A 43-year-old Malay man presented to our facility with a three-month history of fever, non-productive cough and weight loss. He was a chronic smoker and had no significant medical history. Results of a physical examination were unremarkable. A chest radiograph revealed a large right lower zone lung lesion, and a subsequent computed tomography (CT) scan of the thorax and abdomen revealed a large heterogeneously enhancing soft tissue mass in the right lower lobe of the lung with intra-cavitary extension into the left atrium via the right inferior pulmonary vein (Figure ). Transthoracic needle aspiration of this mass was suggestive of carcinoma. Surgery was performed for the resection of this mass; a right posterior lateral thoracotomy was performed, followed by a right lower lobectomy. The left atrium was opened at the inferior part of the superior pulmonary vein and the tumor resected with a small cuff of left atrium. The entire tumor and right lower lobe was delivered en bloc, and the left atrial defect subsequently patched. Histology demonstrated a high-grade clear cell sarcomatoid tumor, suggestive of metastatic clear cell renal cell carcinoma, a diagnosis specifically considered by the pathologist. On immunohistochemistry, the lesion was focally positive for epithelial membrane antigen (EMA), CD10 and vimentin, but negative for anticytokeratin CAM5.2, thyroid transcription factor-1 (TTF-1), smooth muscle actin (SMA), S100, HMB-45, Melan-A, Hepar and synaptophysin. However, as no renal lesion was evident on the CT scan (Figure ), a diagnosis of alveolar soft part sarcoma was considered. An additional extensive investigation did not reveal a primary lesion or any other metastatic lesions.\nThen, four months later, our patient developed a subcutaneous mass in his left loin. A CT scan of the abdomen confirmed a large 11 cm tumor occupying nearly the entire right kidney with involvement of the pelvicalyceal system and proximal ureter (Figure ). The tumor also extended into the right renal vein and the inferior vena cava, with a 2 cm soft tissue nodule was seen in the subcutaneous layer of the left flank. Further imaging of the thorax demonstrated multiple lung nodules, a large right pleural-based mass and an enlarged subcarinal lymph node. A bone scan was performed, and suggested involvement of the right humeral head and multiple thoracic vertebrae. Excision biopsy of the subcutaneous nodule was performed, and histology demonstrated a tumor morphologically similar to the initially resected lung lesion, suggestive of a high-grade clear cell renal cell carcinoma with sarcomatoid differentiation (Figure ). On immunohistochemistry, the tumor was strongly positive for vimentin, CD10, focally positive for epithelial membrane antigen, melan-A and negative for TTF-1, S100, inhibin and synaptophysin (Figure ) The positive vimentin and negative inhibin results weighed against the likelihood of an adrenocortical tumor.\nOur patient was given palliative first-line therapy of sunitinib, with initial best response of stable disease. After three cycles of sunitinib, the disease progressed; our patient declined any further therapy and he eventually died 13 months after his initial lung resection.
In June 2019, a 53-year-old man was admitted to a local hospital due to a palpable “right neck mass”. He had no fever, dizziness, fatigue, abdominal pain, backache, frequent urination, urgency, or changes in urine color. There was no other positive clinical sign on physical examination. No family history of hereditary diseases was detected. After surgical resection, a metastatic squamous cell carcinoma was diagnosed pathologically (, left panel). In the following PET-CT (Positron Emission Tomography-Computed Tomography) scan showed nodular iso-density foci in the upper pole of the left kidney, with a diameter of about 28.5 mm, SUVmax value of 8.3, increased FDG (fluorodeoxyglucose) metabolism, indicative of malignant lesions, and semi-oval infarct foci in the center of the right kidney. On July 29, 2019, renal puncture was performed, and the pathological diagnosis was epithelial tumor based on the immunohistochemical positive results of relevant markers. SPECT/CT (Single Photon Emission Computed Tomography) showed no obvious abnormalities in blood flow perfusion, uptake and excretion in both kidneys.\nFor further surgical treatment, the patient was transferred to our hospital on August 12, 2019. The renal artery CTA (Computed Tomographic Angiography) results showed an oblong iso-density foci of about 3.4 * 2.1 cm in the middle of the right kidney, and a 4.4 * 4.2 cm-like circular iso-density lesion in the upper left kidney (). The local boundary was unclear from the adjacent renal parenchyma. It was slightly protruded on the surface of the renal parenchyma, and the lesion was slightly uneven and enhanced by enhanced scan. There was no obvious abnormality in the diagnosis of bilateral renal artery CTA. Kidney magnetic resonance imaging (MRI) confirmed a 2.9 * 1.5 cm circular abnormal signal lesion in the middle of the right kidney and a 3.6 cm diameter circular abnormal signal lesion in the upper pole of the left kidney, which was isointense on T1-weighted imaging (T1WI), a low signal area on fST2WI, and hyperintense on DWI. The signal of the ADC map was reduced, and a slight uneven enhancement was seen by enhanced scan. Based on the above findings, the possible diagnosis was a malignant tumor of the kidney.\nOn August 19, 2019, a laparoscopic radical nephrectomy (left) was performed under general anesthesia. On December 12, 2019, the patient was admitted to the hospital due to a “right kidney mass”. After completing the relevant examinations, the “Da Vinci Robot-Assisted Laparoscopic Partial Right Nephrectomy” was successfully performed. No complication was observed and the patient was discharged six days after surgery. The patient’s condition currently remains stable. PET-CT scan re-examination found no local recurrence or distant metastasis one year after the operation.\nHistological examination of the radical nephrectomy specimen of the left kidney showed a mixed pattern of mucinous tubular and spindle cell carcinoma (MTSCC) with papillary adenoma (, middle panel). Microscopy examination of the partial nephrectomy of the right kidney revealed a papillary renal cell carcinoma (PRCC) (, right panel). The histological morphology and immunohistochemical results of renal tumor were different from those of neck tumor. PAX8 staining showed positive expression ().\nTo further investigate their genetic characteristics, whole exome sequencing (WES) was performed separately. A total of 304 putative somatic variants of 225 genes were identified in neck tumor tissues, of which 10 were identified as driver gene mutations, including CDKN2A, KMT2D and NSD1 mutations that are common drivers of head and neck squamous cell carcinoma (HNSC) (). Similarly, the WES results of renal tumor samples revealed 361 somatic variants in 219 genes in the left kidney and 270 somatic variants in 207 genes in right kidney, including five and four driver gene variants, respectively ( and ). The three lesions have both private and shared mutation genes shown in . Similarly, 51, 58 and 47 shared gene variants were detected respectively between left & right kidney, left kidney& neck, and right kidney & neck. Thirty-eight common mutated genes were shared in all three tumor tissues. For the driver gene mutations, the right nephropathy foci shared one driver gene mutation with the left kidney (WT1) and the neck lesions (CREBBP), respectively. But no driver mutated gene was shared in all three tissues ().\nIn addition, a clonal evolution analysis was performed to examine the heterogeneity of tumor evolution among different lesions. We used a previously reported hierarchical Bayesian clustering model () to define clones and subclones based on clusters of SNVs sharing similar cancer cell fractions (CCF). CCF distributions are shown in . These clones and subclones were shared between the spatially distinct lesions. Correspondent clonal components also existed in different lesions, especially some driver gene mutations, such as NFKB2, WT1, GTF2I, etc. The clone evolution analysis showed that the clone components of the initial left renal primary lesion and the final cervical squamous cell carcinoma lesion were different. The left renal tumor was mainly composed of clones 3, 4, and 7, the right renal tumor was mainly composed of clones 2, 3, and 6, while the cervical mass was mainly composed of clones 4 and 6 (). Therefore, the primary clones in the metastatic lesions may not be derived from the primary clones in the left kidney tumor. Instead, they may have originated from the subclones generated before the diagnosis. Some driver gene variants detected in clones with different lesions were unique and some were shared. The putative dynamic mutation profiles during the disease course are represented in . These results can serve as a strong complement to histopathological findings, suggesting that these lesions may have evolved from the original focus, although there are differences in the pathological morphology of different lesions.