Primary adenosquamous carcinoma of the prostate with rapid elevation of prostate-specific antigen: a case report.

A previously healthy 57-year-old East Asian male visited his physician owing to the observation of elevated PSA levels of 50.93 ng/ml on an annual health check. His PSA levels 1 and 2 years earlier were 2.25 ng/ml and 1.38 ng/ml, respectively, both of which were within the normal range (0–4 ng/ml). Within 1 month after his health checkup, his PSA level rapidly increased from 50.93 ng/ml to 98.97 ng/ml. On digital rectal examination, the prostate was stony hard all around. Histopathological examination of a prostate needle biopsy specimen revealed a mixture of AC and SCC components at a ratio of 1:3 (Fig.  1 a). Immunohistochemical examination showed positive staining for CAM5.2, CEA, CK5/6, and p40 within the same specimen (Fig.  1 b–e). The SCC component was negative for PSA (Fig.  1 f), while the AC component was positive (Fig.  1 g). According to the Gleason grading system, the AC component was evaluated as Gleason score 5 + 5 = 10. Fig. 1 Histopathological findings of biopsy specimens. Hematoxylin and eosin staining showed atypical cells with severe nuclear atypia and abundant eosinophilic cytoplasm proliferating in a small alveolar to cord-like and diffuse pattern ( a ). Immunohistochemical examination showed positive staining for CAM5.2 ( b ), CEA ( c ), CK5/6 ( d ), and P40 ( e ). PSA staining was negative in the SCC component ( f ) and positive in the AC component ( g ). GATA3 staining was negative ( h ) Histopathological findings of biopsy specimens. Hematoxylin and eosin staining showed atypical cells with severe nuclear atypia and abundant eosinophilic cytoplasm proliferating in a small alveolar to cord-like and diffuse pattern ( a ). Immunohistochemical examination showed positive staining for CAM5.2 ( b ), CEA ( c ), CK5/6 ( d ), and P40 ( e ). PSA staining was negative in the SCC component ( f ) and positive in the AC component ( g ). GATA3 staining was negative ( h ) The patient was referred to our hospital for treatment 1 month later, by which time his PSA level had increased further to 161.89 ng/ml. Magnetic resonance imaging (MRI) showed that the tumor extended from the ventral transitional zone at the base of the prostate to the left peripheral zone and both seminal vesicles, along with bladder invasion (Fig.  2 a), exhibiting high signal intensity on diffusion-weighted imaging (Fig.  2 b). An 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography ( 18 F-FDG PET/CT) scan showed significant accumulation in the left internal iliac and obturator lymph nodes, as well as in the spine, including the fifth cervical and fourth lumbar vertebrae, and in the pelvic bone (Fig.  3 a). Bone scintigraphy revealed numerous accumulations in the spine and pelvic bone, and the accumulation in the fourth lumbar vertebra was widespread, with the vertebra being almost completely replaced by the tumor. We additionally performed GATA3 immunostaining to rule out prostate invasion by urothelial carcinoma, which yielded a negative result (Fig.  1 h). On the basis of these findings, the tumor was diagnosed as primary ASC of the prostate. This patient had no family history of prostate cancer. Fig. 2 Prostate MRI at diagnosis. T2-weighted imaging showed an irregular tumor throughout the prostate with bladder invasion (white arrow) ( a ). Diffusion-weighted imaging showed high signal intensity in the prostate tumor ( b ) Fig. 3 FDG-PET/CT scan. PET/CT at the time of diagnosis showed left internal iliac and obturator lymph node metastases, as well as multiple bone metastases ( a ). A total of 5 months after hormonal therapy initiation, FDG-PET/CT showed multiple lung, pleural, lymph node, pancreatic, peritoneal, bone, dural, and skeletal muscle metastases ( b ), including bilateral iliopsoas muscle metastases (white arrows) ( c ) and left deltoid muscle metastasis (white arrow) ( d ) Prostate MRI at diagnosis. T2-weighted imaging showed an irregular tumor throughout the prostate with bladder invasion (white arrow) ( a ). Diffusion-weighted imaging showed high signal intensity in the prostate tumor ( b ) FDG-PET/CT scan. PET/CT at the time of diagnosis showed left internal iliac and obturator lymph node metastases, as well as multiple bone metastases ( a ). A total of 5 months after hormonal therapy initiation, FDG-PET/CT showed multiple lung, pleural, lymph node, pancreatic, peritoneal, bone, dural, and skeletal muscle metastases ( b ), including bilateral iliopsoas muscle metastases (white arrows) ( c ) and left deltoid muscle metastasis (white arrow) ( d ) Hormonal therapy using degarelix and abiraterone was initiated. One month after treatment initiation, the PSA level rapidly decreased from 161.89 ng/ml to 0.70 ng/ml. However, a computed tomography (CT) scan performed 3 months after treatment initiation revealed enlargement of both internal iliac lymph nodes, with the left-sided lymph node involving the ureter and causing hydronephrosis, although PSA levels were stably low. Radiotherapy (RT) was then administered to the internal iliac lymph nodes bilaterally, as well as to the prostate and fourth lumbar vertebra metastasis. Despite these treatments, the disease progressed, and an FDG-PET/CT scan showed multiple sites of metastases in the lung, pleura, lymph nodes, pancreas, peritoneum, bone, dura, and skeletal muscle as an extremely rare metastatic site (Fig.  3 b–d). Microsatellite instability (MSI) testing was conducted to assess the possibility of pembrolizumab treatment; however, the patient died before receiving the test result, which was not MSI-high.

Primary adenosquamous carcinoma (ASC) of the prostate is an extremely rare histological variant, accounting for less than 1% of all prostate cancers [ 1 ]. This aggressive variant is pathologically characterized by the presence of both adenocarcinoma (AC) and squamous cell carcinoma (SCC) components. Therefore, levels of prostate-specific antigen (PSA), a tumor marker for prostate AC, vary depending on the ratio of each component but are typically lower in patients with ASC of the prostate as compared with patients with prostate AC [ 1 ]. Although there have been reports on ASC of the prostate, its clinical features remain unknown, and no established treatment has been developed [ 1 – 20 ]. Here, we present a case of ASC that presented very high levels of PSA.

Our case of primary ASC of the prostate had a rapidly elevated PSA level and developed uncommon skeletal muscle metastasis. Continued accumulation of similar cases is essential for improving our understanding and developing better management strategies for this rare prostate cancer variant.

ASC of the prostate is reportedly the least common variant of prostate cancer, with an incidence rate of 0.03 cases per million per year [ 21 ]. PSA is widely used worldwide as a tumor marker for prostate AC [ 7 ] and its level is typically lower in subtypes other than AC. Therefore, patients with ASC usually visit a hospital after having symptoms [ 10 ]. As a result, ASC is often found at an advanced stage, which should be a factor contributing to poor prognosis. In our case, ASC of the prostate was found following observation of elevated PSA levels, which continued to increase rapidly thereafter. Guttuso et al . reported a case of ASC of the prostate with a markedly elevated PSA level of 274 ng/ml [ 19 ]. In their case, the tumor consisted mainly (80%) of the AC component. In our case, the PSA level was markedly elevated, although the AC component accounted for only 25% of the tumor. The elevated PSA levels could have been the result of acute lysis of PSA-positive elements, such as AC and normal prostate epithelial cells, caused by rapid proliferation of the SCC component. ASC of the prostate can be primary or secondary. Primary ASC of the prostate potentially arises from multipotent cells within the prostate (de novo) [ 7 ], while secondary ASC occurs through treatment-associated squamous metaplasia, which is triggered by androgen deprivation therapy (ADT) or RT. Our patient had no history of ADT or RT, suggesting that he had developed primary ASC of the prostate. Prostate cancer with skeletal muscle metastasis is exceptionally rare, with only limited cases reported in literature. Among 500 autopsy cases, 0.8% demonstrated skeletal muscle metastases, predominantly originating from lung, head and neck, or thyroid cancers [ 22 , 23 ]. To our knowledge, this is the first case of ASC of the prostate with skeletal muscle metastasis (Table  1 ). Table 1 Clinical features of cases of adenosquamous carcinoma of the prostate in literature Author Age Baseline PSA (ng/ml) Gleason score Component Primary/secondary Treatment Metastatic sites during follow-up Follow-up (months) Outcome Moyana et al . 67 13.3 4 + 3 AC  80% Secondary TURP, DES, RT, orchiectomy Bone 36 Alive with disease 72 12 5 + 4 AC  90% Secondary RT, ADT Liver, LN 24 Died of disease 74 9 3 + 4 AC 80%, SCC 20% Secondary TURP, DES, RT, orchiectomy Lung, bone 6 Alive with disease Gattuso et al . 60 274 2 + 3 AC 80%, SCC 10% Primary RP, RT, CAB LN, bladder, ureter 12 Died of disease Orhan et al . 56 11.1 4 + 5 AC  90% Primary ADT Bone 1 Died of disease Bassler et al . 55 8.5 4 + 3 AC 50%, SCC 50% Primary CAB, RT None N/A N/A Turhan et al . 54 20 3 + 2 AC 90%, SCC 10% Primary None None 12 Died of disease Kim et al . 73 30.3 4 + 4 SCC dominant Secondary TURP, orchiectomy Bone 7 Died of disease Helal et al . 65 WNL 9 AC dominant Secondary RT, TPE Lung, liver, LN 6 Died of disease 73 WNL 8 AC dominant Secondary RT, orchiectomy Lung, liver, LN 16 Died of disease Egilmez et al . 58 12 N/A AC 10%, SCC 90% Primary ADT None 1 Died of disease Xu et al . 49 6.41 N/A N/A Primary RP None 15 Alive with no disease Zhang et al . 62 30.5 5 + 5 AC dominant Secondary ADT, TURP Bone, LN, rectum 8 Died of disease Mishra et al . 60 2.14 N/A AC 60%, SCC 40% Primary ADT Bone 9 Died of disease Acosta et al . 57 21.5 4 + 3 AC 70%, SCC 5–10% Secondary RP, ADT, RT, chemotherapy None 5 Alive with disease Eze et al . 75 4.21 5 + 4 AC 5%, SCC 95% Primary RP, RT, ICI, chemotherapy Lung, pararectal LN 9 Alive with disease Hennessey et al . 66 12.7 5 + 5 AC 10–20%, SCC 80–90% Primary RARP, ADT, RT, chemotherapy LN 20 Alive with no disease Kitamura et al . 76 13.37 5 + 5 AC 50%, SCC 50% Secondary TURP, CAB, RT, chemotherapy Bone, lung 13 Died of disease Azzi et al . 62 3.11 6 AC  99% Primary RT, chemotherapy Lung, liver 9 Died of disease Isharwal et al . 63 3.85 N/A AC 50%, SCC 50% Primary ADT, ARPI, RT, chemotherapy Bone, LN 19 Alive with disease Yang et al . 60 4.96 5 + 4 AC 80%, SCC 20% Primary TURP LN, bone, lung N/A N/A Oyogoa et al . 63 14.8 5 + 4 AC 50%, SCC 50% Primary ADT, chemotherapy, ARPI, RT, 177Lu-PSMA-617 Bone, LN, liver, lung 24 Died of disease Demianets et al . 48 9.34 4 + 5 AC 75%, SCC 25% Primary RARP, ADT Lung, liver, bone 8 Died of disease Shigehisa et al . (present case) 57 161.89 5 + 5 AC 25%, SCC 75% Primary ADT, ARPI Lung, LN, pancreas, peritoneum, bone, dura, skeletal muscle 6 Died of disease PSA prostate-specific antigen, WNL within normal limits, AC adenocarcinoma, SCC squamous cell carcinoma, N/A not available, TURP transurethral resection of prostate, DES diethylstilbestrol, RT radiotherapy, ADT androgen deprivation therapy, RP radical prostatectomy, CAB combined androgen blockade, TPE total pelvic exenteration, ICI immune checkpoint inhibitor, RARP robot-assisted radical prostatectomy, ARPI androgen receptor pathway inhibitor, PSMA prostate-specific membrane antigen, LN lymph node Clinical features of cases of adenosquamous carcinoma of the prostate in literature PSA prostate-specific antigen, WNL within normal limits, AC adenocarcinoma, SCC squamous cell carcinoma, N/A not available, TURP transurethral resection of prostate, DES diethylstilbestrol, RT radiotherapy, ADT androgen deprivation therapy, RP radical prostatectomy, CAB combined androgen blockade, TPE total pelvic exenteration, ICI immune checkpoint inhibitor, RARP robot-assisted radical prostatectomy, ARPI androgen receptor pathway inhibitor, PSMA prostate-specific membrane antigen, LN lymph node There are no established treatments for ASC of the prostate due to its rarity. Table 1 presents the clinical features of cases of ASC of the prostate reported in literature. Previous reports suggest that ASC of the prostate is resistant to conventional ADT, given the presence of SCC components, which lack androgen receptor expression. Some cases have shown responses to platinum-based chemotherapy, similar to SCC at other organ sites. In our case, hormonal therapy with degarelix and abiraterone was commenced immediately upon diagnosis because of the rapid elevation in PSA levels. Reportedly, since nivolumab, an immune checkpoint inhibitor, might be effective in programmed cell death 1 (PD-1)-positive cases [ 8 ], we performed an MSI test in our case, but the result was negative, indicating that pembrolizumab was not applicable for the tumor in our case. Comprehensive genomic profiling might be useful to understand the pathogenesis and identify therapeutic targets for this rare, aggressive prostate cancer variant.

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