Case 1 -
Paraganglioma of the Bladder
Robert H. Young
Massachusetts General Hospital
Click on each slide thumbnail image for an enlarged view
A 40-year-old man presented with gross hematuria and at cystoscopy was found to have a bulky bladder
tumor. This was resected transurethrally.
Diagnosis: Paraganglioma of the Bladder
Case 1 - Figure A - Low power view showing epithelioid neoplasm with predominantly diffuse growth and involvement of muscle bundles.
Case 1 - Figure B - High power view showing nested pattern of tumor cells with abundant cytoplasm. Blood vessels are conspicuous.
Case 1 - Figure C - Tumor cell necrosis.
This tumor was selected to highlight an important pitfall in the interpretation of bladder tumors,
namely the misdiagnosis of paraganglioma as transitional cell carcinoma, and selected other issues in the
differential diagnosis of bladder cancer. I have seen several cases of bladder paraganglioma
misdiagnosed initially as invasive transitional cell carcinoma. This was pointed out in one of the
classic papers on paraganglioma of the bladder from the AFIP,1 but it is something that is often
forgotten. It is not surprising that muscle involvement is common because paraganglia, which give rise
to these neoplasms, are situated in the deeper aspects of the bladder wall. In the misdiagnosed cases I
have seen another problematic aspect in addition to the muscle involvement has sometimes been a nested
pattern reminiscent of what one may see in transitional cell carcinomas occasionally as has been much
popularised in recent years because of the propensity for such tumors, particularly when cytologically
low grade, to be underdiagnosed as benign lesions. Other confusing features of paraganglioma of the
bladder include a diffuse growth and some tumors have cytologic atypia which may enhance the chance of a
misdiagnosis as carcinoma.2-4 Although in general immunohistochemistry plays a relatively limited
role in the evaluation of bladder tumors it certainly can be important in confirming the diagnosis of
paraganglioma. With regard to the differential diagnosis of a nested carcinoma with paraganglioma the
vascularity of the paraganglioma is a very helpful feature but it is not always particularly striking.
In essence, anytime one sees a bladder tumor with a striking nested pattern the possibility of a
paraganglioma should at least be thought of, if only briefly, to have it excluded or validated by an
overall evaluation of the constellation of findings. If routine H & E appearances are not
definitive, and on careful examination they usually are, immunohistochemistry should be definitive.
However, appropriate stains will obviously only be ordered if the pathologist considered a paraganglioma
diagnosis based on the H & E.
The differential diagnosis of primary invasive carcinoma of the bladder can be considered
in four broad categories A. Mimicry of it by a non-neoplastic lesion such as nephrogenic adenoma, B.
The converse problem, namely, a deceptive pattern of bladder neoplasia being misinterpreted as a benign
process, C. Confusion with other primary tumors as the seminar case represents, and D. Mimicry of a
primary tumor by a secondary or metastatic tumor. The first two issues have been extensively reviewed in
recent years by this writer and others 5-8 so in the remainder of the talk, and this handout, I will
focus on the last two problems.
Although there are miscellaneous other patterns, the differential diagnosis of bladder
carcinoma from the pattern-based viewpoint can be considered for the most part in four broad categories:
papillary, nested, diffuse and spindled. The differential diagnosis of papillary carcinoma is limited,
one important non-neoplastic lesion to keep in mind being papillary-polypoid cystitis.9 This is a
particularly treacherous lesion when a patient has a fistula to the bladder, which may impart a
carcinoma-like picture at cystoscopy and a morphology reminiscent of papillary carcinoma under the
microscope. It is one of several areas in bladder pathology where clinicopathologic correlation is
crucial in establishing the correct diagnosis. One specific pattern of invasive carcinoma is the
so-called micropapillary pattern that may simulate serous carcinoma.10 Perhaps the most important
facet of this variant of bladder cancer that is only recently highlighted is that it enters into the
differential diagnosis of serous carcinoma at metastatic sites in a female patient. In my experience
there is generally merging with more typical foci of transitional cell neoplasia although sampling may
obviously limit the extent to which this is appreciable.
The paraganglioma is of course an important category of nested neoplasia of the bladder as we have
already considered. So also are the now well known nested transitional cell carcinomas which may have a
deceptive morphology which I will not review here because of the recent attention they have received.
One benign primary tumor that may have a nested pattern is the inverted papilloma. Although these tumors
typically grow in very compact aggregates they may, particularly at their periphery, have nests that are
somewhat dispersed from the more packed lesion and such nests can seemingly "drift off" from the "parent"
lesion and be potentially misinterpreted as an invasive nested transitional cell carcinoma. That the
bulk of the lesion has the typical picture of inverted papilloma is helpful and mere knowledge of this
phenomenon may be crucial.
The diffuse pattern of bladder carcinoma can be problematic by raising the issue of
malignant lymphoma or even plasmacytoma on low power examination. I cannot add to the experience
presented some years ago in a paper written from our group.11 Generally, reasonable sampling shows
some clues to the epithelial nature of the lesion and although the pattern may suggest lymphoma or
plasmacytoma cytologic features are not compatible with those entities on close scrutiny. There will be
cases, however, in which in a limited sample immunohistochemical stains to sort out the differential
diagnosis are justified.
The final pattern of primary bladder carcinoma I will briefly review is the spindle cell
pattern of so-called sarcomatoid carcinoma. This is a famous pattern of carcinoma of the kidney but I
think it fair comment that until we wrote a paper on this topic in 1988 it was, to some degree,
overlooked.12 Since that time a number of other authors have contributed to our knowledge of this
area 13-19 and it accounts for a significant number of the cases of bladder pathology sent to me in
consultation. The issue often revolves around the distinction between an inflammatory pseudotumor and a
sarcomatoid carcinoma with an edematous to myxoid appearance.20 Although the cells of inflammatory
pseudotumor may be plump and have prominent nucleoli, mitotic figures are generally relatively infrequent
and the pleomorphism of carcinoma is absent. Immunohistochemistry for cytokeratins is not that reliable
in this distinction although recently staining for Alk1 has surfaced as a potential aid although whether
it will prove to be totally reliable remains to be seen.21,22
Metastatic tumors to the bladder, secondary involvement from the prostate excluded, has
overall not received the same degree of attention as have metastatic tumors to certain other areas, ovary
being one classic example. However, I have seen some striking examples in which a patient has presented
with a bladder tumor that has been a manifestation of spread from outside the genitourinary tract and
several examples of this will be presented in the seminar. Two recent contributions, one an original
peer reviewed paper and one a review by the same group present recent data on this topic (23,24) and a
source of comprehensive references on tumors spreading to the bladder. Those workers found that tumors
secondary to the bladder from adjacent sites, or more distant sites, accounted in aggregate for 2.3
percent of all malignant bladder tumors in their surgical pathology material. The commonest primary
sites of the neoplasms usually spreading my direct extension where, in descending order of frequency, the
colon, prostate, rectum and cervix. Tumors that spread to the bladder from more distant sites only
accounted for slightly more than four percent of all secondary bladder neoplasms and were usually from
the skin, lung, or breast. The authors commented that relatively few of the secondary tumors have unique
histologic features and knowledge of the history and appropriate clinical evaluation are important in
establishing the correct diagnosis, comments I would certainly second. I would only add that it is often
the astuteness of the pathologist in picking up a somewhat unusual morphology that leads to the history
being investigated or the patient further investigated by the appropriate studies.
- Leestma JA, Price EG, Jr. Paraganglioma of the urinary bladder. Cancer 28:1063-1072, 1971.
- Grignon DJ, Ro JY, Mackay B, Ordonez NG, El-Naggar A, Molina T, Shum DT, Ayala AG. Paraganglioma of
the urinary bladder: immunohistochemical, ultrastructural, and DNA flow cytometric studies. Hum Pathol
- Pugh RCB, Gresham GA, Mullaney J. Phaeochromocytoma of the urinary bladder. J Pathol Bacteriol
- Das S, Bulusu NV, Lowe P. Primary vesical pheochromocytoma. Urology 21:20-25, 1983.
- Talbert ML, Young RH. Carcinomas of the urinary bladder with deceptively benign-appearing foci: a
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- Murphy WM, Deana DG. The nested variant of transitional cell carcinoma: A neoplasm resembling
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- Drew PA, Furman J, Civantos F, Murphy WM. The nested variant of transitional cell carcinoma: An
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- Young RH, Oliva E. Transitional cell carcinomas of the urinary bladder that may be underdiagnosed. A
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- Young RH. Papillary and polypoid cystitis. A report of eight cases. Am J Surg Pathol 12:542-546,
- Amin MB, Ro JY, El-Sharkawy T et al. Micropapillary variant of transitional cell carcinoma of the
urinary bladder. Histologic pattern resembling ovarian papillary serous carcinoma. Am J Surg Pathol
- Zukerberg LR, Harris NL, Young RH. Carcinomas of the urinary bladder simulating malignant lymphoma.
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- Murata T, Soga T, Tajima K et al. Sarcomatoid carcinoma of the urinary tract. Pathology
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- Torenbeek R, Blomjous CEM, deBruin PC, et al. Sarcomatoid carcinoma of the urinary bladder.
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- Foschini MP, Pilato F, D'Aversa C, et al. Sarcomatoid carcinoma of the urinary bladder. Report of
five cases. J Urol Pathol 6:139-152, 1997.
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- Ikegami H, Iwasaki H, Ohjimi Y et al. Sarcomatoid carcinoma of the urinary bladder: A
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- Jones EC, Young RH. Myxoid and sclerosing sarcomatoid transitional cell carcinoma of the urinary
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- Cook JR, Dehner LP, Collins MH et al. Anaplastic lymphoma kinase (ALK) expression in the
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- Cessna MH, Zhou H, Sanger WG et al. Expression of ALK1 and p80 in inflammatory myofibroblastic tumor
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- Bates AW, Baithun SI. Secondary neoplasms of the bladder are histological mimics of nontransitional
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