Signalment:  

9-month-old male C57BL/6 TRAMP mouse, (Mus musculus).This mouse was a control animal that was part of a novel imaging modality study. No clinical signs reported.

Gross Description:  

This mouse was presented alive in good body condition. There is a focally extensive, 1.2 x 1.0 x 1.0 cm, mottled pale tan to red, firm, somewhat circumscribed mass around the neck of the urinary bladder. All other organs and tissues are within normal gross limits.

Histopathologic Description:

Prostate gland: There is a regionally extensive, invasive, unencapsulated mass arising from and replacing most of the anterior prostate lobe, with infiltration and effacement of other prostate lobes and the urinary bladder. The mass is comprised of sheets and anastomosing lobules of cells with scant fibrovascular stroma. The cells are pleomorphic (polygonal, elongated, round) with poorly defined cell borders enclosing small amounts of eosinophilic cytoplasm. The nuclei are round to ovoid with coarsely clumped chromatin and single inconspicuous nucleoli. A range of 15 to 25 and an average of 20 mitoses per 400X field is noted. Anisocytosis and anisokaryosis is marked (>3 fold). Apoptosis/single cell necrosis is noted throughout the mass, and there is multifocal to coalescing central lytic necrosis with hemorrhage throughout the mass. Within most remaining glands of the anterior lobe and the other lobes of the prostate gland, there are changes consistent with prostatic intraepithelial neoplasia (PIN), including areas of epithelial stratification, micropapillary formation, and cribriform structure formation.

Morphologic Diagnosis:  

1. Prostate gland (anterior lobe), poorly-differentiated prostatic carcinoma. 
2. Prostate gland (all lobes), high-grade prostatic intraepithelial neoplasia (PIN).

Condition:  

Prostatic carcinoma

Contributor Comment:  

Transgenic adenocarcinoma of mouse prostate (TRAMP) is a transgenic mouse engineered to express the SV40 virus large T and small t oncoproteins in the secretory epithelial cells of the prostate under the control of the androgen-responsive minimal rat probasin promoter.(1,3,4) Expression of these transgenes results in inhibition of p53 and Rb tumor suppressor function.(1)

The TRAMP model has been based on either C57BL/6 or C57BL/6 TRAMP x FVB hybrid mouse strains.(1,3,4) The prostate tumors observed in male TRAMP mice progress in a stepwise fashion through different preneoplastic and neoplastic lesions, which is a feature of prostate tumors in humans.(1,3) In TRAMP mice, commonly observed lesions include:(1)

1. 6- to 12-week old mice: hyperplastic epithelial lesions or prostatic intraepithelial neoplasia (PIN). 
2. 12- to 24-week old mice: well-differentiated prostatic adenocarcinoma.
3. >24-week old mice: poorly-differentiated prostatic adenocarcinoma, with development of metastases (commonly iliac lymph nodes and lungs). 
4. 33- to 52-week old mice: death. 

TRAMP prostate tumors share other similarities with human prostate tumors, including metastases to distant sites, development of androgen independence, and neuroendocrine differentiations.(1,3) As such, TRAMP mice have been extensively used to study the molecular events important in prostate cancer progression in humans. 

The classification and grading of lesions in transgenic mouse models of prostatic tumors (including and mainly those observed in TRAMP mice) can be confusing and controversial. The most widely used scheme for classifying such tumors originates from the 2004 Bar Harbor Meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee.(4) This classification scheme refined and stressed the importance of PIN lesions based on a wide body of published work. Recently, a grading scheme was proposed that incorporates some data and concepts developed and published since the 2004 Bar Harbor classification scheme, which in summary includes:(1)

• Grade 0: Normal. Prostate glands lined by a monolayer of cuboidal to columnar epithelium with basally-oriented nuclei.
• Grade 1: Low-grade PIN. Crowding and occasional stratification of prostate epithelial cells, with increased nuclear to cytoplasmic ratio. 
• Grade 2: Moderate-grade PIN. Similar to low-grade PIN, but there is more frequent stratification. 
• Grade 3: High-grade PIN. Similar to moderate-grade PIN, but hyperplastic epithelial cells can form papillary projections and/or cribriform patterns. 
• Grade 4: Phyllodes-like tumor. Consists of papillary projections of loose stroma with loosely-arranged stellate mesenchymal cells. 
• Grade 5: Well-differentiated adenocarcinoma. Invasive tumor consisting primarily of well-differentiated tubules or acini. There is marked cellular and nuclear atypia, and high mitotic indices. 
• Grade 6: Moderately-differentiated adenocarcinoma. Invasive tumor that consists of a mass of epithelial cells, some of which form recognizable acini or tubules. There is marked cellular and nuclear atypia, and high mitotic indices.
• Grade 7: Poorly-differentiated carcinoma (neuroendocrine type). Invasive tumors composed of solid sheets of polygonal to elongated cells. There is marked cellular and nuclear atypia, and high mitotic indices.

JPC Diagnosis:  

Prostate gland: Prostatic carcinoma, high grade, with adjacent prostatic intraepithelial neoplasia (PIN).

Conference Comment:  

The contributor has given a comprehensive overview of this important mouse model and given a clear summary of the different classification schemes. We concur with the contributors use of the 2012 proposed grading scheme, which classifies the intraepithelial proliferative lesions as PIN rather than atypical hyperplasia for this model because, as the authors note, PIN lesions in TRAMP mice are clearly precursors of more invasive and aggressive carcinomas.(1)

Physicians from the Joint Pathology Center (JPC) Genitourinary subspecialty were consulted on this case. These pathologists were impressed by the striking lack of differentiation within this aggressive tumor and noted that the histological features closely approximate the neuroendocrine phenotype described as a grade 7 in the paper previously referenced. Apparently this microscopic appearance is rare in human prostatic carcinomas, which are generally diagnosed and treated well before reaching this stage. JPC pathologists also expressed agreement that the changes in the remaining glands of the prostate gland are consistent with high-grade prostatic intraepithelial neoplasia, which represents an intermediate stage between normal epithelium and invasive malignant carcinoma. In human medicine, PIN is clinically significant in that it provides relatively early identification of patients at risk for malignancy.(2)

References:

1. Berman-Booty LD, Sargeant AM, Tosol TJ, et al. A review of the existing grading schemes and a proposal for a modified grading scheme for prostatic lesions of TRAMP mice. Toxicol Pathol. 2012;40:5-17.

2. Brawer MK. Prostatic intraepithelial neoplasia: an overview. Rev Urol. 2005;7(suppl 3);11-18.

3. Chiaverotti T, Couto SS, Donjacour A, et al. Dissociation of epithelial and neuroendocrine carcinoma lineages in the transgenic adenocarcinoma of mouse prostate model of prostate cancer. Am J Pathol. 2008;172:236-246.

4. Schappell SB, Thomas GV, Roberts RL, et al. Prostate pathology of genetically engineered mice: definitions and classification. The consensus report from the Bar Harbor Meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee. Cancer Res. 2004;64:2270-2305.

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4-1. Prostate

4-2. Prostate

4-3. Prostate

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