Three cases of patients with different pathologically-proven prostatic neuroendocrine malignancies were described above. Next, each case is discussed in light of previous literature published on the clinical, pathological-biological, and imaging features of the entity it represents, with the aim of summarizing the roles different PET radiotracers play in each entity.
Treatment-induced neuroendocrine differentiation of prostatic adenocarcinoma. The primary therapeutic modality for metastatic adenocarcinoma of the prostate is either surgical or biochemical androgen deprivation therapy (ADT) [16–17]. Upon initiation of therapy, the prostate cancer is considered castration-sensitive, as minimizing androgen levels and function effectively control cancer growth [18]. The process of tiNED refers to a phenotypic differentiation of some of the malignant cells from an epithelial-like phenotype to a neuroendocrine-like phenotype, probably as a consequence of the selective pressure induced by treatment-induced fall in androgen levels or block of androgen's action [19–20]. This phenomenon was suggested as one of the mechanisms leading to castration-resistant prostate cancer (CRPC), namely, disease progression in spite of androgen deprivation [21]. Formation of CRPC (via tiNED mechanism or other mechanisms) is usually suspected in cases of either clinical or radiographic progression of pre-existing disease [22–23]. A rise in the serum PSA levels can be a sign of CRPC, but in cases of tiNED-mediated castration resistance, PSA levels may be stable or only moderately elevated, and chromogranin A blood levels may be rising [24–26]. Clinically, the change in metabolic and regulatory pathways of the malignant cells frequently leads to the appearance of a more aggressive disease, with possible visceral metastases, lytic skeletal metastases, and a dismal prognosis [27–28].
As a consequence of tiNED, the change in cellular phenotype may be evident on functional imaging with PET-CT. While prostatic adenocarcinoma usually shows high PSMA expression [29–33] and much lower avidity to [18F]FDG and radiolabeled somatostatin-analogues [9–10, 34–36], this uptake profile could change given the process of tiNED. In the relevant clinical context, a reduced PSMA uptake over time should raise the possibility of tiNED [37–38]. In fact, a study that evaluated gene expression in tumors with tiNED showed a suppression in FOLH1 (the PSMA gene) expression and an elevation of SSTR-2 gene expression [37], and in one reported case of a pathologically-proven tiNED, an extensive pelvic, nodal and skeletal disease showed no radiotracer uptake of 68Ga-PSMA-ligand and an intense avidity to both 68Ga-DOTANOC and [18F]FDG [38].
Several reports support the possible high [18F]FDG-avidity in cases of tiNED, particularly in soft tissue tumor lesions [39–43]. In a study that included 23 CRPC patients with “clinical NED” (elevated blood levels of chromogranin A), 22% of 510 bone metastases and 95% of 82 soft tissue metastases were [18F]FDG-avid [40]. Liu et al. reported a case of a patient with CRPC with pathologically-proven tiNED whose [18F]FDG-PET-CT showed intense radiotracer avidity in the primary prostatic tumor and in multiple nodal, hepatic and pulmonary metastases [41].
There are also supporting evidences that tumor cells after tiNED overexpress SSTRs [44–47]. Savelli et al. used 68Ga-DOTANOC in six CRPC patients, two of whom had metastases that showed variable SSTR expression [44]. In a subsequent study by Gofrit et al., 12 patients with CRPC underwent 68Ga-DOTATATE PET-CT and all of them had at least 1 blastic metastasis with radiotracer uptake, six of them showed widespread uptake and 4 of them demonstrated uptake in lytic bone lesions or lymph node metastases [45]. Among relevant case reports, one patient had 68Ga-DOTANOC-avid lung and skeletal metastases [46], and another CRPC patient had multiple 68Ga-DOTANOC-avid hepatic and lymph node metastases, none of which were detected on PET-CT with 68Ga-PSMA-ligand [47].
To summarize, in cases of adenocarcinoma with tiNED, the cellular phenotypic change may cause a change in radiotracers uptake profile and shift to a more aggressive disease with possible parenchymal progression. As evident in the presented case, lower PSMA-avidity may be demonstrated in lesions involved in tiNED. The reviewed papers above also support possible SSTR expression and glucose hypermetabolism in these lesions.
Prostatic adenocarcinoma with de-novo neuroendocrine differentiation. While PET imaging of prostatic adenocarcinoma with neuroendocrine differentiation has been studied mostly in the context of the effect of ADT (as discussed above), dNED of hormonally-naïve prostatic adenocarcinoma is less understood from a biological and functional imaging standpoints.
Up to 100% of prostatic adenocarcinomas probably exhibit some degree of dNED, depending on the neuroendocrine markers used, and more frequently in high-grade tumors and high-stage disease [48–51]. Still, true rates of adenocarcinoma with dNED are unknown [24, 48]. With the exception of metastatic disease, most studies have not demonstrated that dNED of prostatic adenocarcinoma independently affects patient prognosis [52–57], and therefore, when neuroendocrine cells are not easily detectable by routine haematoxylin and eosin (H&E) staining, immunohistochemical staining is not indicated on clinical routine. Therefore, dNED is practically reported only in cases where NE features are prominent [4, 48]. As long as P-NEC is confidently ruled out, prostatic adenocarcinoma with dNED should be treated like other adenocarcinomas, depending mainly on the stage of the disease [58].
There are no studies on the specific population of prostatic adenocarcinoma with dNED that investigated PET avidity profile for [18F]FDG, somatostatin-analogues or PSMA-ligands. The presented case here of dNED represents a unique example of the use of PET imaging for providing complementary data to pathology, and to the best of our knowledge, this is the first reported case of a pathologically-proven adenocarcinoma with dNED that underwent both PSMA-, FDG-, and DOTATATE-PET scans. With the extensive data that support the use of PSMA-PET in staging prostatic adenocarcinoma [14, 29, 31], and given the assumed high (underreported) rates of dNED among prostatic adenocarcinomas, if dNED is reported on pathology, we believe that radiolabeled PSMA-ligand should be the PET radiotracer of choice for whole-body staging, and this case supports its superiority.
Primary prostatic neuroendocrine carcinomas. Primary prostatic small cell carcinoma, a high grade neoplasm, constitutes the majority of P-NEC, and still is rare [59–61]. The incidence rate of prostatic small cell carcinoma is about 0.35 cases per million per year, occurring usually in men aged 70 and above [4, 60–61]. The diagnosis of prostatic small cell carcinoma is based on a classic morphology, similar to that observed in small cell lung carcinoma (SCLC), with high-grade features. Approximately 90% of prostatic small cell carcinoma will exhibit immunohistochemical positivity for at least one neuroendocrine marker, negativity for PSA, with Ki-67 labeling usually greater than 50%. TTF1 is often positive. Around 60% of patients are found to be metastatic at the time of diagnosis of this aggressive disease, and the reported 2- and 5-year survival rates are 27.5% and 14.3%, respectively [59]. Some challenges arise before making this diagnosis, among which is ruling out the possibility that the prostatic lesion represents involvement with lymphoma or secondary spread of SCLC [5, 62–64].
Due to its rarity, prostatic small cell carcinoma was not studied specifically in the field of PET imaging. Still, [18F]FDG has been well studied for its utility in imaging small cell carcinoma arising elsewhere in the body [65] and in imaging high-grade neuroendocrine tumors (NETs) of other organs [12–13, 66], data that support the use of [18F]FDG as a PET radiotracer of choice for staging and follow-up of prostatic small cell carcinoma as well. In line with that, the malignant lesions in the presented case showed high [18F]FDG-avidity.
In the context of prostatic primary neuroendocrine tumors, two other diagnoses should be mentioned, both having distinct pathological diagnostic features and seem very rare, with anecdotal reported cases only. The first is large cell neuroendocrine carcinoma, a high-grade neuroendocrine carcinoma of the prostate that have been associated with rapid progression and widespread metastasis to lymph nodes, bone, liver, lung, brain, and meninges. Documented survival is limited, often less than 13 months from diagnosis [4, 48, 67–70]. The second is well-differentiated NET (carcinoid tumor) of the prostate [4, 48], an entity that was reported in young men (30 years or less), some of whom with a diagnosis of multiple endocrine neoplasia syndrome [48, 71–72]. Some studies that used radiolabeled somatostatin-analogues for PET imaging of NET patients reported the inclusion of cases of NETs with prostatic origin [73–76]. As with carcinoid tumors arising in other locations, mitotic rates and Ki-67 staining index are usually low, making radiolabeled somatostatin-analogues appropriate for functional imaging in such cases [13].