Rare Tumor-to-Tumor Metastasis Takes an Unusual Direction

A 67-year-old man with a history of smoking was diagnosed with diffuse large B-cell lymphoma in 2006. Due to bone marrow involvement and the patient’s intermediate/high risk on the International Prognostic Index, his initial stage upon diagnosis was IVB.

He was treated with 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and achieved a complete response. (At the time of this case report, he remained relapse-free.)

During that same year, he was found to have a left papillary renal cell carcinoma (RCC), identified according to the American Joint Committee on Cancer (AJCC), 6th edition, as type 2, Fuhrman grade 3-4, stage III by pT3N0M0, and underwent a radical nephrectomy by laparoscopy. Over the following 4 to 5 years, he received regular clinical and imaging follow-ups.

Five years later, in 2011, a third primary tumor was detected and identified as stage I acinar adenocarcinoma of the prostate (pT2AN0M0, Gleason 3+3 per AJCC 7th edition), with an initial prostate-specific antigen level of 7.6 ng/mL. Treatment involved a radical prostatectomy and extended lymphadenectomy. He again remained relapse-free.

In 2015, the patient experienced an isolated left para-aortic lymph node relapse, for which he underwent a complete lymph node resection. Pathology identified the tissue as compatible with a papillary RCC type 2 metastasis. Since there was no evidence of disease at another site, the patient was slated for follow-up assessments every 3 months.

In 2018, a routine CT scan revealed a nonspecific pulmonary nodule in the center of the left upper lobe. This was not treated but kept under observation.

In July 2019, a repeat thoracic CT scan of the nodule showed 21 mm of mixed solid and ground-glass opacity; clinicians noted it had increased in diameter by 19% since the previous year’s scan.

A PET-CT scan revealed nodules and micronodules with soft tissue density in both lung fields. Several showed high metabolic activity, and suggested possible metastatic involvement. Specifically, clinicians noted a left para-aortic hypermetabolic adenopathy that infiltrated the left psoas minor muscle and another hypermetabolic focus in the left posterior muscle wall of the retroperitoneum. Given the likelihood that these were metastases, both were biopsied.

Results of the lung nodule biopsy suggested a primary pulmonary adenocarcinoma with a lepidic pattern, while findings of the retroperitoneal mass biopsy revealed a papillary adenocarcinoma compatible with a primary renal tumor.

In January 2020, the patient underwent a left upper lobectomy and mediastinal lymph node dissection by thoracoscopy. The histopathology assessment of the left upper lobe identified a 2.0 × 1.5 cm-nodule composed of a lung adenocarcinoma with an intratumoral metastasis measuring 0.2 cm in diameter from a papillary RCC (figure). The second, smaller nodule was identified as an RCC metastasis, measuring 1.0 × 0.5 cm.

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Figure: (A) Intratumoral metastasis of the papillary renal cell carcinoma type 2 measuring 0.2 × 0.2 cm, surrounded by a lung adenocarcinoma; (B) The circle encloses the intratumoral metastasis (hematoxylin and eosin stain, 10× magnification).

The lung adenocarcinoma was staged as pT1bN0M0R0 IA2 (AJCC, 8th edition); since histopathology identified no adverse risk factors, no adjuvant treatment was offered.

Although the patient’s RCC was low risk on the International Metastatic RCC Database Consortium scale, the patient experienced pain and weight loss due to its progressive metastasis and high tumor burden. Thus, he underwent systemic therapy with sunitinib in April 2020.

In September 2020, CT images of the chest and abdomen revealed stable neoplastic disease. The patient had increasing shortness of breath, so clinicians discontinued treatment with sunitinib, which resolved his dyspnea. He underwent transthoracic echocardiography and an ischemia induction test, with normal results.

In October 2020, the patient began having significant pain related to the retroperitoneal disease. Though the disease was stable, the patient underwent palliative resection performed by a urologic oncologist.

In November 2020, the patient’s last follow-up visit found him to be without symptoms and with stable neoplastic disease, as shown by a PET-CT scan. After consultation with his oncologist, the patient decided to remain under close observation with no active treatment.

To investigate the possibility that the cancer was hereditary, clinicians requested a germline mutation testing panel of 105 genes using next-generation sequencing; however, no alterations were noted.

Discussion

Clinicians presenting this case of tumor-to-tumor metastasis in a man with a history of papillary RCC said that they believed it was one of the first reported instances in which a primary lung adenocarcinoma was the recipient site and RCC was the metastatic donor.

Although various donor-recipient combinations have been documented, this case represented the reverse of the pattern of metastasis most commonly reported: lung cancer as the most frequent metastatic donor, and RCC as the most frequent recipient tumor, which occurs in up to 65% of cases, the authors said.

In general, metastasis from one primary tumor to another is a rare phenomenon, with fewer than 200 cases reported since it was initially characterized in 1902, they noted.

They said that this case meets the 1969 criteria for a true tumor-to-tumor metastasis, which require evidence that:

• More than one primary tumor is present
• The recipient tumor is a true benign or malignant neoplasm
• The second metastatic neoplasm is a true metastasis with established growth in the host’s tumor, not the result of contiguous growth (“collision tumor”) or embolization of tumor cells

This definition excludes tumors that have metastasized to the lymph nodes with existing lymphoreticular malignant tumors.

Several theories have been proposed to explain the occurrence of tumor-to-tumor metastasis, the authors wrote. The 1889 theory of “soil and seed” suggested that availability of a fertile microenvironment (soil) allows development of the tumor (the seed). Conversely, the “mechanical” theory put forth in 1928 suggested that site of metastasis depends on how many viable tumor cells are delivered to the target organ, which may also be determined by anatomical considerations such as location and extent of vascularization.

Overall, lungs are the second most frequent site for metastatic involvement by extra-thoracic tumors, representing up to 54% of cases, the authors noted: “RCC metastases are present in up to 30% of patients, and the lungs, in addition to non-regional lymph nodes, are probably the most frequently involved organs (70%).”

They also cited a study of RCC metastasis distribution among more than 11,000 patients identified in the National Inpatient Sample from 1998 to 2007. This study identified the lung as the most common site of metastases, accounting for 45% of cases, followed by bone (30%), lymph node (22%), liver (20%), adrenal glands (9%), and brain (9%).

The kidneys’ high blood volume, along with the high lipid and glycogen content of RCC, make it a good recipient of lung cancer metastases, the group wrote, adding that the mechanisms behind the reverse phenomenon noted in this patient’s case are not clear. The group hypothesized that the inflammatory microenvironment of the lung adenocarcinoma may attract and host metastatic RCC tumor cells, as seen in a report of RCC metastasizing to the oral cavity after tooth extraction.

The authors said that another possible explanation for the patient’s case is the potential for synchronous primary pulmonary tumors to present in patients with a history of renal cancer. They pointed to a case series of 151 patients with pulmonary metastatic RCC in which 2% of the patients had synchronous non-small cell lung cancer, although this series did not report any cases of tumor-to-tumor metastasis.

The case report patient was followed closely due to his oncologic history, which assisted in the timely diagnosis of the tumor-to-tumor metastasis and led to the curative management of his lung adenocarcinoma, the authors wrote.

In most cases, metastasis from a malignant tumor to another primary tumor is a rare event that usually represents a diagnostic challenge and requires a careful pathological study to ensure precise diagnosis and appropriate treatment, the group concluded.

Last Updated August 16, 2021