| Abstract|| |
Context: Micropapillary variant of urothelial carcinoma (MPUC) is a rare but well-recognized tumor of the urinary bladder. Tumors with micropapillary areas accompanying conventional urothelial carcinoma are more aggressive compared to conventional urothelial carcinoma and show variable keratin 7, keratin 20 and human epidermal growth factor receptor 2 (Her 2)neu expression. Aim: The aim of the study was to analyze the clinical, morphological and immunohistochemical profile of MPUC. Materials and Methods: Transurethral resection of bladder tumor (TURBT) chips of seven cases of invasive MPUC with subsequent cystoprostatectomy specimens of five patients was reviewed. Epithelial membrane antigen (EMA), Keratin 7, Keratin 20, and Her 2 immunohistochemistry were performed in all cases. Follow-up information was available for all patients (2-36 months). Results: All seven patients were male, and their ages ranged from 50 to 62 years. All cases presented with hematuria. The micropapillary pattern was seen in 20-95% of the tumor. All cases showed extensive lymphatic emboli with detrusor muscle invasion. Lymph node metastasis was present in all cases undergoing cystoprostatectomy except one. Keratin 7 and abluminal pattern of EMA positivity were seen in all cases. Keratin 20 was positive in five cases (71%), and Her 2neu positivity was seen in four cases. Three patients died 2, 3, and 6 months after initial diagnosis, among which two were Her 2 positive and one was Her 2 negative. There was no clear prognostic significance of Her 2 positivity. Conclusion: (1) MPUC is a rare but highly aggressive tumor. (2) Micropapillary is usually the predominant pattern. (3) Keratin 7 is expressed universally, whereas Keratin 20 expression is variable. (4) Her 2 expression has no clear influence on the survival.
Keywords: Detrusor invasion, Her 2neu, lymph node metastasis, lymphovascular emboli, micropapillary urothelial carcinoma
|How to cite this article:|
Chatterjee D, Das A, Radotra BD. Invasive micropapillary carcinoma of urinary bladder: A clinicopathological study. Indian J Pathol Microbiol 2015;58:2-6
|How to cite this URL:|
Chatterjee D, Das A, Radotra BD. Invasive micropapillary carcinoma of urinary bladder: A clinicopathological study. Indian J Pathol Microbiol [serial online] 2015 [cited 2020 May 27];58:2-6. Available from: http://www.ijpmonline.org/text.asp?2015/58/1/2/151153
| Introduction|| |
Urinary bladder carcinoma is a relatively common malignancy, and it is the seventh most common malignancy worldwide.  It is a tumor of the elderly, and the common presenting symptoms include painless hematuria, increased frequency, and dysuria.  The commonest type of urinary bladder carcinoma is papillary urothelial carcinoma, which comprises >90% of all bladder tumors. This variety shows male predilection with male:female ratio of 3.5:1. The other histological types of urinary bladder carcinoma include adenocarcinoma, squamous cell carcinoma, neuroendocrine tumor, melanocytic tumors, mesenchymal tumors, etc.
Many variants of papillary urothelial carcinoma have been described; however, the conventional urothelial carcinoma remains the most common type. In addition, other variants have also been described. Micropapillary variant of urothelial carcinoma (MPUC) is a rare but well-recognized variant of urothelial carcinoma. It has distinctive morphological patterns. It shows a predominantly micropapillary architecture (usually >50% area), but the area of involvement may vary.  The tumor cells show abluminal positivity for epithelial membrane antigen (EMA). It is usually regarded as a high-grade tumor with aggressive clinical behavior. It is usually seen in elderly patients, with marked male preponderance (10:1 to 5:1).  The patients often present at higher stage of disease. Detrusor muscle invasion is a common feature and seen early in the course. However, superficial, noninvasive micropapillary carcinoma has also been described in the literature.  The exact immunohistochemical features and clinical behavior of this tumor are not well-characterized. Most of the information available on this entity are in the form of either single case report or short series. ,, The clinical course is variable; some patients die rapidly whereas some have a prolonged survival. Variable human epidermal growth factor receptor 2 (Her 2)neu positivity has been reported in this tumor. The significance of Her 2 positivity in invasive micropapillary carcinoma of the urinary bladder is not clear.  The data on the relationship between Her 2 positivity and clinical behavior and survival are limited because of the rarity of this particular tumor.
In this study, we described the morphological and immunohistochemical characteristics of the invasive MPUC with clinicopathological correlation.
| Materials and Methods|| |
From 2011 to February 2014, eight cases of MPUC were diagnosed in the department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh. Among these, one case was diagnosed on referral material and no follow-up information was available. Thus, it was excluded from the study. Rest all seven cases were diagnosed in bladder biopsies/transurethral resection of bladder tumor (TURBT). Five of these patients subsequently underwent radical cystoprostatectomy. The slides of all seven TURBT chips and five cystectomy specimens were reviewed with detail morphological analysis. Immunohistochemistry (IHC) were performed for Keratin 7 (Dako, dilution 1:150), Keratin 20 (Dako, dilution 1:50), EMA (Dako, dilution 1:100), and Her 2neu (Dako, dilution 1:300). IHC was performed in at least one representative section of each specimen. Her 2 was considered positive in cases with complete strong membranous positivity in >10% tumor cells. The clinical details including the survival data were also noted with a follow-up period from 2 months to 36 months.
| Results|| |
All seven patients were male with age ranging between 50 and 62 years [Table 1]. The initial presentation was the hematuria in all seven patients and three patients also complained of dysuria. All the patients had undergone TURBT along with detrusor muscle biopsy. Histological examination revealed tumor with variable areas with micropapillary pattern, ranging from 20% to >95%. The proportion of micropapillary pattern was >90% in three cases, three cases had micropapillary component occupying around 50-60% and one case diagnosed on biopsy showed 20% micropapillary component. There was no significant difference of micropapillary component between initial biopsy and the radical surgery specimen except one case (case 6) which showed 20% micropapillary pattern in the biopsy; however, cystectomy showed 50% micropapillary areas. Invasive micropapillary pattern was characterized by small nests of tumor cells forming slender papillae lying within lacunae of tissue retraction artifact [[Figure 1]a and b]. They lacked a fibrovascular core. One case also showed prominent (30% area) pseudoglandular pattern with central clearing, also known as ring form [[Figure 1]c]. Surface high-grade urothelial carcinoma component was present at least focally in three cases to 50% in one case. The papillary urothelial carcinoma component present was high grade in all cases. Solid pattern, squamoid differentiation, and glandular differentiation were uncommon and were present very focally (<5% each) [Table 1]. One case diagnosed in biopsy, however showed predominant solid areas (50%, case 7). One case showed focal presence of goblet cells with mucin production; highlighted by Alcian blue/periodic acid-Schiff stain [[Figure 1]d]. The tumor cells showed moderate to severe nuclear atypia with hyperchromatic nuclei and frequent mitotic activity. Occasional giant cells were seen. All cases showed detrusor muscle invasion and lymphovascular emboli [[Figure 1]e]. Of the five patients undergoing radical surgery, four cases showed lymph node metastasis. One patient (case 6) who received neo-adjuvant chemotherapy prior to surgery did not show lymph node metastasis.
|Figure 1: (a) Gross photograph of micropapillary carcinoma showing diffuse thickness of the urinary bladder. Histology showing predominant micropapillary architecture (b) (H and E, ×100), pseudoglandular or ring pattern (c) (H and E, ×200), focal glandular pattern with goblet cells (d) (H and E, ×200) and extensive deep muscle invasion (e) (H and E, ×40). Immunohistochemistry showing abluminal epithelial membrane antigen positivity (f) (IP, ×200), strong cytoplasmic cytokeratin (CK)7 positivity in tumor cells and adjacent normal urothelium (g) (IP, ×100), strong cytoplasmic CK20 expression in tumor cells (h) (IP, ×200) and complete strong membranous Her 2 positivity (i) (IP, ×200)|
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Immunohistochemical analysis revealed EMA positivity in all the cases. It showed abluminal pattern of positivity [[Figure 1]f]. All seven cases had diffuse cytoplasmic keratin 7 positivity (100%), and five cases showed keratin 20 positivity (71%) [[Figure 1]g and 1h]. The adjacent normal urothelium in all cases showed strong positivity for both keratin 7 and keratin 20. Her 2 was positive in four cases [[Figure 1]i]. One case showed equivocal result and two cases were completely negative. There was no significant correlation between Her 2 expression and lymphovascular emboli, lymph node metastasis or deep muscle invasion.
Clinical follow-up information was available for all seven patients. Four patients received postoperative chemotherapy, while two received neo-adjuvant chemotherapy. One patient did not receive any chemotherapy. Three patients died 2, 3, and 6 months after the initial diagnosis. The rest four patients are doing well 36 months, 12 months, and 4 months (two patients) following surgery. Among the five patients showing Her 2 positivity or equivocal result, two patients died 2 and 3 months after initial biopsy whereas the other three patients were alive. Of the two Her 2 negative patients, one had died, and one was alive at last follow-up. Although the number of cases is too less to evaluate for statistical significance, it appears that Her 2 positivity did not confer prognostic significance. One patient underwent radical surgery after receiving neo-adjuvant chemotherapy (case 6). The morphology of the tumor in the radical surgery specimen was similar to the initial biopsy specimen, and there were no significant chemotherapy-induced changes.
| Discussion|| |
Conventional papillary urothelial carcinoma is the most common type of invasive urinary bladder carcinoma. Many other variants are described, which include urothelial carcinoma with squamoid differentiation, with glandular differentiation, with trophoblastic differentiation, nested variant, microcystic variant, micropapillary variant, plasmacytoid variant, sarcomatoid variant, and some others. These variants are rare, but proper recognition of them is important as they carry prognostic significance. MPUC is a well-recognized variant. Since the initial description by Amin et al., many cases have been reported in the literature, mainly in the form of single case reports or short series. ,,, Though rare, the presence of this pattern has definite diagnostic and prognostic significance. Micropapillary architecture can be present either focally or may be the predominant pattern. , It may be admixed with other patterns including high-grade urothelial carcinoma (transitional cell carcinoma [TCC]), squamoid differentiation, glandular differentiation, mucin production, etc.  It is important to recognize the micropapillary pattern as MPUC is regarded as a high-grade tumor with aggressive behavior. Muscle invasion is common, and patients usually present at a higher clinical stage. Micropapillary architecture has been described initially in breast carcinoma. Invasive micropapillary carcinoma of the breast gained special attention for its property of showing extensive lymphovascular emboli and lymph nodal metastasis. Similarly, MPUC also shows a propensity for extensive lymphatic emboli. Thus, it is very important to recognize micropapillary pattern in small biopsies, even when focally present. The overall survival of MPUC is poor compared to conventional urothelial carcinoma. , In this series, micropapillary pattern was the predominant in most of the cases (50-95%). Although present only in 20% of the area in one biopsy, the following cystoprostatectomy had a majority of micropapillary areas. Other patterns were present very focally. One case showed a pseudoglandular pattern, occupying nearly 30% of the area. This may resemble adenocarcinoma, especially in small biopsy. An abluminal pattern of EMA positivity is helpful in detecting this pattern. All cases had detrusor muscle invasion and lymphovascular emboli, indicating the aggressive nature of this tumor. An aggressive management including radical surgery and neo-adjuvant chemotherapy may give good results.  Noninvasive micropapillary carcinoma has also been reported in the literature. They are associated with noninvasive high grade TCC or carcinoma in situ.  Noninvasive micropapillary carcinoma shows much better prognosis than invasive MPUC. However, in a small biopsy, it may be difficult to determine whether the micropapillary pattern is invasive or not. The significance of this finding in biopsy is that it may predict an aggressive behavior of the tumor and should invoke deep muscle biopsies when seen in the initial biopsy.
It is important to differentiate between an MPUC and a high-grade TCC with extensive retraction artifact. MUC1 immunostain shows basal (reverse apical) staining pattern in MPUC, but it can be seen in a small proportion of high-grade TCC with retraction artifact as well. An immunohistochemical panel including MUC1, Her 2, and CA125 has shown limited usefulness to differentiate between the two.  Morphologically, MPUC shows small tight clusters with branching micropapillae, back to back lacunae, and multiple tumor cell nests within single lacuna, whereas high-grade TCC shows larger confluent nests with little space around them. A good interobserver agreement has been seen among urologic pathologists in diagnosing MPUC.  Invasive micropapillary carcinoma has been described in various other organs including breast, lung, ovary, and other anatomic locations. , Metastatic micropapillary carcinoma to the urinary bladder can produce significant diagnostic dilemma.  Lotan et al. have discussed in detail the immunohistochemical profile for detection of the primary site of invasive micropapillary carcinoma.  Invasive micropapillary carcinoma of the breast is positive for estrogen receptor (ER) and mammaglobin, an ovarian primary is positive for ER, WT-1, and PAX8, lung primaries shows positivity for thyroid transcription factor-1 and MPUC shows uroplakin and keratin20 positivity. Pan-uroplakin is considered to be the most sensitive marker for invasive micropapillary carcinoma of urinary bladder origin. Micropapillary carcinoma of breast and ovary are frequently associated with calcification. Calcification in MPUC has not been described in the literature, and none of our cases showed calcification.
Some authors have described the immunohistochemical profile of MPUC previously. Usually, the tumors show universal positivity for MUC1 (EMA), MUC2, and keratin 7. The majority of the cases show positivity for uroplakin (70-90%), whereas keratin20 (30-50%) and CA125 positivity are variable. , MUC1 is characterized by abluminal pattern of positivity. In our series, all cases showed MUC1 (EMA) and keratin 7 positivity, whereas keratin 20 was positive in 71% cases. These observations are consistent with the previous studies. Urothelial carcinoma is usually positive for keratin20. Hence, it appears that there is a loss of keratin20 positivity in MPUC. Her 2 positivity has been described recently in MPUC. Her 2 overexpression has been observed in a variable proportion of tumors, ranging from 25% to 40%. , A small proportion (<10%) of conventional papillary urothelial carcinoma can also show Her 2 positivity. The exact prognostic significance of Her 2 positivity has not beenwell described. In our study, one patient with Her 2 positive tumor died 2 months after initial biopsy, whereas three other patients with Her 2 positivity were doing well at last follow-up. A recent study has shown a high frequency of activating extracellular domain Her 2neu (ERBB2) mutation in MPUC.  Her 2neu is often amplified in MPUC as detected by fluorescent in situ hybridization (FISH) and is associated with a poorer outcome. , However, this correlation does not hold true for protein level of Her 2 expression as identified by immunohistochemistry. Only a subset of patient with Her 2 positivity shows ERBB 2 over-expression. It may be beneficial to institute Her 2 targeted therapy for patients showing ERBB2 over-expression. Unlike invasive micropapillary carcinoma of the breast, MPUC cells do not express ER.
Micropapillary histology is known to have an aggressive clinical course. These tumors show more frequent lymphovascular emboli, early muscle invasion and lymph node metastasis. These patients show more locally aggressive disease, higher tumor node metastasis stage, and multifocality. However, it has not been shown as an independent prognostic factor. Although it shows extensive lymphatic emboli, the overall survival of MPUC patients is equivalent to stage-matched conventional urothelial carcinoma. , All of our cases showed lymphovascular emboli and detrusor muscle invasion.
| Conclusion|| |
Micropapillary urothelial carcinoma is an aggressive variant of urothelial carcinoma, presenting frequently with deep muscle invasion and lymphovascular embolization. The micropapillary component may be variable and should be reported even if present focally as it is accompanied by aggressive behavior of the tumor. Micropapillary histology in biopsy may not be representative of the resection specimen. Thus, it emphasizes the need to mention all patterns present in a given biopsy. High-grade urothelial carcinoma and micropapillary carcinoma are often difficult to distinguish, but MPUC is characterized by abluminal pattern of positivity for EMA. Her 2 expression is variable; knowledge about its exact significance is limited. Her 2neu overexpression as detected by FISH indicates a poor prognosis, whereas Her 2 positivity detected by IHC did not show a good prognostic correlation. Her 2neu IHC and FISH are not entirely correlated and so an algorithmic approach is needed. Larger studies including Her 2 expression and targeted therapy to Her 2neu are required to determine the significance of Her 2 expression by MPUC in prognosis and for therapy.
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Prof. Ashim Das
Department of Histopathology, Room No. 504, 5th Floor, Research A Block, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None