The micropapillary variant of urothelial carcinoma is a recently described, rare variant of tumour that was added to the World Health Organization (WHO) classification in 2004. Owing to its rarity, most urologists and pathologists throughout the world may be unfamiliar with its diagnostic features and biological behaviour. This article reviews the literature regarding the micropapillary variant of urothelial carcinoma.
The micropapillary variant of urothelial carcinoma was first described in 1994 by Amin et al.1 at the University of Texas MD Anderson Cancer Center.
Micropapillary urothelial carcinoma is an aggressive subtype of urothelial neoplasm that invades as small clusters of cells. The micropapillary variant of urothelial carcinoma is a rare variant that consists of delicate filiform or papillary (micropapillary) processes.
The incidence of the micropapillary variant of urothelial carcinoma has been reported to be between 0.6% and 8.2%.2,3 Approximately 500 cases of the micropapillary variant of urothelial carcinoma have been reported in the literature.4 It has been suggested that the recent rise in prevalence reflects increased awareness of this clinical entity; however, the variable proportion occupied by this tumour has been explained by the lack of established criteria for diagnosis and less than perfect interobserver reproducibility.1,5–8 A number of authors have stated that the micropapillary variant is more common in males than in females, with a male to female ratio of 5:1 to 10:1, which is higher than the male to female ratio in conventional urothelial carcinoma.1,5–8
The diagnostic criteria for the micropapillary variant of urothelial carcinoma can be summarized as follows:5
The presence of any tissue showing a micropapillary pattern should lead to a diagnosis of micropapillary component of urothelial carcinoma because even small micropapillary foci are associated with poor prognosis.
The micropapillary variant is primarily defined by the pattern of invasion. Typically small clusters of cells invade, and the mean diameter of clusters is less than 4.5 cells. In addition, the nuclei are predominantly peripheral and have a rosette-like appearance.
Prominent retraction that produces spaces around clusters occurs and, on microscopic examination, this simulates lymphatic involvement. Multiple clusters can be seen in the same retraction space and focal intracytoplasmic mucin (MUC) can be observed.
Aggressive invasion is characteristic in that the carcinoma appears to melt through the muscularis propria and quite often there is little or no evidence of stromal response. In general, the tumour is assumed to have involved the muscularis propria even if muscle involvement is not demonstrated in the specimen received. It has been recommended that, in such cases, the histology report should mention the poor prognosis and the high probability of undetected spread.
Cytoplasmic vacuoles are commonly found and large vacuoles with surrounding cells may produce ring forms.
The overlying surface of the micropapillary variant may show usual metastases and retain the micropapillary pattern.
Watts and Hansel8 stated that micropapillary urothelial carcinoma may manifest as a papillary, sessile, polypoid, ulcerative or infiltrative mass varying in size from microscopic to > 10 cm.
Microscopic and immunohistochemical staining characteristics
Microscopic examination of micropapillary urothelial carcinoma reveals a micropapillary architecture that is reminiscent of the papillary configuration observed in ovarian papillary serous neoplasms. It has also been reported that the micropapillary pattern may manifest either:
in the invasive component as small, tight cell nests or balls that are contained in lacunae or stromal retraction spaces, which simulate lymphovascular invasion, or
With regard to immunohistochemical staining characteristics, it has been reported that a small proportion of the tumour-containing spaces in fact represent lymphovascular invasion, which is evident on immunohistochemical staining with endothelial markers, for example factor VIIIR-Ag, Ulex europaeus agglutinin 1 lectin, CD31, CD34 and D2-40.1,5,9
According to some authors:
Most of the tumour-containing lacunae do not have endothelial lining and they do not constitute lymphovascular invasion.
Psammoma bodies, which are found in ovarian papillary serous neoplasms, are very rare in the micropapillary variant of urothelial carcinoma.
Most of the micropapillary variants of urothelial carcinomas exhibit deep muscle invasion, hence it is pertinent to remind clinicians of the invasive potential of the micropapillary variant of urothelial carcinoma when they take biopsies mainly from the superficial layer and do not include the deeper muscle.1,5,9
Amin10 reported that:
The micropapillary variant of urothelial carcinoma often accompanies conventional urothelial carcinoma and the micropapillary proportion of the tumour may be confined to small foci or predominate.
There are currently no cut-off values for the proportion of the micropapillary component that would lead to a diagnosis of the micropapillary variant of urothelial carcinoma. Some authors have suggested 5–10% as the lower limit, but other authors have adopted a non-committal attitude, using the terminology urothelial carcinoma, high-grade, with micropapillary histology (40%).10
Some authors6 have claimed that the presence of any micropapillary component is associated with an inferior outcome whereas, according to others,11 a larger micropapillary component is associated with a poorer clinical outcome.
Some authors12,13 have recommended that the presence and proportion of the micropapillary variant should be stated in the histology report, irrespective of the criteria used to define the micropapillary variant. In addition, it has been reported that the micropapillary variant of urothelial carcinoma may be associated with carcinoma in situ and can coexist with adenocarcinoma.
Other authors have reported the coexistence of the micropapillary variant of urothelial carcinoma and (a) small cell carcinoma,13 (b) sarcomatoid carcinoma,14 (c) pleomorphic giant cell carcinoma,15 (d) the lipoid variant16 or the plasmacytoid variant of urothelial carcinoma.17
Urine cytology in the micropapillary variant of urothelial carcinoma
According to Sakuma et al.,18 urine cytology smears in patients with the micropapillary variant of urothelial carcinoma exhibit papillary/spheroid clusters of tumour cells showing a high nuclear grade. Solitary tumour cells tend to be infrequent and the background is relatively clear, which is a reflection of the growth pattern of the tumour (which tends to be transmural rather than superficial).
The differential diagnoses of the micropapillary variant include:
Conventional urothelial carcinoma. Multiple or small tumour nests in lacunar spaces are diagnostic of the micropapillary variant of urothelial carcinoma, whereas large or branching nests with anastomoses and confluence would suggest otherwise.19 Disagreement may occur if there is a mixture of tumour nests of variable size and diverse configuration.19 Kwon and Ro19 suggested that it would be reasonable to diagnose the micropapillary variant if at least one high-power field area shows the pure, classical micropapillary variant without any readily identifiable contradictory characteristics. Ohtsuki et al.20 reported that MUC1, cancer antigen 125 (CA125), Her/neu and KL-6 may be specific for the micropapillary variant of urothelial carcinoma; however, a study by Sangoi et al.21 did not confirm these findings.
Metastatic disease. Metastatic serous papillary carcinoma of the ovary and primary peritoneal serous carcinoma are examples of diseases that should be included in the differential diagnosis of the micropapillary variant of urothelial carcinoma.5 Some useful histological and immunohistochemical characteristics that may be beneficial in differentiating the micropapillary variant from metastatic disease include the presence of typical urothelial carcinoma or immune reactivity to cytokeratin (CK) 20, high-molecular-weight CK, thrombomodulin and uroplakin III. In addition, some authors5,22 believe that in some situations it may become necessary to differentiate between the primary micropapillary variant and metastatic tumours that have originated from the lung, breast, pancreas, colon, stomach or salivary glands. In this case, it would be appropriate to combine immunohistochemical markers, for example, uroplakin III and CK20 (in bladder-origin tumour), CK20 and CDX2 (in colon-origin tumour), thyroid transcription factor 1 (in lung origin tumour), oestrogen receptor and mammaglobin (in breast-origin tumour) and Wilms’ tumour 1 and PAX8 (in ovarian origin tumour). These combinations of markers can be used to differentiate between the micropapillary variant of urothelial carcinoma and primary carcinomas of the urinary tract, lung, breast, ovary and colon; however, there are no specific markers for tumours of pancreas and salivary gland.
Pathogenesis and molecular changes
There is no consensus of opinion regarding the pathogenesis of the micropapillary variant of urothelial carcinoma. According to Nassar,23 tumour cells in the micropapillary variant of urothelial carcinoma exhibit reversed polarity and those facing the stroma acquire apical secretory characteristics, which is evident on ultrastructural examination as well as immunohistochemical staining for MUC1 (a surface glycoprotein that is present on the apical/luminal surface). Nassar23 postulated that this unusual interface might result in the detachment of tumour cells from the stroma and, thus, facilitate stromal invasion.
Samaratunga and Khoo11 postulated that the micropapillary variant of urothelial carcinoma may be a form of glandular differentiation that is based upon immunoreactivity to CA125, and other authors5 have concurred as micropapillary carcinoma in other organs is most commonly a variant of adenocarcinoma. However, according to Lopez-Beltran et al.,24 the facts that CA125 is occasionally expressed in conventional urothelial carcinoma whereas other tumour markers of glandular differentiation (for example, MUC5A, MUC6 and CDX2) are rarely expressed and the micropapillary variant usually coexists with conventional urothelial carcinoma suggest that the micropapillary variant of carcinoma of the urinary bladder is of urothelial origin.
Compérat et al.25 reported that:
The micropapillary variant of urothelial carcinoma is associated with overexpression of Aurora A (a key player in genomic integrity), in comparison with conventional urothelial carcinoma.
The expression of Aurora A is associated with poor clinical outcome in patients with carcinoma of the urinary bladder.
Enhanced expression of Aurora A may be a mechanism behind the increased chromosome copy number and total nuclear DNA content, contributing to the clinical aggressiveness of the micropapillary variant of urothelial carcinoma.
Maranchie et al.26 reported that p53 abnormalities are rarer in the micropapillary variant than in conventional urothelial carcinoma, whereas the opposite is the case for the H-ras abnormalities. Kwon and Ro19 are of the opinion that the report by Meranchie et al.26 suggests the existence of distinct molecular pathways for the micropapillary variant of urothelial carcinoma. However, Kwon and Ro19 stated that the number of cases in the report is too small for generalization and that there has not been any further studies to corroborate the findings of Meranchie et al.26
Treatment and outcome
Most cases of the micropapillary variant of urothelial carcinoma are muscle invasive at the time of initial presentation and frequently tend to be associated with metastases to the lymph nodes and distant organs. In view of this, Kwon and Ro19 recommended that a deep biopsy should be carried out if muscle invasion is identified after superficial sampling.
According to Kwon and Ro,19 conventional urothelial carcinoma that has not invaded the muscle can be treated with intravesical bacillus Calmette–Guerin (BCG) and radical cystectomy can be performed in cases of muscle-invasive disease. Although the aforementioned conventional approach to the management of the micropapillary variant of urothelial carcinoma is adopted in most institutions, Kamat et al.4 have recommended early cystectomy for non-muscle-invasive micropapillary variant on the basis that it will eventually develop into muscle-invasive disease and the response to second-line systemic chemotherapy is limited. Kamat et al.4 reported a 72% 10-year survival rate among patients who had undergone early cystectomy for the non-muscle-invasive micropapillary variant. In comparison, none of the patients with the micropapillary variant survived following treatment according to the conventional treatment protocol. Kamat et al.4 stated that, on the whole, the prognosis is mostly poor, with the 5-year and 10-year overall survival rates of in the largest study being 74% and 54%, respectively.
Amin et al.,1 in 1994, reported 18 cases of transitional cell carcinoma of the urinary bladder containing a micropapillary component. The micropapillary variant component was > 90% in three cases, between 50% and 90% in nine cases and < 50% in six cases. The mean age of patients was 66.6 years (range 41–81 years) with a male predominance and a male to female ratio of 5 : 1. The micropapillary component was part of the surface non-invasive transitional cell carcinoma in 16 cases and part of the invasive portion of the transitional cell carcinoma in all 18 cases. Of the 18 patients, eight had metastases, and in all such cases the micropapillary component predominated (≥ 50%). Local recurrence was documented in one case and the tumour was locally invasive into pelvic structures in three cases. Amin et al.1 also reported that histological examination revealed that (a) the surface micropapillary component comprised slender, delicate filiform processes or small papillary clusters of tumour cells, (b) the deep micropapillary component was composed of infiltrating tight clusters of micropapillary aggregates that were often present within lacunae, (c) vascular lymphatic invasion was consistently present in the micropapillary areas, (d) the cytological features of the micropapillary component were those of grade 3 transitional cell carcinoma, (e) a concurrent transitional cell carcinoma in situ was identified in 10 cases, (f) a non-invasive papillary transitional cell component was identified in all cases and (g) glandular differentiation of the invasive transitional cell carcinoma was identified in five cases. Furthermore, Amin et al.1 reported that the initial stage of the tumour at presentation was usually high; one patient had stage A tumour, nine patients had stage B tumour, six patients had stage C tumour and two patients had stage D tumour. With regard to follow-up data, Amin et al.1 reported that:
The mean follow-up was 44.8 months and ranged between 6 months and 96 months.
Four patients were living with the disease, seven patients had died from the disease and there was no evidence of disease in seven patients.
In five cases, DNA ploidy analysed by static image analysis showed non-diploid indices within the micropapillary transitional cell component, and in three cases the DNA index of the micropapillary component (non-invasive, invasive or at metastatic site) exceeded the DNA index of the non-invasive papillary transitional cell carcinoma.
Amin et al.1 concluded that:
Their data suggested that a surface micropapillary component as a bladder biopsy specimen is a poor prognostic histological feature.
If the biopsy does not contain muscularis propria, deeper biopsies should be carried out to determine the presence of muscle invasion.
Vang and Abrams,27 in 2000, reported the case of a 79-year-old woman who was evaluated for a ureteral stricture related to laser ablation of a tumour 6 months previously in a different institution. Ureteroscopic examination revealed an exophytic papillary tumour, which was resected and examined histologically. Histological examination revealed that:
The tumour was characterized by delicate papillae with thin stromal cores and numerous secondary micropapillae that were lined by small cuboidal to low columnar cells with uniform low- to intermediate-grade nuclei, reminiscent of a serous borderline tumour of Müllerian origin. The cell linings were one to four layers thick and mitotic figures were easily identified.
The underlying stroma appeared oedematous and contained scattered chronic inflammatory cells.
There was no evidence of invasion.
After confirming that the patient did not have any gynaecological neoplasm, Vang and Abrams27 reported that the differential diagnoses included papillary nephrogenic adenoma, clear cell carcinoma and the micropapillary variant of transitional cell carcinoma. In view of the striking resemblance to serous carcinoma and the presence of significant mitotic activity, Vang and Abrams27 felt that their case represented a case of micropapillary transitional cell carcinoma (WHO grade 1–2) occurring in the ureter. The authors concluded that:
In their opinion, this tumour had some unique features (no areas of grade 3 nuclei or invasion) that had not been reported in tumours occurring in the urinary bladder.
The transitional cell nature of the tumour cells was supported by the immunohistochemical staining pattern.
The anatomical distribution of micropapillary transitional cell carcinoma had expanded to include the ureter and this tumour should be considered in the differential diagnosis for papillary lesions occurring in the ureter.
Yiagan and Humphrey,28 in 2001, described micropapillary transitional cell carcinoma as a recently defined, aggressive variant of bladder cancer whose cytological features in urine had not been previously characterized. They studied the urine cytological features of three cases of micropapillary variant of transitional cell carcinoma of the urinary bladder and concurrent biopsy findings. In all cases, the tumour was similar to low-grade urothelial lesions of the bladder and presented as micropapillary clusters in urine, but high-grade nuclear features within these helped to differentiate the tumours from a flat, high-grade urothelial carcinoma.
Yiagan and Humphrey28 concluded that:
The micropapillary type of transitional cell carcinoma is a distinct morphological entity with an aggressive clinical course.
Although rare, it is important to recognize its presence in urinary cytology to distinguish it from the more indolent low-grade papillary lesions and high-grade urothelial carcinoma, which continuously shed single malignant urothelial cells.
Sugino et al.29 describe the case of a 77-year-old man who presented with visible haematuria. Computed tomography (CT) revealed a bladder tumour with left iliac and para-aortic lymph node metastasis. He received two courses of cisplatin, cyclophosphamide and doxorubicin chemotherapy, which resulted in a minimal response. He underwent radical cystectomy and a retroperitoneal lymph node dissection with bilateral ureterocutaneostomy reconstruction. Histological examination revealed a micropapillary variant of transitional cell carcinoma (grade 3, pT1pN2M1) and the patient died of pelvic recurrence 7 months after initiation of chemotherapy. His autopsy findings confirmed peritonitis carcinomatosis and lung metastases.
Samaratunga and Khoo11 investigated whether or not the prognosis in micropapillary urothelial carcinoma is related to the proportion of the micropapillary component and studied the immunohistochemical features of micropapillary variant of urothelial carcinoma. They examined the specimens of 20 patients who underwent cystectomy for micropapillary urothelial carcinoma of the urinary bladder and stratified the tumours by the extent of the micropapillary component (i.e. focal < 10%, moderate 10–50%, extensive > 50%) and this was correlated with tumour stage and prognosis. Of the 20 patients, 16 were male and four were female and they were aged between 56 and 81 years with a mean age of 69 years. All the cases had high-grade morphology in the micropapillary carcinoma and typical urothelial carcinoma. The authors reported that:
All cases with extensive micropapillary component (n = 4) were of a high pathological stage (pT3 or pT4) and all patients died from their disease or from other causes.
In 80% of patients with moderate micropapillary component (8 out of 10 cases) the tumour was staged as pT3 or pT4 and 50% either died from their disease or were alive with disease.
In five out of six patients (84%) with a focal micropapillary component, the tumour was graded as pT1 or pTa.
In high-stage cases, the most invasive component was the micropapillary component.
Patients with high-stage disease had an 85% risk of having advanced micropapillary carcinoma at presentation.
All patients with pT2 or lower-stage tumours had micropapillary carcinoma on prior transurethral resections of bladder tumour.
In high-stage carcinomas, the proportion of surface micropapillary component and urothelial carcinoma in situ was 30% and 54%, respectively, in comparison with 85% and 28% in lower-stage carcinomas.
The immunohistochemical staining pattern of the micropapillary component and typical urothelial carcinoma was similar, with both types staining positive for CK7, CK20, epithelial membrane antigen, carcinoembryonic antigen and CK 34betaE12. CA125 staining was seen in the micropapillary component in 43% of cases.
Samaratunga and Khoo11 concluded that:
Micropapillary urothelial carcinoma is a high-grade carcinoma and patients’ prognosis is related to the proportion and location of the micropapillary component.
Disease with a moderate or extensive micropapillary component is at high risk of being advanced at presentation.
If the micropapillary component is on the surface and accounts for < 10% of the tumour, there is a high chance that it will be detected at an early stage.
The morphology and immunohistochemical profile of the micropapillary component suggest that it is a form of glandular differentiation in urothelial carcinoma.
Dhouib et al.30 reported two cases of micropapillary carcinoma of the urinary bladder in 2005. The first patient was a 71-year-old woman and the second was a 68-year-old man, both of whom presented with urinary symptoms. Cystoscopy revealed a papillary tumour on the bladder wall in both cases. Both patients underwent transurethral resection of their tumours. Histological examination of the resected tumours showed an invasive micropapillary carcinoma that consisted of small solid nests lying in small clear spaces that were not stained with the antibody CD34. It was reported that the lacunar histological pattern did not appear to represent invasion of vascular spaces. Only one case showed an association with urothelial carcinoma and neither of the cases showed muscle invasion. No recurrence or metastases were observed after the initial diagnosis in either case. The 71-year-old woman was followed up for 6 months and the 68-year-old man for 3 months.
Trabelsi et al.31 reported the case of a 70-year-old man in 2008 who presented with visible haematuria of 2 weeks duration. Magnetic resonance imaging (MRI) revealed a urinary bladder tumour in the dome area extending to the perivesical adipose tissue. Transurethral biopsy showed a high-grade micropapillary carcinoma and muscle invasion. He then underwent radical cystectomy with lymph node dissection and the histological examination of the specimen revealed a high-grade, purely micropapillary carcinoma of the urinary bladder invading the perivesical adipose tissue. At 6 months’ follow-up, there was no evidence of recurrence or metastasis.
According to Guo et al.,32 in 2009, the micropapillary variant of urothelial carcinoma is rare and most studies have focused on the urinary bladder rather than the upper urinary tract. Guo et al.32 identified 11 cases of the micropapillary variant in the upper urinary tract in their institution and investigated the pathological features and clinical significance by reviewing the histology slides and clinical information (Figures 1–5 show examples of the histological features). The average age of the patients was 64.2 years (range 22–76 years) and the tumours were located in the renal pelvis (n = 5), ureter (n = 4) and ureteropelvic junction (n = 2). The micropapillary component accounted for an average of 45% (range 10–80%) of the tumour and was associated with conventional urothelial carcinoma. Guo et al.32 also reported that:
Lymphovascular invasion was present in all cases and metastasis to the lymph nodes was present in four out of five patients whose lymph nodes were dissected.
Two patients presented with pT2 disease and both were alive without evidence of disease at 85 and 119 months after surgery.
The other nine patients presented with pT3 or pT4 disease: four died from the disease at an average of 18 months and, of the five surviving patients, four developed distant metastases and one (with limited follow-up of 6 months) showed no evidence of recurrence.
Guo et al.32 concluded that:
Micropapillary urothelial carcinoma of the upper urinary tract often presents at an advanced stage with lymphovascular invasion and distant metastasis.
The presence of micropapillary urothelial carcinoma, even when focal, indicates a poor clinical course.
Zhang et al.33 reported on three patients with the micropapillary variant of urothelial carcinoma of the upper urinary tract who were evaluated and treated between 2009 and 2011.
All three patients were treated surgically and, after a median follow-up of 12 months, the median overall survival was 12 months. One patient presented with stage II, one with stage III and one with stage IV disease. Zhang et al.33 reported the results following treatment of the three patients as follows:
The patient with stage II disease was alive with limited follow-up, which showed no evidence of disease.
The patient with stage III disease developed metastasis to the cervical lymph nodes 3 months later. Radiotherapy was performed, but the patient died 6 months after the initial diagnosis.
The patient with stage IV disease underwent systematic chemotherapy, but developed distant metastases (including port-site metastasis) and died 12 months after the initial diagnosis.
Compérat et al.6 studied transurethral resections of the bladder tumours in 72 patients in whom urothelial carcinoma with a micropapillary component was diagnosed between 1998 and 2008. Fifty-seven patients underwent radical cystectomy and the tumours were classified according to pathological stage and percentage of micropapillary component (< 10%, 10–49%, 50–100%). This was correlated with clinical data and follow-up. Significant factors in univariate analysis were entered into a multivariate analysis. The authors reported that, based on the bladder tumour specimens, 12 had pTa tumours, 33 had pT1 tumours and 27 had pT2 tumours, with 23% also exhibiting urothelial carcinoma in situ. Following cystectomy, the micropapillary component was upstaged in 79% of cases. Twenty-five patients (35%) had metastases at presentation or nodal metastases at cystectomy and 27 patients (38%) died from the disease. The mean survival was 17.8 months. Of the 12 patients with pTa micropapillary variant component, eight were treated by cystectomy and all of them had invasive carcinoma, including five (62%) with pT2 to pT4 disease. Three patients (25%) died as a result of their disease. Seven patients in whom the micropapillary variant accounted for < 10% of the tumour underwent cystectomy. Six of these patients had invasive carcinoma, including two (33%) with pT2 to pT4 disease, and one (15%) of these patients died from the disease. According to Compérat et al.6 univariate analysis showed that the proportion of the micropapillary variant component on transurethral tumour specimens, as well as the pathological stage, predicted recurrence (P = 0.03). On multivariate analysis, carcinoma in situ predicted recurrence (P = 0.003); the proportion of the micropapillary variant component did not remain significant in predicting disease-specific survival but pathological stage did (P = 0.04). Compérat et al.6 drew the following conclusions:
Any amount of micropapillary variant of urothelial carcinoma, including < 10%, is significant in urothelial carcinoma and should be reported.
Surface micropapillary variant of urothelial carcinoma is associated with invasive carcinoma in most cases, which are often at a high pathological stage.
Adequate sampling to include detrusor muscle is crucial in such cases.
It is important that associated carcinoma in situ is recognized and reported as this also has an impact on the clinical outcome.
Cheng et al.34 reported on four patients with the micropapillary variant of urothelial carcinoma. In one the tumour was located in the urinary bladder and in the other three the tumours originated in the kidney and/or ureter. All lesions were confirmed pathologically and treated by radical surgery. Three of the four patients were found to have advanced disease and, despite adjuvant chemotherapy, two died after 15 and 10 months. The third and fourth patients were alive at a follow-up of 5 and 27 months, respectively. Cheng et al.34 concluded that:
Clinically, the micropapillary variant of urothelial carcinoma is far more aggressive than conventional urothelial carcinoma.
Patients suffering from the micropapillary variant of urothelial carcinoma should be diagnosed promptly and treated aggressively.
Lopez-Beltran et al.24 reported on the clinicopathological features of 13 cases of invasive micropapillary variant of urothelial carcinoma. The micropapillary component varied from 50% to 100% of the tumour specimen, and in 10 cases, the micropapillary component constituted > 70% of the tumour, with five cases exhibiting pure micropapillary carcinoma. Lopez-Beltran et al.24 observed that the architectural pattern of the tumours varied from solid expansile nests with slender papillae within tissue retraction spaces to pseudoglandular growth with prominent ring-like structures (seen in two cases, 15%) and invasive micropapillary carcinoma with squamous differentiation (seen in two cases, 15%). Histological examination revealed that the individual tumour cells had abundant eosinophilic cytoplasm and nuclei with prominent nucleoli and irregular distribution of chromatin, as well as frequent mitotic figures. Most neoplastic cells had nuclei of low to intermediate nuclear grade with occasional nuclear pleomorphism. Eight mixed cases had concurrent conventional high-grade urothelial carcinoma with squamous (in thee cases) or glandular differentiation (in one case). All patients had advanced stage carcinoma (pT > 2) and immunohistochemical staining in eight patients (62%) revealed that both micropapillary and associated conventional urothelial carcinomas were positive for MUC1 and MUC2, CK7, phosphatase and tensin homologue (PTEN), p53 and Ki-67. Her2/neu was positive in four cases, uroplakin in 10, CK20 in eight, 34betaE12 in seven, CA125 in three and p16 was positive in three cases. MUC5A, MUC6 and CDX2 were negative in micropapillary cases. The mean follow-up for all the cases was 10 months and ranged from 2 to 21 months. Lopez-Beltran et al.24 stated that univariate analysis showed survival differences between invasive micropapillary and conventional urothelial carcinoma (P < 0.0001). The authors made the following summary statements:
The invasive micropapillary variant of urothelial carcinoma is an aggressive variant that is associated with poor prognosis and often presents at an advanced stage.
The immunophenotype of invasive micropapillary carcinoma supports a urothelial origin; immunoreactivity to Her2/neu and PTEN may be relevant in terms of future targeting therapy.
The morphological diversity of micropapillary carcinoma may represent a diagnostic pitfall in limited samples, when its distinction from conventional urothelial carcinoma is critical for its clinical management.
Ishii et al.35 studied the correlation between clinical features and histological, immunohistochemical and molecular findings for eight micropapillary variants of urothelial carcinomas and 35 urothelial carcinomas by evaluating expression of MUC1, Ki-67, p53, CD147, CD34, D2–40 and extracellular matrix proteins. They reported that the Ki-67 labelling index was significantly higher in urothelial carcinoma than in the micropapillary variant but densities of venous and lymphatic tumour emboli were significantly higher in the cases of the micropapillary variant and lymph node metastasis was more frequent, with a poorer prognosis. Tenascin-C and fibronectin also showed significantly greater expression in the micropapillary variant of urothelial carcinoma than in the urothelial carcinoma at the epithelial–mesenchymal interfaces. The authors further reported that sequencing showed point mutations of KRAS exon 1 in three micropapillary variants of urothelial carcinoma at significantly higher frequency than in conventional urothelial carcinoma. Ishii et al.35 stated that occupation rate of the micropapillary variant area in the tumour showed a significant inverse correlation with overall survival and that their histopathological findings provide clues to why prognosis is poorer in patients with the micropapillary variant of urothelial carcinoma than in the usual urothelial carcinoma.
Matsumura et al.36 reported the case of a 45-year-old man who presented to hospital with haematuria. He was diagnosed with a bladder tumour and underwent transurethral resection. Histological examination of the specimen identified a poorly differentiated adenocarcinoma invading the urinary bladder muscle layer. He went to a different hospital, where the histology of his resected tumour was reviewed and a final diagnosis of micropapillary variant of urothelial carcinoma of the urinary bladder was made and treated with radical cystectomy and pelvic lymph node dissection. Following the operation, he received three courses of gemcitabine and cisplatin as adjuvant chemotherapy. The patient remained free of tumour recurrence and metastasis for 28 months after the cystectomy.
Radulovic et al.37 reported the case of a 79-year-old woman who was found to have micropapillary carcinoma of the ureter. According to these authors:
Micropapillary urothelial carcinoma is a rare aggressive variant of urothelial carcinoma, associated with advanced tumour stage, a strong tendency to invade lymphovascular spaces and metastases to lymph nodes and other organs, often resulting in a poor prognosis.
One of the most prominent histological features is the presence of small, round, empty spaces surrounding infiltrating tumour nests. If detected, even a small focus of micropapillary pattern may be therapeutically significant; the higher the proportion of micropapillary component, the worse the prognosis.
Radical nephroureterectomy is the treatment of choice, even in cases of superficially invasive disease.
The micropapillary variant of urothelial carcinoma has been well studied in the urinary bladder; however, only a few cases of the micropapillary variant involving the upper urinary tract have been described.
Amin and Epstein38 have described non-invasive micropapillary urothelial carcinoma as consisting of slender tufts of urothelial carcinoma that lack fibrovascular cores, analogous to ovarian papillary serous tumours of borderline malignancy. Amin and Epstein38 identified 18 non-invasive micropapillary urothelial carcinoma cases from the Pathology Department of the Johns Hopkins Hospital, in the USA, who were treated between 2000 and 2011. The authors reported that none of the patients had a history of invasive urothelial carcinoma, but they identified two patterns of non-invasive micropapillary urothelial carcinoma: (1) a variant of non-invasive high-grade papillary urothelial carcinoma (n = 13 cases) and (2) a variant of urothelial carcinoma in situ (carcinoma in situ micropapillary urothelial carcinoma) (n = 5 cases, with two of these patients also having high-grade papillary urothelial carcinoma/micropapillary urothelial carcinoma). Amin and Epstein38 reported that, of the 18 patients, 16 (89%) were male and the mean age was 71.8 years (range 54–87 years). The authors also reported that, of the 12 patients who were initially treated by means of surveillance, BCG or intravesical chemotherapy, four did not experience recurrence and showed no evidence of the disease at 6, 21, 24 and 39 months. Four patients experienced recurrences, but three showed no evidence of the disease at 36, 52 and 72 months; however, the fourth, whose last follow-up was at 84 months, experienced recurrence at this time. One patient was alive at 11 months with the disease and one patient died of other causes at 1 month. Two patients progressed to pT2 and pT3 disease, one at 5 months and one at 21 months. Amin and Epstein38 concluded that it is critical to differentiate and clearly specify in pathology reports whether micropapillary urothelial carcinoma is invasive or non-invasive because invasive micropapillary urothelial carcinoma is aggressive and is commonly understaged, whereas non-invasive micropapillary urothelial carcinoma is not necessarily associated with adverse outcome.
Moriyama et al.39 reported the case of a 62-year-old man who underwent nephroureterectomy for a left ureteric tumour. Histological examination of the resected specimen revealed a micropapillary variant of urothelial carcinoma of the ureter and the micropapillary carcinoma was found in 10% of the tumour. Two months after the operation, the patient underwent MRI, which showed liver and para-aortic lymph node metastases. He received three cycles of gemcitabine–cisplatin therapy and the metastases were no longer visible when the patient underwent CT.
Heymann et al.40 compared 25 cases of histologically confirmed micropapillary variant of urothelial carcinoma from 21 patients with 25 cases of histologically confirmed high-grade conventional urothelial carcinoma. Heymann et al.40 reported that:
In cases of the micropapillary variant of urothelial carcinoma cases, cell clusters were identified in 13 out of 25 specimens from 10 patients. Six of the 13 specimens containing cell clusters corresponded to surgical pathology specimens, in which micropapillary carcinoma accounted for at least 50% of the total carcinoma.
On the other hand, only one of the 12 urine specimens devoid of cell clusters corresponded to surgical specimens, in which micropapillary carcinoma accounted for at least 50% of total carcinoma.
Cytomorphological features of urinary specimens from patients with histologically confirmed micropapillary carcinoma were generally similar to those from patients with high-grade conventional urothelial carcinoma.
According to Heymann et al.:40
The micropapillary variant of urothelial carcinoma is a rare variant of urothelial carcinoma that is associated with a poor prognosis.
Definitive surgery may represent the optimal management of low-stage tumours.
Urine cytology is indispensable in the screening and follow-up of urinary tract cancer. Nevertheless, cytopathological criteria for the diagnosis of the micropapillary variant of urothelial carcinoma and its differentiation from conventional urothelial carcinoma are not well defined.
Heymann et al.40 concluded that further investigation of the core cytopathological characteristics of the micropapillary variant of urothelial carcinoma, in the form of exfoliative urine cytology, is warranted to refine the diagnostic criteria.
Heudel et al.41 reviewed the records of 11 patients with micropapillary bladder cancer who were treated in their institution from 1994 to 2007, and these patients accounted for 1.2% of the urothelial carcinomas treated in that institution. They reported that the mean age of the patients was 60 years and the majority of the patients (72%) were diagnosed after 2004. After a median follow-up of 31.7 months, the median overall survival was 19 months. Two patients presented with stage II, one with stage III and eight with stage IV disease. All five patients who had node-positive metastases and were treated with radical surgery and adjuvant chemotherapy suffered from a relapse but had been disease free for 9.6 months. Heudel et al.41 concluded that:
Early diagnosis of the micropapillary variant of urothelial carcinoma, based upon the understanding of its morphological characteristics, is essential in the adoption of treatment strategy of such a tumour. Knowledge of the potential aggressive nature of this variant of urothelial carcinoma is vital in the formation of an aggressive treatment approach.
The micropapillary variant of urothelial carcinoma may be under-reported (to the knowledge of the author, only approximately 500 cases have so far been reported), perhaps because many pathologists have not encountered the micropapillary variant and are unfamiliar with its histological characteristics.
There is a great need for urologists and oncologists throughout the world to report cases of the micropapillary variant of urothelial carcinoma that they encounter so that the true biological behaviour of the tumour can become known. There is also a need for multicentre trials of the various management options for the micropapillary variant of urothelial carcinoma in order to generate a consensus management guidelines.
Meanwhile, early radical surgery has been suggested as a treatment option, and this should be performed promptly after the diagnosis of micropapillary variant of urothelial carcinoma.