The most common primary malignant renal tumors are clear cell, papillary, and chromophobe RCC, comprising 70% to 80%, 14% to 17%, and 4% to 8% of all RCCs. [1] The majority of clear cell RCC have alterations of the von Hippel-Lindau (VHL) gene, located at chromosome 3p25. The aberrant expression of VHL results in constitutive activation of the hypoxia-inducible factor (HIF) pathway, and overexpression of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and other proteins. Inactivation of the VHL gene also enhances tumor cell growth through the mammalian target of the rapa mycin (mTOR) pathway. [2] Approximately, 20% to 30% of patients with clear cell RCC have metastatic disease at the time of diagnosis, and another 30% subsequently develop metastasis after resection of the tumor. The metastasis may involve almost anybody site, including odd locations, such as soft tissue, brain, skin, parathyroid, ovary, and others.[3]

The main differential diagnoses of metastatic clear cell RCC to the lung include primary NSCLC, particularly a subtype of pulmonary adenocarcinoma, metastatic chromophobe or papillary RCC, metastatic hepatocellular carcinoma (HCC) and a few others. Both clear cell RCC and chromophobe RCC have some overlapping features. However, in chromophobe RCC, the nuclei reveal a hyperchromatic chromatin pattern without prominent nucleoli. The nuclear size of chromophobe RCC are variable and pleomorphic. Binucleation is another feature commonly seen in chromophobe RCC. Tumor cells have abundant cytoplasm, and well-defined cell borders (so-called “vegetable cell” appearance). Some tumor cells may also reveal large irregular hyperchromatic nuclei and dense cytoplasm. In papillary RCC, tumor cells are arranged in papillae with fibrovascular cores. Typical papillary RCC can be focally or predominately composed of cells with clear or foamy cytoplasm. However, tumor cells of papillary RCC contain medium- to large-sized cuboidal cells with uniform nuclei, and a moderate amount granular cytoplasm. The nuclei are irregular with coarse chromatin and prominent nucleoli. Some tumor cells may reveal moderate pleomorphism and are arranged in two- or three-dimensional groups with papillary configurations. Tumor cells may have abundant intracytoplasmic hemosiderin. The presence of foamy macrophages is another helpful morphologic feature. Finally, recently descripted papillary clear cell RCC can occur either sporadically or be associated with end-stage renal disease. The typical features are that of a low-grade clear cell tumor with focal or extensive papillary growth pattern. [4] In adenocarcinoma of the lung, particularly the subtype of ADC with clear cell features, tumor cells are arranged in three dimensional tight clusters and acinar structures. Some of the tumor cells may have intracytoplasmic mucin. These features are suggestive of glandular differentiation. The nuclei of the tumor cells have coarse chromatin, irregular nuclear membranes and prominent nucleoli. The cytoplasm of the tumor cells is vesicular and lacy. [5] Other helpful diagnostic features for a poorly differentiated adenocarcinoma are marked variation in cell size, prominent nucleoli, distinct margination of the chromatin at the nuclear membrane, and the presence of cohesive three-dimensional clusters.  Approximately 15-25% of lung adenocarcinoma are associated with KRAS mutations and are found in tumors from both former/current smokers and never smokers. In contrast, EGFR mutations are found in approximately 10% of NSCLC in USA and in 35% in East Asia, manly in non-smokers women. KRAS mutations are identified predominantly in tumors with wild type for EGFR or ALK, therefore, they are not overlapping with other oncogenic mutations and appear to define a distinct molecular subset of NSCLC. KRAS mutations are shown to be a negative predictor of response to anti-TKIs (tyrosine-kinase inhibitors) therapies such as erlotinib and gefitinib in NSCLC. Currently, there is no direct anti-KRAS therapies. Mutations of EGFR occur in exons 18-21 leading to activation of downstream pro-survival signaling pathways. Mutations in exons 18, 19 and 21 are associated with response to TKIs. [6,7] The features of granular cytoplasm and prominent nucleoli may be confused with HCC. In metastatic HCC, the tumor cells are arranged in loosely cohesive clusters and scattered individual cells. Tumor cells are much larger in size, have a high N:C ratio, large nuclei and prominent nucleoli. Many “naked” nuclei can be found on smears. The cytoplasm is dense and has a granular appearance. Finally, some morphologic features of tumor cells may point to the primary site of the metastatic tumor. For example, metastatic breast carcinoma typically exhibit intracytoplasmic lumina. Psammoma bodies are usually associated with ovarian, endometrial and/or fallopian tube serous carcinoma. [5]

Immunocytochemistry is very useful to confirm a suspected diagnosis of metastatic clear cell RCC. Helpful immunohistochemical markers include vimentin, CK7, carbonic anhydrase IX, kidney-specific cadherin, and CD117. Chromophobe RCC is usually positive for kidney-specific cadherin, CD117, and CK7, but negative for carbonic anhydrase IX and vimentin. Clear cell RCC would typically demonstrate staining patterns that are directly the opposite. Typical papillary RCC can be focally or predominately composed of cells with clear or foamy cytoplasm. Strong, diffuse, positive staining for AE1/AE3 keratins and AMACR is helpful to confirm the diagnosis. Unlike classic clear cell or papillary RCC, papillary clear cell RCC is strongly positive for CK7, but is negative for AMACR. Another tumor type with clear and eosinophilic cells forming papillae is Xp11.2 translocation carcinoma. This tumor is typically negative or focally positive for CK and epithelial membrane antigen. [3, 8] Primary lung adenocarcinomas are usually positive for TTF-1 and Napsin A.