What's behind 68Ga-PSMA-11 uptake in primary prostate cancer PET? Investigation of histopathological parameters and immunohistochemical PSMA expression patterns

Abstract

Purpose: Prostate-specific membrane antigen (PSMA-) PET has become a promising tool in staging and restaging of prostate carcinoma (PCa). However, specific primary tumour features might impact accuracy of PSMA-PET for PCa detection. We investigated histopathological parameters and immunohistochemical PSMA expression patterns on radical prostatectomy (RPE) specimens and correlated them to the corresponding ⁶⁸Ga-PSMA-11-PET examinations.

Methods: RPE specimens of 62 patients with preoperative ⁶⁸Ga-PSMA-11-PET between 2016 and 2018 were analysed. WHO/ISUP grade groups, growth pattern (expansive vs. infiltrative), tumour area and diameter as well as immunohistochemical PSMA heterogeneity, intensity and negative tumour area (PSMA_%neg) were correlated with spatially corresponding SUV_max on ⁶⁸Ga-PSMA-11-PET in a multidisciplinary analysis.

Results: All tumours showed medium to strong membranous (2-3 +) and weak to strong cytoplasmic (1-3 +) PSMA expression. Heterogeneously expressed PSMA was found in 38 cases (61%). Twenty-five cases (40%) showed at least 5% and up to 80% PSMA_%neg. PSMA_%neg, infiltrative growth pattern, smaller tumour area and diameter and WHO/ISUP grade group 2 significantly correlated with lower SUV_max values. A ROC curve analysis revealed 20% PSMA_%neg as an optimal cutoff with the highest sensitivity and specificity (89% and 86%, AUC 0.923) for a negative PSMA-PET scan. A multiple logistic regression model revealed tumoural PSMA_%neg (p < 0.01, OR = 9.629) and growth pattern (p = 0.0497, OR = 306.537) as significant predictors for a negative PSMA-PET scan.

Conclusions: We describe PSMA_%neg, infiltrative growth pattern, smaller tumour size and WHO/ISUP grade group 2 as parameters associated with a lower ⁶⁸Ga-PSMA-11 uptake in prostate cancer. These findings can serve as fundament for future biopsy-based biomarker development to enable an individualized, tumour-adapted imaging approach.

Keywords: Glutamate carboxypeptidase II; Immunohistochemistry; Neoplasm staging; Positron emission tomography; Prostatic neoplasms.

Fig. 1

Overview of the different immunohistochemical PSMA staining patterns. (A) shows complete negativity, while (B) depicts low expression of cytoplasmic (1 +) and moderate membranous (2 +) PSMA staining. In (C), a moderate membranous and cytoplasmic (2 +) staining is shown. (D) illustrates low cytoplasmic (1 +) and strong membranous (3 +) expression. (E) shows moderate (2 +) cytoplasmic and strong membranous (3 +) expression, while (F) shows diffuse strong (3 +) cytoplasmic and membranous expression. Scale bar 100 µm

Fig. 2

Overview of the different immunohistochemical PSMA heterogeneity patterns. (A) shows homogenous strong and diffuse positivity. (B) depicts heterogenous PSMA positivity with focal weaker expression (arrowheads) in different components of the carcinoma, without negative areas. In (C), the circled carcinoma (continuous line) consists of approximately 30% (dotted line) negative areas, whereas in (D), roughly 80% of the marked invasive carcinoma shows negativity. Scale bar 5 mm

Fig. 3

Patient inclusion flowchart

Fig. 4

Examples of infiltrative and expansive growth patterns. (A, C) is an example of a prostate carcinoma growing between normal glands (arrowheads in C) refered to as infiltrative growth pattern. (B, D) depicts a prostate carcinoma which homogenously consists of tumour glands comprising at least 3 circles of 5 mm² each (radius 1.26 mm). This is regarded as expansive growth pattern. While both cases (A, B) have tumour diameters in a similar range (12 mm and 7 mm, respectively), identical Gleason patterns (both 4 + 4, WHO/ISUP grade group 4) and similar PSMA expression (both cytoplasmic 2 + and membranous 3 +) (E, F) the SUV_max values are clearly different (SUV_max 6.1 vs. 20.1) (G, H). (A, B) Scale bar 5 mm. (C, D) Scale bar 0.5 mm

Fig. 5

ROC curve analysis for PSMA_%neg and negative PET scan. A cutoff value of 20% PSMA_%neg yielded sensitivity of 89% and specificity of 86% (area under curve 0.923) for a negative PSMA-PET scan (defined as SUV_max < 5)

Fig. 6

Column plots with standard error of mean (SEM) and scatter plots showing relations between SUV_max values and different tissue characteristics. Significant lower SUV_max values could be found in prostate carcinomas with PSMA IHC negative area (PSMA_%neg) ≥ 20% (A), an infiltrative growth pattern (B), WHO/ISUP grade groups 2 and 3 (C) but not in carcinomas with low cytoplasmic or membranous PSMA staining intensities (D, E). SUV_max values significantly correlated with maximum tumour diameter (r = 0.318, p = 0.015, Pearson’s correlation) as well as tumour area (r = 0.426, p < 0.01, Pearson’s correlation) (F, G). *p < 0.05, **p < 0.01

Fig. 7

Examples of PSMA expression on immunohistochemistry (IHC) and ⁶⁸Ga-PSMA-PET results. (A) Illustration of a prostate carcinoma with a strong homogenous PSMA expression (left) and a high SUV_max located in the anterior right part of the gland. (B) Example of a prostate carcinoma (circled) showing almost no PSMA IHC staining (80% negative tumour area) and also lacking PSMA-PET positivity in the corresponding area. (C) is a case that shows a predominantly PSMA IHC-positive prostate carcinoma (only 5% completely PSMA-negative glands) with a low PSMA-PET positivity (SUV_max 4). Note the small diameter of this carcinomatous focus (8.7 mm). (D) Conversely, this carcinoma with a diameter of 22 mm shows a high PSMA-PET positivity (SUV_max 13.33) despite a heterogenous, largely lacking PSMA IHC expression (almost 70% negative areas). Scale bar 5 mm