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Page 6 of 8 Fiordoliva et al. J Cancer Metastasis Treat 2019;5:59 I http://dx.doi.org/10.20517/2394-4722.2019.23

Literature review revealed that most PAC-associated SIAD cases are high grade and high stage
adenocarcinoma. Actually, SIAD can be linked to neuroendocrine evolution at disease progression.
[16]
Pure small-cell carcinoma of the prostate is extremely rare, accounting for < 0.5% of all cases . About
50% of small cell carcinomas (SCC) have a history of usual PAC. Frequently, at initial diagnosis SCC
[17]
are seen admixed with adenocarcinoma of the prostate . In these cases, Gleason score is assigned
only to the conventional adenocarcinoma component. According to the SEER database, the presence
[18]
of concomitant high-grade PAC is an independent predictor of poorer cancer-specific mortality .
Recent data on in vitro and in vivo studies related to the molecular mechanism of NE
transdifferentiation of PCa cells suggest that PCa cells undergo a transdifferentiation process to
become NE-like cells, acquiring NE phenotype and NE markers. Common molecular alterations
between PAC and SCC components of mixed prostate tumors under conditions of androgen
deprivation sustain the hypothesis that small cell carcinoma represents a transdifferentiation
from PAC . The model of divergent-differentiation consider instead the hypothesis of a common
[19]
stem cell progenitor that can differentiate into both adenocarcinoma and SCC. According to this
model, hormonal therapy determinates a selective pressure resulting in development of SCC from a
[20]
subpopulation of hormone-independent cells and consequently inducing hormonal resistance . The
more aggressive behavior compared with conventional PAC is due to expression of genes involved in
cellular proliferation, mitosis, neuroendocrine differentiation, along with downregulation of genes
[21]
encoding cell adhesion molecules . This biological molecular phenotype is the reason behind the
high proliferation rate, the rapid spreading and the great tendency to metastasize. Further preclinical
results, deriving mostly from SCLC cell lines, seem to confirm the relation between hyponatremia,
directly or through vasopressin receptors and cell proliferation, resistance to programmed cell
death, angiogenesis and metastatization. Mitogen-activated protein kinase (MAPK) pathway is
the main intracellular signalling which leads to tumoral growth and spreading [22,23] . SIAD onset
may guide physicians to perform a tumor biopsy in order to obtain a new morphological and
[24]
immunohistochemical characterization .

Neuroendocrine prostatic cancer is generally managed by chemotherapy regimens similar to those for
SCLC. Prognosis is poor with a median survival of 7 months.

It is still unclear how SIAD arises from prostatic carcinoma with neuroendocrine differentiation but it
may involve an ectopic production of ADH from carcinoma cells, as detected immunohistochemically
in the tumor tissue .
[25]

In our case-report, SIAD appeared at progression of disease, with metastatic spread to the liver. In
particular a dedifferentiation of cancer cells was reported, which lost prostatic markers to acquire
fully neuroendocrine characteristics. Only focal neuroendocrine prostatic markers were reported in
the primary prostatic cancer [Figure 1], while liver metastasis presented neuroendocrine carcinoma
[Figure 4]. Our case supports the hypothesis that histological evolution to neuroendocrine features
accompanies to metastatic spread and often with paraneoplastic syndrome as SIAD.

DECLARATIONS
Authors’ contributions
Conception and design of the study and performed data analysis and interpretation: Fiordoliva I,
Marcantognini G, Rinaldi S
Performed data acquisition, as well as provided administrative, technical and material support:
Cimadamore A, Montironi R, Berardi R