spontaneous regression in renal cell carcinoma:pptx

spontaneous regression

1. Spontaneous Regression of Tumors: An Unresolved M ystery 21.11.2014 Dr. Saurabh Samdariya Senior Resident Radiation Oncolog y

2. The Case March 2009: Passing blood in urine since 2 weeks CECT Abdomen and pelvis: A large heterogeneously enhancing hypodense right renal mass with central necrosis measuring 7.8 x 6.8 x 5.7 cm with displacement of upper calyx. There was perinephric fat stranding with infiltration of right psoas muscle. Mr. Alex (Name changed)/62 year/Male/businessman/No comorbidities/ No family h/o-Malignancy, TB, Diabetes Mellitus etc /No habit of consumption of tobacco/alcohol

3. The Case X Ray Chest PA Soliatry radiodense lesion cicrcular in shape with irregular margins in Right upper lobe of right lung. suspicious for metastasis CECT thorax well-defined lobulated soft tissue density lesion measuring 2.5 x 2.1 cm in apical segment of right upper lobe of lung abutting adjacent pleura strongly suggestive of a metastatic lesion FNAC Proved to be of renal origin

4. Treatment April 2009: Right sided Radical nephrectomy Histopathology Report Microscopy Renal cell carcinoma clear cell type with sarcomatoid component. Fuhrman nuclear grade-3. Areas of hemorrhage and necrosis +. 0/3 Hilar lymph nodes + for tumor cells. Renal vascular and ureteric cut margins were free Gross Examination A large unifocal greyish white tumor measuring 7.5 x 7.0 x 6.2 cm of upper pole of kidney. Tumor invaded renal capsule & perinephric fat but Renal fascia was free of tumor.

5. Final Diagnosis Right sided RCC clear cell type (Post N ephrectomy) pT 3a N M 1(LUNG) —AJCC Stage IV On Follow up Serial X-ray chest were done initially monthly for the first year. The lung lesion gradually reduced in size and after 9 months of surgery, completely disappeared X ray chest PA at 9 months of follow up

6. Spontaneous Regression of Tumors

7. Introduction A subject of great interest and speculation since decades. It is an exceptional and well documented biological event . Definition: Spontaneous Regression of neoplasms occurs when the malignant tumor mass partially or completely disappears without any treatment or as a result of a therapy considered inadequate to influence systemic neoplastic disease .* The disease may/may not get cured & may not be complete/permanent. * Kaiser et al, In Vivo 2000 Nov-Dec; 14(6): 773-788

8. History….from prayers to infections The phenomenon is historically also known as, Saint Peregrine Tumor. In 13 th Century, Saint Peregrine, a priest, developed a large bone tumor and was planned for amputation. On the night before surgery, he prayed intensely and, as is mentioned in history, awoke without any tumor ! * Coleys toxin: Vaccine containing two killed bacteria: the Gram-positive Streptococcus pyogenes and the Gram-negative Serratia marcescens . The latter bacteria increased the virulence of the former.[14 ]. Coley stressed that the technique of administration and the ability of the vaccine to induce mild to moderate fever was of paramount importance in the regression of cancer.[15,1] He successfully used his vaccine, in treating a man bedridden with an inoperable sarcoma involving the abdominal wall, pelvis, and bladder . The sarcoma regressed completely and the patient was followed up until his death from a heart attack 26 years later. Coley emphasized that the induction of fever was the key aspect of his treatment, a strong febrile reaction was the symptom most associated with tumor regression * Pack GT (1967): St Peregrine, OSM-the patron saint of cancer patients, CA Cancer J Clin 17: 83-4

9. Tumor where regression is seen Renal cell carcinoma (commonly clear cell type) NEUROBLASTOMA (especially Stage 4S, biological type1 which has hyperdiploidy , TrkA +, no MYCN amplification) Lymphomas (NHL: Lymphomatoid papulosis:CD30 + primary cutaneous T cell lymphoma) Leukemias (JMML, TMD, AML with t(8,16) Malignant melanoma Merkel cell carcinomas Wilms tumor (few case reports)

10. The duration of tumor regression is variable and recrudescence is sometimes observed. 4 Partial regression is more commonly seen. Regression has been observed after removal of the primary disease but elimination of the primary tumor does not seem to be necessary since regressions are also reported in the absence of nephrectomy or other primary tumor Manipulations. 5 Spontaneous regression of metastatic renal cell carcinoma was first reported in 1928 by Bumpus Fever generates inflammatory factors with co-stimulatory activity, which activate resting dendritic cells (DC), leading to the activation of anergic T cells, maybe accomplished by a second process, where a possible physical damage of cancer cells leads to a sudden supply of cancer antigens to DC .”

11. RCC Usually metastatic cases with nephrectomy/sunitinib 1% cases Temporary (3-6 mnths ) Recrudescence is common Neuroblastoma Usually INSS stage 4S tumors, biological type-1 category ( TrkA +, hyperdiploid , MycN negative) 5 % cases Usually donot reappear Recrudescence is less common Leukemia Usually JMML (later vasculitis) , AML (t (8.16), TMD (later leukemia) 1 % cases Temporary (3-6 mnths ) Recrudescence is less common common

12. Mechanisms underlying spontaneous regression of tumors

13. Table 1 Summary of Various Proposed Mechanisms involved in spontaneous regression of tumours   Sl no Category Mechanism   Immune Response   IL-18 stimulates T cell, NK cell activity, and IFN-α production that induces anti-tumor immune responses. CD8+ T cells target tumor-associated antigens that are expressed to immune cells (viral antigens, melanocyte differentiation antigens and cancer-testis antigens). 2.   Genetic Crisis   Terminal differentiation Vascular compromise. Genomic instability. Inhibition of telomerase. e.g.: Neuroblastoma 3.   Apoptosis Expression of variety of proteases e.g.: solitary cutaneous mastocytomas and differentiation of Neuroblastoma. 4.   Anti-angiogenic Factors Ornithine decarboxylase (ODC) overexpression is associated with the formation of spontaneous skin carcinomas in some transgenic mice. ODC stimulates dermal vascularization. Treatment with difluoromethylornithine , an inhibitor of ODC, causes a decrease in blood vessel count and regression of the tumors. Thalidomide, IFN-α and matrix metalloproteinases (MMP’s). 5.   Other Production of immune response by immune recognition of tumor cells Viruses infect lymphoma cells & make them more recognizable to immune cells. Cytokine signals may induce lymphoma cells to differentiate or die naturally by apoptosis. High stress may raise natural steroids and cause temporary regressions. Inflammation caused by immune system activity against the tumor. Hypoxia may cause them to implode when central necrosis starts.

14. Some Other M echanisms Spontaneous Regression of Cancer Proteases Apoptotic cell death Immune recognition Cytokine signaling Thalidomide IFN-α MMP DFMO Terminal differentiation vascular compromise Genomic instability Inhibition of telomer ase IL-18, IFN-α Genetic Antiangiogenic factors Cytotoxic Immune Response CD-8 mediated cell death Inflammation & Hypoxia

15. Summary Spontaneous regression is a well documented but rare phenomenon noted in some tumors. Most are temporary & Possible explanation of this phenomenon is multifactorial though immunological factors are the most probable underlying mechanism. E xact mechanism remains to be elucidated

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