the patients with plasmacytoid carcinoma, 27% versus 45% (RR 1.4, p=0.04) (Table 2). Cancer specific survival (36% v 57%, RR 1.7, p=0.01) and local recurrence free survival (63% v 81%, RR 2.0, p=0.01) were also significantly decreased in the patients with plasmacytoid carcinoma. There was a non-significant trend toward decreased distant metastasis free survival (p=0.07). When patients with plasmacytoid carcinoma were matched 1:2 with a cohort of patients with typical urothelial carcinoma for age, gender, ECOG performance status, and pathologic tumor stage, only peripheral tumor margin positivity remained significantly different between the two cohorts (30% positive margins with plasmacytoid carcinoma versus 5% with of urothelial carcinoma. Additionally, although there was a difference in overall, cancer specific, local recurrence free, and distant metastasis free survival, this did not reach statistical significance (Table 2) (Supplementary Figures 1-3).
Page 7 of 19
8 DISCUSSION Plasmacytoid carcinoma of the urinary bladder is a rare variant of bladder cancer, accounting for only 1% of cancers in our cystectomy registry. In our experience, patients with plasmacytoid carcinoma treated by radical cystectomy presented with locally advanced disease, with 83% of patients presenting with extravesical spread (pT3 or pT4). As a result, patients are much more likely to have positive radial surgical margins compared to patients with typical urothelial carcinoma. Another important contributor to the high rate of margin positivity is the pattern of spread and the lack of desmoplastic reaction characteristic of these tumors, such that the plane between tumor and normal tissue is difficult to discern surgically. Not surprisingly, we noted an increased rate of local recurrence in these patients, with 28% experiencing local recurrence compared to 16% of UC patients, likely related to the high rate of positive margins. It is critical that plasmacytoid carcinoma is recognized by the pathologist preoperatively such that care can be given to obtaining negative surgical margins at cystectomy. Other studies have also reported a high rate of surgical margin positivity ranging from 11 to 60% (Supplementary Figure 5).4-6 In addition, Kaimakliotis et al noted a high rate of invasive tumor at the ureteral margin with 32% of patients with plasmacytoid carcinoma having a positive ureteral margin compared to less than 4% for patients with urothelial carcinoma.6 In our cohort, 5 patients (11%) had a positive final ureteral margin for invasive carcinoma.
Our experience with outcome is similar to previous reports. Patients with plasmacytoid carcinoma had worse cancer specific outcomes compared to patients with urothelial carcinoma. The difference in outcome was evident even when patients with plasmacytoid carcinoma were matched for prognostic features with patients with urothelial carcinoma (36% 5-year cancer specific survival for patients with plasmacytoid carcinoma compared to 51% with patients with urothelial carcinoma) although this did not
Page 8 of 19
9 reach statistical significance likely due to the small number of patients with plasmacytoid carcinoma. This finding is in contrast to our previous reports of variant histologies such as squamous and glandular differentiation, nested variant, and micropapillary carcinoma that showed matched patients had similar outcomes.14-16 However, the high rate of locally advanced disease in the plasmacytoid variant is similar to our findings regarding squamous and glandular differentiation, nested variant, and micropapillary urothelial carcinoma.14-16 Finally, we found a significant increase in cancer specific and overall mortality in plasmacytoid carcinoma patients when the final pathology from cystectomy was locally advanced versus organ confined (T3/T4 versus T1/T2). Thus, early detection and aggressive treatment is critical to the outcome in these patients.
The rarity of plasmacytoid carcinoma makes it difficult to define the optimal treatment strategy. Non muscle invasive tumors have successfully been managed with resection and intravesical BCG therapy.5 Caution must be taken, however, as the concern in these instances is under-staging, as clinical staging based on imaging may not be indicative of pathologic staging secondary to the discohesive nature of spread of tumor cells and the lack of desmoplastic reaction. The role of chemotherapy in the neoadjuvant or adjuvant setting continues to be defined. Dayyani reported on 31 patients with plasmacytoid carcinoma, 16 with localized disease at presentation.4 Five patients received neoadjuvant chemotherapy with cisplatin based regimens (MVAC or GC), with four patients exhibiting pathologic downstaging, and a complete response (ypT0N0) in three patients. Adjuvant chemotherapy was given in an additional 7 patients. Combining their localized and metastatic patients (15 patients), they noted that plasmacytoid carcinomas chemosensitive in general, however recurrence was common, and survival outcomes inferior to urothelial carcinoma. Keck reported on 32 patients with plasmacytoid
Page 9 of 19
10 carcinoma, 16 of who received adjuvant chemotherapy and noted an overall survival of 23 months, which was significantly worse than a comparable group of patients with urothelial carcinoma.7
Unfortunately, genomic markers were unable to be obtained from our specimens. A recent study by AlAhmadie et al, demonstrated nonsense mutations in CDH1 with loss of E-cadherin expression in patients with plasmacytoid variant bladder cancer.17
CONCLUSION Plasmacytoid carcinoma of the urinary bladder is an aggressive histologic variant so that early detection, and accurate pathologic recognition and clinical staging are critical to improving patient survival. This histologic variant is associated with locally advanced disease at radical cystectomy resulting in a high rate of surgical margin positivity. The optimal treatment modality continues to be defined, however aggressive resection to obtain a negative margins, and systemic chemotherapy in the adjuvant or neoadjuvant setting have shown promise.
Page 10 of 19
11 REFERENCES 1. 2. 3. 4.
5. 6. 7.
8. 9.
10.
11. 12. 13.
Sahin AA, Myhre M, Ro JY, et al: Plasmacytoid transitional cell carcinoma. Report of a case with initial presentation mimicking multiple myeloma. Acta cytologica. 35: 277-80, 1991. Zukerberg LR, Harris NL and Young RH: Carcinomas of the urinary bladder simulating malignant lymphoma. A report of five cases. The American journal of surgical pathology. 15: 569-76, 1991. Eble JN SG, Epstein JI: Pathology and genetics: tumours of the urinary system and male genital organs. WHO Classification of Tumours. Lyon: IARC press, 2004. Dayyani F, Czerniak BA, Sircar K, et al. Plasmacytoid urothelial carcinoma, a chemosensitive cancer with poor prognosis, and peritoneal carcinomatosis. The Journal of urology. 189: 165661, 2013. Fritsche HM, Burger M, Denzinger S, et al. Plasmacytoid urothelial carcinoma of the bladder: histological and clinical features of 5 cases. The Journal of urology. 180: 1923-7, 2008. Kaimakliotis HZ, Monn MF, Cheng L, et al: Plasmacytoid bladder cancer: variant histology with aggressive behavior and a new mode of invasion along fascial planes. Urology. 83: 1112-6, 2014. Keck B, Wach S, Stoehr R, et al: Plasmacytoid variant of bladder cancer defines patients with poor prognosis if treated with cystectomy and adjuvant cisplatin-based chemotherapy. BMC cancer. 13: 71, 2013. Lopez-Beltran A, Requena MJ, Montironi R, et al: Plasmacytoid urothelial carcinoma of the bladder. Human pathology. 40: 1023-8, 2009. Raspollini MR, Sardi I, Giunti L, et al: Plasmacytoid urothelial carcinoma of the urinary bladder: clinicopathologic, immunohistochemical, ultrastructural, and molecular analysis of a case series. Human pathology. 42: 1149-58, 2011. Ricardo-Gonzalez RR, Nguyen M, Gokden N, et al: Plasmacytoid carcinoma of the bladder: a urothelial carcinoma variant with a predilection for intraperitoneal spread. The Journal of urology. 187: 852-5, 2012. Ro JY, Shen SS, Lee HI, et al: Plasmacytoid transitional cell carcinoma of urinary bladder: a clinicopathologic study of 9 cases. The American journal of surgical pathology. 32: 752-7, 2008. Mai KT, Park PC, Yazdi HM, et al: Plasmacytoid urothelial carcinoma of the urinary bladder report of seven new cases. European urology. 50: 1111-4, 2006. Aldousari S, Sircar K and Kassouf W: Plasmacytoid urothelial carcinoma of the bladder: a case report. Cases journal. 2: 6647, 2009.
14.
Kim SP, Frank I, Cheville JC, et al: The impact of squamous and glandular differentiation on survival after radical cystectomy for urothelial carcinoma. The Journal of Urology. 188: 405-9, 2012.
15.
Linder BJ, Frank I, Cheville JC, et al: Outcomes following radical cystectomy for nested variant of urothelial carcinoma: A matched cohort analysis. The Journal of Urology. 189: 1670-5, 2013.
16.
Wang JK, Boorjian SA, Cheville JC, et al: Outcomes following radical cystectomy for micropapillary bladder cancer versus pure urothelial carcinoma: a matched cohort analysis. World Journal of Urology. 30: 801-6, 2012.
17.
Al-Ahmadie HA, Iyer G, Lee BH, et al: Frequent somatic CDH1 loss-of-function mutations in plasmacytoid variant bladder cancer. 48: 356-8, 2016.
Page 11 of 19
12
Figure 1 a) Cystectomy specimen showing diffusely thickened rigid bladder wall with lack of intraluminal mass. b) Plasmacytoid carcinoma is characterized by non-cohesive cells resembling lymphocytes, plasma cells and monocytes. Scattered cells show intraluminal vacuoles with eccentric nuclei resembling signet ring cells but lacking intracellular mucin.
Page 12 of 19
13
Figure 2 Plasmacytoid carcinoma cancer specific survival by stage
Supplementary Figure 1 Matched overall survival Supplementary Figure 2 Matched cancer specific survival. Supplementary Figure 3
Page 13 of 19
14
Matched local recurrence free survival Supplementary Figure 4 The infiltrating tumor lacks an associated stromal reaction, and the pattern of spread resembles lobular carcinoma of the breast. Supplementary Figure 5 Literature Summary
Page 14 of 19
15
Table 1. Clinico-pathologic features of patients with plasmacytoid carcinoma and typical urothelial carcinoma
Number of patients Age at surgery (yrs) median (IQR) Male Gender
Plasmacytoid carcinoma 46 68 (60, 73) 36 (78%)
Urothelial carcinoma 972 68 (62, 75) 805 (83%)
ECOG performance status
p value
0.2 0.4 0.6
0
32 (74%)
772 (81%)
1
8 (19%)
138 (14%)
2+
3 (7%)
49 (5%)
Neoadjuvant chemotherapy
4 (9%)
60 (6.2%)
0.5
17 (37%)
111 (11%)
<0.0001
Adjuvant chemotherapy Pathologic Tumor Stage
<0.0001
≤T1
1 (2%)
286 (29%)
T2
7 (15%)
274 (28%)
T3
21 (46%)
358 (37%)
T4
17 (37%)
54 (6%)
pN+
13 (29%)
183 (19%)
0.1
Positive Tumor Margin
14 (30%)
18 (2%)
<0.0001
Page 15 of 19
16
Table 2 Survival Outcomes
5 yr OS 5 yr CSS 5 yr Local RFS 5 yr Distant Metastasis FS 5 yr OS 5 yr CSS 5 yr Local RFS 5 yr Distant Metastasis FS
Pure UC 45% 57% 81%
Unmatched Plasmactyoid RR UC 27% 1.4 36% 1.6 63% 2.7
p value 0.04 0.01 0.01
62%
45%
1.6
0.07
38% 51% 69%
Matched 27% 1.2 36% 1.4 63% 1.2
0.5 0.2 0.6
60%
44%
0.4
1.3
Page 16 of 19
17 EDITORIAL COMMENT Byron H. Lee, MD, PhD (corresponding author) Department of Urology Glickman Urological and Kidney Institute Cleveland Clinic 9500 Euclid Ave., Q10-1 Cleveland, OH 44195 Tel: (216) 444-0526 Fax: (216) 636-4492 Email: [email protected] Gopa Iyer, MD Genitourinary Oncology Service Department of Medicine Memorial Sloan Kettering Cancer Center Hikmat A. Al-Ahmadie, MD Department of Pathology Memorial Sloan Kettering Cancer Center
Bladder cancer is the fifth most common cancer diagnosed in the United States and can display a diverse array of histologic variants. Plasmacytoid urothelial carcinoma (PUC) is a rare histologic variant that is characterized by malignant cells growing in an infiltrating discohesive pattern with minimal stromal reaction. Clinically, PUC is associated with upstaging at cystectomy, high rates of surgical margin positivity and lymph node involvement, predilection for peritoneal recurrence, and poor outcomes when compared with urothelial carcinoma, not otherwise specified (UC, NOS) 1-5.
In this study, the authors performed a retrospective review of 46 patients with PUC identified between 1980 to 2009 at a single institution and compared oncologic outcomes with patients who had UC, NOS. Of note, 4/46 (9%) of patients received neoadjuvant chemotherapy and 17/46 (37%) of patients received adjuvant chemotherapy. The authors found that PUC is associated with increased pathologic stage and positive surgical margins at cystectomy as well as inferior recurrence free survival, cancer
Page 17 of 19
18 specific survival, and overall survival. Given the rarity of PUC, this series represents one of the largest in the published literature and corroborates the experiences at other institutions.
Nonetheless, the optimal care strategy for patients with PUC remains to be determined. Since understaging is common, many authors support early cystectomy for these patients. However, the role of perioperative systemic therapy needs to be better defined. Some studies report sensitivity to cisplatin-based chemotherapy but with early relapse while others showed no benefit for patients receiving chemotherapy. Data for response to chemotherapy across studies is limited by factors that are difficult to overcome for a rare tumor such as retrospective design, differences in chemotherapeutic regimen and setting (neoadjuvant, adjuvant, or definitive), and inclusion/exclusion criteria for percent variant histology. Molecular characterization revealed somatic CDH1 alterations in 84% of PUC; however, there are currently no therapies that can be used to target this pathway. Nonetheless, the presence of other actionable mutations was identified and these patients may potentially benefit from targeted therapies. Additionally, ERCC2 mutations predict for sensitivity to platinum-based chemotherapy in patients with UC, NOS 6, 7, and a similar study can be performed to determine whether ERCC2 mutations also predict for response in patients with PUC. Ultimately, innovative clinical trial methods will be needed to identify novel therapies for patients with PUC.
Page 18 of 19
19 References 1.
2.
3. 4.
5. 6. 7.
Dayyani F, Czerniak BA, Sircar K, et al. Plasmacytoid urothelial carcinoma, a chemosensitive cancer with poor prognosis, and peritoneal carcinomatosis. The Journal of urology. 2013;189:1656-1661. Keck B, Wach S, Stoehr R, et al. Plasmacytoid variant of bladder cancer defines patients with poor prognosis if treated with cystectomy and adjuvant cisplatin-based chemotherapy. BMC cancer. 2013;13:71. Kaimakliotis HZ, Monn MF, Cary KC, et al. Plasmacytoid variant urothelial bladder cancer: is it time to update the treatment paradigm? Urologic oncology. 2014;32:833-838. Kaimakliotis HZ, Monn MF, Cheng L, et al. Plasmacytoid bladder cancer: variant histology with aggressive behavior and a new mode of invasion along fascial planes. Urology. 2014;83:11121116. Al-Ahmadie HA, Iyer G, Lee BH, et al. Frequent somatic CDH1 loss-of-function mutations in plasmacytoid variant bladder cancer. Nature genetics. 2016;48:356-358. Van Allen EM, Mouw KW, Kim P, et al. Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer discovery. 2014;4:1140-1153. Liu D, Plimack ER, Hoffman-Censits J, et al. Clinical Validation of Chemotherapy Response Biomarker ERCC2 in Muscle-Invasive Urothelial Bladder Carcinoma. JAMA oncology. 2016;2:1094-1096.
Page 19 of 19