PRE-CLINICAL PHASE

PIN or Prostatic Intraepithelial Neoplasia

A Premalignant Lesion

Definition and Prevalence in biopsies

PIN or prostatic intraepithelial neoplasia is a premalignant proliferation arising within the prostate. PIN will be identified in up to 16% of men who have had transrectal ultrasound guided prostate biopsies. PIN is most commonly found in the peripheral zone. In PIN the cellular arrangement shows preservation of duct and gland architecture with progressive disruption of the basal cell layer with increasing grades of PIN while invasion of the stroma is lacking. Other histologic or biologic changes that have been reported include: loss of neuroendocrine and secretory differentiation, nuclear and nucleolar abnormalities, neovascularity, increased proliferative potential and genetic instability with variation of DNA content. With increasing degrees of PIN an increasing degree of nuclear aberration is seen along with increasing basal cell disruption. PIN has an intact or fragmented basal cell layer, whereas cancer (PC) lacks a basal cell layer. Basal cell specific immunostaining for Cytokeratin is present in PIN but is absent in areas of PC.

PIN is graded from the lowest grade (Grade I) with the least changes to the highest grade (Grade III) with the most severe changes. Most medical papers categorize PIN as either high grade or low grade. High grade PIN and Grade III PIN are used synonomously. PC is associated more with high grade PIN than low grade. PIN appears to predate the appearance of PC by more than 5 years.

Association of PIN with PC

In various series in which high grade PIN was found, PC in subsequent biopsies was found in 33-100% of cases.1 In one study, PIN was detected in a total of 66 men: 21 with low grade PIN and 45 with high grade PIN. Repeat biopsies revealed PC in 5/21 or 24% of the low grade group and in 26/45 or 58% of the high grade group.2

In another study 100 patients with high grade PIN were compared to 112 without PIN. PC was identified in 35% of subsequent biopsies from the PIN group compared with 13% in the control group. The likelihood of cancer increased as the interval from the initial biopsy increased. High grade PIN, patient age and PSA were highly significant predictors of PC with PIN having the highest risk ratio of 14.93. PIN was more predictive of PC in older patients and those with a serum PSA of >4ng/ml. 3

Need for Systematic Rebiopsies in PIN to detect PC

There is a random distribution of PIN in its association with PC. Systematic biopsies of the entire gland in men with PIN are therefore preferable to obtaining biopsies only from sites of previously documented PIN. If repeat biopsies had been performed only on the same side as previously documented high grade PIN then 35% of prostate carcinomas would have been missed. 2

There is also a correlation between quantity of PIN and the mulifocality of concurrent PC. 4 Patients with PIN should be considered an important study population for therapies aimed at chemoprevention of PC. Agents such as retinoic acid analogs, synthetic vitamin D, genistein, lycopene, modified citrus pectin, 5 a reductase inhibitors, low fat diet, green tea should be studied in such patients to see if the incidence of documented PC on subsequent biopsies will decline with a particular treatment.

Relationship of PIN to age

152 prostate glands were examined at autopsy in young male patients( less than the age of 50) dying from traumatic causes in Wayne County Michigan. 5 36 of 152 or 24% of these prostate glands had PIN. Of these 36 cases, 31 were low grade PIN and 5 were high grade PIN. Of those 5 patients with high grade PIN histological PC was identified in all 5. In the low grade PIN population there were 6/28 or 21% with histologic cases of PC.

Low grade PIN was identified in the 3rd decade of life (20-29) in 3/35 or 9% of patients, in 11/55 or 20% of those males in the 4th decade of life and in 22/50 or 44% of men in their 5th decade. High grade PIN was not seen until the 5th decade. The incidence of histologic cancer was 15/55 or 27% in the 4th decade and 17/50 or 34% in the 5th decade. These slides were reviewed by well-known pathologists.

The average tumor dimension was 2.25 mm with Gleason's scores ranging from 2-5. Of interest is that in the 7 reported series of histological cancer involving 1,888 asymptomatic males, only 389 cases of PC or 20.6% were reported 5. Of the 224 males less than the age of 50, only 11 or 4.9% were found to have histologic PC. This is surprisingly at variance with the 32/152 or 21% reported by the authors of this study. Please see the tables below.

 

Age range	10-19	20-29	30-39	40-49	Totals
Decade	2nd	3rd	4th	5th
# patients	12	35	55	50	152
gland wt. *	22	27	33	39
Pin #(%)
low grade	0(0)	3(9)	11(20)	17(34)	31
high grade	0(0)	0(0)	0(0)	5(10)	5
PIN %	0	9	20	44	36/152(24)
PC #(%)	0/12(0)	0/35(0)	15/55(27)	17/50(34)	32/152(21)

* = mean prostate gland weight

In the above table low grade PIN is shown to start in the 20-29 age range and increase almost twofold for each of the next two decades. High grade PIN was not seen to start until the 40-49 age range and in all 5 cases PC was also found. Histologic cancer begins in the 4th decade and increases slightly in the next decade. These findings are also shown proportionately in respect to the age ranges, and to the overall population of 152 patients studied in the scatter table below. The table below also points out that low grade PIN occurs without association with PC in 25/31 or 81% of cases and with PC in 6/31 or 19% of cases in the age ranges of 20-49 in the patient population studied.

 

10-19	20-29	30- 39	40-49
# 12	# 35	# 55	# 50
			PC PC PC
		PC PC PC PC PC	PC PC PC
		PC PC PC PC PC PC PC PC	PC PC PCL PCL
		PCL PCL	PCL PCL LG LG LG LG
	LG LG LG	LG LG LG LG LG LG LG LG LG	LG LG LG LG LG LG LG LG LG PCH PCH PCH PCH PCH

LG = low grade PIN

PCL = histologic prostate cancer also found in patient with low grade PIN

PC = histologic prostate cancer found isolated without PIN

PCH = histologic prostate cancer also found in patient with high grade PIN

Based on these findings, our recommendations are as follows:

1. Patients with high grade PIN need to have regular monitoring of serum PSA levels along with digital rectal examinations. These should be done at a minimum of 6 month intervals. Any trends showing significant increase in PSA or changes in the DRE should prompt earlier rebiopsies of the prostate under TRUSP guidance. Considerations for calculations of PSA velocity and doubling times in such patients may be of additive value.

2. The use of tools such as PSA II and possibly the Prostasure blood test may be helpful in decisions regarding intensity of rebiopsies.

3. We should be performing repeat biopsies on patients with high grade PIN at regular intervals. This may be anytime between three to twelve months, depending on circumstances relating to the findings in items 1 and 2 above.

4. Patients with high grade PIN should be considered as having occult PC until proven otherwise.

REFERENCES

1. Keetch DW, Humphrey P, Stahl D, Smith DA and Catalona WJ: Morphometric analysis and clinical followup of isolated prostatic intraepithelial neoplasia in needle biopsy of the prostate. J. Urol. , 154:347, 1995.

2. Shepherd D, Keetch DW, Humphrey PA, et.al. Repeat biopsy strategy in men with isolated prostatic intraepithelial neoplasia on prostate needle biopsy. J Urol 156, 460-463, 1996.

3. Davidson, D, Bostwick DG, Qian J, Wollan PC, Oesterling JE, Rudders RA, Siroky M and Stilmant M: Prostatic intraepithelial neoplasia is a risk factor for adenocarcinoma: predictive accuracy in needle biopsies. J Urol., 154:1295-1299, 1995.

4. Weinstein, MH, & Epstein JI: Significance of high-grade prostatic intraepithelial neoplasia on needle biopsy. Hum Path., 24:624, 1993.

5. Sakr WA, Haas GP, Cassin BF, Pontes JE and Crissman JD: The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol. 150:379-385, 1993.

Prostate Cancer Research Institute (PCRI)
 

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