Cervical Lymphadenopathy as Initial Presentation of Foamy Gland Adenocarcinoma of the Prostate: A Case Report

Introduction

Prostate cancer (PCa) is a leading cause of cancer-related morbidity and mortality in men worldwide.¹ While early-stage disease is often asymptomatic, progression leads to lower urinary tract symptoms.² Advanced PCa commonly metastasizes to bone (65–75% of cases)³ and regional pelvic lymph nodes.⁴ However, PCa rarely metastasizes to distant lymph nodes, such as the axilla and cervical regions. Once primary PCa progresses to metastatic PCa, the outcome is poor. Most PCa are conventional acinar adenocarcinomas; however, a rare variant known as foamy gland adenocarcinoma was recognized in the 2016 WHO classification.⁵ A review of reported foamy gland adenocarcinoma cases reveals that initial presentation is typically urinary (Table 1).^6–8 In contrast, we report a unique case of foamy gland adenocarcinoma presenting with left cervical lymph node metastasis as the initial symptom to highlight that this rare variant can present with distant lymphadenopathy, emphasizing the need for clinicians and pathologists to consider metastatic prostate cancer in the differential diagnosis of cervical masses, even in the absence of urinary symptoms.

Table 1 Case Reports of Foamy Gland Adenocarcinoma of the Prostate

Case Presentation

In early April 2021, an 81-year-old male presented to the outpatient clinic with a chief complaint of an enlarged left cervical lymph node. A cervical ultrasound performed on April 1 showed a normal thyroid gland and multiple left supraclavicular lymph node enlargements. On April 11, he was admitted to the surgical ward of The 948th Hospital of the People’s Liberation Army in Wusu City, Xinjiang Uygur Autonomous Region, China (specific time points are illustrated in Figure 1). He had a history of hypertension, coronary artery disease, and pulmonary tuberculosis. Physical examination revealed multiple firm, non-tender, and movable lymph nodes in the left supraclavicular fossa (level Vb), measuring approximately 1.5×1.0 × 1.0 cm.

Figure 1 Specific time points corresponding to the diagnostic process of this case.

Based on these findings, an excisional biopsy of the nine left supraclavicular lymph nodes was performed on April 12; the largest measured 3.0×3.0 × 2.0 cm. Concurrently, laboratory tests revealed a markedly elevated total PSA (33.26 ng/mL), while other tumor markers were within normal limits. The preliminary pathological report from the primary hospital, issued on April 14, indicated “suspected metastatic carcinoma.” To identify the primary tumor, further imaging was obtained. A prostate MRI (April 18) revealed a PI-RADS 5 lesion in the transition zone, with suspected local invasion and pelvic lymph node metastasis, Vertebral MRI showed bone metastases (Figure 2). Chest CT with intravenous contrast indicated chronic bronchitis. A whole-body PET/CT scan was not performed for comprehensive staging, as this modality was unavailable at the treating hospital.

Figure 2 Diagnostic images of the case. (A) Cervical ultrasonography showing enlarged left supraclavicular lymph nodes (indicated by arrows) that were secondarily involved by metastatic carcinoma. (B) Prostate magnetic resonance imaging (MRI) shows a PI-RADS 5 lesion (indicated by arrows) in the transition zone. (C) Vertebral MRI demonstrating abnormal signals consistent with bone metastases in the spine (indicated by arrows).

For a definitive diagnosis, the biopsy specimen was referred to our pathology department for consultation on April 22. Histology showed a poorly differentiated carcinoma replacing nodal architecture, with cells featuring abundant clear cytoplasm (Figure 3A), which was negative for periodic acid–Schiff (PAS) (Figure 3B). Immunohistochemistry (IHC) was positive for AE1/3, CAM5.2, PSA, and P504S (Figure 3C–F), and negative for CK7 (Figure 3H) and other markers (CK34βE12, CD56, Syn, S-100, Vimentin, P63, SMA). Ki-67 was 60%+ (Figure 3G). The IHC profile was highly suggestive of a prostatic origin. Notably, this histological assessment was initially made without the clinical context of the elevated PSA or imaging findings, as the consultation request provided only basic information (age, sex, and biopsy site). This suspicion prompted an active review of the patient’s full clinical history and correlation with the subsequently available PSA and MRI results, culminating in the definitive diagnosis of metastatic prostate foamy gland adenocarcinoma.

Figure 3 Histopathological results of the lesion. (A) Hematoxylin and eosin staining showed metastatic, poorly differentiated adenocarcinoma in lymph nodes. (B) Foam cells were negative for PAS. IHC staining was positive for (C) AE1/3, (D) CAM5.2, (E) PSA, and (F) P504S. IHC staining (G) negative for CK7; (H) positive for Ki-67. (A–H) (200× magnification).

The final stage was T4N1M1b (clinical stage IVA). Given the patient’s advanced age, multiple comorbidities, and advanced disease, he was not considered a surgical candidate. He opted for conservative management with androgen deprivation therapy, consisting of subcutaneous goserelin (3.6 mg implant every 28 days) and oral bicalutamide (50 mg once daily), along with zoledronic acid (4 mg via intravenous infusion every 28 days) for bone protection. Following treatment initiation, the patient’s condition remained clinically stable for the subsequent months. He reported manageable symptoms and maintained a reasonable performance status during follow-up. Unfortunately, in January 2023, he contracted COVID-19 and died from complications of the infection, with an overall survival of 9 months from diagnosis.

Discussion

Foamy gland adenocarcinoma is a rare subtype of prostate cancer (PCa), predominantly affecting elderly men and typically presenting with urinary symptoms. In contrast, our case was remarkable for its initial presentation as distant lymph node metastasis, highlighting a unique diagnostic challenge for clinicians and pathologists.

The diagnosis in this case integrated histomorphology, IHC, and clinical correlation. Evaluation of the left cervical lymph node biopsy revealed replacement by epithelioid cells expressing prostatic markers (eg, PSA, P504S), while serology showed elevated PSA and imaging identified a primary prostate lesion.

The first diagnostic challenge was the rarity of the initial manifestation. Prostate cancer typically presents with local urinary symptoms and commonly metastasizes to regional pelvic lymph nodes.² In contrast, distant metastasis to cervical or axillary nodes is rare. To our knowledge, there have been 17 reports describing 50 cases of PCa with peripheral lymph node metastasis as the initial clinical presentation involving cervical, supraclavicular, and axillary lymph nodes. Among these cases, 41 cases occurred in the left cervical or supraclavicular regions,^9–19 4 occurred in the right cervical or supraclavicular regions,^10,20–22 3 occurred in the bilateral cervical regions,^17,18,23 1 occurred in the left axilla region,²⁴ and 1 case did not specify the location of the cervical region.²⁵ It is important to note that adenocarcinomas originating from internal abdominal organs, including those of the genitourinary tract, can metastasize to a broader range of cervical lymph nodes beyond the supraclavicular region, potentially involving levels II through IV along the internal jugular chain.^26,27 In our case, the enlargement of lymph nodes was noted in the left supraclavicular region. After a thorough search, we found that cervical lymph node metastasis occurs in only about 0.4% of patients with PCa.^28,29 This low incidence rate for initial manifestation makes our diagnosis difficult.

The second challenge was the microscopically atypical cell morphology. The most common pathological type is acinar adenocarcinoma in PCa. The 2022 WHO classification of acinar adenocarcinoma in the prostate includes four variants, namely atrophic pattern adenocarcinoma, pseudohyperplastic adenocarcinoma, microcystic adenocarcinoma, and foamy gland adenocarcinoma.³⁰ The foamy gland adenocarcinoma is a rare type of prostatic acinar adenocarcinoma and shows fused glandular structures with a focal cribriform pattern with cells having abundant foamy cytoplasm.³¹ Due to the atypical and rare histological morphology of PCa, the pathological diagnosis is difficult.

Lastly, this is a consultation case. The absence of clinical information contributed to the challenge in diagnosis. When the cervical lymph nodes are enlarged, especially when a large number of tumor cells appear in the lymph nodes, it is easy to diagnose it as metastatic carcinoma. However, most cancers that metastasize to cervical lymph nodes originate from primary cancers of the head and neck.³² The most common primary sites include the oral cavity, salivary glands with non-mucosal neoplasms, and thyroid glands. The rarity of such metastases from distant sites is exemplified by a documented case in which cervical lymph node metastasis was ultimately attributed to a metachronous salivary gland carcinoma, not to the patient’s concurrent prostate cancer.³³ Therefore, metastatic cancers of the cervical chain originating from non-head and neck origin are rare. The absence of clinical imaging, serological data, and other information makes it easy for pathologists to initially assume this is a case of head and neck carcinoma. In this case, the initial pathological evaluation was performed without knowledge of the elevated PSA or the prostate MRI results, exemplifying this exact challenge.

IHC plays a principal role in differential diagnosis. In this case, a broad panel of markers, including 5 positive and 8 negative markers were used to confirm the diagnosis of metastatic PCa (PSA and P504S positive, CK7 negative) and to rule out other diseases, such as metastatic myoepithelial carcinoma (P63 and SMA negative), neuroendocrine carcinoma (CD56 and Syn negative), and mucoepidermoid carcinoma (special staining of PAS showed negative). The diagnosis was greatly aided by the CK7-negative profile, which, in conjunction with the morphology, strongly suggested a prostatic origin. The diagnostic value of CK7 in this context stems from its low expression in prostate cancers among other epithelial tumors.^34–36 This underscores the indispensability of a comprehensive IHC panel in resolving such diagnostic dilemmas.

The management of foamy gland adenocarcinoma follows standard prostate cancer protocols (eg, radical prostatectomy).^37,38 Its prognosis is comparable to conventional acinar adenocarcinoma and depends on typical prognostic factors such as PSA level, stage, and Gleason score.³⁹ For patients with isolated or symptomatic cervical metastases, local control options including surgical excision (cervical lymph node dissection) followed by radiotherapy and/or chemotherapy may be considered, in addition to systemic therapy.⁴⁰

Conclusion

In conclusion, we present a rare case of foamy gland adenocarcinoma of the prostate that manifested initially with left supraclavicular lymphadenopathy. This case highlights significant diagnostic pitfalls, including its atypical presentation mimicking a head and neck primary, its uncommon histological variant, and the challenges posed by incomplete clinical information during initial pathological consultation. Therefore, prostate carcinoma should be included in the differential diagnosis of metastatic carcinoma in cervical lymph nodes, even in the absence of urological symptoms. A comprehensive immunohistochemical panel, including prostate-specific markers, is essential for accurate diagnosis in such challenging scenarios.