64-year-old man with a history of
"bladder cancer" who was
recently diagnosed with recurrent urothelial carcinoma on urine cytology. Cystoscopy revealed a 1.5
cm papillary mass in the trigone.
Papillary urothelial carcinoma, high grade, with
lamina propria Invasion; No muscularis propria is present for evaluation
At re-biopsy, muscularis propria invasion was present. At cystectomy, there was invasion into
perivesical adipose tissue and lymph node metastases.
72-year-old man who presented with gross hematuria.
Cystoscopy revealed an ulcerated mass in the trigone with probable extension to the prostatic
Invasive urothelial carcinoma, high grade, with
muscularis propria and prostatic stromal invasion
Invasive Urothelial Carcinoma/ Staging
Anatomy of the Bladder Wall
Urothelium: The urothelium was described in
detail in the section on flat lesions.
Lamina Propria: The lamina propria is the region of the bladder below the
basement membrane of the urothelium, but superficial to the muscularis propria. It consists
predominantly of very hypocellular, loosely collagenized stroma. Rare, scattered stromal cells that are
often multinucleated (similar to stromal cells described in fibroepithelial polyps) are common in the
lamina propria. In addition, prominent medium-sized blood vessels are commonly present and may be
associated with small wispy fascicles of smooth muscle (muscularis mucosae).
 The muscularis
mucosae is often incomplete, consisting of irregular, isolated fascicles. In men with benign prostatic
hypertrophy, the muscularis mucosae may become more prominent due to compensatory hypertrophy. Normal
adipose tissue has also been described within the lamina propria, and does not signify extra-vesical
tissue.  The thickness of the lamina propria greatly varies, but is usually thinner in the
trigone and bladder neck.
Muscularis Propria: The muscularis propria or detrusor muscle consists of
large, thick, compact bundles of smooth muscle with variable amounts of interspersed collagen and adipose
tissue. The larger, better developed bundles of muscle distinguish the muscularis propria from the thin
muscularis mucosae. Because of variation in thickness of the lamina propria, the muscularis propria may
be surprisingly superficial in some biopsies.
Adventitia and Perivesical Adipose Tissue: These tissues are deep to the
muscularis propria and consist of loose fibroconnective and adipose tissue; however, they are not sampled
by routine bladder biopsy.
Schematic Representation of Bladder Wall
Patterns of Invasion
Lamina Propria Invasion:
The earliest recognizable
invasion into the lamina propria has two main morphologic patterns: 1) small clusters and individual
neoplastic cells in the stroma, usually with surrounding retraction artifact, and 2) irregular, jagged
projections of epithelium extending from the overlying urothelial carcinoma (papillary carcinoma or
CIS). The neoplastic cells are high-grade in the vast majority of cases and may show increased
cytoplasmic eosinophilia when compared to the overlying non-invasive tumor (paradoxiacal maturation
similar to that seen in superficial invasive squamous cell carcinoma of the uterine cervix). There may
be no stromal response, stromal retraction, peritumoral edema and inflammation, stromal myxoid change,
and/or stromal desmoplasia.
Muscularis Propria Invasion: Muscularis propria invasion is defined by
carcinomas invading between thick bundles of smooth muscle. There is a spectrum of morphologic patterns
and stromal reactions identical to those seen in lamina propria invasion. It should be emphasized that
some deeply invasive tumors do not have a stromal response, but extend between the fascicles of the
muscularis propria in a non-destructive pattern similar to adenoma malignum of the uterine cervix.
Adipose tissue is commonly present within the muscularis propria and does not signify a pT3 tumor. It is
recommended that bladder biopsy evaluation be restricted to pT2 disease; pT3 and pT4 carcinomas can only
be diagnosed at cystectomy.
Diagnosing invasion in the setting of an endophytic growth pattern:
Endophytic growth of a urothelial carcinoma (represented in the schematic below) is not
defined as stromal invasion despite the extension deep into the lamina propria. It is characterized by
invaginated, interanstomosing cords of urothelium with a relatively smooth, pushing border. It is
usually associated with an overlying papillary urothelial neoplasm. In this setting, invasion is only
diagnosed when there is also a focus fitting the histologic criteria for lamina propria or muscularis
propria invasion as discussed above.
Endophytic (Inverted) Urothelial Neoplasia: a Non-invasive Pattern of Growth
This pattern of urothelial neoplasia is infrequent and has not received a great deal of attention in
textbooks. It should be emphasized that the entire spectrum of urothelial neoplasia can grow in this
endophytic pattern. We recommend a diagnostic approach identical to that used for papillary neoplasms
(i.e.- the same diagnostic categories and the same cytologic and architectural criteria [WHO
2004/ISUP]). These tumors should also be staged as otherwise typical urothelial neoplasms, keeping in
mind that the endophytic component, on its own merit, is defined as
Endophytic (Inverted) Urothelial Neoplams*
* With the exception of inverted papilloma, these tumors are staged as non-invasive, with lamina
propria invasion, or with invasion of the muscularis propria depending on other associated histologic
- Inverted papilloma
- Urothelial neoplasm of low malignant potential, endophytic (inverted) pattern
- Urothelial carcinoma, low-grade, endophytc (inverted) pattern
- Urothelial carcinoma, high-grade, endophytc (inverted) pattern
Most centers follow the AJCC cancer staging guidelines as follows: 
The most important distinction for papillary neoplasms on biopsy evaluation is pT1 vs. pT2 disease.
Urologists usually favor conservative management with intravesical treatments for high-grade pTa and any
pT1 disease. The diagnosis of pT2 carcinoma is generally the threshold for surgical management
(cystectomy) or radiation therapy. The histologic parameters and reporting discussed in this section
should allow the urologist to easily assign a T stage to the patient, and to select the appropriate
- pT0 : No evidence of primary tumor
- pTa : Non-invasive papillary carcinoma
- pTis : Carcinoma in situ
- pT1 : Tumor invades subepithelial connective tissue (lamina propria)
- pT2 :Tumor invades muscularis propria
- pT2a: inner half
- pT2b: outer half
- pT3 : Tumor invades perivesical tissue
- pT3a: microscopically
- pT3b: macroscopically
- pT4 : Tumor invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall
Grading and Substaging of Invasive Urothelial Carcinoma
Studies suggest that stage is the most important prognostic factor in invasive urothelial carcinoma,
independent of grade.  This is supported by additional studies documenting the capacity of
deeply invasive, cytologically bland carcinomas to produce metastases and cause patient mortality (See
"deceptively bland" urothelial carcinomas discussed in detail in the variants section).
Some authors have suggested the utility of substaging lamina propria invasion based on depth
measurements or relation to the muscularis mucosae.
This is difficult in practice because
bladder biopsies are frequently sectioned in a tangential plane making orientation difficult to assess.
Because of these difficulties and lack of an accepted reproducible method, substaging has not been
adopted under the current systems of staging and classification.
Pitfalls in the Diagnosis of Invasive Urothelial Carcinoma
1) Adipose tissue in lamina propria: As discussed above, adipose tissue is
commnly found in the lamina propria and should not be taken as evidence of invasion into perivesical
adipose tissue in biopsy specimens. 
2) Involvement of muscularis mucosae:
 Invasive urothelial
carcinoma involving smooth muscle must be carefully assessed to determine its anatomic location. In
general, muscularis mucosae is characterized by small, discontinuous, thin fascicles of smooth muscle,
often adjacent to the medium sized, thin-walled blood vessels typical of the lamina propria. Muscularis
propria, in contrast, is comprised of thick, compact, well-formed bundles of smooth muscle. This
distinction is critical because it is often the factor dictating whether or not a cystectomy is performed
(pT1 vs. pT2). In difficult cases where the distinction is not clear, a descriptive diagnosis such as
"with invasion of smooth muscle, indeterminate type" followed by comment describing the diagnostic
problem may be necessary. A re-biopsy usually resolves most cases.
3) Urothelial carcinoma in situ involving von Brunn nests: The smooth,
round contour and lobular configuration of von Brunn nests (despite colonization by high-grade urothelial
cells) are the most useful features for the distinction from invasive carcinoma. The presence of small,
irregular clusters, single cells, or retraction artifact would favor stromal invasion.
4) Colonization of prostatic glands: At the bladder base, the muscularis
propria becomes continuous with the fibromuscular stroma of the prostate. If prostatic tissue is
biopsied, it may closely mimic a glandular pattern of invasion into the muscularis propria. The presence
of secretory-type prostatic epithelium in the glands aids in this distinction. If the glands become
colonized by urothelial neoplasia, this distinction becomes very difficult. The smooth, round contours
of the epithelium, the lack of a stromal response, the identification of adjacent prostate glands, and
the location of the biopsy (bladder base/prostatic urethra) should all suggest the possibility of the
colonization of prostatic glands by urothelial neoplasia, and argue against invasion.
5) Endophytic growth patterns:
 As described above, endophytic
growth of a urothelial neoplasm, when present in the absence of other patterns, is not defined as
6) Overdiagnosis of vascular invasion: Retraction artifact around nests of
infiltrating urothelial carcinoma is very common. True vascular invasion in the lamina propria is rare,
and, in our experience, is frequently overdiagnosed. We require tumor emboli in an obvious vascular
space (with smooth muscle evident in the vascular wall)
or immunohistochemical confirmation 
to render a diagnosis of angiolymphatic invasion.
Sign-out Approach: Reporting
A simple diagnostic template is provided below that includes the relevant diagnostic findings needed
for patient management. We avoid the use of the term "muscle invasion" because it does not distinguish
between muscularis propria and muscularis mucosae.
|Papillary urothelial carcinoma, _______ grade (WHO2004/ISUP)
- non-invasive; muscularis propria is present/not present for evaluation
- with lamina propria invasion; muscularis propria is present, but not involved/ not present
- with muscularis propria invasion
Selected References for Invasive Urothelial Carcinoma/Staging
- Reuter VE. Urinary bladder and ureter. In: Sternberg SS, ed. Histology for Pathologists., 2nd ed. New York: Raven Press, 1997:835-847.
- Ro JY, Ayala AG, El-Naggar A. Muscularis mucosa of urinary bladder: importance for staging and treatment. Am J Surg Pathol 1987;11:668-673.
- Philip AT, Amin MB, Tamboli P, et al. Intravesical adipose tissue. Quantitative study of its presence and location with implications for therapy and prognosis. Am J Surg Pathol 2000;24;1286-1290.
- Amin MB, Gomez JA, Young RH. Urothelial transitional cell carcinoma with endophytic growth patterns: a discussion of patterns of invasion and problems associated with assessment of invasion in 18 cases. Am J Surg Pathol 1997;21:1057-1068.
- Jiminez RE, Keane TE, Hardy H, Amin MB. pT1 urothelial carcinoma of the bladder: criteria for diagnosis, pitfalls, and clinical implications. Adv Anat Pathol 2000;7:13-25.
- Holmang S, Hedelin H, Anderstrom c, et al. The importance of the depth on invasion in stage pT1 bladder carcinoma: a prospective cohort study. J Urol 1997;157:800-804.
- Cheng L, Weaver AL, Neumann RM, et al. Substaging of T1 bladder carcinoma based on the depth of invasion: a new proposal. Cancer 1999;86:1035-1043.
- Younes m, Sussman J, true LD. The usefulness of the level of the muscularis mucosae in the staging of invasive transitional cell carcinoma of the urinary bladder. Cancer 1990;66:543-548.
- Ramani P, Birch BR, Harland SJ et al. Evaluation of endothelial markers in detecting blood and lymphatic channel invasion in pT1 transitional carcinoma of bladder. Histopathol 1991;19:551-554.
- American Joint Commission on Cancer. AJCC cancer staging manual, 6th ed. New York:Lippincott-Raven,2002:335-340.
- Drew PA, Furman J, Civantos F, et al. The nested variant of transitional cell carcinoma: an aggressive neoplasm with innocuous histology. Mod Pathol 1996;9:989-994.
- McKenney JK, Gomez JA, Desai S, Lee MW, Amin MB. Morphologic expressions of urothelial carcinoma in situ. A detailed evaluation of its histologic patterns with emphasis on carcinoma in situ with microinvasion. Am J Surg Pathol 2001;25:356-362.
- Jiminez RE, Gheiler E, Oskanian P, Tiguert R, Sakr W, Wood DP, Pontes JE, Grignon DJ. Grading the invasive component of urothelial carcinoma of the bladder and its relationaship with progression-free survival. Am J Surg Pathol 2000;24:980-7.