What is the appropriate management for a 43-year-old male with a retroperitoneal mass, positive for Leukocyte Common Antigen (LCA), S100, INSM1, and SALL4, and negative for Pancytokeratin (Pan CK)?

Differential Diagnosis: Germ Cell Tumor vs. Lymphoma

This immunohistochemical profile (LCA+, S100+, INSM1+, SALL4+, Pan-CK-) in a 43-year-old male with a retroperitoneal mass is most consistent with an extragonadal germ cell tumor, specifically a mixed germ cell tumor with possible primitive neuroectodermal tumor (PNET) components, and requires immediate multidisciplinary evaluation at a specialized center with measurement of serum tumor markers (AFP, hCG, LDH) and testicular ultrasound to exclude a primary testicular source. 1

Critical Immunohistochemical Interpretation

The staining pattern provides crucial diagnostic information:

• SALL4 positivity is highly specific for germ cell tumors and is the most important marker in this panel for establishing the diagnosis 2, 3
• LCA (CD45) positivity initially suggests lymphoma, but can be seen in certain germ cell tumor components and does not exclude this diagnosis 1
• S100 and INSM1 positivity suggest neuroectodermal differentiation, which can occur in germ cell tumors with PNET transformation 4
• Pan-cytokeratin negativity argues against carcinoma but does not exclude germ cell tumors, particularly those with primitive or undifferentiated components 1

Immediate Diagnostic Workup Required

Before proceeding with treatment, complete the following evaluation:

• Serum tumor markers: AFP, hCG, and LDH must be obtained immediately, as elevated markers confirm germ cell tumor and guide prognosis 2, 3
• Testicular ultrasound: Essential to exclude a burned-out primary testicular tumor, as retroperitoneal germ cell tumors can be metastatic from occult testicular primaries 2, 3
• CT chest: Required to evaluate for mediastinal involvement or pulmonary metastases, as mediastinal nonseminomatous germ cell tumors carry worse prognosis 2
• Karyotype consideration: If dysgerminoma is suspected in the differential, particularly in younger patients 1

Management Algorithm

If Germ Cell Tumor Confirmed (Most Likely Diagnosis)

Primary treatment is cisplatin-based chemotherapy followed by surgical resection of residual masses. 2

Chemotherapy Approach:

• For retroperitoneal extragonadal germ cell tumors: Use VIP (etoposide, ifosfamide, cisplatin) × 4 cycles as first-line therapy 2
• Rationale: VIP is preferred over BEP (bleomycin, etoposide, platinum) to avoid pulmonary toxicity, particularly important given the need for subsequent surgical resection 2

Post-Chemotherapy Management:

• Retroperitoneal lymph node dissection (RPLND) is mandatory for all residual masses after chemotherapy, regardless of size, as viable tumor or teratoma may persist 4, 5, 6
• Cannot predict histology preoperatively: No reliable preoperative parameters accurately predict whether residual masses contain necrosis, teratoma, or viable tumor 6
• Elevated hCG predicts viable cells in residual masses (p=0.014), requiring aggressive surgical approach 6

Special Consideration: PNET Component

If primitive neuroectodermal tumor is confirmed:

• PNET in germ cell tumors carries adverse prognosis and is rarely eradicated by chemotherapy alone 4
• Surgical resection is critical: RPLND should be performed even for clinical stage I disease if PNET is present in the primary specimen 4
• Chemotherapy resistance: Only 3 of 23 patients with metastatic PNET achieved complete remission with chemotherapy alone in one series, with 2 subsequently relapsing 4

If Lymphoma Cannot Be Excluded

The LCA positivity requires consideration of lymphoma in the differential:

• Core needle biopsy may be insufficient: If lymphoma remains in the differential after initial pathology review, consider repeat biopsy with flow cytometry and additional immunohistochemical staining 1
• Avoid inappropriate resection: The goal is to prevent major surgical resection of a chemotherapy-sensitive tumor like lymphoma 1

Prognostic Factors

Key factors affecting outcome:

• Serum tumor marker levels: Elevated AFP or hCG at presentation and their response to therapy are critical prognostic indicators 2
• Presence of PNET: Associated with worse outcomes and requires aggressive surgical management 4
• Completeness of resection: R0 or R1 resection after chemotherapy is associated with best long-term survival 5

Common Pitfalls to Avoid

• Do not proceed directly to surgery: Chemotherapy must precede surgical resection in extragonadal germ cell tumors to optimize outcomes 2
• Do not omit testicular ultrasound: Failure to identify a testicular primary alters staging and management 2, 3
• Do not skip post-chemotherapy RPLND: Even with complete radiographic response, residual masses require surgical resection as viable tumor or teratoma may persist 4, 6
• Do not use surveillance for pathologic stage II disease with high-risk features: While some pN2 patients may not require adjuvant chemotherapy after primary RPLND, this patient requires chemotherapy first given the extragonadal presentation 5

Referral to Specialized Center

This patient must be managed at a center with extensive expertise in germ cell tumors, as adherence to evidence-based guidelines is associated with improved survival outcomes in rare and complex sarcomas and germ cell tumors 1, 2