Case 16

A 64 year-old male was found to have a 14 cm retroperitoneal mass encasing the right kidney and a 4.3 cm mass in the right kidney parenchyma.

The right kidney mass:

1. What is the diagnosis by morphology? A panel of stains below if needed:

   A. Clear cell renal cell carcinoma

   B: Angiomyolipoma

   C: Paraganglioma

   D: Chromophobe renal cell carcinoma

   E: Clear cell papillary renal cell tumor

   F: Oncocytoma

IHC

• PAX8
• Pan-keratin
• CAIX
• AMACA

See All Options

You can vote for more than one answer.

Answer

The correct answer is D. By morphology, this tumor shows large pale cells with prominent cell membranes (plant-like) and perinuclear haloes. Classically, it arranged as solid sheets, separated by often hyalinized vascular septa. CK7 is frequently diffusely expressed in > 75% of ChRCCs and C-KIT/CD117 are positive; oncocytoma are negative for CK7. Angiomyolipoma will be negative for PAX8 and Pan-keratin; ChRCC is negative for AMACA, CAIX, and CK20. Hale colloidal iron can show diffuse cytoplamic staining in ChRCC. A screenshot of a nice paper summarizing the IHC in kidney tumors are showed below:

Li J, Wilkerson ML, Deng FM, Liu H. The Application and Pitfalls of Immunohistochemical Markers in Challenging Diagnosis of Genitourinary Pathology. Arch Pathol Lab Med. 2024 Jan 1;148(1):13-32. doi: 10.5858/arpa.2022-0493-RA. PMID: 37074862.

2. The perirenal fat section is shown above. Could you guess the stain?

   A: MDM2

   B: P53

   C: CDK4

   D: Pan-keratin

   E: P16

   F: S100

   
   

Answer

The correct answer is E. However, A, C, and F are correct as well. Although IHC is absolutely not recommended in well differentiated liposarcoma. Several stains can be positive including MDM2, S100, CKD4, P16.

P16 is a surrogate IHC for several conditions including HR HPV infections:

The exact mechanism is much more complex when trying to understand:

Wai, K.C.; Strohl, M.P.; van Zante, A.; Ha, P.K. Molecular Diagnostics in Human Papillomavirus-Related Head and Neck Squamous Cell Carcinoma. Cells 2020, 9, 500. https://doi.org/10.3390/cells9020500

Normal uninfected cell. Cyclin D-cyclin dependent kinase (CDK) 4/6 complex initiates phosphorylation of the tumor suppressor protein, pRb. The hyperphosphorylation of pRb leads to release of the transcription factor E2F into its active state, which drives the expression of downstream gene products allowing the cell to transition from the G1 to S phase. As a cyclin kinase inhibitor, p16 is a tumor suppressor and negative regulator of the cyclin D-CDK 4/6 complex.

HPV infected cell. When the transcription factor E2F is bound to pRb, it remains inactive. The overexpression of the E7 oncoprotein by high-risk HPV subtypes disrupts the E2F-pRb complex by displacing E2F and binding to pRb. The subsequent release of E2F into its active state drives the expression of downstream gene products, allowing the cell to transition from the G1 to S phase. In a regulatory feedback attempt to inhibit further cell proliferation, p16 is upregulated, and thus can be a surrogate for HPV+ tumors.

P53 and E6 story: The overexpression E6 oncoprotein acts via a separate mechanism. E6 binds to the tumor suppressor protein, p53, and ultimately leads to degradation of p53. Loss of the regulatory function of p53 causes aberrant propagation of the cell cycle and prevents apoptosis.

The whole CDK4/6, RB, p16, p53, E2F matches the other two scenarios that RB1 loss tumors namely: angiofibroma, spindle cell lipoma, acral fibromyxoma, myofibroblastoma, atypical spindle cell/pleomorphic lipomatous tumor, pleomorphic liposarcoma can have diffusely positive p16; and in this case, p16 positive in WDLPS (MDM2 regulates P53 and there is probably a balance of P53 and RB and they are both inhibit cell cycle. loss of MDM2 cause loss of P53 and there will be less RB -> more p16 ? pure imagination if it makes sense).

Reference:

Wai, K.C.; Strohl, M.P.; van Zante, A.; Ha, P.K. Molecular Diagnostics in Human Papillomavirus-Related Head and Neck Squamous Cell Carcinoma. Cells 2020, 9, 500. https://doi.org/10.3390/cells9020500 

Li J, Wilkerson ML, Deng FM, Liu H. The Application and Pitfalls of Immunohistochemical Markers in Challenging Diagnosis of Genitourinary Pathology. Arch Pathol Lab Med. 2024 Jan 1;148(1):13-32. doi: 10.5858/arpa.2022-0493-RA. PMID: 37074862.

https://www.pathologyoutlines.com/topic/softtissuewdliposarcoma.html

Case credit: UCSD Pathology

Author: Wangpan Jackson Shi, MD