- Email: [email protected]
Intraglomerular metastasis from pancreatic cancer
Intraglomerular Metastasis From Pancreatic Cancer Hideki Yokoi, MD, Masumi Nakata, MD, Kazutomo Sawai, MD, Toshiyuki Yoshida, BS, Masao Koshikawa, MD, Saori Joyama, MD, Atsuo Tanaka, MD, Masahisa Goto, MD, PhD Satoshi Ueda, MD, PhD, Hideto Senzaki, MD, PhD, Akira Sugawara, MD, PhD, and Takashi Kuwahara, MD, PhD ● Few case reports have shown the presence of metastatic tumor cells in renal glomeruli. We report one case with intraglomerular metastasis proved at renal biopsy. A 60-year-old man suffered from weight loss and fever of unknown origin. Urinalysis revealed proteinuria with cellular and granular casts. Because vasculitis was suspected, renal biopsy was performed. Presence of tumor cells occupying the glomerular capillary lumina was shown by means of light microscopy and electron microscopy. Laboratory findings revealed elevated leukocyte count (28.9 ⴛ 103/mm3), serum granulocyte colony-stimulating factor (G-CSF) (77 pg/mL), and serum CA 19-9 (21,885 U/mL). The patient soon developed disseminated intravascular coagulation and died. Autopsy findings revealed pancreatic cancer showing positive staining for G-CSF and CA 19-9. Tumor cells in the glomerular capillary lumina showed positive staining for CA 19-9 and proliferating cell nuclear antigen (PCNA). These results suggest that the pancreatic tumor cells producing G-CSF were entrapped in the glomerular capillary lumina where they proliferated. This may have been the first step in renal metastasis. © 2001 by the National Kidney Foundation, Inc. INDEX WORDS: Renal metastasis; granulocyte colony-stimulating factor (G-CSF)–producing pancreatic cancer; CA 19-9; tumor emboli; glomeruli; proliferating cell nuclear antigen (PCNA).
T
HE INCIDENCE of metastatic renal cancer was established at 4.5% (2,163 out of 48,106 cases) on the basis of a series of autopsies reported in Japan.1 The primary sites of metastatic renal tumors identified as solid tumors are the lungs (5.1%), stomach (3.0%), and pancreas (2.7%). Renal metastatic lesions were found to be solitary or multiple; there is no mention of intraglomerular metastasis. A few cases with tumor cells in the glomeruli have been reported, mostly identified at autopsy,2 with only one case identified at biopsy.3 Cancer producing granulocyte colony-stimulating factor (G-CSF) first was reported in 1974 by Robinson4; since then, many instances of its occurrence have been reported. Lung cancers account for most cases, and pancreatic cancers are reported less frequently.5 No published study has dealt with whether cancer producing G-CSF is likely to metastasize or not. It is thought that metastasis begins from tumor cells extravasating into tissue and proliferating there. According to a study on the mechanism of metastasis, however, it has been proposed that endothelium-attached tumor cells proliferate inside capillary lumina before extravasation.6 We report a case of tumor cells proliferating in the glomerular capillary lumina and originating from G-CSF-producing pancreatic cancer as detected by light microscopy, immunohistochemical staining, and electron microscopy.
CASE REPORT A 60-year-old man began to lose weight accompanied by a low fever. Three months later, the patient was admitted for high fever and cough. On admission, he was febrile (37.3°C), and crackles were audible over the lower half of the bilateral lungs, whereas the abdomen was normal without evidence of edema. Laboratory findings were as follows: 0.4 g/d of urinary protein; urine sediments with cellular and granular casts showing 10 to 20 red blood cells and 1 to 4 white blood cells per high-power field; leukocytes, 28,900/mm3 (70% neutrophils, 14% lymphocytes, 9% eosinophils); hemoglobin, 12.0 g/dL; hematocrit, 36.4%; platelets, 38.8 ⫻ 104/ mm3; total protein, 6.2 g/dL; albumin, 2.7 g/dL; serum creatinine, 0.5 mg/dL; aspartate aminotransferase, 26 IU/L; alanine aminotransferase, 29 IU/L; lactate dehydrogenase, 430 IU/L; serum amylase, 57 IU/L; C-reactive protein, 15.16 mg/dL; C3, 126 mg/dL; C4, 45 mg/dL; and CH50, 30.2 U/mL; antinuclear antibody, proteinase-3, and myeloperoxidase antineutrophil cytoplasmic antibody were negative. A chest radiograph showed the bilateral air-space reticular opacities and fluid accumulation, consistent with pneumonia. A puncture of the right pleural effusion revealed exudative effusion, cytologic class 3; negative culture; and an adenosine deaminase level of 14.7 IU/L (normal ⫽ ⬍50
From the Departments of Nephrology, Respiratory Medicine, and Pathology, Saiseikai Nakatsu Hospital, Osaka, Japan. Received June 19, 2000; accepted in revised form December 5, 2000. Address reprint requests to Takashi Kuwahara, MD, PhD, Saiseikai Nakatsu Hospital, 2-10-39 Shibata, Kita-ku, Osaka, 530-0012, Japan. E-mail: [email protected] © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3706-0026$35.00/0 doi:10.1053/ajkd.2001.24541
American Journal of Kidney Diseases, Vol 37, No 6 (June), 2001: pp 1299-1303
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IU/L). Several antibiotics were administered with no effect. Renal ultrasonography on admission showed normal kidney size without mass lesion. Renal biopsy was performed because vasculitis was suspected on the basis of the patient’s high fever, hypereosinophilia, and urinary abnormalities.
Renal Biopsy Findings Light microscopic specimens embedded in paraffin contained two glomeruli, frozen sections for immunohistochemistry contained five glomeruli, and electron microscopic specimens contained one glomerulus. All glomeruli were enlarged, and only a slight increase in mesangial cells and the matrix was observed. In almost all glomeruli, a cluster of atypical cells was found in the capillary lumen (Fig 1A). Arteries, arterioles, and capillaries of the interstitium appeared normal. Electron microscopy showed that tumor cells with anisokaryosis, increased nuclear-to-cytoplasmic ratio, and large nucleoli had accumulated along the glomerular capillary basement membrane and had filled and spread out along the lumen (Fig 1B). No immunoglobulins or complements were detected by immunostaining. These findings were consistent with findings for intraglomerular metastasis and suggested that there was little possibility of secondary nephritis. After renal biopsy, additional laboratory examinations revealed elevations in the serum CA 19-9 level of 21,885 U/mL (normal ⫽ ⬍37 U/mL) and the G-CSF level of 77 pg/mL (normal ⫽ ⬍30 pg/mL). Computed tomography (CT) scan of the abdomen showed no mass lesion, but only a cyst in the tail of the pancreas and no dilation of the pancreatic duct. Multiple low-density lesions ranging in diameter from 1 to 1.5 cm seen in the liver were consistent with metastatic liver tumors, but no lesions were seen in the kidneys. Findings on abdominal ultrasonography were the same as those on CT scan. An upper gastrointestinal fiber showed signs of erosive gastritis, and a colon fiber revealed small colon polyps belonging to histologic group 1 or 2. Although pancreatic tumor was suspected, endoscopic retrograde cholangiopancreatography or arteriography was not performed because of the patient’s deteriorating general condition. The patient developed disseminated intravascular coagulation and died on the 46th hospital day.
Autopsy Findings The pancreas had a normal weight of 120 g and contained a 2.3-cm tumor in the tail that compressed the pancreatic main duct. The tumor showed focal petechia and a smooth cyst at its peripheral side (Fig 2A). Microscopic examination
YOKOI ET AL
showed a poorly differentiated adenocarcinoma without any cystic lesions. Tumor cells proliferated diffusely and contained eosinophilic cytoplasm with anisokaryosis (Fig 2B). Immunohistochemical staining using the monoclonal antihuman G-CSF antibody (5.24, Oncogene Science, NY) showed positive results (Fig 2C). Both kidneys had a normal weight of 140 g (left) and 130 g (right) and showed multiple small metastatic lesions. Light microscopy showed that many glomeruli had tumor emboli and that all arteries, arterioles, and capillaries except glomeruli had few tumor emboli. The cytoplasm and nuclei of the tumor cells in the glomeruli were positive for anti–CA 19-9 antibody (116-NS-19-9, CIS bio international, Paris, France) and for anti–proliferating cell nuclear antigen (PCNA) antibody (PC10, Novocastra Laboratories Ltd, Newcastle upon Tyne, UK) (Fig 3). Tumor cells in the glomeruli were negative for antihuman G-CSF antibody. These findings indicate that the pancreatic cancer cells proliferated in the glomerular capillary lumina. The reason for G-CSFnegative staining in the glomeruli is not clear, but the smaller amount of G-CSF antigen in the glomeruli compared with that in the pancreas may be related to this negative staining. Fibrin thrombi were observed in the glomeruli, consistent with findings for disseminated intravascular coagulation. The lower lobe of the right lung had an abscess, and the lower lobe of the left lung was pneumonic. Both lungs showed pleural tumor dissemination, and the left lung contained multiple metastatic lesions. The lower lobe of the right lung showed hemorrhagic infarctions and an obstructed pulmonary artery containing fibrin thrombi and tumor emboli. In addition to lesions identified in lung and kidney, metastatic lesions as well as bilateral carcinomatous pleuritis, carcinomatous epicarditis, and carcinomatous peritonitis were observed in liver, both adrenal glands, stomach, thyroid, and bone.
DISCUSSION
Metastases of cancers to the kidney often are seen at autopsy but rarely are found while patients are alive. A review of autopsies described in the literature revealed renal metastases from solid tumors in approximately 4.5% of patients with cancers.1 The major primary sites of metastatic renal tumors are lung, stomach, and pancreas. Metastases from pancreatic carcinomas to the kidney have been reported and account for
™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™3 Fig 1. Renal biopsy. (A) Light photomicrograph of a glomerulus shows atypical cells in the capillary lumen (arrow) and the increase in mesangial cells and the matrix. (Hematoxylin-eosin stain.) (B) Electron photomicrograph of a portion of a glomerulus shows three tumor cells with anisokaryosis collected together along the basement membrane. No destruction of the basement membrane was observed. BM, basememt membrane; T, tumor cell. Fig 2. Autopsy findings. (A) Gross appearance of the pancreas shows a cyst of the pancreas (arrow) and a pancreatic 2.3-cm tumor (arrowhead) with petechiae in the tail, which compressed the pancreatic main duct. (B) Light photomicrograph of the primary pancreatic tumor shows poorly differentiated adenocarcinoma. (C) Immunohistochemical stain of the pancreas shows pancreatic cancer cells positive for anti-G-CSF antibody. Fig 3. (A) Immunohistochemical stain of the kidney shows the cytoplasm of tumor cells (arrow) in the glomerulus positive for anti–CA 19-9 antibody at autopsy. (B) Immunohistochemical stain of the kidney shows the nuclei of tumor cells positive for anti-PCNA antibody (arrow).
Fig 1.
Fig 2.
Fig 3.
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6% to 9% of all metastases to the kidney.1,7,8 Because the renal blood flow accounts for approximately 20% of cardiac output, kidneys are likely to be vulnerable to hematogenous metastases. However, the renal glomeruli rarely are observed as sites of metastases. A few cases of intraglomerular metastasis have been reported the primary malignancies of which were mainly pulmonary cancers, pancreatic adenocarcinomas, and hematologic malignancies.2,3 Only one case has been proved by biopsy.3 In 1974, Robinson4 reported a patient with tumors producing G-CSF as a result of elevated CSF in serum and urine. So far, hundreds of tumors producing G-CSF have been reported,5,7,9-11 most of which are lung, stomach, thyroid, gallbladder, and liver tumors. Several pancreatic cancers have been reported,9-11 but only a few of these have been proved immunohistochemically to produce G-CSF. The cytoplasm around the Golgi apparatus is stained mainly by G-CSF in the tumor cells.12 Tumors producing G-CSF are potentially highly malignant, are highly capable of proliferating, and have a poor prognosis. The mechanism of renal metastasis is unclear, but it has been documented that several factors are necessary for this metastasis. First, with regard to mechanical factors, filtration pressure and slowing down of the blood flow in the glomerular capillary lumen enables tumor cells to come in contact with the endothelium. For the second stage, the tumor cells need some adhesion molecules to attach themselves to the endothelium. CA 19-9 (sialyl-Lewisa) is a ligand of endothelial leukocyte adhesion molecule-1 (ELAM-1),13,14 which plays an important role in the adhesion of human cancer cells to human umbilical vein endothelial cells.15 It has been reported that human umbilical vein endothelial cells can express vascular cell adhesion molecule-1, intracellular adhesion molecule-1, and ELAM-1 in response to stimulation with various cytokines.13,14 In normal kidney, ELAM-1 is not expressed in the glomerulus except for the glomerular parietal epithelium, but under inflammatory conditions, such as IgA nephropathy, lupus nephritis, and diabetic nephropathy, the glomerular and renal interstitial capillary endothelium starts to express ELAM-1.16,17 For the third stage,
YOKOI ET AL
tumor cells need to extravasate from the capillary lumen to the tissue and to proliferate in the organ of the final metastasis. Analysis of a model of pulmonary metastasis produced by injecting tumor cells expressing green fluorescent protein into immunosuppressed mice indicates, however, that extravasation is rare and that instead proliferation of tumor cells attached to the vascular endothelium is observed.6 This finding indicates that tumor cells tend to proliferate inside the vessel before extravasating to the tissue. In the case presented here, it is possible that tumor cells expressing CA 19-9 had bound to the ELAM-1 on the surface of the glomerular endothelium so that tumor cells could attach themselves along the capillary lumen. It is reported that ELAM-1 expression increases in response to stimulation of interleukin-1 or tumor necrosis factor-␣. Several cytokines have been found to be produced simultaneously and G-CSF production to be secondary to interleukin-1 production in some culture cells from G-CSF–producing tumors.18 It is suspected that the glomerular endothelium in our case expressed ELAM-1 under inflammatory circumstances. As for intravascular tumor proliferation, the nuclei of tumor cells showed positive staining with PCNA antibody, indicating proliferation in the capillary lumen, although PCNA-positive tumor cells may have remained lodged in the vessels. It seems, however, that the entire tumor emboli were too large to pass through the capillary lumen in the interstitium. As a first step in renal metastasis, tumor cells may stay and proliferate in the glomerular capillary lumen. Although the mechanism of metastasis is not clear, we can observe tumor cells proliferating inside the vessels, indicating that this may be the initial step in the metastasis. It also seems that G-CSF and CA 19-9 may play a role in tumor cells attaching to the endothelium. Further investigations are necessary to identify the exact site of adhesion molecules and cytokines involved in renal metastasis. REFERENCES 1. Machinami M: Annual of the Pathological Autopsy Cases in Japan, Vol 39. Tokyo, Japan, The Japanese Society of Pathology, 1996, pp 1111-1202 2. Sridevi D, Jain D, Vasishata RK, Joshi K: Intraglomerular metastasis: A necropsy study. J Clin Pathol 52:307-309, 1999
INTRAGLOMERULAR METASTASIS
3. Belghiti D, Hirbec G, Bernaudin JF, Pariente EA, Martin N: Intraglomerular metastases. Report of two cases. Cancer 54:2309-2312, 1984 4. Robinson WA: Granulocytosis in neoplasia. Ann N Y Acad Sci 230:212-218, 1974 5. Ohtsubo K, Mouri H, Sakai J, Akasofu M, Yamaguchi Y, Watanabe H, Gabata T, Motoo Y, Okai T, Sawabu N: Pancreatic cancer associated with granulocyte-colony stimulating factor production confirmed by immunohistochemistry. J Clin Gastroenterol 27:357-360, 1998 6. Al-Mehdi AB, Tozawa K, Fisher AB, Shientag L, Lee A, Muschel RJ: Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: A new model for metastasis. Nat Med 6:100-102, 2000 7. Fujimoto K, Ozono S, Okamoto S, Tsujimoto S, Oyama N, Yamada H, Hirao Y, Okajima E: A case of metastatic renal tumor: Review of 74 cases reported in Japan. Hinyokika Kiyo 36:581-585, 1990 (Japanese with English abstr) 8. Wagle DG, Moore RH, Murphy GP: Secondary carcinomas of the kidney. J Urol 114:30-32, 1975 9. Wu M, Cini JK, Yunis AA: Purification of a colonystimulating factor from cultured pancreatic carcinoma cells. J Biol Chem 254:6226-6228, 1979 10. Fukushima N, Sasatomi E, Tokunaga O, Miyahara M: A case of pancreatic cancer with production of granulocyte colony-stimulating factor. Am J Gastroenterol 96:258-259, 2001 11. Uematsu T, Tsuchie K, Ukai K, Kimoto E, Funakawa T, Mizuno R: Granulocyte-colony stimulating factor produced by pancreatic carcinoma. Int J Pancreatol 19:135-139, 1996 12. Shimamura K, Fujimoto J, Hata J, Akatsuka A, Ueyama Y, Watanabe T, Tamaoki N: Establishment of specific monoclonal antibodies against recombinant human
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granulocyte colony-stimulating factor (hG-CSF) and their application for immunoperoxidase staining of paraffinembedded sections. J Histochem Cytochem 38:283-286, 1990 13. Takada A, Ohmori K, Takahashi N, Tsuyuoka K, Yago A, Zenita K, Hasegawa A, Kannagi R: Adhesion of human cancer cells to vascular endothelium mediated by a carbohydrate antigen, sialyl Lewis A. Biochem Biophys Res Commun 179:713-719, 1991 14. Walz G, Aruffo A, Kolanus W, Bevilacqua M, Seed B: Recognition by ELAM-1 of the sialyl-Lex determinant on myeloid and tumor cells. Science 250:1132-1135, 1990 15. Takada A, Ohmori K, Yoneda T, Tsuyuoka K, Hasegawa A, Kiso M, Kannagi R: Contribution of carbohydrate antigens sialyl Lewis A and sialyl Lewis X to adhesion of human cancer cells to vascular endothelium. Cancer Res 53:354-361, 1993 16. Hirata K, Shikata M, Matsuda M, Akiyama K, Sugimoto H, Kushiro M, Makino H: Increased expression of selectins in kidneys of patients with diabetic nephropathy. Diabetologia 41:185-192, 1998 17. Ogawa T, Yorioka N, Ito T, Ogata S, Kumagai J, Kawanishi H, Yamakido M: Precise ultrastructural localization of endothelial leukocyte adhesion molecule-1, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 in patients with IgA nephropathy. Nephron 75:54-64, 1997 18. Tsuyuoka R, Takahashi T, Sasaki Y, Taniguchi Y, Fukumoto M, Suzuki A, Nakamura K, Kobayashi S, Kudo T, Nakao K: Colony-stimulating factor-producing tumours: Production of granulocyte colony-stimulating factor and interleukin-6 is secondary to interleukin-1 production. Eur J Cancer 30A:2130-2136, 1994
T
HE INCIDENCE of metastatic renal cancer was established at 4.5% (2,163 out of 48,106 cases) on the basis of a series of autopsies reported in Japan.1 The primary sites of metastatic renal tumors identified as solid tumors are the lungs (5.1%), stomach (3.0%), and pancreas (2.7%). Renal metastatic lesions were found to be solitary or multiple; there is no mention of intraglomerular metastasis. A few cases with tumor cells in the glomeruli have been reported, mostly identified at autopsy,2 with only one case identified at biopsy.3 Cancer producing granulocyte colony-stimulating factor (G-CSF) first was reported in 1974 by Robinson4; since then, many instances of its occurrence have been reported. Lung cancers account for most cases, and pancreatic cancers are reported less frequently.5 No published study has dealt with whether cancer producing G-CSF is likely to metastasize or not. It is thought that metastasis begins from tumor cells extravasating into tissue and proliferating there. According to a study on the mechanism of metastasis, however, it has been proposed that endothelium-attached tumor cells proliferate inside capillary lumina before extravasation.6 We report a case of tumor cells proliferating in the glomerular capillary lumina and originating from G-CSF-producing pancreatic cancer as detected by light microscopy, immunohistochemical staining, and electron microscopy.
CASE REPORT A 60-year-old man began to lose weight accompanied by a low fever. Three months later, the patient was admitted for high fever and cough. On admission, he was febrile (37.3°C), and crackles were audible over the lower half of the bilateral lungs, whereas the abdomen was normal without evidence of edema. Laboratory findings were as follows: 0.4 g/d of urinary protein; urine sediments with cellular and granular casts showing 10 to 20 red blood cells and 1 to 4 white blood cells per high-power field; leukocytes, 28,900/mm3 (70% neutrophils, 14% lymphocytes, 9% eosinophils); hemoglobin, 12.0 g/dL; hematocrit, 36.4%; platelets, 38.8 ⫻ 104/ mm3; total protein, 6.2 g/dL; albumin, 2.7 g/dL; serum creatinine, 0.5 mg/dL; aspartate aminotransferase, 26 IU/L; alanine aminotransferase, 29 IU/L; lactate dehydrogenase, 430 IU/L; serum amylase, 57 IU/L; C-reactive protein, 15.16 mg/dL; C3, 126 mg/dL; C4, 45 mg/dL; and CH50, 30.2 U/mL; antinuclear antibody, proteinase-3, and myeloperoxidase antineutrophil cytoplasmic antibody were negative. A chest radiograph showed the bilateral air-space reticular opacities and fluid accumulation, consistent with pneumonia. A puncture of the right pleural effusion revealed exudative effusion, cytologic class 3; negative culture; and an adenosine deaminase level of 14.7 IU/L (normal ⫽ ⬍50
From the Departments of Nephrology, Respiratory Medicine, and Pathology, Saiseikai Nakatsu Hospital, Osaka, Japan. Received June 19, 2000; accepted in revised form December 5, 2000. Address reprint requests to Takashi Kuwahara, MD, PhD, Saiseikai Nakatsu Hospital, 2-10-39 Shibata, Kita-ku, Osaka, 530-0012, Japan. E-mail: [email protected] © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3706-0026$35.00/0 doi:10.1053/ajkd.2001.24541
American Journal of Kidney Diseases, Vol 37, No 6 (June), 2001: pp 1299-1303
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IU/L). Several antibiotics were administered with no effect. Renal ultrasonography on admission showed normal kidney size without mass lesion. Renal biopsy was performed because vasculitis was suspected on the basis of the patient’s high fever, hypereosinophilia, and urinary abnormalities.
Renal Biopsy Findings Light microscopic specimens embedded in paraffin contained two glomeruli, frozen sections for immunohistochemistry contained five glomeruli, and electron microscopic specimens contained one glomerulus. All glomeruli were enlarged, and only a slight increase in mesangial cells and the matrix was observed. In almost all glomeruli, a cluster of atypical cells was found in the capillary lumen (Fig 1A). Arteries, arterioles, and capillaries of the interstitium appeared normal. Electron microscopy showed that tumor cells with anisokaryosis, increased nuclear-to-cytoplasmic ratio, and large nucleoli had accumulated along the glomerular capillary basement membrane and had filled and spread out along the lumen (Fig 1B). No immunoglobulins or complements were detected by immunostaining. These findings were consistent with findings for intraglomerular metastasis and suggested that there was little possibility of secondary nephritis. After renal biopsy, additional laboratory examinations revealed elevations in the serum CA 19-9 level of 21,885 U/mL (normal ⫽ ⬍37 U/mL) and the G-CSF level of 77 pg/mL (normal ⫽ ⬍30 pg/mL). Computed tomography (CT) scan of the abdomen showed no mass lesion, but only a cyst in the tail of the pancreas and no dilation of the pancreatic duct. Multiple low-density lesions ranging in diameter from 1 to 1.5 cm seen in the liver were consistent with metastatic liver tumors, but no lesions were seen in the kidneys. Findings on abdominal ultrasonography were the same as those on CT scan. An upper gastrointestinal fiber showed signs of erosive gastritis, and a colon fiber revealed small colon polyps belonging to histologic group 1 or 2. Although pancreatic tumor was suspected, endoscopic retrograde cholangiopancreatography or arteriography was not performed because of the patient’s deteriorating general condition. The patient developed disseminated intravascular coagulation and died on the 46th hospital day.
Autopsy Findings The pancreas had a normal weight of 120 g and contained a 2.3-cm tumor in the tail that compressed the pancreatic main duct. The tumor showed focal petechia and a smooth cyst at its peripheral side (Fig 2A). Microscopic examination
YOKOI ET AL
showed a poorly differentiated adenocarcinoma without any cystic lesions. Tumor cells proliferated diffusely and contained eosinophilic cytoplasm with anisokaryosis (Fig 2B). Immunohistochemical staining using the monoclonal antihuman G-CSF antibody (5.24, Oncogene Science, NY) showed positive results (Fig 2C). Both kidneys had a normal weight of 140 g (left) and 130 g (right) and showed multiple small metastatic lesions. Light microscopy showed that many glomeruli had tumor emboli and that all arteries, arterioles, and capillaries except glomeruli had few tumor emboli. The cytoplasm and nuclei of the tumor cells in the glomeruli were positive for anti–CA 19-9 antibody (116-NS-19-9, CIS bio international, Paris, France) and for anti–proliferating cell nuclear antigen (PCNA) antibody (PC10, Novocastra Laboratories Ltd, Newcastle upon Tyne, UK) (Fig 3). Tumor cells in the glomeruli were negative for antihuman G-CSF antibody. These findings indicate that the pancreatic cancer cells proliferated in the glomerular capillary lumina. The reason for G-CSFnegative staining in the glomeruli is not clear, but the smaller amount of G-CSF antigen in the glomeruli compared with that in the pancreas may be related to this negative staining. Fibrin thrombi were observed in the glomeruli, consistent with findings for disseminated intravascular coagulation. The lower lobe of the right lung had an abscess, and the lower lobe of the left lung was pneumonic. Both lungs showed pleural tumor dissemination, and the left lung contained multiple metastatic lesions. The lower lobe of the right lung showed hemorrhagic infarctions and an obstructed pulmonary artery containing fibrin thrombi and tumor emboli. In addition to lesions identified in lung and kidney, metastatic lesions as well as bilateral carcinomatous pleuritis, carcinomatous epicarditis, and carcinomatous peritonitis were observed in liver, both adrenal glands, stomach, thyroid, and bone.
DISCUSSION
Metastases of cancers to the kidney often are seen at autopsy but rarely are found while patients are alive. A review of autopsies described in the literature revealed renal metastases from solid tumors in approximately 4.5% of patients with cancers.1 The major primary sites of metastatic renal tumors are lung, stomach, and pancreas. Metastases from pancreatic carcinomas to the kidney have been reported and account for
™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™3 Fig 1. Renal biopsy. (A) Light photomicrograph of a glomerulus shows atypical cells in the capillary lumen (arrow) and the increase in mesangial cells and the matrix. (Hematoxylin-eosin stain.) (B) Electron photomicrograph of a portion of a glomerulus shows three tumor cells with anisokaryosis collected together along the basement membrane. No destruction of the basement membrane was observed. BM, basememt membrane; T, tumor cell. Fig 2. Autopsy findings. (A) Gross appearance of the pancreas shows a cyst of the pancreas (arrow) and a pancreatic 2.3-cm tumor (arrowhead) with petechiae in the tail, which compressed the pancreatic main duct. (B) Light photomicrograph of the primary pancreatic tumor shows poorly differentiated adenocarcinoma. (C) Immunohistochemical stain of the pancreas shows pancreatic cancer cells positive for anti-G-CSF antibody. Fig 3. (A) Immunohistochemical stain of the kidney shows the cytoplasm of tumor cells (arrow) in the glomerulus positive for anti–CA 19-9 antibody at autopsy. (B) Immunohistochemical stain of the kidney shows the nuclei of tumor cells positive for anti-PCNA antibody (arrow).
Fig 1.
Fig 2.
Fig 3.
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6% to 9% of all metastases to the kidney.1,7,8 Because the renal blood flow accounts for approximately 20% of cardiac output, kidneys are likely to be vulnerable to hematogenous metastases. However, the renal glomeruli rarely are observed as sites of metastases. A few cases of intraglomerular metastasis have been reported the primary malignancies of which were mainly pulmonary cancers, pancreatic adenocarcinomas, and hematologic malignancies.2,3 Only one case has been proved by biopsy.3 In 1974, Robinson4 reported a patient with tumors producing G-CSF as a result of elevated CSF in serum and urine. So far, hundreds of tumors producing G-CSF have been reported,5,7,9-11 most of which are lung, stomach, thyroid, gallbladder, and liver tumors. Several pancreatic cancers have been reported,9-11 but only a few of these have been proved immunohistochemically to produce G-CSF. The cytoplasm around the Golgi apparatus is stained mainly by G-CSF in the tumor cells.12 Tumors producing G-CSF are potentially highly malignant, are highly capable of proliferating, and have a poor prognosis. The mechanism of renal metastasis is unclear, but it has been documented that several factors are necessary for this metastasis. First, with regard to mechanical factors, filtration pressure and slowing down of the blood flow in the glomerular capillary lumen enables tumor cells to come in contact with the endothelium. For the second stage, the tumor cells need some adhesion molecules to attach themselves to the endothelium. CA 19-9 (sialyl-Lewisa) is a ligand of endothelial leukocyte adhesion molecule-1 (ELAM-1),13,14 which plays an important role in the adhesion of human cancer cells to human umbilical vein endothelial cells.15 It has been reported that human umbilical vein endothelial cells can express vascular cell adhesion molecule-1, intracellular adhesion molecule-1, and ELAM-1 in response to stimulation with various cytokines.13,14 In normal kidney, ELAM-1 is not expressed in the glomerulus except for the glomerular parietal epithelium, but under inflammatory conditions, such as IgA nephropathy, lupus nephritis, and diabetic nephropathy, the glomerular and renal interstitial capillary endothelium starts to express ELAM-1.16,17 For the third stage,
YOKOI ET AL
tumor cells need to extravasate from the capillary lumen to the tissue and to proliferate in the organ of the final metastasis. Analysis of a model of pulmonary metastasis produced by injecting tumor cells expressing green fluorescent protein into immunosuppressed mice indicates, however, that extravasation is rare and that instead proliferation of tumor cells attached to the vascular endothelium is observed.6 This finding indicates that tumor cells tend to proliferate inside the vessel before extravasating to the tissue. In the case presented here, it is possible that tumor cells expressing CA 19-9 had bound to the ELAM-1 on the surface of the glomerular endothelium so that tumor cells could attach themselves along the capillary lumen. It is reported that ELAM-1 expression increases in response to stimulation of interleukin-1 or tumor necrosis factor-␣. Several cytokines have been found to be produced simultaneously and G-CSF production to be secondary to interleukin-1 production in some culture cells from G-CSF–producing tumors.18 It is suspected that the glomerular endothelium in our case expressed ELAM-1 under inflammatory circumstances. As for intravascular tumor proliferation, the nuclei of tumor cells showed positive staining with PCNA antibody, indicating proliferation in the capillary lumen, although PCNA-positive tumor cells may have remained lodged in the vessels. It seems, however, that the entire tumor emboli were too large to pass through the capillary lumen in the interstitium. As a first step in renal metastasis, tumor cells may stay and proliferate in the glomerular capillary lumen. Although the mechanism of metastasis is not clear, we can observe tumor cells proliferating inside the vessels, indicating that this may be the initial step in the metastasis. It also seems that G-CSF and CA 19-9 may play a role in tumor cells attaching to the endothelium. Further investigations are necessary to identify the exact site of adhesion molecules and cytokines involved in renal metastasis. REFERENCES 1. Machinami M: Annual of the Pathological Autopsy Cases in Japan, Vol 39. Tokyo, Japan, The Japanese Society of Pathology, 1996, pp 1111-1202 2. Sridevi D, Jain D, Vasishata RK, Joshi K: Intraglomerular metastasis: A necropsy study. J Clin Pathol 52:307-309, 1999
INTRAGLOMERULAR METASTASIS
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