Abstract and references

Abstract and references
Eosinophilic renal tumours – useful adjuncts for diagnosis
Dr Patricia Harnden (St. James’ University Hospital, Leeds)
Learning points
 Morphological distinction between granular variant conventional carcinoma,
chromophobe carcinoma and oncocytoma is not absolute.
 In difficult cases, extensive sampling may identify more characteristic areas of
conventional or chromophobe carcinoma.
 Chromophobe carcinoma and oncocytoma have a common cell of origin and
overlapping genetic features.
 “Gold standard” to identify tumour subtypes should be based on patient outcomes
(benign course) not opinion.
 Immunohistochemical results affected by case selection and methodology.
 Ultrastructure may be helpful1 but danger of sampling error.
The distinction between the granular variant of conventional renal carcinomas, the
eosinophilic variant of chromophobe carcinoma and oncocytoma is important for prognosis
and could become essential for the selection of patients for targeted therapies. Interpretation
of studies of differential diagnostic features, whether morphological, immunohistochemical or
genetic, is hindered by the difficulties of establishing a diagnostic “gold standard”. In a
selected series, morphological features for the diagnosis of oncocytoma were validated
against favorable patient outcomes,2 but this approach is rare and most studies are based on
morphological opinion, and should be interpreted with caution. Furthermore, the group of
conventional carcinomas used for comparison may only include a small proportion of the
granular variant,3 therefore the reported frequencies of antigen expression may be for clear
cell predominant tumours. The high levels of endogenous biotin binding proteins in
mitochondria rich granular cells can lead to erroneous results with the avidin-biotin based
detection system.4 Finally, chromophobe carcinoma and oncocytoma are thought to both
originate from distal tubules and share genetic abnormalities, therefore distinction even by
ancillary methods may not be possible. In fact, the true nature of oncocytomas and their
classification as benign tumours has been questioned.5
References
1. Krishnan B, Truong LD. Renal epithelial neoplasms: the diagnostic implications of
electron microscopic study in 55 cases. Hum Pathol.2002;33(1):68-79.
2. Amin MB, Crotty TB, Tickoo SK, Farrow GM. Renal oncocytoma: a reappraisal of
morphologic features with clinicopathologic findings in 80 cases. Am J Surg Pathol.
1997;21(1):1-12.
3. Mazal PR, Exner M, Haitel A, et al. Expression of kidney-specific cadherin
distinguishes chromophobe renal cell carcinoma from renal oncocytoma. Hum Pathol.
2005;36(1):22-28.
4. Banks RE, Craven RA, Harnden P, Selby PJ. Use of a sensitive EnVision +-based
detection system for Western blotting: avoidance of streptavidin binding to
endogenous biotin and biotin-containing proteins in kidney and other tissues.
Proteomics. 2003;3(4):558-561.
5. Van der Kwast T, Perez-Ordonez B. Renal oncocytoma, yet another tumour that does
not fit in the dualistic benign/malignant paradigm? J Clin Pathol. 2007;60(6):585-586.
Histopathology and genetics of familial renal cell carcinoma
Professor Holger Moch (University Hospital Zurich)
No abstract or references submitted
Urine cytology- new adjuncts
Dr Ash Chandra (St. Thomas’ Hospital, London)
Learning points
 Urine cytology retains its leading role in the detection of new and recurrent bladder
tumours
 Specificity of cytological diagnosis should be maintained through review and audit
 Biomarkers may be used as an adjunct to cytology in
i) the detection of residual or recurrent tumour following treatment
ii) providing supportive evidence for abnormal cytology when no clinical disease is
evident
iii) instrumented samples collected from the urinary tract
 The use of biomarkers in conjunction with cytology may increase the interval for
surveillance cystoscopy when both tests are negative
 Some biomarkers (BTA, NMP) may be positive in inflammatory conditions of the
bladder while tests like FISH may detect genetic abnormalities in the absence of a
clinical lesion
 Blue light cystoscopy is a valuable investigation for persistent positive or suspicious
cytology
Urine cytology is a highly specific test for potentially lethal, high-grade urothelial neoplasms.
Its sensitivity for low-grade urothelial neoplasms is low, however, these are not lifethreatening neoplasms and are best detected by direct visualisation at cystoscopy.
Urinary biomarkers are being developed to improve the detection of low-grade neoplasms
and to lend support to equivocal and suspicious cytological diagnoses. How successful have
biomarkers been as adjuncts to cytology in the prediction of urothelial neoplasia?
References
1. Hajdinjak T. UroVysion FISH test for detecting urothelial cancers: Meta-analysis of
diagnostic accuracy and comparison with urinary cytology testing. Urol Oncol 2008
(epub ahead of print)
2. Budman LI, Kassouf W, Steinberg JR. Biomarkers for detection and surveillance of
bladder cancer. Can Urol Assoc J 2008;2(3):212-21
3. Moonen PM, Merckx GF, Peelen P et al. UroVysion compared with cytology and
quantitative cytology in the surveillance of non-muscle-invasive bladder cancer. Eur
Urol 2007;51(5):1275-80
4. Akkad T, Brunner A, Pallwein L et al. Fluorescence in situ hybridization for detecting
upper urinary tract tumors- a preliminary report. Urology 2007;70(4):753-7
5. May M, Hakenberg OW, Gunia S et al. Comparative diagnostic value of urine
cytology, UBC-ELISA, and fluorescence in situ hybridization for detection of
transitional cell carcinoma of urinary bladder in routine clinical practice. Urology
2007;70(3):449-53
6. Rodgers M, Nixon J, Hempel S et al. Diagnostic tests and algorithms used in the
investigation of haematuria: systematic reviews and economic evaluation. Health
Technology Assessment 2006;10(18):iii-iv, xi-259.
Spindle cell tumours of bladder
Dr Elizabeth Montgomery (John Hopkins Hospital, Baltimore, USA)
Learning points
 To identify bladder lesions that have been termed “post-operative spindle cell nodule”,
“Pseudosarcomatous myofibroblastic proliferations of the bladder”, and “inflammatory
myofibroblatic tumors/ IMT”.
 To review ALK gene and protein alterations in bladder IMT
 To discuss reporting of such cases and the need for caution in a small subset.
 To outline pertinent immunohistochemical pitfalls in the differential diagnosis of
spindle cell tumors of the bladder.
 To understand clinicopathologic parameters of bladder vascular lesions associated
with malignancy.
 To note the occasional correlation of bladder neurofibromas with neurofibromatosis.
Introduction
Theoretically any mesenchymal tumor can arise in the bladder, but they are seldom
encountered in practice. Various vascular 1, nerve sheath2,3, true smooth muscle neoplasms,
and rhabdomyosarcomas can be encountered in the bladder. Most recently, attention has
been drawn to lesions variably termed “post-operative spindle cell nodule”,
“Pseudosarcomatous myofibroblastic proliferations of the bladder”, and “inflammatory
myofibroblatic tumors”, which are probably more common than some of the others, and
sometimes difficult to diagnose with complete confidence.
Pseudosarcomatous myofibroblastic proliferations / inflammatory myofibroblatic
tumors
Pulmonary lesions called “inflammatory pseudotumors” were known for many years and were
regarded as part of a spectrum of lesions called “plasma cell granulomas” 4-8 Various terms
were applied: inflammatory pseudotumor, plasma cell granuloma, plasma cell pseudotumor,
xanthomatous pseudotumor, pseudosarcomatous myofibroblastic proliferation, and
inflammatory myofibrohistiocytic proliferation 9. Subsequently, similar tumors were described
in the abdomen and other soft tissue sites 9,10. As we have learned more about a wide
spectrum of lesions in this family of myofibroblastic proliferations in a host of anatomic sites 1119
, questions concerning their etiology and biologic potential remain.
Advances in
understanding of the molecular biology of these tumors, launched by the discovery of a “hot
spot” at 2p23 flanking the ALK gene by Griffin et al20, have provided some insights, but other
questions remain unanswered. Following the report by Griffin and her colleagues 20 of these
alterations in soft tissue lesions, other investigators confirmed similar alterations in other
sites, including the lung, the classic site21. Immunohistochemistry for the protein product
confirmed protein expression in subsets of these lesions in a range of anatomic sites 18,19,22-29,
although Cessna et al noted that this staining was not wholly specific 28. These tumors have
been linked, on the one hand, to nodular fasciitis 30, and, on the other hand, to cells of the
accessory immune system that have been variously called fibroblastic reticulum cells, myoid
cells, and dictyocytes 31.
Inflammatory Myofibroblastic Tumor and Inflammatory Fibrosarcoma of Soft Tissues
Although these lesions were originally described as separate entities, they are now
recognized as ends of a spectrum of tumors unified by a common molecular profile 9,26,32-35.
They are grouped together by the WHO 36,37. Gene fusions involving anaplastic lymphoma
kinase (ALK) at chromosome 2p23 have been described 22,35,38,39. By immunohistochemistry,
ALK has been detected in about 60% of cases, a finding that can sometimes be exploited for
diagnosis22. In a subset of cases, ALK C-terminal kinase domain is fused with tropomyosin Nterminal coiled-coil domain and other cases have shown fusion of ALK with the clathrin heavy
chain 35.
Bladder
A spindle cell lesion in the bladder reminiscent of nodular fasciitis was described in 1980 as
“reactive pseudosarcomatous response” 40 and subsequently, this process was found
elsewhere in the genitourinary tract 41-43. Identical lesions were subsequently encountered in
patients who had undergone prior instrumentation, and these were called “post-operative
spindle cell nodules”44,45. Other terms have included inflammatory pseudotumor, nodular
fasciitis, pseudomalignant spindle cell proliferation, pseudosarcomatous myofibroblastic
proliferation, pseudosarcomatous myofibroblastic tumor, and inflammatory myofibroblastic
tumor 25. The unifying feature of these lesions is their proclivity to mimic both sarcomas 46and
spindled carcinomas47, the latter compounded by their expression of various keratins23,42,43,4650
. It has been assumed that, since these tumors have been benign in small follow-up
studies47, that they were unrelated to lesions with similar names in other anatomic sites and,
thus, more akin to nodular fasciitis51,52. However, they differ from nodular fasciitis in their
capacity to infiltrate deeply into the detrusor muscle.
The identification of ALK alterations in some bladder lesions suggests that, despite the
lesions’ frequent similarity to nodular fasciitis, they could be neoplastic23,25,51-54. It has also led
to re-evaluation of their relationship to similar proliferation in the soft tissues. Since those in
the bladder often appear fasciitis-like with a loose myxoinflammatory appearance, whereas
those in other sites can be fascicular, sclerosed, or laden with plasma cells and foam cells,
bladder lesions had been regarded simply as counterparts of nodular fasciitis.
In our own material, bladder lesions are highly likely (about 70%) to be ALK reactive on
immunohistochemistry and to harbor ALK alterations on FISH studies (about 75%; we found
ALK alterations in both post-instrumentation and de novo lesions), certainly supporting that
most are not simply reactive processes.
Most cases display nuclear p53 on
immunohistochemistry as well as keratin reactivity.
Most patients with bladder lesions are adult (mean age in 40s with a range from childhood to
elderly patients) males (about 3:1) who present with hematuria. There is a history of
instrumentation in about 20% of patients. Some lesions are quite cellular with mitoses and
necrosis, and bladder wall invasion is not uncommon.
The vast majority of patients have an indolent course (although 10-25% experience
recurrences), but we have recently encountered 2 cases in which biopsies showing bladder
IMT preceded (1 and 2m, respectively) biopsies showing sarcomatoid carcinoma; even on rereview the bladder IMT in these 2 cases were morphologically indistinguishable from other
cases of bladder IMT, with FISH demonstrating ALK alterations in the bladder IMT areas in 1
of the 2 cases. These 2 patients both died of their carcinomas. A further case displayed
overtly sarcomatous features and displayed ALK alterations by FISH and the patient
subsequently died of this malignant neoplasm. As such, currently, when we encounter
atypical features in these lesions, we now advise caution and do not render an unequivocally
benign interpretation. When lesions appear typical and fasciitis-like, we note that most are
benign but mention recurrences and even association with malignant neoplasms as remote
possibilities.
The question remains as to whether bladder IMT is the same lesion as lesions called IMT in
the rest of the body. Bladder lesions are far more likely to express keratin than those in other
sites and are certainly less likely to metastasize [although metastases are rare in soft tissue
examples]. They do share molecular alterations and should for the present at least be
regarded as a subtype of the general family of IMT. Conservative management and follow-up
is advised for most cases.
Sarcomatoid Carcinoma
It is well known that some sarcomatoid urothelial carcinomas exhibit myxoid features
mimicking IMT. IMT often expresses cytokeratin, and sarcomatoid urothelial carcinoma
sometimes shows weak or focal immunoreactivity for cytokeratin, making the differential
diagnosis even more difficult. Finding marked cytologic atypia, atypical mitotic figures, and
nonmyxoid areas with marked increased cellularity usually allows for a diagnosis of
sarcomatoid carcinoma, but the most useful feature is the identification of an in situ or
invasive “typical” epithelial component.
Bladder Muscle Tumors
Leiomyomas and leiomyosarcomas of the bladder are rare (the Mayo clinic was only able to
amass a small series; 55) and appear similar to those elsewhere in the body.
Leiomyosarcomas can also express cytokeratin. Leiomyosarcomas and leiomyomas lack
ALK-1.
In the pediatric setting, embryonal rhabdomyosarcoma is the key contender in the differential
diagnosis, an entity readily separated by application of an immunohistochemical panel that
includes MyoD1 or myogenin.
Vascular Tumors
These lesions are rare; we were only able to accumulate 13 (3 hemangiomas, 3 intravascular
papillary endothelial hyperplasias, 2 arteriovenous malformations (AVMs), 1 epithelioid
hemangioendothelioma (EHE), and 4 angiosarcomas). All patients were adults. Hematuria
was the most common presentation of both benign and malignant lesions. Histologically,
benign and malignant lesions were similar to their counterparts in other organ systems; the
papillary endothelial hyperplasias were all associated with radiation. A key finding was that
benign lesions involved the submucosa and spared the muscularis propria of the organ
whereas sarcomas involved the muscularis propria.
Nerve Sheath Tumors
These are rare 2,3; we have only encountered 8 cases, that tend to present with bladder
infections and hematuria.
The patients had neurofibromas of various types and
schwannomas as well as an unusual epithelioid subtype. Importantly, in a subset, the lesions
were a manifestation of neurofibromatosis.
References
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lesions of the bladder. Am J Surg Pathol 2008;32:1213–1219.
2. Lewin MR, Dilworth HP, Abu Alfa AK, Epstein JI and Montgomery E. Mucosal benign
epithelioid nerve sheath tumors. Am J Surg Pathol 2005;29:1310–1315.
3. Wang W, Montgomery E and Epstein JI. Benign nerve sheath tumors on urinary
bladder biopsy. Am J Surg Pathol 2008;32:907–912.
4. Weinberg PB, Bromberg PA and Askin FB. "Recurrence" of a plasma cell granuloma
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5. Warter A, Satge D and Roeslin N. Angioinvasive plasma cell granulomas of the lung.
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6. Umiker WO and Iverson L. Postinflammatory tumors of the lung; report of four cases
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7. Spencer H. The pulmonary plasma cell/histiocytoma complex. Histopathology
1984;8:903–916.
8. Matsubara O, Tan-Liu NS, Kenney RM and Mark EJ. Inflammatory pseudotumors of
the lung: progression from organizing pneumonia to fibrous histiocytoma or to plasma
cell granuloma in 32 cases. Hum Pathol 1988;19:807–814.
9. Coffin CM, Watterson J, Priest JR and Dehner LP. Extrapulmonary inflammatory
myofibroblastic tumor (inflammatory pseudotumor). A clinicopathologic and
immunohistochemical study of 84 cases. Am J Surg Pathol 1995;19:859–872.
10. Meis JM and Enzinger FM. Inflammatory fibrosarcoma of the mesentery and
retroperitoneum. A tumor closely simulating inflammatory pseudotumor. Am J Surg
Pathol 1991;15:1146–56.
11. Sciot R. et al. Inflammatory myofibroblastic tumor of bone: report of two cases with
evidence of clonal chromosomal changes. Am J Surg Pathol 1997;21:1166–72.
12. Wenig BM, Devaney K and Bisceglia M. Inflammatory myofibroblastic tumor of the
larynx. A clinicopathologic study of eight cases simulating a malignant spindle cell
neoplasm. Cancer 1995;76:2217–2229.
13. Rose AG, McCormick S, Cooper K and Titus JL. Inflammatory pseudotumor (plasma
cell granuloma) of the heart: report of two cases and literature review. Arch Pathol Lab
Med 1996;120:549–554.
14. Hurt MA and Santa Cruz DJ. Cutaneous inflammatory pseudotumor. Lesions
resembling "inflammatory pseudotumors" or "plasma cell granulomas" of
extracutaneous sites. Am J Surg Pathol 1990;14: 764–773.
15. Kapusta LR, Weiss MA, Ramsay J, Lopez-Beltran A. and Srigley JR. Inflammatory
myofibroblastic tumors of the kidney: a clinicopathologic and immunohistochemical
study of 12 cases. Am J Surg Pathol 2003;27: 58–66.
16. Van Weert S, Manni JJ and Driessen A. Inflammatory myofibroblastic tumor of the
parotid gland: case report and review of the literature. Acta Otolaryngol 2005;125:
433–437.
17. Rodrigues M, Taylor RJ, Sun CC and Wolf JS. Inflammatory myofibroblastic tumor of
the larynx in a 2-year-old male. ORL J Otorhinolaryngol Relat Spec 2005; 67:101–
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18. Rabban JT, Zaloudek CJ, Shekitka KM and Tavassoli FA. Inflammatory
myofibroblastic tumor of the uterus: a clinicopathologic study of 6 cases emphasizing
distinction from aggressive mesenchymal tumors. Am J Surg Pathol 2005;29;1348–
1355.
19. Petridis AK, Hempelmann RG, Hugo HH, Eichmann T. and Mehdorn HM. Metastatic
low-grade inflammatory myofibroblastic tumor (IMT) in the central nervous system of a
29-year-old male patient. Clin Neuropathol 2004;23:158-166.
20. Griffin CA et al. Recurrent involvement of 2p23 in inflammatory myofibroblastic
tumors. Cancer Res 1999;59: 2776–2780.
21. Yousem SA, Shaw H & Cieply K. Involvement of 2p23 in pulmonary inflammatory
pseudotumors. Hum Pathol 2001;32:428–433.
22. Cook JR et al. Anaplastic lymphoma kinase (ALK) expression in the inflammatory
myofibroblastic tumor: a comparative immunohistochemical study. Am J Surg Pathol
2001;25: 1364–1371.
23. Freeman A et al. Anaplastic lymphoma kinase (ALK 1) staining and molecular
analysis in inflammatory myofibroblastic tumours of the bladder: a preliminary
clinicopathological study of nine cases and review of the literature. Mod Pathol
2004;17: 765–771.
24. Chun YS, Wang L, Nascimento AG, Moir CR and Rodeberg DA. Pediatric
inflammatory myofibroblastic tumor: anaplastic lymphoma kinase (ALK) expression
and prognosis. Pediatr Blood Cancer 2005;45:796–801.
25. Tsuzuki T, Magi-Galluzzi C & Epstein JI. ALK-1 expression in inflammatory
myofibroblastic tumor of the urinary bladder. Am J Surg Pathol 2004;28:1609–1614.
26. Sigel JE, Smith TA, Reith JD and Goldblum JR. Immunohistochemical analysis of
anaplastic lymphoma kinase expression in deep soft tissue calcifying fibrous
pseudotumor: evidence of a late sclerosing stage of inflammatory myofibroblastic
tumor? Ann Diagn Pathol 2001;5:10-4.
27. Ma Z et al. Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in
inflammatory myofibroblastic tumor. Genes Chromosomes Cancer 2003;37:98–105.
28. Cessna MH et al. Expression of ALK1 and p80 in inflammatory myofibroblastic tumor
and its mesenchymal mimics: a study of 135 cases. Mod Pathol 2002;15:931–938.
29. Chan JK, Cheuk W and Shimizu M. Anaplastic lymphoma kinase expression in
inflammatory pseudotumors. Am J Surg Pathol 2001;25:761–768.
30. Nochomovitz LE and Orenstein JM. Inflammatory pseudotumor of the urinary bladder-possible relationship to nodular fasciitis. Two case reports, cytologic observations,
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31. Nonaka D, Birbe R and Rosai J. So-called inflammatory myofibroblastic tumour: a
proliferative lesion of fibroblastic reticulum cells? Histopathology 2005;46:604–613.
32. Coffin CM, Dehner LP and Meis-Kindblom JM. Inflammatory myofibroblastic tumor,
inflammatory fibrosarcoma, and related lesions: an historical review with differential
diagnostic considerations. Semin Diagn Pathol 1998;15:102–110.
33. Coffin CM, Humphrey PA and Dehner LP. Extrapulmonary inflammatory
myofibroblastic tumor: a clinical and pathological survey. Semin Diagn Pathol
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34. Meis-Kindblom JM, Kjellstrom C & Kindblom LG. Inflammatory fibrosarcoma: update,
reappraisal, and perspective on its place in the spectrum of inflammatory
myofibroblastic tumors. Semin Diagn Pathol 1998;15:133–143.
35. Bridge JA et al. Fusion of the ALK gene to the clathrin heavy chain gene, CLTC, in
inflammatory myofibroblastic tumor. Am J Pathol 2001;159: 411–415.
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myofibroblastic tumors. Am J Pathol 2000;157: 377–384.
39. Sirvent N. et al. ALK probe rearrangement in a t(2;11;2)(p23;p15;q31) translocation
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prostate: immunohistochemical, ultrastructural, and DNA flow cytometric analyses of
nine cases. Hum Pathol 1993;24:1203–1210.
43. Horn LC, Reuter S & Biesold M. Inflammatory pseudotumor of the ureter and the
urinary bladder. Pathol Res Pract 1997;193:607–612.
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47. Iczkowski KA et al. Inflammatory pseudotumor and sarcoma of urinary bladder:
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48. Jones EC, Clement PB and Young RH. Inflammatory pseudotumor of the urinary
bladder. A clinicopathological, immunohistochemical, ultrastructural, and flow
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2003;38:187–190.
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neoplasms of the urinary bladder: a clinicopathologic comparison of leiomyoma and
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Diagnosis of small foci adenocarcinoma of prostate on needle biopsy
Professor Jonathan Epstein (John Hopkins Hospital, Baltimore, USA)
Learning Points
 The diagnosis of cancer on needle biopsy is typically based on a constellation of
morphological features.
 There are only a few pathognomonic features of prostate cancer.
 Most common mimickers of gland forming prostate cancer are partial atrophy, postatrophic hyperplasia, and adenosis.
 One of the most common mimickers of poorly differentiated prostate cancer on needle
biopsy is non-specific granulomatous prostatitis.
 Immunohistochemical stains for basal cell markers and AMACR must be used as
adjuncts rather than as the primary tools of prostate cancer diagnosis, as benign
mimickers of cancer can share the immunoprofile with cancer.
Evaluating an atypical focus in a needle biopsy of the prostate should be a methodical
process. When reviewing needle biopsies, one should develop a mental balance sheet where
on one side of the column are features favoring the diagnosis of carcinoma and on the other
side of the column are features against the diagnosis of cancer (see below).1-3 At the end of
evaluating a case, hopefully all of the criteria are listed on one side of the column or the other
such that a definitive diagnosis can be made. It is always helpful to first identify glands that
you are confident are benign, and then compare these benign glands to the atypical glands
which you are considering to diagnose as adenocarcinoma of the prostate. The greater the
number of differences between the recognizable benign glands and the atypical glands the
more confidently a malignant diagnosis can be established. In general, the diagnosis of
cancer should be based on a constellation of features rather than relying on any one criterion
by itself.
The only pathognomonic features of prostate cancer are: 1) perineural invasion; 2)
glomerulations; and 3) mucinous fibroplasia.
Favoring Cancer
Architectural
Infiltrative pattern
Small glands
Crowded glands
Nuclear
Prominent nucleoli
Enlargement
Hyperchromasia
Mitotic figures
Apoptotic bodies
Against Cancer
Lobularity
Larger glands
Branching glands
Prominent nucleoli yet adjacent PIN
(r\o PINATYP)
Similar nuclear changes to adjacent
benign glands (r\o adenosis)
Nuclear atypia with inflammation
(r\o reactive atypia)
Cytoplasmic
Amphophilic cytoplasm
Sharp luminal border
Luminal
Blue-tinged mucinous secretions
Pink amorphous secretions
Crystalloids
Pale-clear cytoplasm
Luminal undulations or papillary infolding
Corpora amylacea
References
1. Epstein JI. Diagnosis and reporting of limited adenocarcinoma of the prostate on
needle biopsy. Mod Pathol 2004;17:307–315.
2. Epstein JI, Netto G. Prostate Biopsy Interpretation. 4th Edition. Lippincott William
and Wilkins, New York (2007).
3. Eble JN, Sauter G, Epstein JI, Sesterhenn I. WHO Classfication of Tumours.
Pathology and Genetics. Tumours of the Urinary and Male Reproductive System.
IARC Press, Lyon France (2004)
High grade PIN and its mimickers: frequency, diagnosis and clinical implications
Professor Jonathan Epstein (John Hopkins Hospital, Baltimore, USA)
Learning Points
 Low grade PIN (LGPIN) should not be commented on the pathology report.
 High grade PIN (HGPIN) has several patterns: flat, tufted, micropapillary, and
cribriform.
 Mimickers of HGPIN included cribriform hyperplasia, basal cell hyperplasia, central
zone, ductal and acinar adenocarcinoma, and intraductal carcinoma.
 PINATYP must be differentiated from HGPIN and cancer.
 The risk of cancer following HGPIN does not warrant immediate rebiopsy.
High grade PIN (HGPIN) has several patterns: flat, tufted, micropapillary, and cribriform. 1 The
distinction of HGPIN and LGPIN is based on nucleolar prominence.2 Mimickers of HGPIN
included cribriform hyperplasia, basal cell hyperplasia, central zone, ductal and acinar
adenocarcinoma, and intraductal carcinoma (IDC-P).3,4 The definition of IDC-P on needle
biopsy is based on objective morphological criteria that either architecturally or cytologically
clearly exceed those seen in high grade PIN.3 It is critical to distinguish between HGPIN and
IDC-P, as the latter is treated by definitive therapy used to treat prostate cancer. LGPIN
should not be mentioned in pathology reports for several reasons: 1) lack of reproducibility in
its diagnosis even by uropathology experts; 2) difficult and subjective to distinguish LGPIN
from mild variations of normal; and 3) not associated with increased risk of cancer on
rebiopsy.5 The median incidence of HGPIN on needle biopsy is 5%.5 The risks of finding
cancer in repeat biopsies performed within a year following a benign or HGPIN diagnosis are
not appreciably different.5 Because of the lack of much data on the long-term risk of cancer
following biopsy of HGPIN, and the potential medicolegal consequences of not following up
on a HGPIN diagnosis, a reasonable approach is to perform repeat biopsy 2-3 years following
a HGPIN diagnosis on needle biopsy.
References
1. Bostwick DG, Amin MB, Dundore P, Marsh W, Schultz DS. Architectural patterns of
high-grade prostatic intraepithelial neoplasia. Hum Pathol 1993;24:298–310.
2. Epstein JI, Grignon DJ, Humphrey PA, et al. Interobserver reproducibility in the
diagnosis of prostatic intraepithelial neoplasia. Am J Surg Pathol 1995;19:873–886.
3. Guo CC, Epstein JI. Intraductal carcinoma of the prostate: Histologic features and
clinical significance. Mod Pathol 2006;19:1528–1535.
4. Epstein JI, Netto G: Prostate Biopsy Interpretation. 4th Edition. Lippincott William
and Wilkins, New York (2007).
5. Epstein JI, Herawi M. Prostate needle biopsies containing prostatic intraepithelial
neoplasia or atypical foci suspicious for carcinoma: implications for patient care. J Urol
2006;175:820–834.
Common pitfalls in the diagnosis of testicular neoplasms – experience from a referral
practice
Dr Jeffery Theaker (Southampton General Hospital)
Learning points
 Accurate pathological diagnosis of testicular tumours is important as it guides clinical
management.
 The majority of tumours are accurately diagnosed.
 Referral and audit experience has highlighted several areas where there is a higher
potential for misdiagnosis.
 These problem areas can generally be resolved by careful histological assessment
and the use of appropriate immunohistochemistry.
 Germ cell tumours can present as metastatic disease and biopsy samples from the
metastatic masses may not show classical histological patterns.
Central histological review of testicular tumours treated by the Wessex Regional Oncology
Unit has been routine practice for 20 years. Whilst the vast majority of germ cell tumours are
accurately diagnosed, personal experience has highlighted areas in which there appear to be
diagnostic difficulties. We have reported major discrepancies in tumour typing in 23 of 499
(5%) external cases reviewed between 1992 and 2002 with patient treatment changed in 19
(4%).1 The most important of these which have a significant impact on patient management
relate to the recognition of embryonal carcinoma, usually as part of a seminoma dominated
combined germ cell tumour, the overall areas of spermatocytic seminoma and intratubular
germ cell neoplasia and the recognition of rare malignant transformations in teratoma. Other
difficult areas have less impact on treatment such as the recognition of yolk sac tumour
components and small foci of choriocarcinoma. The recognition of vascular invasion is also
an important part of the assessment of non-seminomatous germ cell tumours and will impact
on patient management. An overlapping pattern of diagnostic errors has been reported from
other referral practices which include examples of tumours which can be confused with
classical pattern seminoma.2
We are just about to start collecting data for a third 5 year cycle. My subjective impression is
that the number of major discrepancies has significantly reduced. This probably reflects the
introduction of cancer site specific MDTs in all major hospitals with speciality lead
pathologists and it would be expected that overall standards have generally risen.
Recognition of the problem areas also allows focussed training initiatives.
The failure to recognise a non-seminomatous germ cell component in a dominant seminoma
may relate to a lack of confidence in recognising the smaller element. Combined germ cell
tumours are common such that one should always specifically look for non-seminomatous
elements when reporting a seminoma. Classical seminomas can also show overlapping
histological features with solid yolk sac and Sertoli cell tumours. It is always of value to know
the serum markers at the time of reporting. Problems surrounding the accurate diagnosis of
spermatocytic seminoma probably relate to its relative rarity and this is exacerbated further
with the even rarer “anaplastic” variant which can more closely simulate seminoma or
embryonal carcinoma. These problem areas can generally be easily addressed by
immunohistochemistry.3 The two commonest somatic malignancies arising in teratomas are
PNET and rhabdomyosarcoma and are generally recognised by overgrowth and their
cytological features. Areas of immature neuroepithelial tissue are not uncommon in adult
teratoma and there are no clear criteria for deciding when a diagnosis of PNET can be
justified. An arbitrary minimum quantum of overgrowth to at least a x 4 objective field with no
intervening organised teratomatous element has been suggested. Accurate recognition of
vascular invasion is important and influences therapy in stage 1 non-seminomatous disease.
In my experience, vascular invasion is not usually restricted to one focus and is seen away
from the tumour edge in the interstitium and towards the hilum or in the tunica. Assessment of
vascular invasion in seminoma is often very difficult because of smear artefact but currently
has no important impact on clinical management.
Most histopathologists will encounter diagnostic biopsies from metastatic deposits from
unknown primary sites (or a primary mediastinal germ cell tumour). A possible primary
testicular germ cell tumour should always be considered in young (ish) men. Common modes
of presentation include abdominal masses (with back pain), nodal or brain metastases. Ask
the clinicians to examine the testes and to perform serum markers if not done. Metastatic
seminoma in needle biopsies may lack classical histological features and the paucity of tissue
makes assessment more difficult. Immunohistochemistry is of paramount value. PLAP is
often negative in metastatic seminoma but CD117 can be more helpful. The introduction of
antibody OCT3/4 has been a significant advance.4 This shows nuclear expression in a very
high proportion of classical pattern seminomas and embryonal carcinomas, but not other
germ cell tumour patterns or somatic malignancies, and is particularly valuable in the
evaluation of tumours presenting as metastases with an unknown primary site. Most such
cases, however, will be metastases from the common primary sites such as lung and a
confident exclusion of germ cell tumour can be of equal value to oncologists. Finally, with
increasing experience of long term survivors following successful chemotherapy, cases of
late relapse with unusual histological patterns (especially yolk sac variants) are being
encountered.
References
1. Delaney RJ, Sayers CD, Walker MA, Mead GM and Theaker JM. The continued value
of central histopathological review of testicular tumours. Histopathol 2005;47:166–169.
2. Ulbright TM. The most common, clinically significant misdiagnoses in testicular tumor
pathology and how to avoid them. Adv Anat Pathol 2008;15:18–27.
3. Theaker JM and Mead GM. Diagnostic pitfalls in testicular germ cell tumours. Curr Diag
Pathol. 2004;10:220–228.
4. Jones TD, Ulbright TM, Eble JN, Baldridge LA and Cheng L. OCT4 staining in
testicular tumors: a sensitive and specific marker for seminoma nad embryonal
carcinoma. Am J Surg Pathol 2004;28:935–940.
General reading
 Berney DM. Staging and classification of testicular tumours – pitfalls from macroscopy
to diagnosis. J Clin Pathol 2008;61:20–24.
 Emerson RE & Ulbright TM – Morphological approach to tumours of the testis and
paratestis. J Clin Pathol 2007;60:866–880.
 Ulbright TM, Amin MB and Young RH. Tumours of testis, adnexa, spermatic cord and
scrotum. Atlas of tumor pathology. AFIP, Third series 25, 1997.
Value of immunocytochemistry and frozen section in urological pathology
Dr Murali Varma (University Hospital of Wales, Cardiff)
Learning points:
 Interpretation of basal cell marker immunoreactivity in prostate glands must take into
account the pattern of immunoreactivity in the suspect glands (ie. basal cell pattern vs.
non-basal cell pattern).
 Basal cell marker immunoreactivity must be assessed in the suspect focus as a
whole; the majority of glands in adenosis and partial atrophy may be HMWCK/p63
negative.
 Unlike basal cell markers, the difference in AMACR immunoreactivity in benign and
malignant prostate glands is quantitative; while AMACR is expressed by benign
prostate glands, it is over-expressed in prostate cancer. Hence careful titration of
AMACR sensitivity (with expression only in malignant glands) is critical.
 Sensitivity of high2 as an urothelial
marker is significantly improved by the use of heat mediated antigen retrieval.
 Oct 3/4 a sensitive and specific marker for classical seminoma and embryonal
carcinoma is particularly useful in the assessment of limited material from metastatic
sites.
 Smoothelin immunohistochemistry has been reported to be positive in muscularis
propria but not hyperplastic muscularis mucosae and so help accurate distinction
between pT1 and pT2 bladder cancer.
While basal cell markers remain the cornerstone for immunohistochemical confirmation of
prostate cancer, the novel positive prostatic marker, AMACR is now widely used to help
establish the diagnosis, particularly in needle biopsies. In this presentation, a morphological
differential diagnosis based approach to prostatic immunohistochemistry will be described
with particular emphasis on the evaluation of immunostaining and the limitations of AMACR.
Distinction between poorly differentiated prostate cancer and urothelial carcinoma is critical
for accurate staging and appropriate therapy. The use of immunohistochemistry to resolve
this differential diagnosis will be discussed with particular emphasis on some technical
aspects that can have a major impact on the sensitivity of commonly employed
immunomarkers. The utility of urothelial markers to distinguish urothelial carcinoma from nonprostatic carcinomas will also be briefly discussed as will the possible role of
immunohistochemistry in the diagnosis of flat urothelial atypia and staging of bladder cancer.
In renal pathology, the most important role of immunohistochemistry is in the differential
diagnosis of tumours with eosinophilic cytoplasm, which will be covered by a previous
speaker. The use of immunohistochemistry to distinguish between other renal tumour
subtypes will be briefly discussed.
The utility of immunohistochemistry in testicular pathology will be covered by a previous
speaker.
Intraoperative frozen section examination is widely used at cystectomy (ureteric and/or
urethral margins) and radical prostatectomy (pelvic lymph node dissection) but its value in
these settings remain controversial and will be discussed. Frozen sections of kidney (outside
renal transplant setting) and testis are rarely performed in the UK and will be covered only
briefly.
References
1. Varma M, Jasani B. Diagnostic utility of immunohistochemistry in morphologically difficult
prostate cancer: review of current literature. Histopathology 2005; 47(1):1–16.
2. Hammerich KH, Ayala GA, Wheeler TM. Application of immunohistochemistry to the
genitourinary system (prostate, urinary bladder, testis, and kidney). Arch Pathol Lab Med.
2008;132(3):432-40.
3. Contemporary immunohistochemical approach to the surgical pathology of the
genitourinary systems. Guest editors: Amin, M and Young, RH. Seminars in Diag. Pathol.
2005;22(1):1-104.
4. Epstein JI, Amin M, Boccon-Gibod L, et al. Prognostic factors and reporting of prostate
carcinoma in radical prostatectomy specimens and pelvic lymphadenectomy specimens.
Scand J Clin Lab Invest Suppl 2005;216:34-63.
5. Truong LD. Krishnan B. Shen SS. Intraoperative pathology consultation for kidney and
urinary bladder specimens. Arch Pathol Lab Med. 2005;129(12):1585-601.
6. Paner GP, Shen SS, Lapetino S et al. Diagnostic utility of antibody to smoothelin in the
distinction of muscularis propria from muscularis mucosae of the urinary bladder. Am J
Surg Pathol. (In Press).