Adenocarcinoma of the Prostate with Paneth cell-like Neuroendocrine Differentiation
Jonathan I. Epstein
A 73 year old man underwent a radical cystoprostatectomy for deeply invasive urothelial carcinoma. A
small, organ confined prostate tumor was also noted.
Tumor was composed of predominantly nests and cords of cells with bright eosinophilic
granules. In addition, high grade prostatic intraepithelial neoplasia (HGPIN) was noted as well as usual
glands of adenocarcinoma of the prostate, Gleason score 3+3=6. The latter also contained similar
granules. Both the nests, cords, and glands were diffusely positive immunohistochemically for
Adenocarcinoma of the Prostate with Paneth cell-like Neuroendocrine Differentiation, where a Gleason
score cannot be assigned, yet a favorable prognosis is predicted.
Prostatic neuroendocrine cells may be visible on routine H&E stained slides, where the cells
resemble Paneth cells in the small intestine. These cells, characterized by small eosinophilic
cytoplasmic granules, are not true Paneth cells as they stain with neuroendocrine markers and are
uniformly negative for lysozyme. Rather, they are designated as "Paneth cell-like neuroendocrine
In some cases, the granules are not as apparent, but the morphology is the same composed of nests and
cords of cells with bland nuclear cytology and amphophilic cytoplasm. Tumor may be PSA negative and
positive for neuroendocrine markers, suggesting the diagnosis of carcinoid tumor. However, tumors may
have focal PSA staining and typically co-exist with usual prostate cancer or HGPIN showing neuroendocrine
differentiation, such that these cases are best considered prostate adenocarcinomas with neuroendocrine
In spite of the cells bland histological appearance, strictly applying the Gleason grading system one
would have to assign a Gleason pattern 5 to these foci with no glandular differentiation. However,
applying the Gleason score to these foci does not accurately reflect their clinical behavior. In cases
with Paneth cell-like NECs, only the conventional adenocarcinoma component should be assigned a Gleason
score. In cases where the entire tumor is composed of Paneth cell-like cells and areas of the tumor lack
glandular differentiation, the tumors should not be assigned a Gleason score and a comment should be
provided as to the generally favorable prognosis of this morphological pattern of neuroendocrine
differentiation. From a practical standpoint, one should not utilize without further explanation the
diagnostic term "prostatic adenocarcinoma with neuroendocrine differentiation" to denote Paneth cell-like
change in an adenocarcinoma, as we have seen such cases misconstrued by clinicians as small cell
Tamas EF, Epstein JI. Prognostic significance of Paneth cell-like neuroendocrine differentiation in
adenocarcinoma of the prostate. Am J Surg Pathol (August) 30: 980-985, 2006.
Other Examples of Preferred Terminology
1. The histological diagnosis of "acute prostatitis" should only be made in the rare setting where
there are sheets of neutrophils within acini and throughout the stroma, intraductal desquamated cellular
debris, stromal edema, and hyperemia. The biopsy or TURP of a man with clinical acute prostatitis is
contraindicated and can result in sepsis or other complications, such as stricture. Consequently,
diagnosing a specimen with focal acute inflammation as "acute prostatitis" can in certain circumstances
result in a urologist being sued. Rather, cases with acute inflammation solely within acini should be
diagnosed as "prostate tissue with acute inflammation".
2. In contrast to bladder or intestinal adenocarcinomas, mucinous adenocarcinoma of the prostate
rarely contains mucin positive signet cells. Some carcinomas of the prostate will have a signet-ring
cell appearance, yet the vacuoles are clear and do not contain intracytoplasmic mucin. These cases
should be diagnosed as "adenocarcinoma of the prostate with signet-ring cell-like features" to
distinguish them from true signet ring cell carcinomas. The presence of a true signet ring cell
adenocarcinoma involving the prostate suggests secondary involvement by a bladder or gastrointestinal
The recommended terminology for papillary carcinoma of the bladder is "non-invasive papillary
urothelial carcinoma" rather than "in-situ papillary urothelial carcinoma". In-situ carcinoma (CIS) is
used to denote flat carcinoma which has significantly different treatment and prognostic implications vs.
non-invasive papillary carcinoma. Clinicians will interpret "in-situ papillary urothelial carcinoma" to
mean that there is also CIS as well as papillary carcinoma.
Another source of potential confusion with terminology relates to the difference between muscularis
propria and muscularis mucosae. In the presence of muscle with invasive carcinoma, specify muscularis
propria (detrusor muscle) invasion as some clinicians understand one synonym and others only understand
the other. Do not use "muscle" invasion without qualifiers as ambiguous between muscularis mucosae and
muscularis propria. If see muscularis mucosae invasion, typically do not comment on in report. Also
specify if muscularis propria present or absent. Do not use the terns "superficial muscle invasion" or
"deep muscle invasion" as synonyms for muscularis mucosae and muscularis propria invasion, respectively.
Clinicians will interpret superficial and deep muscle invasion to mean inner and outer ½ of the
muscularis propria, respectively. If not sure if muscularis mucosae or muscularis propria invasion,
state cannot tell and recommend additional tissue sampling.
There is also potentially confusing terminology relating to atypia in urothelium. Dysplasia is
recommended as the term to denote urothelial preneoplastic changes short of those seen in CIS. "Atypia"
should not be used by itself as ambiguous as to whether preneoplastic or reactive. In the setting of
inflammatory changes, diagnose "Urothelium with inflammation and reactive atypia" or even better
"Urothelium with inflammation and reactive urothelial changes" so that clinicians are not worried that
there is neoplastic atypia.
Finally, be specific when describing squamous metaplasia in the bladder. Glycogenated squamous
metaplasia is a normal finding in the trigone in women with no risk of cancer. Nonkeratinizing squamous
metaplasia is an abnormal finding as a reaction to irritation with no risk of cancer. In contrast,
keratinizing squamous metaplasia carries an increased risk of cancer.
Precise unambiguous terminology in urological pathology reports is important and in some cases
critical. Always consider how the report may be interpreted (or misinterpreted) by clinicians and modify
the report if there is a potential of miscommunication.