We present the first reported case of metastatic type II papillary RCC with radiographic evidence of spontaneous regression at a non-pulmonary site of proven metastases.
Authors: Nicholas E. Power, Stephen A. Poon, Clarisse Mazzola, Jonathan L. Silberstein, Robert J. Motzer, Ana M. Molina, Snehal G. Patel, Jonathan A. Coleman. Department of Surgery, Urology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065
Corresponding Author: Department of Surgery, Urology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Box 213, New York, NY10065. E-mail: [email protected]
Supported by The Sidney Kimmel Center for Prostate and Urologic Cancers and by funds provided by Renal Carcinoma Program Fund.
Spontaneous regression of renal cell carcinoma (RCC) is a rare event that has been almost exclusively associated with the conventional clear cell subtype. We present the first reported case of metastatic type II papillary RCC with radiographic evidence of spontaneous regression at a non-pulmonary site of proven metastases. We highlight the literature on spontaneous regression of RCC and discuss the unique challenges of non-clear-cell metastatic RCC and new therapies in this setting.
Spontaneous regression of renal cell carcinoma (RCC) is a rare event, with most large historic case series citing a 0-1.1% incidence . In the majority of cases reported, metastasis was not confirmed histologically, and conventional clear cell RCC was the identified histology in the primary tumour . Notably, spontaneous regression of papillary RCC (type 2) has been documented only once, at a site of pulmonary metastasis . We report ona case of pT3bN2 high-grade type II papillary RCC in a 63-year-old male with histologically confirmed neck metastasis that spontaneously regressed following cytoreductive partial nephrectomy and retroperitoneal lymph node dissection. Subsequent lymphadenectomy of the site by left-neck dissection was performed following a period of surveillance during which no local or distant progression was identified. Pathology findings revealed 11/47 positive nodes that were consistent with the primary histology. Together with the recently described genetics of type II papillary RCC and the limitations of current systemic therapy in this setting, this case suggests opportunities for additional research.
A 63-year-old male with a 30-year history of sarcoidosis presented with chest pressure of short duration which was investigated at a local emergency department. His cardiac evaluation was negative, but a chest x-ray suggested emphysematous changes and interstitial thickening in the upper lobe of the right lung. A non-contrast CT scan of the chest confirmed a non-specific interstitial pulmonary density in the right upper lobe and suggestion of cystic renal changes in the left kidney. A dedicated CT scan of the neck and chest identified a 4.0 X 3.1 X 3.2 cm (estimated volume 20.8 cc. Estimated tumour volumes are calculated volumes of an ellipsoid: (xyz)π/6) left thoracic inlet mass lateral to the thyroid (Figure 1) which was the only site of mild hypermetabolic activity on subsequent PET scan.
Figure 1a. A dedicated CT scan of the neck and chest.
Figure 1b. A dedicated CT scan of the neck and chest.
A renal sonogram was interpreted to identify a 1.5 cm simple parapelvic cyst in the left kidney. On fine-needle aspirate of the neck mass, the immunoprofile was positive for CD10, CK7, and vimentin with cytoarchitecture considered suggestive of papillary carcinoma. CT urogram identified a 3.2-cm left lower-pole renal mass with a 2-cm left renal hilar lymph node and a 1.8-cm inter-aortocaval lymph node (Figure 2).
Figure 2a-d. CT urogram
The patient was referred to our institution for further management. His history included prior treatment with corticosteroids for sarcoidosis and a family history remarkable for fatal childhood leukemia in 1 sibling and RCC in 2 first degree relatives including mother and 1 sibling. The details regarding tumoursubtype in these individuals were unavailable, though both had undergone nephrectomy without evidence of disease progression over >10 years of follow up. No familial history of symptomatic uterine fibroids or related abnormalities was evident. Pertinent physical examination findings werenotable for a firm, mobile, non-tender supraclavicular left neck mass, normal pulmonary examination, and no evidence of stigmata related to known genetic syndromes including dermatologic abnormalities. Genetic counseling and testing was recommended but declined. Following multi-disciplinary evaluation, cytoreductive robot-assisted laparoscopic partial nephrectomy and retroperitoneal lymph node dissection was performed. Pathology revealed 2.2 cm, pT3bN2 high-grade type II papillary RCC with foci of necrosis, renal hilar fat involvement and 14 of 25 nodes positive (Figures 3 and 4).
Immunohistochemical stains revealed that the tumour was positive for CK7 and racemase, while negative for CA-IX, CD10, 34BE12, supporting the diagnosis.
In follow-up, a CT scan of the chest, abdomen, and pelvis was completed 6 weeks after surgery. In addition to post-surgical changes at the surgical site, decrease in size of the neck mass to 3.2 X 2.0 X 2.3 cm (estimated volume 7.7cc) was observed and no evidence of new metastases identified. The patient elected to forego systemic therapies and observe. (est. volume 5.4cc) and 2.3 X 1.9 X 1.4 cm (est. volume 3.2cc), respectively; Figure 5], with no evidence of local or distant disease progression identified.
Figure 5 a and b. CT scans completed 3 and 6 months postoperatively
By RECIST 1.1 criteria , the neck mass regressed from 3.1 cm short axis to 1.9 cm short axis for a total of 39% response, or equivalent to a partial response (PR). As presurgical FDG-PET imaging did not correlate with all sites of proven tumour burden it was not used to evaluate sites of potential disease during follow-up.
After 11 months of surveillance with no evidence of progression or new metastasis, the patient underwent a selective left-neck dissection. This showed 4 positive nodes in neck levels IV and VI and 7 positive nodes from the left superior mediastinal dissection. These were all consistent, morphologically and immunohistochemically, with the primary type II papillary RCC. At his 3-month follow-up visit, there was no evidence of disease progression or new metastasis on CT scan of the neck, chest, abdomen, and pelvis, and he had recovered fully with only mild residual vocal hoarseness.
Contemporary clinical assessment of tumour burden and response to cancer therapeutics is categorized according to the RECIST 1.1 guideline . Spontaneous regression of cancer, as defined by Everson and Cole in 1966 however, is the “partial or complete disappearance of malignant tumour in the absence of all treatment or in the presence of therapy that is considered inadequate”. Their manuscript identified 176 cases of spontaneous regression in multiple types of cancer, including 31 cases of RCC, the most common malignancy exhibiting this behavior. Unfortunately, 84% of the cases had histologic confirmation of the primary tumours but not the metastatic sites. This raises the possibility that the metastatic sites were actually of benign etiology. Contemporary histologic classification of renal tumoursthat now include the papillary type 2 subtype is also a relatively recent development raising the possibility of similar prior witnessed events which were documented differently. Publications have identified numerous cases of spontaneous regression of metastatic tumours, with the lungs being the most common site . Others include brain, bone, liver, regional lymph nodes, and the adrenal glands [6, 7]. The event of cytoreductive intervention preceedingregression has prompted postulation of a humoral response capable of inducing tumour degeneration at the metastatic site. Cytoreductive nephrectomy was performed in approximately half of the reported cases, but other treatments, such as radiation, embolization, and radiofrequency ablation, have been implicated in the literature [5, 8]. The aetiology of spontaneous regression is unknown, but immunologic mechanisms have been hypothesized. In fact, spontaneous regression phenomena initially led to a surge in cytoreductive nephrectomy for advanced renal cancers. Significant complications and poor outcomes tempered the enthusiasm for this approach, but research to identify “biological response modifiers”, as coined in the original publications, continued. The cytokine era of immunotherapy developed out of these efforts, leading, with the discovery and elucidation of the VHL/VEGF pathway, to the current approach of molecular therapeutics .
Interestingly, manipulation of the primary tumour is not always required for spontaneous regression. In a clinical trial reported by Oliver et al. in 1989, 73 patients with metastatic RCC were placed on surveillance prior to being considered for therapy with interferon alpha .The trial was designed to remove the potential bias of tumour regression. Three complete responses, 2 partial responses, and 4 cases of stable disease >12 months were reported. The 5 cases of spontaneous regression comprised 7% of this cohort.
All published reports of spontaneous regression of RCC in which the histologic subtype was identified have been confirmed cases of clear cell RCC , except one recent report by Lim et al where a histologically confirmed pulmonary metastasis for papillary type II RCC arose 6 years after radical nephrectomy and subsequently regressed over the following year . This case represents, to our knowledge, the first documented case of metastatic papillary RCC in a non-pulmonary site exhibiting regression. Metastatic clear cell RCC has experienced a revolution in management with development of targeted therapies. Metastatic papillary RCC, however, has proven resistant to these therapies [11, 12]. While localized papillary RCC carries a favorable prognosis, metastatic papillary RCC is associated with aggressive and rapidly fatal progression . Genetic mutations have been identified with type II papillary RCC, now associated with the heritable condition of hereditary leiomyomatosis and renal cell carcinoma (HLRCC)as the syndromic model . Mutation of fumarate hydratase (FH, a citric acid cycle enzyme catalyzing the conversion of fumarate to malate), localized to 1q42.3-43, has been implicated . Wild type FH acts as a tumour suppressor; loss of heterozygosity studies revealed the loss of the wild type allele in these renal tumours, and there is low to absent enzymatic activity in patients with only leiomyomatosis . However, unlike von Hippel-Lindau, Birt-Hogg-Dube (BHD) syndromes, or hereditary papillary RCC (HPRC), HLRCC kidney findings predominantly manifest as solitary and unilateral renal tumours with little penetrance, affecting 10-15% of HLRCC families (whereas 80-90% of VHL and HPRC families are affected by RCC) . This finding suggests, according to the Knudsen two-hit hypothesis, the relative conservation and rare mutation event involving the wild-type allele leading to type II papillary RCC. The putative cause for regression of tumour at a nodal site of metastases in this case is speculative. Currently utilized agents targeted at the pathways of angiogenesis have been largely ineffective in metastatic papillary RCC[11, 12]. Conceptually, this is not as discouraging as it first appears; rather, it reveals potential avenues of research to identify signaling pathways specific to papillary RCC and, ultimately, to engineer more efficacious treatment for metastatic disease.
As a closing remark, the authors suggest that, in the absence of a more sensitive and specific definition of spontaneous regression of cancer than the one advocated by Everson and Cole in 1966, perhaps a better method may be proposed to stratify the degree of tumour biometric change along the spectrum of regression. One solution would be to adapt the RECIST 1.1 criteria used primarily to assess clinical response to cancer therapeutics. The presented case may be defined as a RECIST 1.1 spontaneous PR.This standard allows comparison across interventions, including clinical trials specific for papillary renal cancer. Quantification of disease burden may also be calculatedusing tumour volume changes from imaging parameters of index tumoursto provide semi-quantitative data, estimated as 85% reduction in volume in this case (Figure 6).
Histologic and radiographic evidence of partial spontaneous regression of non-pulmonary metastatic type II papillary RCC is presented- the first published case so far as the authors are aware. In the context of the inefficacy of current systemic treatments and the recently described genetics of type II papillary RCC, this case suggests there are exciting opportunities for new research into this disease.
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Date added to bjui.org: 30/03/2011