Interobserver Reproducibility in the Diagnosis of Invasive Micropapillary Carcinoma of the Urinary Tract Among Urologic Pathologists

Abstract

Invasive micropapillary carcinoma (IMPC) of the urinary tract is a well-described variant of the urothelial carcinoma with aggressive clinical behavior. Recent studies have proposed that patients with IMPC on transurethral resection should be treated with radical cystectomy regardless of the pathologic stage. Despite the potentially important therapeutic implications of this diagnosis, interobserver variation in the diagnosis of IMPC has not been studied. Sixty digital images, each from hematoxylin and eosin-stained slides, representing 30 invasive urothelial carcinomas (2 images per case), were distributed to 14 genitourinary subspecialists and each pathologist was requested to classify cases as IMPC or not. These cases included "classic" IMPC (n=10) and urothelial carcinoma with retraction and variably sized nests that might potentially be regarded as IMPC (n=20). The following 13 morphologic features were recorded as positive/negative for all cases independent of the reviewers' diagnoses: columnar cells, elongate nests or processes, extensive stromal retraction, lumen formation with internal epithelial tufting, epithelial ring forms, intracytoplasmic vacuolization, multiple nests within the same lacunar space, back-to-back lacunar spaces, epithelial nest anastomosis/confluence, marked nuclear pleomorphism, peripherally oriented nuclei, randomly distributed nuclei, and tumor nest size. In addition, a mean tumor nest size was calculated for each image based on the number of nuclei spanning the width of the nests. Interobserver reproducibility was assessed and the morphologic features were correlated with the classic IMPC and nonclassic/potential IMPC groups. In addition, the relationships between morphologic features, pathologists' interpretations, and case type (classic IMPC vs. nonclassic/potential IMPC) were evaluated using unsupervised hierarchical clustering analysis. Interobserver reproducibility for a diagnosis of IMPC in the 30 study cases was moderate (kappa: 0.54). Although classification as IMPC among the 10 "classic" IMPC cases was relatively uniform (93% agreement), the classification in the subset of 20 invasive urothelial carcinomas with extensive retraction and varying sized tumor nests was more variable. Multiple nests within the same lacunar space had the highest association with a diagnosis of classic IMPC. These findings suggest that more study of IMPC is needed to identify the individual pathologic features that might potentially correlate with an aggressive outcome and response to intravesical therapy.

The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs—Part B: Prostate and Bladder Tumours

“…The micropapillary variant of urothelial carcinoma has been well documented in the literature [82][83][84][85][86][87][88][89]. Morphologically, it is defined as small nests and aggregates of tumour cells within lacunae.…”

Lymphovascular Invasion in Micropapillary Urothelial Carcinoma: A Study of 22 Cases

“…12 It occurs almost exclusively in association with conventional UC, and the differential diagnosis is frequently conventional UC with retraction artifact. 2,3 Among transurethral resections of bladder with a micropapillary component, 79% are upstaged at subsequent cystectomy. 4 The proportion of MPUC appears to predict poor prognosis, [12][13][14] and at least predicts high pathologic stage and lymph node metastasis.…”

“…It was first described by Amin et al 1 in 1994 and is characterized by small, infiltrating clusters of neoplastic cells that appear to float within clear lacunar spaces and that lack a fibrovascular core ( Figure 1). Micropapillary urothelial carcinoma occurs almost exclusively in the setting of conventional UC, 2,3 and the proportion of MPUC predicts high pathologic stage and lymph node metastasis. 4,5 The overall prognosis is poor; the 5-year and 10-year survival in the largest study were 51% and 24%, respectively.…”

A High Frequency of Activating Extracellular Domain ERBB2 (HER2) Mutation in Micropapillary Urothelial Carcinoma

“…Encompassing approximately 5% of all bladder cancers, MPUC is a clinically important lesion characterized by a distinctive histology that features small micropapillae created by clusters of 4 to 5 cells across, peripherally situated nuclei, and cytoplasmic vacuoles with a strong tendency to develop intralymphatic permeation or simulate lymphovascular involvement because of the production of peritumoral stromal retraction artifacts (6)(7)(8)(9). It is well-accepted that the diagnosis of MPUC indicates an adverse prognosis and pathologists have strongly recommended that even if the minority of a urinary bladder urothelial carcinoma features a MPUC pattern, the diagnosis of MPUC should either be made outright or the tumor should be classified as urothelial carcinoma with MPUC features (6)(7)(8)(9). Among the noteworthy clinicopathologic features of MPUC is the association of metastatic disease at the time of diagnosis for a tumor with either no invasion or limited invasion of the bladder wall.…”