'Prechronous' metastasis in clear cell renal cell carcinoma: a case report
© Poon et al; licensee BioMed Central Ltd. 2011
Received: 7 April 2010
Accepted: 13 May 2011
Published: 13 May 2011
Although metastatic carcinoma in the presence of an occult primary tumor is well recognized, underlying reasons for the failure of the primary tumor to manifest are uncertain. Explanations for this phenomenon have ranged from spontaneous regression of the primary tumor to early metastasis of the primary tumor before manifestation of a less aggressive primary tumor. We report a case of 'prechronous' metastasis arising from clear cell renal cell carcinoma, where metastatic disease initially manifested in the absence of a primary renal tumor, followed by aggressive growth of the primary renal lesion.
A 43-year-old Malay man initially presented to our facility with fever and cough. He subsequently underwent surgical resection of a 9 cm right-sided lung mass found on radiological examination. Histology showed a high-grade clear cell tumor with sarcomatoid differentiation, suggestive of a metastasis from clear cell renal cell carcinoma. However, no concurrent renal lesions were noted on computed tomographic evaluation at that time. Then, four months after lung resection, he presented with a subcutaneous mass in the left loin, as well as right loin discomfort. Computed tomography scanning revealed a 10 cm right renal mass, with renal vein and inferior vena cava invasion, as well as recurrent disease in the right thorax. Histological examination of the excised subcutaneous mass revealed a high-grade carcinoma consistent with clear cell renal cell carcinoma.
This is the first reported case of prechronous metastasis of renal cell carcinoma, with metastatic disease manifesting prior to the development of the primary lesion. The underlying mechanism is uncertain, but our patient's case provides anecdotal support for the early dissemination model of metastasis.
Although metastatic carcinoma in the presence of an occult primary is well recognized as a common clinical scenario of 'carcinoma of unknown primary' , underlying reasons for the failure of a primary tumor to manifest are uncertain. Possible explanations have ranged from spontaneous regression of the primary to an early metastasis. We report a case of 'prechronous' metastasis (see Discussion) arising from clear cell renal cell carcinoma (RCC), with the primary lesion manifesting only after the metastatic lesion was resected.
Our 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.
About 25% to 30% of patients with RCC present with metastatic disease at diagnosis but less than 5% have solitary metastasis. Tumors with sarcomatoid change often have poorer prognosis. Our patient presented initially with a symptomatic metastasis in the absence of an evident primary; the primary tumor manifested only subsequently following metastatectomy. This phenomenon has been reported once before in the setting of lung cancer, where a 51-year-old woman presented with symptomatic brain metastasis , where the lung primary was eventually detected in the left upper lobe five years after resection. We sought a term to best describe this phenomenon. The terms 'synchronous metastasis' and 'metachronous metastasis' are well understood in terms of timing relative to the development of the primary tumor. The former term refers to a concurrent manifestation of metastasis and primary tumor, whereas 'metachronous' refers to the subsequent development of metastasis. Using a similar Greek prefix, the term 'prechronous' clearly describes the phenomenon observed here, where a metastatic lesion manifests prior to the primary lesion. Ours represents the first such report of this phenomenon in renal cell carcinoma, and we briefly discuss possible hypotheses here that may underpin this.
In the standard late dissemination model of metastasis, the metastatic cascade  is a multi-step sequential process in which cancer cells depart from the primary tumor and enter the lymphatics, blood or body cavity. They deposit at nearby or distant sites before proliferating to colonize ectopic tissues. It is recognized that metastases have a predilection for certain sites  and require that these key sites be first seeded . However, there has been recent evidence to support aspects of the early dissemination model, where metastasis occurs early in the life cycle of carcinogenesis. Podsypanina et al. engineered untransformed mouse mammary cells to express inducible oncogenes transgenes that are able to bypass the primary site and phenotypically show up at secondary sites . Kaplan et al. also showed that cancer cells in murine models may relay signals, involving vascular endothelial growth factor receptor 1 (VEGFR1) and fibronectin, to bone marrow cells to migrate to distant organs to establish an environment amenable to metastasis . This phenomenon preceded the formation of micrometastatic colonies in these organs by four to six days. Our case report provides anecdotal but direct support for the early dissemination model of metastasis.
There are some clinical similarities between our case report as described, and the phenomenon of 'burned-out' cancers seen most commonly in germ cell tumors. In the clinical setting of patients with 'burned-out' germ cell tumors, metastatic lesions are first identified in the presence of regressed primary tumors, the latter diagnosed by a distinct histological appearance [7, 8]. However, our case report differs in demonstrating a clear aggressive behavior for the primary tumor upon clinical manifestation post-metastatectomy, with radiological growth from undetectable to an 11 cm lesion over four months, which is inconsistent with a 'burned-out' primary.
We report a case of sarcomatoid clear cell RCC, demonstrating the rare phenomenon of prechronous metastasis. Our report provides direct support for the early dissemination model of metastasis.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
- van de Wouw AJ, Jansen RL, Speel EJ, Hillen HF: The unknown biology of the unknown primary tumour: a literature review. Ann Oncol. 2003, 14: 191-196. 10.1093/annonc/mdg068.View ArticlePubMed
- Furak J, Trojan I, Tiszlavicz L, Micsik T, Puskas LG: Development of brain metastasis 5 years before the appearance of the primary lung cancer: "messenger metachronous metastasis". Ann Thorac Surg. 2003, 75: 1016-1017. 10.1016/S0003-4975(02)04396-5.View ArticlePubMed
- Colombano SP, Reese PA: The cascade theory of metastatic spread: are there generalizing sites?. Cancer. 1980, 46: 2312-2314. 10.1002/1097-0142(19801115)46:10<2312::AID-CNCR2820461031>3.0.CO;2-P.View ArticlePubMed
- Oppenheimer SB: Cellular basis of cancer metastasis: a review of fundamentals and new advances. Acta Histochem. 2006, 108: 327-334. 10.1016/j.acthis.2006.03.008.View ArticlePubMed
- Podsypanina K, Du YC, Jechlinger M, Beverly LJ, Hambardzumyan D, Varmus H: Seeding and propagation of untransformed mouse mammary cells in the lung. Science. 2008, 321: 1841-1844. 10.1126/science.1161621.PubMed CentralView ArticlePubMed
- Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D: VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005, 438: 820-827. 10.1038/nature04186.PubMed CentralView ArticlePubMed
- Mesa H, Rawal A, Rezcallah A, Iwamoto C, Niehans GA, Druck P, Gupta P: "Burned out" testicular seminoma presenting as a primary gastric malignancy. Int J Clin Oncol. 2009, 14: 74-77. 10.1007/s10147-008-0804-0.View ArticlePubMed
- Coulier B, Lefebvre Y, de Visscher L, Bourgeois A, Montfort L, Clausse M, Mailleux P, Gielen I: Metastases of clinically occult testicular seminoma mimicking primary extragonadal retroperitoneal germ cell tumors. JBR-BTR. 2008, 91: 139-144.PubMed
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.