A Case of Unusual Mast Cell Response With Interstitial Cystitis-Like Symptoms to Neoadjuvant Chemotherapy for Muscle-Invasive Transitional Cell Carcinoma of the Bladder

Randomized trials support the use of neoadjuvant chemotherapy in muscle-invasive bladder cancer based on a noted survival advantage, which appeared to be strongly related to downstaging of the cancer to pT0 (complete pathologic response). This report presents a case of an unusual mast cell response along with bladder wall thickening after neoadjuvant chemotherapy. However, the final cystectomy specimen did not reveal any residual tumor (pT0). The authors hypothesize that neoadjuvant chemotherapy could have caused the diffuse mast cell response, and that this profound inflammatory response can be used as a biomarker of complete response to chemotherapy.

NCCN: Continuing Education

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This activity has been designated to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians.

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All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/35435; and 4) view/print certificate.

Release date: December 16, 2013; Expiration date: December 16, 2014

Learning Objectives

Upon completion of this activity, participants will be able to:

  • Describe several treatment options for urinary bladder cancer
  • Summarize possible pathologic responses to cisplatin-based neoadjuvant therapy

An estimated 72,570 people (54,610 men and 17,960 women) will be diagnosed with cancer of the urinary bladder and 15,210 will die of the disease in the United States in 2013.1 Localized bladder cancers constitute approximately 35% of all bladder cancer cases and have an overall 5-year relative survival of 70%.1 Urothelial (transitional cell) carcinomas are the most common histologic subtype in the United States. Cisplatin-based neoadjuvant chemotherapy has been shown to improve survival in patients with localized muscle-invasive bladder cancer.2-5 In the metastatic setting, gemcitabine/cisplatin (GC) showed similar efficacy to MVAC (methotrexate/vinblastine/doxorubicin/cisplatin) in terms of objective response rate, progression-free survival, and overall survival, and had a more favorable toxicity profile.6 Furthermore, in many studies the rate of downstaging with GC use was comparable to that of MVAC.7-9 The GC data in the metastatic setting are extrapolated to the neoadjuvant setting, because they show comparable results with a reduced toxicity profile. Approximately 38% of patients receiving neoadjuvant chemotherapy show a complete pathologic response (pT0) at cystectomy,4 and the remaining patients have either residual disease or progressive disease. This report presents a case of unusual mast cell response to neoadjuvant chemotherapy, suspicious for disease progression on imaging studies.

Case Report

A 51-year-old woman presented with a 3-week history of gross hematuria and dysuria. She was initially treated with antibiotics for a possible urinary tract infection. However, hematuria persisted and a subsequent CT scan of her abdomen and pelvis (with and without contrast) showed an irregular necrotic-appearing mass at the bladder dome measuring 5 x 3 cm (Figure 1). No evidence was seen of lymphadenopathy or metastasis. Cystoscopy confirmed the presence of a mass and she underwent transurethral resection (TUR) of the bladder tumor. After resection, the tumor base was cauterized and a mitomycin cocktail was left indwelling. Hematuria subsided with TUR.

Based on pathology report, patient was started on neoadjuvant chemotherapy with a GC-based regimen for an intended 3 cycles before the planned cystectomy. The dose of gemcitabine was reduced by 20% on day 8 of cycle 1 because of thrombocytopenia. At the end of the second cycle of chemotherapy, the patient again developed significant hematuria, dysuria, and increased urinary frequency. An ultrasonogram of the bladder showed diffuse thickening of the bladder wall in addition to the tumor (Figure 2). She was deemed to have progressive disease based on worsening symptoms and bladder wall thickening on ultrasound, with suspected intramural spread. Repeat CT scan of the abdomen and pelvis with contrast showed a decrease in tumor size to 3 x 1 cm along with bladder wall thickening (Figure 3). This was highly suspicious of disease progression. Therefore, chemotherapy was discontinued and she underwent a robot-assisted radical cystectomy with open construction of an ileal neobladder and an extended bilateral pelvic lymph node dissection.

Figure 1
Figure 1

CT scan showing irregular necrotic mass at bladder dome, measuring 5 x 3 cm (arrow).

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 12; 10.6004/jnccn.2013.0172

Figure 2
Figure 2

Post-void ultrasonogram of bladder showing thickened bladder wall (arrow).

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 12; 10.6004/jnccn.2013.0172

Figure 3
Figure 3

CT scan showing bladder wall thickening (arrow) and decrease in tumor size to 3 x 1 cm.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 12; 10.6004/jnccn.2013.0172

Pathology

The original TUR specimen showed a “high-grade urothelial carcinoma invading into muscularis propria with focal lymphovascular invasion” (Figure 4). Gross inspection of the subsequent cystectomy specimen (Figure 5) showed a firm, orange-tan indurated lesion measuring 1.2 x 0.9 cm located in the posterior aspect of the bladder dome. Microscopic examination revealed an ulcerated granulomatous inflammation, microcalcifications, and fibrosis extending into the muscularis propria, consistent with previous therapy effect (Figure 6). No residual carcinoma was identified (pT0). Interestingly, the muscularis propria showed diffuse mast cells infiltration, up to 33 cells per 1 high-power field (Figure 7), which was confirmed by the CD117 immunohistochemical stain (Figure 8). A total of 24 pelvic lymph nodes were also found to be negative for metastasis.

Figure 4
Figure 4

Transurethral resection showing high-grade urothelial carcinoma invading muscularis propria (asterisks; hematoxylin-eosin, original magnification x100); high-power magnification of carcinoma (inset; original magnification x400).

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 12; 10.6004/jnccn.2013.0172

Figure 5
Figure 5

Gross photograph of the cystectomy specimen showing the residual lesion (circled) at the dome of the bladder.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 12; 10.6004/jnccn.2013.0172

Discussion

This patient was started on neoadjuvant chemotherapy with GC and developed the symptoms of dysuria, urgency, and frequency. In the context of a thickened bladder wall, this development was concerning for disease progression, and the surgery was appropriately preponed. To the authors’ surprise, final pathology results of the cystectomy specimen did not reveal any residual tumor. Chronic inflammation with fibrosis and focal granulomatous inflammation were noted (common reactions to chemotherapy). However, diffuse mast cell infiltration of the bladder wall is unusual.

Figure 6
Figure 6

Microscopic photograph of the bladder lesion showing ulcerated granulomatous inflammation, microcalcifications, and fibrosis extending into the muscularis propria (hematoxylin-eosin, original magnification x20).

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 12; 10.6004/jnccn.2013.0172

Figure 7
Figure 7

Detrusor muscle infiltrated by mast cells (arrows; hematoxylin-eosin, original magnification x200); higher magnification of the mast cells (right inset; original magnification x400) and perineural mast cell involvement (left inset; original magnification x400).

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 12; 10.6004/jnccn.2013.0172

Mastocyte accumulation in the bladder mucosa and detrusor muscle can be seen in multiple conditions, including normal aging, interstitial cystitis, mechanical trauma, and parasitic or bacterial infections. The clinical symptoms of pain, dysuria, and frequency are similar to those observed in interstitial cystitis/bladder pain syndrome, which suggested the possibility of interstitial cystitis in the present patient’s scenario. The diagnosis of interstitial cystitis is predominantly a clinical diagnosis, and no definite pathologic criteria have been established. The primary mechanisms that trigger interstitial cystitis have yet to be elucidated. However, the role of activated mast cells, especially those associated with nerve fibers in the development of interstitial cystitis symptoms, has been suggested by multiple studies.10-14 Animal models also showed that mast cells play a crucial role in the development of pain in cystitis through the release of histamine and tumor necrosis factor.14,15

Diffuse mast cell infiltration of the detrusor muscle along with perineural mast cell accumulation (Figure 7) could explain the aggravation of this patient’s pain after she received 2 cycles of chemotherapy. Furthermore, the patient had exposure to intravesical mitomycin 1 month before the start of neoadjuvant chemotherapy. It is well-known that intravesical mitomycin can cause chemical cystitis, and case reports have been published of eosinophilic cystitis after mitomycin-C intravesical instillation.16 However, most of these cases occurred as a delayed hypersensitivity reaction after multiple intravesical treatments for superficial bladder tumors, and none of them had diffuse mast cell infiltration. This supports the idea that chemotherapy could be one of the factors causing activation and degranulation of mast cells, resulting in a clinical picture similar to interstitial cystitis.

Figure 8
Figure 8

CD117 immunohistochemical stain highlighting the mast cells (arrows; hematoxylin-eosin, original magnification x200).

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 12; 10.6004/jnccn.2013.0172

Conclusions

This type of overwhelming inflammatory response may be a biomarker of complete response to chemotherapy. This phenomenon may be studied and thus developed as a strategy to avoid cystectomy. Moreover, this case also underscores the fact that radiographic appearance does not always correlate with the histopathologic changes in the tumor as a response to systemic chemotherapy.

Dr. George has disclosed that he has received research funding from GlaxoSmithKline plc, and is a consultant and advisory board member for AVEO Pharmaceuticals, Inc., sanofi-aventis U.S. LLC, Bayer HealthCare/Algeta, and Novartis. The remaining authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.

EDITOR

Kerrin M. Green, MA, Assistant Managing Editor, JNCCN—Journal of the National Comprehensive Cancer Network

Ms. Green has disclosed that she has no relevant financial relationships.

CE AUTHORS

Deborah J. Moonan, RN, BSN, Manager, CE Supporter Outreach

Ms. Moonan has disclosed the following relationship with commercial interests: AstraZeneca: Stockholder/Former Employee.

Ann Gianola, MA, Manager, Medical Education Accreditation and Grant Development

Ms. Gianola has disclosed the following relationship with commercial interests: Actelion: Grant/Research Support.

Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations

Ms. Gregory has disclosed that she has no relevant financial relationships.

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Correspondence: Saby George, MD, Genitourinary Program, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263. E-mail: Saby.George@RoswellPark.org

Supplementary Materials

  • View in gallery

    CT scan showing irregular necrotic mass at bladder dome, measuring 5 x 3 cm (arrow).

  • View in gallery

    Post-void ultrasonogram of bladder showing thickened bladder wall (arrow).

  • View in gallery

    CT scan showing bladder wall thickening (arrow) and decrease in tumor size to 3 x 1 cm.

  • View in gallery

    Transurethral resection showing high-grade urothelial carcinoma invading muscularis propria (asterisks; hematoxylin-eosin, original magnification x100); high-power magnification of carcinoma (inset; original magnification x400).

  • View in gallery

    Gross photograph of the cystectomy specimen showing the residual lesion (circled) at the dome of the bladder.

  • View in gallery

    Microscopic photograph of the bladder lesion showing ulcerated granulomatous inflammation, microcalcifications, and fibrosis extending into the muscularis propria (hematoxylin-eosin, original magnification x20).

  • View in gallery

    Detrusor muscle infiltrated by mast cells (arrows; hematoxylin-eosin, original magnification x200); higher magnification of the mast cells (right inset; original magnification x400) and perineural mast cell involvement (left inset; original magnification x400).

  • View in gallery

    CD117 immunohistochemical stain highlighting the mast cells (arrows; hematoxylin-eosin, original magnification x200).

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