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.
A 49-year-old male was presented at our department with lower back pain and walking instability for the last few days. The patient suffered from end-stage renal disease on dialysis for the last 15 years and had a history of successful renal transplantation about 25 years ago. The initial renal insufficiency resulted from a chronic glomerulonephritis and the allograft was rejected 9 years after transplantation due to the same underlying condition. Furthermore, about 2 years ago, he underwent bilateral nephrectomy for solid tumorous masses in both nonfunctioning kidneys. The histologic examination revealed, bilaterally at that time, type 1 papillary renal cell carcinoma (pT1aN0M0, Fuhrman grade II, in sano resection). Additionally, the nonfunctioning transplant kidney was removed about 6 months ago due to recurrent episodes of macrohaematuria, without evidence for a malign tumour. At that time, there were no signs for a metastatic disease.\nAt current presentation, the performed magnetic resonance imaging (MRI) of the spine showed a pathologic facture at the right side of the first and second lumbar vertebral body () from a metastatic solid mass, as well as multiple osteolytic metastases from 7th cervical to 2nd lumbar vertebra. A staging computed tomography (CT) of the thorax and abdomen showed further osseous osteolytic metastatic lesions at the sternum, both scapulae, the bone pelvis, and the left proximal femoral bone. The performed biopsy of the osteolytic metastatic lesion at the second lumbar vertebra revealed a metastatic, mucin-poor variant, of a mucinous tubular and spindle cell carcinoma of the kidney (). A thorough reexamination of the old nephrectomy specimens showed that the tumour of the right kidney was also a mucin-poor variant of a MTSCC of the kidney, while the tumour of the left kidney was confirmed as a papillary RCC.\nHistologically, both the biopsy sample and the nephrectomy-specimen of the right kidney showed a renal cell tumour with a spindle cell component, as well as tubular and papillary parts without any clear cells. Both spindle and tubular-papillary parts were delimited by a basal membrane, forming a ball-shaped, epithelial tumour-growth pattern with spindled nuclear morphology, which did not match a sarcomatoid differentiation. Immunohistochemically, the tumour was negative for desmin and actin and S100 protein, as well as for HMB45, MITF1, MART1, and SOX-10. A positive reaction to Racemase (AMARC), PAX-8, and RCC was found, with focal positivity for CD10. Pan-Cytokeratin (AE1/AE3) and CK7 were negative except from the papillary parts. The Ki67 stain showed focal proliferation rates up to 30%. Furthermore, no mucoid interstitial matrix was found with H&E stain. Only with Alcian blue staining, <1% mucin in cellular areas was observed.\nAccording to our interdisciplinary tumour conference board's recommendation, the patient followed a systemic treatment with pazopanib and focal radiotherapy to lumbar and cervical vertebrae metastases. In further follow-up, irrespective of the started treatment, the tumour spread rapidly and after three months the patient presented with additional hepatic and pulmonary metastases. The patient finally succumbed to the disease a few months later.