Genitourinary Pathology

Micropapillary Carcinoma of the Urinary Bladder

Thomas M. Wheeler
Baylor College of Medicine
Houston, TX


Micropapillary carcinoma of the urinary bladder
Invasive micropapillary carcinoma (IMPCa) has been analyzed as a rare but distinctive variant of carcinoma. IMPCa can involve several different organs in addition to the urinary bladder, including breast, lung, and major salivary glands [1, 2, 3, 4, 5, 6]. Clinical experiences demonstrate that these neoplasms are associated with a high degree of aggressiveness and rapid progression. Patients typically present with high-stage disease with lymph node metastases, as these tumors show a high propensity for lymphovascular invasion [7, 8, 9, 10, 11]. The only exception of aggressive behavior is ovary, where it is considered a low-grade carcinoma and displays indolent behavior, unlike the conventional high-grade serous ovarian carcinoma [12].

The morphology of IMPCa is characterized by tight clusters of neoplastic cells surrounded by clear spaces resembling small, dilated lymphatic channels. The cell clusters are devoid of fibrovascular cores and often display tubular structures in the center. Although an entity-defining feature of IMPCa, the clear spaces are thought to be an artifact of fixation and are not seen on frozen sections [10, 13, 14]. The stroma is typically described as "spongy" (i.e., the clusters of neoplastic cells are separated by delicate strands of fibrous tissue delineating the clear spaces), with little or no reaction (desmoplasia) in the surrounding tissue [4]. Occasionally, a single cystic space contains multiple nests of tumor cells. These features are the hallmark of IMPCa in any organ site. The characteristic morphology of IMPCa is due to a reverse of the polarity of the neoplastic cells where the stroma-facing (basal) surface of the cells acquires apical secretory properties. Peterson described this phenomenon as an "inside-out" growth pattern [15]. One can hypothesize that this reverse in polarization facilitates the secretion by the tumor cells of molecules responsible for stromal and vascular invasion, namely metalloproteinases, permitting easier dissemination of the neoplastic cell clusters. This could also explain why tumors with this morphology display a higher propensity for lymph node metastases compared with conventional carcinomas of similar size.

In the majority of IMPCa of the breast, psammoma bodies are seen (42-62%), whereas they are rare in IMPCa of the lung and usually absent in IMPCa of the urinary bladder and salivary glands [1, 2, 5, 11] . In all sites, a pure invasive micropapillary growth pattern is rarely observed. Usually, this tumor is mixed with other subtypes or variants of carcinoma [1, 2, 5, 7, 14]. In these cases, an abrupt transition is seen between the invasive micropapillary pattern and the other component of the neoplasm. Foci of micropapillary carcinoma tend to be found at the periphery or advancing edge of the tumor rather than in the center [2, 7].


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Case 5 - Figure 1 - transurethral biopsy of bladder tumor
Case 5 - Figure 2 - transurethral biopsy of bladder tumor
Case 5 - Figure 3 - transurethral biopsy of bladder tumor

Case 5 - Figure 4 - cystectomy specimen
Case 5 - Figure 5 - cystectomy specimen
Case 5 - Figure 6 - cystectomy specimen


IMPCa of the Urinary Bladder
This tumor was first described by Amin et al. in 1994 [1]. In their paper, they described two different morphologic patterns: an invasive pattern with a classical IMPCa morphology and a noninvasive component, formed by slender filiform projections with or without fibrovascular cores. Psammoma bodies are usually absent. Almost always, IMPCa is mixed with more conventional papillary or invasive urothelial carcinoma (UC) or adenocarcinoma, forming at least 20% of the neoplasm in the majority (about 80%) of the reported cases. Immunohistochemically, the tumor cells are positive for EMA, CK7, and LeuM1 (100%), CK20 (90%) and CEA (65%) [3]. In one study, immunostaining for HER2 protein was 100% in IMPCa compared to only 43% in conventional UC [16]. In keeping with an aggressive biological behavior, even when presenting as a focal area within a given neoplasm, the majority of the IMPCa of the urinary bladder show lymphovascular invasion (75 – 100%). In most cases, the tumors are high stage, either when seen on initial biopsy or on subsequent cystectomy [2, 3]. In one study, only 5 patients out of 20 survived for 5 years or more [3].

IMPCa of the Breast
The incidence of IMPCa in breast varies from 0.9% (pure form) [17] to 7% (mixed with other subtypes of breast carcinoma) [18]. The majority of the IMPCa cases are mixed with invasive ductal carcinoma NOS (53% to 80%, being described as extensive in half of the cases) or less often with one of the subtypes (including tubular, papillary, mucinous carcinoma, or, more rarely, invasive lobular carcinoma) [7, 11, 18].

Nuclear cytologic features are similar to the accompanying ductal component when present and in most of the cases exhibit a high grade [7, 11, 18]. One of the unique characteristics of IMPCa of the breast is the high percentage of positivity of this lesion for estrogen and progesterone receptors, combined with a high positivity for HER2 over expression [9, 18, 19]. Due to the rapid progression and the aggressive biologic behavior, several studies have demonstrated a high expression of p53 protein in at least 50% of the IMPCa cases [8, 9, 10].

Usually, IMPCa tumors are highly lymphotrophic -- the incidence of lymphovascular invasion (LVI) ranges from 15% to 80% [4, 6, 7, 8, 9, 11, 18]. Walsh et al. demonstrated that 45% of tumors less than 1 cm contained foci of LVI, and LVI also predicted nodal metastases in 81% of the cases [18].

IMPCa of the Lung
In a recently described clinical study, 35 patients with primary lung adenocarcinomas demonstrated a variable amount of micropapillary component [2]. Morphologically, all tumors showed the micropapillary pattern with a mixture of various histologic subtypes (acinar, papillary, solid, and bronchioloalveolar). Of the 15 cases available for immunohistochemical analyses, 80% were positive for TTF-1, 93% for CK7, and 13% for CK20. The cases positive for CK20 were also positive for CK7 and TTF-1 [2].

Due to the aggressive potential of IMPCa of the lung, a high stage at presentation was noted: 26 patients (74%) presented with metastatic disease and an additional six patients (17%) had subsequent metastases. The majority of the metastases demonstrated predominantly or exclusively micropapillary histology, irrespective of the extent of the IMPCa in the primary tumor. Due to the rapid progression of IMPCa of the lung, only 28% of the patients, most treated with surgery and adjuvant chemotherapy, were alive with no evidence of disease after 28 months [2].

IMPCa of the Salivary Glands
In a clinical study, Nagao et al. reported 14 cases of IMPCa of the salivary glands, representing 0.2% of all major salivary gland tumors and 17% of all salivary duct carcinoma cases, the majority involving the parotid gland. Nagao et al. showed that the carcinomas with an IMPCa pattern behave more aggressively than those without IMPCa [5]. LVI and perineural invasion was seen in all cases (compared to 33% and 50% in salivary duct carcinomas without an IMPCa pattern), and the frequency of lymph node metastases at presentation was 100% (compared to 60%).

Due to the aggressive potential of the neoplasm, of the 13 patients with available follow-up information, 9 (69%) died of disease within 2 years after diagnosis.

Immunohistochemically, IMPCa of the salivary glands stained consistently positive for CK7, whereas the staining was consistently negative for CK20. The majority were positive for BRST-2, HER2 oncoprotein, and androgen receptor and negative for estrogen and progesterone receptors [5].

Conclusion
Invasive micropapillary morphology is being increasingly recognized as a prognostically important pattern of adenocarcinoma occurring in various organs including breast, urinary bladder, salivary glands, and lung. There is no clear explanation as to why this particular morphology is so biologically aggressive. Due to its aggressive clinical behavior and rapid progression, it is very important to recognize this component, even when present as a small focus in the primary tumor.

References
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