Prostatic Adenosquamous Carcinoma With a Minute Squamous Component in the Initial Biopsy and Early Liver Metastasis: A Case Report

ABSTRACT

Introduction

We report a case of de novo prostatic adenosquamous carcinoma with a minute squamous component in the initial biopsy and early liver metastasis despite a marked prostate‐specific antigen response.

Case Presentation

A 72‐year‐old man was diagnosed with locally advanced prostate cancer with nodal and multiple bone metastases. Prostate biopsy initially showed adenocarcinoma with a Gleason score of 4 + 5. After leuprolide and abiraterone plus radiotherapy, prostate‐specific antigen decreased from 13.0 to 0.22 ng/mL; however, a liver metastasis developed. Re‐evaluation of the prostate biopsy revealed minute squamous differentiation, and liver biopsy showed metastatic squamous cell carcinoma. Immunohistochemistry showed retained MLH1 and PMS2 expression with loss of MSH2 and MSH6 in both specimens. Genomic profiling showed microsatellite instability‐high status.

Conclusion

Repeat biopsy and molecular‐pathological reassessment may be important when radiographic progression is discordant with prostate‐specific antigen kinetics.

Key Points

• Prostatic adenosquamous carcinoma may be overlooked in the initial biopsy when the squamous component is minimal.

• Radiographic progression despite a favorable PSA response should prompt repeat biopsy of progressive lesions.

• Molecular‐pathological reassessment may help establish the diagnosis and identify therapeutic options.

Abbreviations

AR

androgen receptor

CK5/6

cytokeratin 5/6

CT

computed tomography

MRI

magnetic resonance imaging

MSI‐high

microsatellite instability‐high

PSA

prostate‐specific antigen

1. Introduction

Prostatic adenosquamous carcinoma contains both adenocarcinoma and squamous cell carcinoma components and was first described in 1942 [1]. Squamous malignancies account for approximately 0.5% to 1% of prostatic cancers [2], whereas adenosquamous carcinoma is an exceptionally rare and aggressive subtype with a poor prognosis [3].

We report a case of prostatic adenosquamous carcinoma with a minute squamous component in the initial biopsy specimen. The diagnosis was established after early radiographic progression despite a marked prostate‐specific antigen (PSA) response to treatment.

2. Case Presentation

A 72‐year‐old man presented with painless gross hematuria. He had no notable medical or family history. Urinalysis revealed > 100 red blood cells per high‐power field, and the serum PSA level was 13.0 ng/mL. Contrast‐enhanced computed tomography (CT) showed a prostatic mass and para‐aortic lymphadenopathy. Magnetic resonance imaging (MRI) demonstrated low‐signal‐intensity lesions involving both lobes of the prostate on T2‐weighted imaging, with suspected invasion into the bladder (Figure 1A,B). Right obturator lymphadenopathy was also observed. Bone scintigraphy revealed multiple bone metastases (Figure 1C). Prostate biopsy initially demonstrated adenocarcinoma with a Gleason score of 4 + 5 = 9 in all 12 cores, and the clinical stage was cT4N1M1b.

FIGURE 1.

Radiological findings at diagnosis and during early treatment (A) Axial T2‐weighted magnetic resonance imaging (MRI) showed low‐signal‐intensity lesions (arrowheads) involving both lobes of the prostate. (B) Sagittal T2‐weighted MRI showed tumor invasion (arrowheads) from the prostate into the bladder. (C) Bone scintigraphy revealed multiple bone metastases. (D) Contrast‐enhanced computed tomography (CT) 3 months after treatment initiation revealed a new liver lesion (arrowheads).

Initial treatment consisted of leuprolide plus abiraterone. External beam radiation therapy (39 Gy in 13 fractions) was administered with palliative intent. The prostate was irradiated to control gross hematuria and prevent further local complications associated with bladder invasion, whereas the pelvic bone metastases were irradiated for pain control. Three months after treatment initiation, the PSA level had decreased markedly to 0.22 ng/mL. A follow‐up CT, however, revealed a new liver lesion (Figure 1D). Because this radiographic progression was discordant with the favorable biochemical response, a liver biopsy was performed.

Pathological re‐evaluation of the initial prostate biopsy specimen demonstrated conventional acinar adenocarcinoma admixed with a minute focus of squamous cell carcinoma comprising less than 1% of the tumor. On hematoxylin and eosin staining, the squamous component consisted of nests of polygonal tumor cells with abundant eosinophilic cytoplasm and focal keratinization (Figure 2A, inset). Immunohistochemically, androgen receptor (AR) expression was retained in the adenocarcinoma component but absent in the squamous component (Figure 2B), whereas cytokeratin 5/6 (CK5/6) showed the opposite pattern and highlighted the squamous nests (Figure 2C, inset). In contrast, the liver biopsy specimen showed metastatic squamous cell carcinoma without an identifiable adenocarcinoma component (Figure 2D). The metastatic tumor cells were negative for AR (Figure 2E) and positive for CK5/6 (Figure 2F). These findings supported the diagnosis of liver metastasis from the squamous component of prostatic adenosquamous carcinoma. External beam radiation therapy (55 Gy in 25 fractions) was administered for local control of the liver metastasis. Although the irradiated liver lesion did not enlarge, para‐aortic lymph node metastases progressed, and docetaxel therapy was initiated. Stable disease was maintained after 4 cycles; however, new liver and lung metastases appeared after 5 cycles. Comprehensive genomic profiling using the prostate biopsy specimen was then performed. Cabazitaxel was started, together with additional radiotherapy to liver metastases, but new lung and liver metastases developed after 2 cycles. Genomic profiling revealed microsatellite instability (MSI)‐high status. Immunohistochemistry for mismatch repair proteins was additionally performed on both the initial prostate biopsy and liver metastasis specimens. In tumor cells from both sites, MLH1 and PMS2 expression was retained, whereas MSH2 and MSH6 expression was lost (Figure 3). These concordant findings supported mismatch repair deficiency in both the primary and metastatic lesions and were consistent with MSI‐high status identified by genomic profiling. Pembrolizumab was initiated; however, the patient's general condition deteriorated rapidly, and he died 13 months after initial presentation.

FIGURE 2.

Histopathological and immunohistochemical findings of the prostate and liver biopsy specimens. (A) Hematoxylin and eosin staining of the initial prostate biopsy specimen shows conventional acinar adenocarcinoma admixed with a minute squamous cell carcinoma component. The inset shows a higher‐magnification view of the squamous component, consisting of nests of polygonal tumor cells with abundant eosinophilic cytoplasm and focal keratinization. (B) Immunohistochemical staining for androgen receptor is positive in the adenocarcinoma component but negative in the squamous component. (C) Immunohistochemical staining for cytokeratin 5/6 highlights the squamous component but not the adenocarcinoma component. The inset shows a higher‐magnification view of the cytokeratin 5/6‐positive squamous nests. (D) Hematoxylin and eosin staining of the liver biopsy specimen shows metastatic squamous cell carcinoma without an identifiable adenocarcinoma component. (E) The metastatic tumor cells are negative for androgen receptor. (F) The metastatic tumor cells are positive for cytokeratin 5/6. Scale bars, 100 μm.

FIGURE 3.

Immunohistochemical staining for mismatch repair proteins in the prostate and liver specimens. (A) Hematoxylin and eosin staining of the prostate biopsy specimen. Tumor cells retained MLH1 (B) and PMS2 (C) expression but showed loss of MSH2 (D) and MSH6 (E). (F) Hematoxylin and eosin staining of the liver biopsy specimen. Tumor cells retained MLH1 (G) and PMS2 (H) expression but showed loss of MSH2 (I) and MSH6 (J). Panels F–J were prepared from corresponding serial sections of the same liver biopsy paraffin block. Non‐neoplastic cells served as internal positive controls. These findings supported mismatch repair deficiency in both the primary and metastatic lesions.

3. Discussion

This case highlights several clinical lessons. First, the initial biopsy was interpreted as high‐grade adenocarcinoma because the squamous component occupied less than 1% of the tumor. Re‐evaluation showed nests of polygonal tumor cells with abundant eosinophilic cytoplasm and focal keratinization, indicating that focal squamous differentiation may be overlooked in limited specimens. Approximately two‐thirds of adenosquamous carcinoma cases arise after androgen deprivation therapy or radiotherapy, whereas one‐third arise de novo [4]. Because the squamous component was present before treatment, this case was classified as de novo adenosquamous carcinoma.

Second, PSA kinetics did not reflect the actual biological behavior of the disease. Despite a rapid decline in PSA from 13.0 to 0.22 ng/mL after initial therapy, a new liver metastasis developed within 3 months. This clinicoradiologic discordance was the clue that prompted tissue reassessment and ultimately led to the correct diagnosis. In metastatic prostate cancer with aggressive radiographic features or atypical progression patterns, imaging reassessment and repeat biopsy should be considered even when the PSA response appears favorable.

Third, pathological re‐evaluation clarified the different histological compositions of the primary and metastatic lesions. The prostate specimen contained both adenocarcinoma and squamous cell carcinoma components, with AR positivity in the adenocarcinoma component and CK5/6 positivity in the squamous component. In contrast, the liver metastasis consisted of squamous cell carcinoma showing AR negativity and CK5/6 positivity. These findings suggest that the metastatic lesion was composed predominantly of the squamous component, which may partly explain the discordance between PSA decline and radiographic progression.

Fourth, this case underscores the potential value of molecular and immunohistochemical evaluation in rare prostate cancer subtypes without established standard treatment. Immunohistochemistry for mismatch repair proteins demonstrated retained MLH1 and PMS2 expression with concurrent loss of MSH2 and MSH6 in both the primary prostate specimen and liver metastasis, indicating a shared mismatch repair‐deficient phenotype. MSH2 loss is associated with mismatch repair deficiency and microsatellite instability in prostate cancer [5]. The concordant immunohistochemical and genomic findings in both sites further support the biological continuity between the primary and metastatic lesions.

MSI‐high tumors are potentially sensitive to immune checkpoint inhibitors such as pembrolizumab [6]. However, the disease progressed rapidly despite pembrolizumab therapy. Clinical courses and genomic alterations in reported prostate adenosquamous carcinoma cases are summarized in Table 1.

TABLE 1.

Summary of clinical courses and genomic alterations in reported cases of prostatic adenosquamous carcinoma.

Authors	Age	cTNM	Treatment sequence	OS (months)	Genomic alterations
Kitamura et al. (2021) [4]	76	cTxN1M1c	CAB→DTX → CBZ	13	PIK3CB (p.L50M, p.L538M, intronic variant); APC (p.L1471fs, p.L1489fs); CDKN2A (intronic variant); PTEN (p.Y68fs, p.Y241fs, p.D107Y, p.D280Y); BRCA2 (p.C2646S); RB1 (p.L523*); TP53 (p.A144T, p.A117T, p.A237T, p.A276T, p.V142A, p.V115A, p.V235A, p.V274A, p.P19A, p.P112A, p.P151A, p.P27fs, intronic variant); CDK12 (p.W1450fs, p.W1459fs)
Oyogoa et al. (2024) [7]	63	cT3aN1M1	DTX + CBDCA + ADT → ABI + APA → DTX + CBDCA → 177Lu‐PSMA therapy	16	AR (amplification, 11 copies); ATRX (loss); CDKN1B (splice site variant); MLH1 (loss); MUTYH (p.G393D); PIK3CA (p.E542K); PTEN (loss); SMAD4 (loss); SUFU (loss); TP53 (p.K123R, loss)
Current case	72	cT4N1M1b	ADT + ABI → DTX → CBZ → PEM	13	AKT1 (p.W80R, p.E17K); ARID1A (p.F2141fs59); ASXL1 (p.G646fs12); BCORL1 (p.P1681fs20); CD79A (p.R131fs61); CDKN2A (p.R58*); CHEK1 (p.T226fs19); KEL (p.W532*); KMT2D (p.P2354fs30); MSH2 (loss); MSH3 (p.K383fs32); PIK3CA (p.Y1021C); PIK3R1 (p.N564D); PTEN (p.W274fs2, p.K267fs9); RNF43 (p.G659fs41); SPEN (p.R732*, p.R795*); TSC1 (p.R509*); TP53 (p.R175H, p.P152L, p.V272A, p.R213fs34)

Abbreviations: ABI, abiraterone acetate; ADT, androgen deprivation therapy; APA, apalutamide; CAB, combined androgen blockade; CBDCA, carboplatin; CBZ, cabazitaxel; DTX, docetaxel; OS, overall survival; PEM, pembrolizumab.

Our central message is not limited to MSI‐high status. Rather, a rare mixed histology should be suspected when the clinical course is not adequately explained by the initial biopsy diagnosis or PSA kinetics alone. Repeat biopsy of newly progressive lesions can be crucial for establishing the correct diagnosis and identifying therapeutic options in unusual and aggressive prostate cancers.

4. Conclusion

We report a rare case of prostatic adenosquamous carcinoma with a minute squamous component in the initial biopsy specimen and early liver metastasis despite a marked PSA response to initial therapy.

Ethics Statement

The Ethics Committee of Nagoya City University Hospital (Approval No. 60‐26‐0025) approved the protocol of this research project.

Consent

Written informed consent for the publication of this article and accompanying images was given by the patient.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.