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Renal Cancer: Contemporary

Management John A. Libertino


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Renal Cancer
Contemporary Management
John A. Libertino
Jason R. Gee
Editors
Second Edition

123
Renal Cancer
John A. Libertino • Jason R. Gee
Editors

Renal Cancer
Contemporary Management

Second Edition
Editors
John A. Libertino Jason R. Gee
Professor of Urology Associate Professor of Urology
Tufts University School of Medicine Tufts University School of Medicine
Boston, MA Boston, MA
USA USA

Chairman Department of Urology


Department of Urology MGH Cancer Center
MGH Cancer Center Emerson Hospital
Emerson Hospital Concord, MA
Concord, MA USA
USA

ISBN 978-3-030-24377-7    ISBN 978-3-030-24378-4 (eBook)


https://doi.org/10.1007/978-3-030-24378-4

© Springer Nature Switzerland AG 2020


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A great Leader in medical education and healthcare delivery
Contents

1 Epidemiology, Screening, and Clinical Staging����������������������������   1


Sana N. Siddiqui, Christopher R. Haas, and James M.
McKiernan
Introduction to Epidemiology����������������������������������������������������������    1
Incidence and Mortality Rates over Time����������������������������������������    1
Demographic Factors in Renal Cell Carcinoma������������������������������    3
Risk Factors in the Development of RCC����������������������������������������    3
Smoking ��������������������������������������������������������������������������������������    3
Diet����������������������������������������������������������������������������������������������    4
Obesity ����������������������������������������������������������������������������������������    4
Hypertension��������������������������������������������������������������������������������    4
Chronic Renal Disease����������������������������������������������������������������    5
Family History ����������������������������������������������������������������������������    5
Medications����������������������������������������������������������������������������������    5
Occupational Exposure����������������������������������������������������������������    6
Screening for RCC��������������������������������������������������������������������������    6
Screening of Targeted Populations��������������������������������������������������    7
Clinical Staging��������������������������������������������������������������������������������    8
Renal Vein and IVC Involvement����������������������������������������������������   12
T4 ����������������������������������������������������������������������������������������������������   12
Nodal Status ������������������������������������������������������������������������������������   13
Metastatic Disease ��������������������������������������������������������������������������   13
Improving the TNM Staging System ����������������������������������������������   14
References����������������������������������������������������������������������������������������   14
2 Molecular Biology and Genetics of Renal
Cell Carcinoma�������������������������������������������������������������������������������� 19
Sanaz Ghafouri, David C. Johnson, Kristen Kelly,
Allan Pantuck, and Alexandra Drakaki
Introduction��������������������������������������������������������������������������������������   19
Clear Cell Renal Cell Carcinoma����������������������������������������������������   19
Somatic Alterations����������������������������������������������������������������������   20
Whole Exome Sequencing����������������������������������������������������������   20
DNA Methylation Profiles ����������������������������������������������������������   20
RNA Expression��������������������������������������������������������������������������   20
Integrative Data Analysis ������������������������������������������������������������   21
Prognostic Significance����������������������������������������������������������������   21

vii
viii Contents

Loss of Chromosome 3/VHL Gene Mutations����������������������������   21


Carbonic Anhydrase IX (CAIX)��������������������������������������������������   22
Chromatin-Remodeling Tumor Suppressor Genes����������������������   22
Tumor Suppressor Gene p53 (Chromosome 17) ������������������������   23
Somatic Copy Number Variations������������������������������������������������   24
Loss of 9p������������������������������������������������������������������������������������   24
Loss of 14q����������������������������������������������������������������������������������   24
Gain of 8q������������������������������������������������������������������������������������   24
Papillary Renal Cell Carcinoma������������������������������������������������������   25
Somatic Alterations����������������������������������������������������������������������   25
Whole Exome Sequencing����������������������������������������������������������   26
RNA Expression��������������������������������������������������������������������������   26
Integrative Data Analysis ������������������������������������������������������������   26
Prognostic Biomarkers in Papillary Renal
Cell Carcinoma����������������������������������������������������������������������������   26
Chromophobe RCC��������������������������������������������������������������������������   27
Somatic Alterations����������������������������������������������������������������������   27
Whole Exome/Genome Sequencing��������������������������������������������   27
Integrative Data Analysis ������������������������������������������������������������   28
DNA Methylation Profiles ����������������������������������������������������������   28
Mitochondrial DNA Analysis������������������������������������������������������   28
Immune Signature Analysis ��������������������������������������������������������   29
RNA Expression��������������������������������������������������������������������������   29
Summary��������������������������������������������������������������������������������������   29
References����������������������������������������������������������������������������������������   29
3 Familial and Hereditary Syndromes in Renal
Cell Cancer �������������������������������������������������������������������������������������� 35
Mark Wayne Ball and Peter A. Pinto
Introduction��������������������������������������������������������������������������������������   35
Clinical Features of Hereditary RCC and Genetic Testing��������������   35
Description of Hereditary Syndromes ��������������������������������������������   36
Von Hippel-Lindau����������������������������������������������������������������������   36
Hereditary Papillary Renal Cell ��������������������������������������������������   38
Birt-Hogg-Dubé ��������������������������������������������������������������������������   39
Hereditary Leiomyomatosis and Renal Cell��������������������������������   40
Succinate Dehydrogenase-Deficient Kidney Cancer ������������������   41
BAP1-Associated RCC����������������������������������������������������������������   41
MITF Family Translocation RCC������������������������������������������������   41
Tuberous Sclerosis Complex��������������������������������������������������������   42
Chromosome 3 Translocation Kidney Cancer ����������������������������   42
Management of Hereditary Cancer Syndromes������������������������������   43
Active Surveillance����������������������������������������������������������������������   43
Surgical Management������������������������������������������������������������������   43
Enucleation����������������������������������������������������������������������������������   44
Wide Excision������������������������������������������������������������������������������   45
Conclusions��������������������������������������������������������������������������������������   45
References����������������������������������������������������������������������������������������   45
Contents ix

4 Pathology of Renal Cell Carcinoma ���������������������������������������������� 49


Franto Francis and Ming Zhou
Introduction��������������������������������������������������������������������������������������   49
Pathological Classification of RCC ������������������������������������������������   50
Pathologic and Molecular Characteristics of
Subtypes of RCC�����������������������������������������������������������������������������   50
Renal Cell Carcinoma, Clear Cell Type (CCRCC)����������������������   50
Renal Cell Carcinoma, Papillary Type
(Papillary RCC, PRCC) ��������������������������������������������������������������   52
Renal Cell Carcinoma, Chromophobe Type
(Chromophobe RCC, ChRCC)����������������������������������������������������   54
Other Uncommon Subtypes of Renal Cell Carcinoma����������������   55
Renal Cell Carcinoma, Unclassified Type ����������������������������������   55
Renal Cell Carcinomas in Inherited Cancer Syndromes������������������   55
von Hippel-Lindau Disease (VHLD)������������������������������������������   55
Hereditary Papillary Renal Cell Carcinoma (HPRCC)����������������   59
Hereditary Leiomyomatosis and Renal
Cell Carcinoma (HLRCC) ����������������������������������������������������������   60
Renal Cell Carcinomas in Hereditary Pheochromocytoma
Paraganglioma Syndrome������������������������������������������������������������   61
Renal Tumors in Tuberous Sclerosis Complex (TSC) ����������������   62
Birt-Hogg-Dube Syndrome (BHD)����������������������������������������������   62
Common Benign Renal Tumors������������������������������������������������������   62
Papillary Adenoma����������������������������������������������������������������������   62
Renal Oncocytoma����������������������������������������������������������������������   63
Angiomyolipoma ������������������������������������������������������������������������   64
Pathological Prognosis Parameters for Renal Cell
Carcinoma����������������������������������������������������������������������������������������   64
Stage��������������������������������������������������������������������������������������������   64
WHO/ISUP Nucleolar Grading ��������������������������������������������������   65
Sarcomatoid and Rhabdoid Differentiation ��������������������������������   66
Tumor Necrosis����������������������������������������������������������������������������   66
Microvascular Invasion����������������������������������������������������������������   67
Histologic Subtyping in Localized and Metastatic RCC ����������������   67
Summary������������������������������������������������������������������������������������������   68
References����������������������������������������������������������������������������������������   68
5 Imaging of Renal Cancer���������������������������������������������������������������� 73
Jalil Afnan, Jaclyn A. Therrien, and Christoph Wald
Renal Imaging����������������������������������������������������������������������������������   73
Intravenous Pyelogram (IVP)����������������������������������������������������������   74
Ultrasound (US) ������������������������������������������������������������������������������   75
Computed Tomography (CT)����������������������������������������������������������   79
Magnetic Resonance Imaging (MRI)����������������������������������������������   87
Future Directions ����������������������������������������������������������������������������   95
References����������������������������������������������������������������������������������������   95
x Contents

6 Molecular Imaging for Renal Cell Carcinoma������������������������������ 99


Jian Q. Yu and Yamin Dou
Introduction��������������������������������������������������������������������������������������   99
Primary Renal Cell Carcinoma Diagnosis �������������������������������������� 100
Locoregional Metastasis������������������������������������������������������������������ 102
Distant Metastasis���������������������������������������������������������������������������� 104
Liver Metastasis ������������������������������������������������������������������������������ 105
Lung Metastasis ������������������������������������������������������������������������������ 105
Bone Metastasis ������������������������������������������������������������������������������ 106
Surveillance�������������������������������������������������������������������������������������� 107
Prognostic Values of FDG PET for RCC���������������������������������������� 108
Monitoring Therapeutic Response �������������������������������������������������� 109
Influence on Management���������������������������������������������������������������� 111
Novel Tracers and Future���������������������������������������������������������������� 112
124I-cG250 for Clear Cell RCC�������������������������������������������������� 112
Other Novel Tracers �������������������������������������������������������������������� 114
Conclusion �������������������������������������������������������������������������������������� 115
References���������������������������������������������������������������������������������������� 115
7 Interventional Radiology and Angioinfarction:
Embolization of Renal Tumors ������������������������������������������������������ 119
Sebastian Flacke and Shams Iqbal
Indications for Renal Artery Embolization�������������������������������������� 119
Technical Details������������������������������������������������������������������������������ 119
Central Occlusion���������������������������������������������������������������������������� 119
Combined Central and Peripheral Occlusion���������������������������������� 121
Capillary Occlusion ������������������������������������������������������������������������ 122
Superselective Embolization������������������������������������������������������������ 125
Clinical Value of Transcatheter Tumor Embolization���������������������� 126
Preoperative Embolization���������������������������������������������������������� 126
Palliative Embolization���������������������������������������������������������������� 128
References���������������������������������������������������������������������������������������� 130
8 Natural History, Role of Biopsy, and Active Surveillance
of Renal Masses�������������������������������������������������������������������������������� 133
Benjamin T. Ristau, Anthony Corcoran, Marc C. Smaldone,
Robert G. Uzzo, and David Y. T. Chen
Introduction�������������������������������������������������������������������������������������� 133
Natural History of Untreated Renal Masses������������������������������������ 135
Benign Versus Malignant SRMs�������������������������������������������������� 135
Growth Characteristics of Untreated SRMs�������������������������������� 135
Radiographic Characteristics of SRMs���������������������������������������� 138
Role of Percutaneous Biopsy and Other Diagnostic Modalities������ 139
Traditional Role of Renal Mass Biopsy�������������������������������������� 139
Modern Biopsy Technique and Results �������������������������������������� 140
Complications of Biopsy������������������������������������������������������������� 141
Molecular Biomarkers ���������������������������������������������������������������� 141
Imaging Techniques �������������������������������������������������������������������� 142
Contents xi

Predictive Models and Assessment of SRM


Malignant Potential���������������������������������������������������������������������� 143
Active Surveillance�������������������������������������������������������������������������� 143
The Rationale for AS ������������������������������������������������������������������ 143
Indications for AS������������������������������������������������������������������������ 144
Predictive Tools and Use in the Clinical Setting�������������������������� 144
AS Protocols�������������������������������������������������������������������������������� 148
Radiographic Predictors of Tumor Growth Rate and
Malignant Potential���������������������������������������������������������������������� 148
Small Renal Masses Exhibiting “Zero Net Growth”
While Under Surveillance������������������������������������������������������������ 150
Observed SRMs Progressing to Metastases�������������������������������� 150
Cost-Effectiveness of AS Versus Active Treatment ������������������������ 151
Conclusion �������������������������������������������������������������������������������������� 152
References���������������������������������������������������������������������������������������� 153
9 Rationale for Partial Nephrectomy, Current Practice
Patterns �������������������������������������������������������������������������������������������� 159
Nicholas M. Donin and William C. Huang
Introduction�������������������������������������������������������������������������������������� 159
Epidemiology of Renal Masses ������������������������������������������������������ 160
Heterogeneity of Renal Cortical Tumors ���������������������������������������� 162
History of Partial Nephrectomy ������������������������������������������������������ 163
Oncologic Outcomes in Partial Nephrectomy �������������������������������� 164
Renal Functional Outcomes in Partial Nephrectomy���������������������� 165
Chronic Kidney Disease, Morbidity, and Mortality������������������������ 168
Renal Surgery, Morbidity, and Mortality ���������������������������������������� 170
Complications of Partial Nephrectomy�������������������������������������������� 176
Utilization of Partial Nephrectomy�������������������������������������������������� 177
Candidate Selection ������������������������������������������������������������������������ 178
Small Renal Masses and Partial Nephrectomy in
Clinical Practice Guidelines������������������������������������������������������������ 179
Conclusion �������������������������������������������������������������������������������������� 180
References���������������������������������������������������������������������������������������� 180
10 Objectifying Complexity of Kidney Cancers:
Relationship of Tumor Anatomy and Outcomes �������������������������� 185
Serge Ginzburg, Alexander Kutikov, Robert G. Uzzo, and
Stephen B. Schloss
Basis of Anatomic Classification System Development������������������ 186
Tumor Size �������������������������������������������������������������������������������������� 186
Tumor Location�������������������������������������������������������������������������������� 186
Tumor Depth������������������������������������������������������������������������������������ 187
Contemporary Classification Systems for Renal Masses���������������� 187
Validation of Current Classification Systems���������������������������������� 191
Application of Standardized Classifications������������������������������������ 191
Limitations of Current Classification Systems�������������������������������� 192
The Role of Nephrometry Score in Partial Nephrectomy:
Lahey Experience���������������������������������������������������������������������������� 192
xii Contents

Conclusion �������������������������������������������������������������������������������������� 193


References���������������������������������������������������������������������������������������� 194
11 History of Renal Surgery for Cancer �������������������������������������������� 197
Brendan M. Browne and Karim Joseph Hamawy
The Golden Era of Radical Nephrectomy���������������������������������������� 198
History of Histology������������������������������������������������������������������������ 199
Rise of Partial Nephrectomy������������������������������������������������������������ 200
Modern Renal Surgery �������������������������������������������������������������������� 201
References���������������������������������������������������������������������������������������� 202
12 The Surgical Approaches to Renal Masses and
Their Impact on Postoperative Renal Function���������������������������� 205
John A. Libertino and Robert Hamburger
Introduction�������������������������������������������������������������������������������������� 205
Nephrectomy Versus Partial Nephrectomy: The Rationale
for Partial Nephrectomy and Preservation of Renal Function �������� 205
Illustrative Case: Large Tumor in Solitary Kidney�������������������������� 206
Role of Preoperative CKD on Postoperative Renal
Function Following Partial Nephrectomy���������������������������������������� 207
Role of Warm Ischemia on Postoperative Renal
Function Following Partial Nephrectomy���������������������������������������� 207
Role of Volume on Postoperative Renal Function
Following Partial Nephrectomy ������������������������������������������������������ 211
Combined Role of Ischemia and Volume on Renal
Function Following Partial Nephrectomy���������������������������������������� 212
Conclusion �������������������������������������������������������������������������������������� 213
Surgical Approach to Multifocal or Bilateral Renal Tumors ���������� 213
Summary������������������������������������������������������������������������������������������ 218
References���������������������������������������������������������������������������������������� 218
13 Open Partial Nephrectomy ������������������������������������������������������������ 221
Marianne M. Casilla-Lennon, Patrick A. Kenney, Matthew
Wszolek, and John A. Libertino
Introduction�������������������������������������������������������������������������������������� 221
Historical Perspective���������������������������������������������������������������������� 221
Epidemiology of Small Renal Masses �������������������������������������������� 222
Oncologic Efficacy of Partial Nephrectomy������������������������������������ 223
T1a Tumors�������������������������������������������������������������������������������������� 224
T1b Tumors�������������������������������������������������������������������������������������� 225
>T1 Tumors�������������������������������������������������������������������������������������� 225
Preserving Renal Function: The Rationale Behind PN�������������������� 226
Underutilization of PN�������������������������������������������������������������������� 227
Adoption of Minimally Invasive Techniques ���������������������������������� 228
Objective Analysis of Tumor Complexity���������������������������������������� 229
Preoperative Evaluation ������������������������������������������������������������������ 231
Cardiopulmonary Evaluation ������������������������������������������������������ 232
Renal Evaluation�������������������������������������������������������������������������� 232
Imaging���������������������������������������������������������������������������������������� 232
Prophylaxis���������������������������������������������������������������������������������� 232
Contents xiii

Surgical Techniques ������������������������������������������������������������������������ 233


Approach�������������������������������������������������������������������������������������� 233
Vascular Control�������������������������������������������������������������������������� 233
Kidney Mobilization�������������������������������������������������������������������� 233
Vascular Clamping ���������������������������������������������������������������������� 233
Excision of the Tumor������������������������������������������������������������������ 235
Renorrhaphy�������������������������������������������������������������������������������� 236
Addressing the Adverse Impact of Ischemia������������������������������� 236
References���������������������������������������������������������������������������������������� 237
14 Minimally Invasive Partial Nephrectomy and Ablative
Procedures for Small Renal Masses ���������������������������������������������� 243
Shanta T. Shepherd, Egor Parkhomenko, and David S. Wang
Introduction�������������������������������������������������������������������������������������� 243
Laparoscopic Partial Nephrectomy�������������������������������������������������� 243
Patient Selection �������������������������������������������������������������������������� 243
Patient Positioning ���������������������������������������������������������������������� 244
Access������������������������������������������������������������������������������������������ 244
Procedure ������������������������������������������������������������������������������������ 245
Hilar Clamping���������������������������������������������������������������������������� 246
Tumor Resection�������������������������������������������������������������������������� 247
Reconstruction of the Collecting System������������������������������������ 248
Hemostasis of the Tumor Bed������������������������������������������������������ 248
Closure ���������������������������������������������������������������������������������������� 248
Robotic-Assisted Laparoscopic Partial Nephrectomy
(RALPN)������������������������������������������������������������������������������������������ 248
Patient Positioning ���������������������������������������������������������������������� 248
Access������������������������������������������������������������������������������������������ 249
Procedure ������������������������������������������������������������������������������������ 249
Ablative Techniques������������������������������������������������������������������������ 250
Postoperative Management�������������������������������������������������������������� 251
Complications of Minimally Invasive Partial Nephrectomy������������ 252
Intraoperative Complications���������������������������������������������������������� 252
Vascular Injury ���������������������������������������������������������������������������� 252
Injury to Intra-abdominal Organs������������������������������������������������ 252
Postoperative Complications������������������������������������������������������������ 252
Hemorrhage���������������������������������������������������������������������������������� 252
Urine Leak ���������������������������������������������������������������������������������� 253
Future Directions ���������������������������������������������������������������������������� 253
Conclusion �������������������������������������������������������������������������������������� 253
References���������������������������������������������������������������������������������������� 254
15 Surgery for Renal Cell Carcinoma with Thrombus
Extension into the Vena Cava���������������������������������������������������������� 259
John A. Libertino, Chad Wotkowicz, and Jason R. Gee
Introduction�������������������������������������������������������������������������������������� 259
Preoperative Renal Embolization���������������������������������������������������� 260
Renal Vein Tumor Thrombus ���������������������������������������������������������� 261
Infrahepatic Tumor Thrombus �������������������������������������������������������� 262
xiv Contents

Retrohepatic, Supradiaphragmatic, and Atrial Tumor


Thrombus ���������������������������������������������������������������������������������������� 267
Venovenous Bypass (Caval-Atrial Shunt)���������������������������������������� 267
Liver Mobilization �������������������������������������������������������������������������� 268
Traditional Cardiopulmonary Bypass (Median Sternotomy)���������� 268
Cardiopulmonary Bypass (Minimally Access Approach)���������������� 270
Comparative Effectiveness of Median Sternotomy
Versus Minimal Access Cardiopulmonary Bypass and
Circulatory Arrest for Resection of Renal Cell Carcinoma
with Inferior Vena Caval Extension ������������������������������������������������ 271
Occluded Vasculature Management������������������������������������������������ 274
Caval Wall Resection and Caval Interruption���������������������������������� 274
Minimally Invasive Techniques and Tumor Thrombectomy ���������� 275
A Novel Approach: Combination of Interventional
Radiologic Tumor Extraction and Surgery�������������������������������������� 275
Partial Nephrectomy and Tumor Thrombus������������������������������������ 275
Neoadjuvant Chemotherapy and Tumor Thrombus ������������������������ 276
Tumor Thrombectomy and Metastectomy�������������������������������������� 276
Personal Experience������������������������������������������������������������������������ 277
International Renal Cell Carcinoma: Venous Thrombus
Consortium (IRCC-VTC)���������������������������������������������������������������� 277
References���������������������������������������������������������������������������������������� 279
16 Role of Lymphadenectomy in Renal Cell Cancer ������������������������ 281
Mattias Willem van Hattem, Eduard Roussel, Hendrik Van
Poppel, and Maarten Albersen
Introduction�������������������������������������������������������������������������������������� 281
Anatomy of Regional Lymph Nodes ���������������������������������������������� 281
Extent of LND for RCC and Templates������������������������������������������ 283
Morbidity of LND���������������������������������������������������������������������������� 284
False-Positive and False-Negative CT Findings������������������������������ 285
Prevalence of Lymph Node metastases�������������������������������������������� 285
Predicting Lymph Node Involvement���������������������������������������������� 286
Protocols and Nomograms���������������������������������������������������������� 286
Intra-Operative Lymph Node Assessment ���������������������������������� 287
Sentinel Lymph Nodes���������������������������������������������������������������� 287
Future Options ���������������������������������������������������������������������������� 287
When to Perform a LND?���������������������������������������������������������������� 288
Localized Disease (cT1abN0M0)������������������������������������������������ 288
Localized Disease: Larger Tumours (cT2abN0M0)�������������������� 288
Locally Advanced Disease (cT3-T4N0M0)�������������������������������� 288
Clinical Node-Positive (cT1-4, N+M0) RCC������������������������������ 289
Regional Lymph Node Recurrence�������������������������������������������������� 289
Distant Metastasis and Cytoreduction (cTanyNanyM1)������������������ 290
Conclusion and Future Research ���������������������������������������������������� 291
References���������������������������������������������������������������������������������������� 291
Contents xv

17 Role of Surgery in Locally Recurrent and Metastatic


Renal Cancer������������������������������������������������������������������������������������ 295
Andrew G. McIntosh, Eric C. Umbreit, and Christopher G.
Wood
Kidney Cancer and Recurrence������������������������������������������������������� 295
Recurrence After RN�������������������������������������������������������������������� 295
Recurrence After PN�������������������������������������������������������������������� 297
Local Recurrence Following Primary Ablative Therapy ���������������� 299
Renal Cell Carcinoma Metastasectomy ������������������������������������������ 300
Conclusion �������������������������������������������������������������������������������������� 302
References���������������������������������������������������������������������������������������� 302
18 Management of Non-Clear Cell Renal Cell Carcinoma �������������� 307
Jeremy A. Ross, Pavlos Msaouel, and Nizar M. Tannir
Introduction�������������������������������������������������������������������������������������� 307
Papillary Renal Cell Carcinoma������������������������������������������������������ 308
Chromophobe Renal Cell Carcinoma���������������������������������������������� 311
Translocation Renal Cancer ������������������������������������������������������������ 312
Renal Medullary Carcinoma/Collecting Duct Renal Cell
Carcinoma���������������������������������������������������������������������������������������� 313
Miscellaneous Renal Cancers���������������������������������������������������������� 315
The Role of Surgery in Metastatic Non-Clear Renal Cell
Carcinoma���������������������������������������������������������������������������������������� 315
Immunotherapy�������������������������������������������������������������������������������� 316
Conclusion �������������������������������������������������������������������������������������� 316
References���������������������������������������������������������������������������������������� 317
19 Surgical Management for Transitional Cell Carcinoma
of the Upper Tract���������������������������������������������������������������������������� 325
Jason R. Gee
Epidemiology���������������������������������������������������������������������������������� 325
Biology�������������������������������������������������������������������������������������������� 326
Carcinogenesis �������������������������������������������������������������������������������� 327
Diagnosis and Clinicopathologic Risk Factors�������������������������������� 328
Diagnostic Ureteroscopy: Biopsy When Feasible ���������������������� 329
Clinicopathologic Prognostic Factors������������������������������������������ 329
Endoscopic Approaches to Treatment���������������������������������������������� 330
Treatment with Topical Agents���������������������������������������������������� 332
Nephroureterectomy������������������������������������������������������������������������ 333
Bladder Cuff Removal ���������������������������������������������������������������� 334
Segmental ureteral Resection���������������������������������������������������������� 335
Autotransplantation�������������������������������������������������������������������������� 335
Role of Lymphadenectomy�������������������������������������������������������������� 335
Role of Neoadjuvant Versus Adjuvant Chemotherapy�������������������� 337
References���������������������������������������������������������������������������������������� 337
20 Outcomes: Prognostic Factors, Models, and Algorithms ������������ 345
Kristian D. Stensland and Michael W. Kattan
Introduction�������������������������������������������������������������������������������������� 345
Staging Systems ������������������������������������������������������������������������������ 345
xvi Contents

Grading System�������������������������������������������������������������������������������� 347


Notes on Staging Systems���������������������������������������������������������������� 347
Other Prognostic Factors������������������������������������������������������������������ 348
A Word About Prediction Tools ������������������������������������������������������ 349
Preoperative Models������������������������������������������������������������������������ 350
Postoperative Models���������������������������������������������������������������������� 352
Metastatic RCC Models������������������������������������������������������������������ 355
Conclusion �������������������������������������������������������������������������������������� 356
References���������������������������������������������������������������������������������������� 356
21 Postoperative Surveillance Protocols for Renal Cell
Carcinoma���������������������������������������������������������������������������������������� 361
Megan M. Merrill and Jose A. Karam
Introduction�������������������������������������������������������������������������������������� 361
Natural History of RCC and Recurrence Patterns �������������������������� 361
Distant Recurrence�������������������������������������������������������������������������� 362
Lung �������������������������������������������������������������������������������������������� 362
Bone �������������������������������������������������������������������������������������������� 362
Liver �������������������������������������������������������������������������������������������� 362
Brain�������������������������������������������������������������������������������������������� 362
Lymph Nodes ������������������������������������������������������������������������������ 363
Local Recurrence After Radical Nephrectomy�������������������������������� 363
Recurrence After Partial Nephrectomy�������������������������������������������� 363
Surveillance Following Radical or Partial Nephrectomy���������������� 364
Rationale for Surveillance������������������������������������������������������������ 364
Components of Surveillance�������������������������������������������������������� 365
Prognostic Factors Influencing Recurrence �������������������������������� 366
Surveillance Following Radical or Partial Nephrectomy in
Patients with Sporadic RCC������������������������������������������������������������ 367
Current NCCN and AUA Guidelines ���������������������������������������������� 376
Surveillance for Hereditary RCC���������������������������������������������������� 377
Surveillance Following Ablative Therapies for RCC���������������������� 377
Radiofrequency Ablation ������������������������������������������������������������ 377
Cryoablation�������������������������������������������������������������������������������� 378
Recommendations for Surveillance Following
Radiofrequency Ablation or Cryoablation ���������������������������������� 379
The Future of Surveillance�������������������������������������������������������������� 380
The Incorporation of Molecular Markers into Surveillance
Strategies�������������������������������������������������������������������������������������� 380
Use of F-18 Fluorodeoxyglucose Positron Emission
Tomography in Surveillance and Reducing the Risk of
Radiation Exposure���������������������������������������������������������������������� 380
Cost of Surveillance������������������������������������������������������������������������ 381
Conclusion �������������������������������������������������������������������������������������� 382
References���������������������������������������������������������������������������������������� 382
22 Role of Radiation Therapy in Renal Cancer �������������������������������� 387
Andrea McKee, Arul Mahadevan, and Timothy Walsh
Introduction�������������������������������������������������������������������������������������� 387
Contents xvii

Preoperative Neoadjuvant Radiation������������������������������������������������ 387


Postoperative Adjuvant Radiation���������������������������������������������������� 388
Intraoperative Radiation������������������������������������������������������������������ 390
Stereotactic Body Radiotherapy (SBRT) as Definitive
Treatment ���������������������������������������������������������������������������������������� 391
Palliative Radiotherapy�������������������������������������������������������������������� 392
Stereotactic Radiosurgery and Stereotactic Body
Radiotherapy for Oligometastatic Disease�������������������������������������� 393
Immunoradiotherapy������������������������������������������������������������������������ 395
Conclusion �������������������������������������������������������������������������������������� 396
References���������������������������������������������������������������������������������������� 396
23 Systemic Therapies for the Treatment of Renal Cell
Carcinoma���������������������������������������������������������������������������������������� 401
Eddy J. Chen
Introduction�������������������������������������������������������������������������������������� 401
Background�������������������������������������������������������������������������������������� 401
Drug Profiles������������������������������������������������������������������������������������ 402
Immunotherapy���������������������������������������������������������������������������� 402
VEGF-Receptor Inhibitor Therapies�������������������������������������������� 403
mTOR Inhibitors�������������������������������������������������������������������������� 404
Contemporary Treatment Approaches �������������������������������������������� 404
Neoadjuvant Systemic Therapy �������������������������������������������������� 404
Adjuvant Therapy������������������������������������������������������������������������ 405
Advanced Disease Regimens ������������������������������������������������������ 405
Conclusion �������������������������������������������������������������������������������������� 407
References���������������������������������������������������������������������������������������� 408
24 Unified Approaches to Surgery and Systemic Therapy
for Renal Cell Carcinoma���������������������������������������������������������������� 411
Alejandro Abello and Patrick A. Kenney
Introduction�������������������������������������������������������������������������������������� 411
Adjuvant Therapy���������������������������������������������������������������������������� 411
Contemporary Approach to Quantifying the Risk of
Recurrence ���������������������������������������������������������������������������������� 411
Models Incorporating Clinical and Pathologic Data�������������������� 412
Using Molecular Markers to Improve Prognostication���������������� 412
Adjuvant Trials���������������������������������������������������������������������������� 412
Thalidomide �������������������������������������������������������������������������������� 417
Targeted Agents���������������������������������������������������������������������������� 417
Ongoing or Unreported Adjuvant Trials�������������������������������������� 418
Adjuvant Therapy: Current Status ���������������������������������������������� 418
Neoadjuvant Therapy for Locally Advanced RCC�������������������������� 421
Immunotherapy���������������������������������������������������������������������������� 421
Targeted Therapy������������������������������������������������������������������������� 421
Targeted Therapy Is Active Against the Primary Tumor�������������� 421
Permitting Resection�������������������������������������������������������������������� 423
Enabling Nephron-Sparing Surgery�������������������������������������������� 423
Downsizing Caval Tumor Thrombus ������������������������������������������ 424
xviii Contents

Neoadjuvant Therapy: Current Status������������������������������������������ 425


Integrated Therapy for Metastatic Disease�������������������������������������� 425
Cytoreductive Nephrectomy�������������������������������������������������������� 426
The Importance of Proper Patient Selection�������������������������������� 426
Targeted Therapy and Cytoreductive Nephrectomy�������������������� 427
Treatment Chronology: Upfront Nephrectomy Versus
Presurgical Targeted Therapy������������������������������������������������������ 428
Conclusion �������������������������������������������������������������������������������������� 430
References���������������������������������������������������������������������������������������� 430
25 Defining an Individualized Treatment Strategy for
Metastatic Renal Cancer ���������������������������������������������������������������� 437
Mamta Parikh, Jerad Harris, Sigfred Ian Alpajaro, Primo N.
Lara Jr., and Christopher P. Evans
Relevant Biologic Pathways in RCC ���������������������������������������������� 437
Prognostication�������������������������������������������������������������������������������� 439
Overview of Treatments of mRCC�������������������������������������������������� 440
Surgery ���������������������������������������������������������������������������������������� 440
Systemic Therapy������������������������������������������������������������������������ 441
Molecular Biomarkers �������������������������������������������������������������������� 443
Immune Checkpoint Inhibitor Therapy���������������������������������������� 443
mTOR Inhibitors�������������������������������������������������������������������������� 444
Treatment Paradigm Based on Individualized Factors�������������������� 444
Patient Selection for Cytoreductive Nephrectomy���������������������� 444
Timing of Cytoreductive Nephrectomy �������������������������������������� 447
Patient Selection for Metastasectomy������������������������������������������ 447
Patient Selection for Systemic Therapy �������������������������������������� 447
Patient Selection for Second-Line Therapy and Beyond ������������ 448
Systemic Treatment Considerations Based on Histology������������ 448
Future of Individualized Therapy���������������������������������������������������� 449
Summary������������������������������������������������������������������������������������������ 449
References���������������������������������������������������������������������������������������� 449
Index�������������������������������������������������������������������������������������������������������� 453
Contributors

Alejandro Abello, MD Department of Urology/Yale School of Medicine,


Yale New Haven Hospital, New Haven, CT, USA
Jalil Afnan, MD, MRCS Department of Radiology, Lahey Hospital &
Medical Center, Burlington, MA, USA
Maarten Albersen, MD Department of Urology, UZ Leuven, Leuven,
Belgium
Sigfred Ian Alpajaro, MD Department of Surgery, Section of Urology,
University of Santo Tomas Hospital, Manila, Philippines
Mark Wayne Ball, MD Center for Cancer Research, NCI, NIH, Urologic
Oncology Branch, Bethesda, MD, USA
Brendan M. Browne, MD, MS Department of Urology, Lahey Hospital and
Medical Center, Burlington, MA, USA
Marianne M. Casilla-Lennon, MD Department of Urology, Yale New
Haven Health, New Haven, CT, USA
David Y. T. Chen, MD, FACS Department of Surgical Oncology, Division
of Urology, Fox Chase Cancer Center – Temple University Health System,
Philadelphia, PA, USA
Eddy J. Chen, MD Division of Hematology/Oncology, Massachusetts
General Hospital, Harvard Medical School, Boston, MA, USA
MGH Cancer Center, Emerson Hospital, Concord Mass, USA
Anthony Corcoran, MS, MD Department of Urology, NYU Winthrop
Hospital, Garden City, NY, USA
Nicholas M. Donin, MD Department of Urology, Division of Urologic
Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Yamin Dou, MD Department of Radiology, Tufts School of Medicine,
Lahey Hospital and Medical Center, Burlington, MA, USA
Alexandra Drakaki, MD, PhD David Geffen School of Medicine of UCLA,
Institute for Urologic Oncology, Los Angeles, CA, USA
Christopher P. Evans, MD Department of Urologic Surgery, UC Davis,
Sacramento, CA, USA

xix
xx Contributors

Sebastian Flacke, MD, PhD Department of Radiology, Lahey Hospital and


Medical Center, Burlington, MA, USA
Franto Francis, MD, PhD Department of Pathology, University of Texas
Southwestern Medical Center, Dallas, TX, USA
Jason R. Gee, MD Tufts University School of Medicine, Boston, MA, USA
Department of Urology, MGH Cancer Center, Emerson Hospital, Concord,
MA, USA
Sanaz Ghafouri, MD Department of Internal Medicine, Ronald Reagan
UCLA Medical Center, Los Angeles, CA, USA
Serge Ginzburg, MD Urology Institute of Southeastern Pennsylvania,
Einstein Hospital System, Philadelphia, PA, USA
Department of Urology, Fox Chase Cancer Center, Philadelphia, PA, USA
Christopher R. Haas, MD Department of Urology, New York-Presbyterian,
Columbia University Irving Medical Center, Herbert Irving Pavilion, New
York, NY, USA
Karim Joseph Hamawy, MD Department of Urology, Lahey Hospital and
Medical Center, Burlington, MA, USA
Robert Hamburger, MD Department of Medicine, Boston University
School of Medicine, Boston VA Health Care System, Boston, MA, USA
Jerad Harris, BS Department of Urologic Surgery, UC Davis, Sacramento,
CA, USA
Mattias Willem van Hattem, MD Department of Urology, UZ Leuven,
Leuven, Belgium
William C. Huang, MD Department of Urology, Division of Urologic
Oncology, NYU Langone Medical Center, New York, NY, USA
Shams Iqbal, MD Department of Radiology, Lahey Hospital and Medical
Center, Burlington, MA, USA
David C. Johnson, MD, MPH Department of Veterans Affairs/UCLA
National Clinician Scholars Program, West Los Angeles Veterans Affairs
Hospital, Los Angeles, CA, USA
Jose A. Karam, MD, FACS Urology and Translational Molecular Pathology,
MD Anderson Cancer Center, Houston, TX, USA
Michael W. Kattan, PhD Department of Quantitative Health Sciences,
Cleveland Clinic, Cleveland, OH, USA
Kristen Kelly, MD Department of Internal Medicine, Ronald Reagan UCLA
Medical Center, Los Angeles, CA, USA
Patrick A. Kenney, MD Department of Urology/Yale School of Medicine,
Yale New Haven Hospital, New Haven, CT, USA
Contributors xxi

Alexander Kutikov, MD Division of Urology and Urologic Oncology,


Department of Urology, Fox Chase Cancer Center, Temple University School
of Medicine Center, Philadelphia, PA, USA
Primo N. Lara Jr., MD Hematology/Oncology, Department of Internal
Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA, USA
UC Davis School of Medicine, Sacramento, CA, USA
John A. Libertino, MD Tufts University School of Medicine, Boston, MA,
USA
Department of Urology, MGH Cancer Center, Emerson Hospital, Concord,
MA, USA
Arul Mahadevan, MD Department of Radiation Oncology, Sophia Gordon
Cancer Center, Lahey Clinic Medical Center, Burlington, MA, USA
Andrew G. McIntosh, MD Department of Urology, University of Texas
MD Anderson Cancer Center, Houston, TX, USA
Andrea McKee, MD Department of Radiation Oncology, Sophia Gordon
Cancer Center, Lahey Clinic Medical Center, Burlington, MA, USA
James M. McKiernan, MD Department of Urology, New York-Presbyterian,
Columbia University Irving Medical Center, Herbert Irving Pavilion, New
York, NY, USA
Megan M. Merrill, DO Department of Urology, Kaiser Permanente South
Sacramento, Sacramento, CA, USA
Pavlos Msaouel, MD Department of Genitourinary Medical Oncology, UT
MD Anderson Cancer Center, Houston, TX, USA
Allan Pantuck, MD, MS Institute of Urologic Oncology, Department of
Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Mamta Parikh, MD, MS Hematology/Oncology, Department of Internal
Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA, USA
Egor Parkhomenko, MD Department of Urology, Boston University
School of Medicine, Boston, MA, USA
Peter A. Pinto, MD NIH Clinical Center, Urologic Oncology Branch,
Bethesda, MD, USA
Hendrik Van Poppel, MD, PhD Department of Urology, UZ Leuven,
Leuven, Belgium
Benjamin T. Ristau, MD, MHA Department of Surgery/Division of
Urology, UConn Health, Farmington, CT, USA
Jeremy A. Ross, MD Cancer Medicine, Fellowship Program, UT MD
Anderson Cancer Center, Houston, TX, USA
Eduard Roussel, MD Department of Urology, UZ Leuven, Leuven, Belgium
xxii Contributors

Stephen B. Schloss, MD Department of Urology, MGH Cancer Center,


Emerson Hospital, Concord, MA, USA
Shanta T. Shepherd, MD Department of Urology, Boston University
School of Medicine, Boston, MA, USA
Sana N. Siddiqui, DO, MS Department of Urology, New York-Presbyterian,
Columbia University Irving Medical Center, Herbert Irving Pavilion, New
York, NY, USA
Marc C. Smaldone, MD, MSHP, FACS Department of Surgery, Fox Chase
Cancer Center – Temple University Health System, Philadelphia, PA, USA
Kristian D. Stensland, MD, MPH Division of Urology, Lahey Hospital and
Medical Center, Burlington, MA, USA
Nizar M. Tannir, MD, FACP Genitourinary Medical Oncology, UT MD
Anderson Cancer Center, Houston, TX, USA
Jaclyn A. Therrien, DO Section Head Body Imaging, Department of
Radiology, Lahey Hospital & Medical Center, Burlington, MA, USA
Eric C. Umbreit, MD Department of Urology, University of Texas MD
Anderson Cancer Center, Houston, TX, USA
Robert G. Uzzo, MD Department of Surgical Oncology, Division of
Urology, Fox Chase Cancer Center – Temple University Health System,
Philadelphia, PA, USA
Christoph Wald, MD, PhD, MBA Department of Radiology, Lahey
Hospital & Medical Center, Burlington, MA, USA
Timothy Walsh, MD Department of Radiation Oncology, Tufts University
School of Medicine, Boston, MA, USA
David S. Wang, MD Department of Urology, Boston University School of
Medicine, Boston, MA, USA
Christopher G. Wood, MD, FACS Department of Urology, University of
Texas MD Anderson Cancer Center, Houston, TX, USA
Chad Wotkowicz, MD Department of Urology, Lahey Clinic Medical
Center, Burlington, MA, USA
Matthew Wszolek, MD Department of Urology, Massachusetts General
Hospital, Boston, MA, USA
Jian Q. Yu, MD, FRCPC Department of Diagnostic Imaging, Fox Chase
Cancer Center, Philadelphia, PA, USA
Ming Zhou, MD Department of Pathology and Laboratory Medicine, Tufts
Medical Center, Boston, MA, USA
Tufts Medical Center and Tufts School of Medicine, Boston, MA, USA
Epidemiology, Screening,
and Clinical Staging 1
Sana N. Siddiqui, Christopher R. Haas,
and James M. McKiernan

Introduction to Epidemiology Europe, as well as North America [4]. In the


United States, kidney cancer ranks as the eighth
Kidney cancer among adults includes malignant most commonly diagnosed cancer, where approx-
tumors arising from the renal parenchyma and imately 1.7% of men and women will be diag-
renal pelvis, but the differential of a renal mass nosed with kidney or renal pelvis cancer at some
should also include benign tumors and inflamma- point in their lifetime [5]. According to the
tory causes as summarized in Table 1.1. Tumors Surveillance, Epidemiology, and End Results
arising from the renal pelvis are mostly of the (SEER) program, the prevalence of kidney and
urothelial cell type and comprise less than 10% renal pelvis cancer in 2015 was estimated to be
of kidney carcinomas. Renal cell carcinoma 505,380 in the United States. The National
(RCC), also known as renal cell adenocarcinoma, Cancer Institute (NCI) reports that within the
accounts for 90% of kidney carcinomas and is United States, there will be an estimated 65,340
much more common than benign tumors or other new cases in 2018 with a male-to-female pre-
malignant cancers [1]. Renal cell carcinoma is dominance of about 2:1 and almost 15,000 deaths
divided into a variety of histologic subtypes, due to kidney and renal pelvis cancers. As a
which may differ in clinical features and progno- result, kidney cancers account for 3.8% of all
sis. The most common form of RCC is the clear new cancer cases and 2.5% of all cancer deaths,
cell type, comprising 75% of new cases; this is and remain the twelfth leading cause of cancer
followed by the papillary, chromophobe, medul- death. Among all new diagnoses of kidney cancer
lary, and collecting duct subtypes which make up in the United States, 5-year survival is 76% [5].
10%, 5%, 1%, and 1%, respectively [2].
Kidney cancer is the fourteenth most common
cancer worldwide, with over 400,000 new cases I ncidence and Mortality Rates over
in 2018. It is the ninth most commonly occurring Time
cancer in men and the fourteenth most commonly
occurring cancer in women [3]. The highest inci- From 1992 to 2015, the incidence of kidney can-
dence rates can be found in Northern and Eastern cer in United States increased at 2.4%/year; how-
ever, this increase has slowed to a near plateau
S. N. Siddiqui · C. R. Haas (*) · J. M. McKiernan from 2008 to 2015 [6]. This increase in RCC
Department of Urology, New York-Presbyterian, incidence was most notable in localized and
Columbia University Irving Medical Center,
regional disease rather than metastatic RCC in
Herbert Irving Pavilion, New York, NY, USA
e-mail: siddiqs1@amc.edu; crh2109@cumc. which the overall incidence has been stable.
columbia.edu Incidence-based mortality rates increased from

© Springer Nature Switzerland AG 2020 1


J. A. Libertino, J. R. Gee (eds.), Renal Cancer, https://doi.org/10.1007/978-3-030-24378-4_1
2 S. N. Siddiqui et al.

Table 1.1 Differential diagnosis of a renal mass


Malignant Benign Inflammatory
Renal cell carcinoma Simple cyst Abscess
 Clear cell Angiomyolipoma Focal pyelonephritis
 Papillary Oncocytoma Xanthogranulomatous pyelonephritis
 Chromophobe Renal adenoma Infected renal cyst
 Collecting duct carcinoma Metanephric adenoma Tuberculosis
Urothelium derived Cystic nephroma Rheumatic granuloma
 Urothelial cell carcinoma Mixed epithelial/stromal tumor
 Squamous cell carcinoma Reninoma
 Adenocarcinoma Leiomyoma
Sarcoma Fibroma
 Leiomyosarcoma Hemangioma
 Liposarcoma Vascular malformation
 Angiosarcoma Pseudotumor
 Hemangiopericytoma
 Malignant fibroid histiocytoma
 Synovial sarcoma
 Osteogenic sarcoma
 Clear cell sarcoma
 Rhabdomyosarcoma
 Wilms tumor
 Primitive neuroectodermal tumor
 Carcinoid
 Lymphoma
 Metastasis
 Invasion by adjacent neoplasm

1992 and peaked in 2001, but then started to Another likely explanation for the higher inci-
decline with the sharpest decline in recent years dence of kidney cancer observed in developed
of 32% from 2013 to 2015 [6]. countries is the greater availability and more lib-
In the last decade, 18 countries experienced eral use of abdominal computed tomography
increased incidence rates for both men and women, imaging techniques resulting in more incidental
with sharper increases occurring in Latin America, findings of renal masses [8]. Within the United
Brazil, Thailand, and Bulgaria [4]. Reporting bias, States Medicare population, 43% of patients
advancement in health record systems, and acces- receive a CT of the chest or abdomen over a
sibility to healthcare providers should also be con- 5-year period [9]. Tandem with the detection of
sidered in comparing rates accurately between more incidental renal masses is the increased
regions. Increasing incidence and a decreasing diagnosis of small renal masses <4 cm, which
mortality-to-incidence ratio have been found to be now account for 48–66% of new RCC diagnoses
correlated with increasing human development [7]. Tumor size has extensively been shown to be
index levels and gross domestic product per capita correlated with risk of metastasis with a 25%
[7]. One explanation for the rising incidence in increased odds of metastasis with each cm
developed nations is the higher prevalence of risk increase in tumor diameter [10]. In patients with
factors for RCC (such as smoking, obesity, physi- tumor diameter <3 cm, the risk of metastasis is
cal inactivity, and hypertension) present in devel- remote with several active surveillance cohorts
oped countries. Increased access to care and reporting 0–1.1% metastatic events occurring in
availability of advanced therapeutics have been tumors <3 cm [11]. In addition to improvements
postulated to account for the decreased mortality- made in local and systemic therapies for RCC,
to-incidence ratio [6]. the decreasing mortality rates from RCC can also
1 Epidemiology, Screening, and Clinical Staging 3

partly be attributed to the lead-time bias from population [5]. Despite being diagnosed at a
earlier diagnosis and treatment of small renal younger age with more localized disease, black
masses [6]. In states and developed nations that RCC patients also had a significantly lower sur-
have aimed to curtail advanced radiologic testing, vival rate than all other ethnicities [13]. The dis-
there has been recent data to suggest that the inci- parity in survival rates between black patients
dence of renal cancer has plateaued [12]. and other ethnicities is unknown, but can be par-
tially explained by stressors associated with
socioeconomic status, comorbidities such as
 emographic Factors in Renal Cell
D hypertension, and lower likelihood of undergoing
Carcinoma nephrectomy or receiving systemic therapies for
metastatic disease [15, 16].
Renal cancer is twice as common in males as RCC tumor subtype also varies among racial
females, and the rate of incidence has continued to groups. Looking at 18 US population-based reg-
rise twice as rapidly in males compared to females. istries of the SEER program in 2011, a study
A 2008 study looking at retrospective data of found that among 84,255 RCC patients, clear cell
39,434 patients from 1988 to 2004 in the California RCC is more common in white populations than
Cancer Registry determined that overall, females black populations (50% vs. 31%), and the papil-
showed a higher percent of localized cancer than lary subtype presents more often in people of
males which may be responsible for a higher rela- African or Caribbean descent than Caucasian
tive survival rate in females. Potential explana- descent (23% vs. 9%). These authors also found
tions for differences in survival rates also include that compared to whites, blacks were four times
biological differences in the tumor, more exten- more likely to have papillary RCC than clear cell
sive use of healthcare system by females, and a RCC, while Asian or Pacific Islanders were less
higher prevalence of hypertension in males [13]. likely to have papillary or chromophobe RCC
With a median age at RCC diagnosis of than white patients [17]. Other rare and aggres-
64 years old, RCC is primarily a malignancy of sive subtypes of RCC such as collecting duct car-
the elderly. In fact, 53.9% of patients are diag- cinoma and renal medullary carcinoma have been
nosed between the ages of 55 and 74, while less linked to African American heritage, with renal
than 10% are diagnosed at less than 45 years of medullary carcinoma seen almost exclusively
age [5]. As mortality rates continue to decrease in with sickle cell trait [18, 19].
the United States and overall RCC incidence
rises, the incidence of RCC in the elderly will
also likely continue to rise. Of note, adolescents  isk Factors in the Development
R
and young adults more commonly present with of RCC
rare histologic subtypes such as translocation
carcinoma or renal medullary carcinoma. Though Risk factors for renal cell carcinoma include male
RCC in younger patients is rare, translocation gender, age, smoking, diet, obesity, hypertension,
carcinomas account for up to 50% of all RCC in renal disease, family history, certain medication
patients under the age of 40. [14] use, and occupational exposures. While some
Along with sex and age, race is an important components such as gender and age have been dis-
factor in the epidemiology of RCC. Within the cussed under demographics, current literature
United States, SEER data shows that black and regarding the remaining factors is described below.
Hispanic patients have a higher incidence rate
than all other ethnicities, while Asian and Pacific
Islander patients have the lowest incidence rates. Smoking
Caucasians had an incidence of 22.2 per 100,000
person-years between 2011 and 2015 in compari- According to the International Agency for
son to 25.3 per 100,000 person-years in the black Research on Cancer (IARC) and the US Surgeon
4 S. N. Siddiqui et al.

General, smoking is a well-established causal this includes beer, wine, and liquor. A dose-­
risk factor for RCC. Male smokers are shown to dependent risk reduction was discovered in a
have a 50% increased relative risk (RR) and pooled analysis of 12 prospective studies, show-
female smokers are shown to have a 20% ing a 28% lower risk in those who drank more
increased RR for developing these tumors. A than 15 grams per day. Interestingly, no associa-
2005 meta-analysis of 24 studies shows that the tion was found between total fluid intakes from
overall combined RR for developing RCC in other beverages, such as water, juice, milk, tea,
someone who has ever smoked a cigarette was coffee, or soda, implying that alcohol itself is a
1.38 (95% CI = 1.27–1.5). Furthermore, this data modifying factor [25].
reported a dose-response relationship of increas-
ing RR with more exposure to cigarette smoke. A
promising finding from the study indicated that a Obesity
greater length of abstinence from smoking actu-
ally reduced the RR, but this finding requires fur- Obesity was first shown to be associated with
ther investigation [20]. RCC as early as 1984 when McLaughlin et al.
Compared to non-smokers, current smokers conducted a case-control analyses that suggested
with RCC were shown to be at an increased risk body mass index (BMI) and RCC in women were
for death with an HR of 1.7 (95% CI = 1.2–2.5) related [26]. Since then, much more literature has
[21]. Smokers were seen to have a higher likeli- been published regarding the relationship
hood of increased stage or even metastases at between waist-to-hip ratios, weight gain during
diagnosis. Similarly to chronic obstructive pul- adulthood, and mechanisms of its influence on
monary disease (COPD), the pathogenesis of kidney cancer [27]. The World Cancer Research
cigarette smoking in RCC is linked to carbon Fund reports that since the 1980s, obesity has
monoxide exposure and chronic tissue hypoxia. continued to increase in both resource-rich coun-
Smokers with RCC were also shown to have tries as well as low- and middle-income countries
increased DNA damage and mutations within [28]. Between genders, there is an estimated 24%
peripheral blood lymphocytes due to increased risk in men and 34% increased risk in
N-nitrosamine and benzo[α]pyrene diol exposure women for every 5 kg/m increase in BMI [29].
compared to a control group [22, 23]. Proposed mechanisms for the development of
RCC include insulin resistance, sex hormone
dysregulation, inflammatory responses, and oxi-
Diet dative stress [30]. In light of the significant asso-
ciation between obesity and development of
Many different foods and substances have been RCC, further research is needed to elucidate
researched to look for increased risk of causal mechanisms and preventative strategies.
RCC. Most notably, consumption of fruits and
vegetables is shown to be inversely related to the
development of RCC in a meta-analysis review- Hypertension
ing 13 prospective studies [24]. The role of high
fat and protein consumption is more controver- According to the Centers for Disease Control and
sial because while it has been considered a risk Prevention, about 75 million American adults
factor in the past, a large multicenter European had high blood pressure in 2011. This translates
cohort study revealed that there is no significant into 1 in 3 adults having a chronic condition that
association between the development of RCC increases risk for several diseases, such as heart
and these nutrients [20]. disease, renal failure, and stroke [31]. While
Like fruits and vegetables, alcohol has also chronic hypertension is a leading cause for devel-
been inversely associated with renal cancer risk; opment of chronic kidney disease, several studies
1 Epidemiology, Screening, and Clinical Staging 5

have shown that hypertension is an independent Family History


risk factor for developing RCC. In a meta-­
analysis of 13 case-control studies from 1966 to While there are several inheritable conditions
2000, hypertensive patients were found to have a that portend an increased risk of RCC, the vast
pooled odds ratio of 1.75 for having RCC [32]. majority of RCC occurs sporadically. The ques-
Independent dose-dependent and time-dependent tion of whether there is an association between
effects of hypertension were further elucidated in family history and sporadic RCC was explored
a 2011 study that showed increasing odds ratios by a study at the University of Texas MD
of RCC with worsening control of blood pressure Anderson Cancer Center. Using several analytic
and longer duration of hypertensive diagnosis strategies, the authors were able to establish sig-
[33]. Lastly, a Swedish cohort study found an nificant association between family history of
association with decreased RCC risk after a kidney cancer and sporadic RCC. Furthermore,
reduction in blood pressure, suggesting that higher risk of developing RCC was found in
effective hypertension control may lower risk patients who had an affected sibling rather than a
[27]. Like the association with obesity and RCC, parent or child with an RR of 3.52 (95%
the findings relating blood pressure to increased CI = 1.70–3.04) found on meta-analysis [38].
cancer risk also present an opportunity to enact These findings stress that while dominant famil-
preventative measures. ial RCC syndromes such as VHL, hereditary pap-
illary renal cancer, and Birt-Hogg-Dubé disease
exist, there is a role for recessive effects in the
Chronic Renal Disease inheritance of sporadic RCC.

Patients with end-stage renal disease (ESRD)


who undergo renal transplantation after long-­ Medications
term hemodialysis or with acquired cystic dis-
ease have all been shown to have an increased Researchers have studied a variety of antihyper-
risk for multiple forms of malignancy, ranging tensive medications, including diuretics, calcium
from immune deficiency-related malignancy to channel blockers, and beta-blockers, to explore
urinary tract tumors [31]. Post-transplant kidney an association with RCC independent of hyper-
cancer is particularly seen in native kidneys of tension. Results have remained inconsistent with
transplanted patients with acquired cystic kidney some showing doubled risk for RCC with long-­
disease (ACKD). ACKD is present in 40% of term diuretic use while others have presented data
graft recipients at time of transplant and appears that was not statistically significant [39]. A 2017
in another 16% of patients after transplant [34]. A study published by Colt et al. found that while
retrospective study looking at the outcomes of there was no relationship between any antihyper-
RCC in native kidneys of transplant patients tensive drug class and overall RCC, there was
determined that the median interval between some significant data regarding specific histo-
transplantation and RCC occurrence was logic subtypes. The authors found that long-­term
5.6 years and that ACKD was present in 83% of use of diuretics (OR = 3.1, 95% CI = 1.4–6.7) and
these transplanted patients [35]. The 2018 having ever used calcium channel blockers
European Association of Urology guidelines (OR = 2.8, 95% CI = 1.1–7.4) were associated
reinforce the risk of RCC in patients with ESRD, with papillary RCC, but associations with clear
stating that the risk is at least ten times higher cell RCC were weak or not significant [40].
than in the general population [36]. Furthermore, Possible mechanisms for the carcinogenic effects
RCC in patients with ESRD is notably less of antihypertensive medications include conver-
aggressive, found in younger patients, and often sion of diuretics to nitroso derivatives in the stom-
multicentric and bilateral [37]. ach, chemical effects on renal tubular epithelium
6 S. N. Siddiqui et al.

over long periods of time, and calcium channel nitrate, and radon, has not been established as a
blockers inhibiting apoptosis to facilitate division risk factor for RCC but is being explored [1]. The
of malignant cells [41, 42]. most extensively examined substance is trichlo-
Similarly to studies on antihypertensive medi- roethylene (TCE), a degreaser used for metal
cations, individual studies examining analgesic’s cleaning that is also present in adhesives, paint
association with RCC have largely been inconsis- removers, typewriter correction fluids, and spot
tent. Among the most commonly used analgesics, removers [46]. The US Environmental Protection
acetaminophen has been implicated with RCC Agency 2001 draft TCE health risk assessment
risk. A large case-control analysis of the US concluded that epidemiologic studies do show an
Kidney Cancer Study showed a positive trend for increased risk of kidney cancer in association
developing RCC with increasing duration of with TCE [47]. TCE is considered a Group 2A
over-the-counter use of acetaminophen, with a “probably” human carcinogen by the International
twofold risk observed for those who took acet- Agency for Research on Cancer (IARC).
aminophen ≥10 years [43]. However, the effect
size was diluted to an odds ratio of 1.5 when pre-
scription use of acetaminophen was included. A Screening for RCC
meta-analysis of four cohort and nine case-­
control studies supported this finding with a sum- Although 30% of patients present with metastatic
marized odds ratio of 1.25 (95% CI = 1.1–1.4) disease, the remainder are diagnosed with local-
[44]. A potential biological explanation for acet- ized RCC and may be candidates for definitive
aminophen’s effects is the depletion of glutathi- treatment [48]. Screening programs for earlier
one at higher doses and the subsequent rise in detection and treatment have the potential to
N-acetyl-p-benzoquinone imine (NAPQI). improve survival outcomes if the ideal screening
NAPQI is able to disrupt homeostasis in both regimen is identified. The Wilson and Jungner
kidney and liver cells by binding covalently to criteria for suitable screening include the follow-
DNA [44]. ing: the condition should be a significant health
Nonsteroidal anti-inflammatory drugs problem, there should be a recognizable latent or
(NSAIDs) have also been examined for poten- early symptomatic stage, and there should be an
tially increasing RCC risk. A large meta-analysis accepted treatment for patients with recognized
identifying 20 studies found increased risk of disease [49]. In regard to RCC, well-established
RCC with non-aspirin NSAID use (RR = 1.25, treatments with minimal risk are available for
95% CI = 1.06–1.46), but no relationship between localized tumors. There is currently no recom-
aspirin use and RCC [45]. Other meta-analytic mendation for screening for RCC, but several
reviews have not shown a positive association techniques and regimens have been explored.
between RCC and NSAID use, including the US Cost-effective techniques that have been
Kidney Cancer Study which looked at NSAID explored for early detection of RCC include urine
use and aspirin use in heart regimens [44]. dipstick and biomarkers. Identifying hematuria
Theories for NSAID-mediated RCC carcinogen- on dipstick has not been reliable for RCC due to
esis reference the inhibition of prostaglandin syn- a stronger association with bladder cancer, low
thesis leading to chronic subacute renal injuries; diagnostic yield, as well as poor sensitivity and
these in turn could cause DNA damage and specificity. When comparing incidence of all
uncontrolled cell proliferation. hematuria in patients with RCC to hematuria in
patients with urothelial carcinoma, the rates are
35% versus 94%, respectively [50]. A Korean
Occupational Exposure study that performed 56,632 dipsticks as part of a
checkup on individuals over the age of 20 found
Exposure to agents classically considered carci- hematuria in 3517 patients, but only three cases
nogenic, including cadmium, uranium, arsenic, of RCC were detected among these patients [51].
1 Epidemiology, Screening, and Clinical Staging 7

This is most likely because microscopic hematu- observational studies that were completed, nine
ria is a common finding and less likely to indicate of which were published before 2004 [53]. Of
cancer in a younger, low-risk population. On the these trials, a 1999 Japanese study screened
other hand, biomarkers such as aquaporin 1 219,640 patients (ages 29–70 years) over 13 years
(AQP1) and perilipin 2 (PLIN2) are soluble uri- and detected 193 cases of RCC. These patients
nary proteins with the potential for high specific- were followed to show a 97.4% cumulative sur-
ity and sensitivity, but they still require larger vival rate after 5 years and 94.6% at 10 years
prospective trials [52]. These biomarkers are spe- [58]. A large-scale randomized controlled screen-
cific to clear cell and papillary histologic sub- ing trial would help determine whether these
types, implying that they would produce results indicate a lead-time bias or truly represent
false-negative results in patients with variant his- improved survival outcome.
tology [53]. Other screening considerations include the
Computed tomography (CT) scanning is cur- psychological impact on patients and over-­
rently used to screen for a wide variety of malig- diagnosis of small renal masses that may never
nancies in middle-aged Americans. These become clinically significant. A false-positive
screening practices include but are not limited to screening result may result in a similar degree of
abdominal CTs for detection of aortic aneu- patient harm as a false-negative result. Studies
rysms, CT colonography, CT angiography, and have shown that 15–30% of small renal masses
chest CTs for lung cancer. In an era where many are found to be benign after surgical excision
patients are receiving CT imaging, researchers [59]. As a result, clinicians must contemplate the
have attempted to detect solid abdominal organ psychological and emotional impact of deliver-
malignancies simultaneously. One study ing an incorrect diagnosis and potential harm
screened 4543 healthy patients over 40 years old from more unnecessary testing or invasive
who had received an abdominal CT, but solid procedures.
organ malignancy prevalence was only found to
be 0.1%, and therefore, the method was deemed
ineffective [54]. The US Preventive Services Screening of Targeted Populations
Task Force recognizes that despite the not infre-
quent detection of extracolonic incidental With the establishment of known risk factors and
lesions on CT, only 3% require definitive treat- understanding of inheritable conditions, high-­
ment [55]. As a result of the overall low inci- risk populations do exist and screening has been
dence of malignant renal masses detected on evaluated for these patients. In 2005, the
screening CT with increased costs and burdens European Association of Urology guidelines had
to the patient and healthcare system, CT has not recommended annual ultrasounds of native kid-
been found to be a cost-­effective screening strat- neys in patients who have received transplants
egy for RCC. due to their higher risk for developing RCC [60].
Compared to CT, ultrasound has the benefit of Examining other risk factors, Starke et al. identi-
using benign sound waves instead of ionizing fied 925 patients as high-risk individuals for
radiation while also being less expensive. A 2018 bladder cancer based on age ≥50, smoking with
cost-benefit analysis for sonographic screening ≥10 pack-year history, and occupational carcino-
shows that at $36 US dollars per ultrasound, the gen exposure of ≥15 years. After following these
opportunity to prevent metastatic RCC is worth patients for 6.5 years, ten of the patients were
considering [56]. However, ultrasound is less diagnosed with RCC, indicating a prevalence of
accurate in detecting renal masses than CT, espe- RCC in these patients that is roughly ten times
cially with less sensitivity in detecting lesions higher than the general population [61]. Since
under 3 cm in size [57]. There also is a lack of then, algorithms for early screening and
randomized trials to support the use of ultrasound ­management have been proposed for asymptom-
screening for RCC. Rossi et al. identified ten atic high-­
risk patients [56]. These targeted
8 S. N. Siddiqui et al.

screening methods may be endorsed in the future, mutation of fumarate hydratase (FH), which is a
even if screening of the general population is not. gene that encodes an enzyme in the TCA cycle.
Incidence of von Hippel-Lindau disease is HLRCC-­associated kidney cancer has the poten-
1 in 36,000 live births with a penetrance of over tial to be lethal, and therefore, testing in sus-
90% by the age of 65, making it the most com- pected patients begins as early as 8 years old.
mon hereditary renal cancer syndrome [62]. The Patients who are affected with HLRCC should
von Hippel-Lindau gene, VHL, is a tumor sup- subsequently have annual abdominal MRIs to
pressor gene on the short arm of chromosome 3 screen for kidney tumors [67].
(3p25.3). The gene encodes a protein that is part
of the VCB-CUL2 ubiquitin ligase complex,
which is responsible for degradation of hypoxia-­ Clinical Staging
inducible factor 1 (HIF-1) and insulin-like growth
factor 1 (ILGF-1). Loss of VHL activity leads to Clinical staging systems are developed to classify
cell growth and angiogenesis due to downstream malignant diseases in a uniform manner with
enhanced expression of factors such as VEGF, prognostic capability. They are used to guide
PDGFB, EPO, and TGF-α. CNS hemangioblas- treatment and planning decisions and manage
tomas, clear cell renal carcinomas, pheochromo- expected outcomes by stratifying the risk of can-
cytomas, and pancreatic tumors have all been cer progression. Ultimately, uniform staging sys-
described as part of the phenotypical classifica- tems allow for the comparison of patient
tions of VHL. As patients with VHL have a 70% outcomes worldwide [68]. Flocks and Kadesky
lifetime risk of developing RCC with a mean age proposed one of the earliest kidney cancer stag-
of clinical diagnosis at age 40, screening with ing systems in 1958, including organ-confined,
annual abdominal MRIs from the age of 16 is locally invasive, locally metastatic, and distant
recommended [63]. MRI is preferred over CT to metastatic disease [69]. The predominant TNM
avoid the substantial cumulative radiation expo- staging system used currently (tumor, nodes,
sure annual CT scans would incur. Pathologic metastases) was developed in 1974 by the
examination of nephrectomy specimens from American Joint Committee on Cancer (AJCC)
patients with VHL has revealed that nearly all and the Union Internationale Contre le Cancer,
complex cysts contain RCC [64]. Even normal-­ renamed the Union for International Cancer
appearing parenchyma on CT may harbor large Control (UICC) [70]. This TNM staging system
numbers of microscopic tumor foci, explaining has had several major revisions to improve prog-
the high risk of multiple and bilateral RCC in nostic accuracy with the most recent update pub-
VHL [65]. lished in 2017 after a structured review process
Other autosomal dominant disorders that with input from several professional groups
increase a patient’s risk for RCC include heredi- (Tables 1.2 and 1.3) [71].
tary papillary renal carcinoma, Birt-Hogg-Dubé In 1987, T1 and T2 renal lesions were divided
(BHD) syndrome, and hereditary leiomyomato- at 2.5 cm in largest dimension by imaging,
sis and renal cell carcinoma (HLRCC). The which did not differentiate well between surviv-
American Urological Association states that als for these groups [72]. In 1997, T2 disease
genetic counseling should be strongly recom- started at 7 cm for greater differentiation from
mended for patients suspected of having familial T1 [73]. The 2002 AJCC update further subdi-
RCC [66]. These conditions generally require vided T1 disease, T1a ≤4 cm and T1b 4–7 cm
screening in the form of germline mutation test- [74]. Work done by the Cleveland Clinic con-
ing rather than biomarkers. In BHD families or tributed to this development [75]. They described
patients who present with cutaneous fibrofollicu- 485 patients who underwent partial nephrec-
lomas, familial pneumothorax, or oncocytic tomy prior to 1997, finding that 5-year cancer-
RCC pathology, germline FLCN testing should specific survival was better with tumor diameter
begin at age 21. HLRCC involves a germline ≤4 cm compared to 4–7 cm and >7 cm (Fig. 1.1).
Another random document with
no related content on Scribd:
The Holy Virgin’s Descent into Hell. (XII. century.)
In spite of the prohibition of the Church, apocryphal
literature reached Russia from Byzantium by way of Bulgaria,
and not only spread all over Russia as a possession of the
people, but even crept into ecclesiastical literature, serving
frequently the same purpose as the writings of the Church
Fathers. These apocryphal productions, of which there is a
very large number, held sway over the people from the twelfth
to the seventeenth century, and even now form the
background of many popular tales and songs, especially of
those of the “wandering people” and beggars. One of the
most beautiful stories of this kind is The Holy Virgin’s Descent
into Hell, the Russian manuscript of which goes back to the
twelfth century. Similar stories were also current in Italy,
where there were colonies of Bulgarian Manicheans, who
were most active in disseminating them. Dante was, no doubt,
acquainted with them when he wrote his Divine Comedy.
The Holy Virgin wished to see the torments of the souls, and She
spoke to Michael, the archistrategos: “Tell me all things that are upon
earth!” And Michael said to Her: “As you say, Blessed One: I shall tell
you all things.” And the Holy Virgin said to him: “How many torments
are there, that the Christian race is suffering?” And the
archistrategos said to Her: “Uncountable are the torments!” And the
Blessed One spoke to him: “Show me, in heaven and upon earth!”
Then the archistrategos ordered the angels to come from the
south, and Hell was opened. And She saw those that were suffering
in Hell, and there was a great number of men and women, and there
was much weeping. And the Blessed One asked the archistrategos:
“Who are these?” And the archistrategos said: “These are they who
did not believe in the Father and the Son and the Holy Ghost, but
forgot God and believed in things which God has created for our
sakes; they called everything God: the sun and the moon, the earth
and water, beasts and reptiles. They changed Troyán, Khors, Velés,
Perún[100] to gods, and believed in evil spirits. They are even now
held in evil darkness, therefore they suffer such torments.”
And She saw in another place a great darkness. Said the Holy
Lady: “What is this darkness, and who are those who dwell therein?”
Spoke the archistrategos: “Many souls dwell in this place.” Spoke the
Holy Virgin: “Let the darkness be dispersed that I may see the
torment.” And the angels who watched over the torment answered:
“We have been enjoined not to let them see light until the coming of
your blessed Son who is brighter than seven suns.” And the Holy
Virgin was saddened, and She raised Her eyes to the angels and
looked at the invisible throne of Her Father and spoke: “In the name
of the Father and the Son and the Holy Ghost! Let the darkness be
taken off that I may see this torment.”
And the darkness was lifted, and seven heavens were seen, and
there dwelt there a great multitude of men and women, and there
was loud weeping and a mighty noise. When the Holy Virgin saw
them, She spoke to them, weeping tears: “What have you done,
wretched and unworthy people, and what has brought you here?”
There was no voice, nor an answer from them. And the watching
angels spoke: “Wherefore do you not speak?” And the tormented
said: “Blessed One! We have not seen light for a long time, and we
cannot look up.” The Holy Virgin looking at them wept bitterly. And
the tormented, seeing Her, said: “How is it, Holy Virgin, you have
visited us? Your blessed Son came upon earth and did not ask for
us, nor Abraham the patriarch, nor Moses the prophet, nor John the
Baptist, nor Paul the apostle, the Lord’s favourite. But you, Holy
Virgin and intercessor, you are a protection for the Christian
people.”... Then spoke the Holy Virgin to Michael the archistrategos:
“What is their sin?” And Michael said: “These are they who did not
believe in the Father and the Son and the Holy Ghost, nor in you,
Holy Virgin! They did not want to proclaim your name, nor that from
you was born our Lord Jesus Christ who, having come in the flesh,
has sanctified the earth through baptism: it is for this that they are
tormented here.” Weeping again, the Holy Virgin spoke to them:
“Wherefore do you live in error? Do you not know that all creation
honours my name?” When the Holy Virgin said this, darkness fell
again upon them.
The archistrategos spoke to Her: “Whither, Blessed One, do you
want to go now? To the south, or to the north?” The Blessed One
spoke: “Let us go out to the south!” And there came the cherubim
and the seraphim and four hundred angels, and took the Holy Virgin
to the south where there was a river of fire. There was a multitude of
men and women there, and they stood in the river, some to their
waists, some to their shoulders, some to their necks and some
above their heads. Seeing this, the Holy Virgin wept aloud and asked
the archistrategos: “Who are they that are immerged up to their
waists in the fire?” And the archistrategos said to Her: “They are
those who have been cursed by their fathers and mothers,—for this
the cursed ones suffer torment here.” And the Holy Virgin said: “And
those who are in the fiery flame up to their necks, who are they?”
The angel said to Her: “They are those who have eaten human flesh,
—for this they are tormented here.” And the Holy One said: “Those
who are immerged in the fiery flame above their heads, who are
they?” And the archistrategos spoke: “Those are they, Lady, who
holding the cross have sworn falsely.”... The Holy One spoke to the
archistrategos: “I beg you this one thing, let me also enter, that I may
suffer together with the Christians, for they have called themselves
the children of my Son.” And the archistrategos said: “Rest yourself
in paradise!” And the Holy One said: “I beg you, move the hosts of
the seven heavens and all the host of the angels that we may pray
for the sinners, and God may accept our prayer and have mercy
upon them. I beg you, order the angelic host to carry me to the
heavenly height and to take me before the invisible Father!”
The archistrategos so ordered, and there appeared the cherubim
and seraphim and carried the Blessed One to the heavenly height,
and put Her down at the throne of the invisible Father. She raised
Her hands to Her blessed Son and said: “Have mercy, O Master,
upon the sinners, for I have seen them, and I could not endure: let
me be tormented together with the Christians!” And there came a
voice to Her and said: “How can I have mercy upon them? I see the
nails in my Son’s hands.” And She said: “Master! I do not pray for the
infidel Jews, but for the Christians I ask Thy forgiveness!” And a
voice came to Her: “I see how they have had no mercy upon my
children, so I can have no mercy upon them.”
Spoke again the Holy One: “Have mercy, O Master, upon the
sinners,—the creation of Thine own hands, who proclaim Thy name
over the whole earth and even in their torments, and who in all
places say: “Most Holy Lady, Mother of God, aid us!” Then the Lord
spoke to Her: “Hear, Holy Mother of God! There is not a man who
does not praise Thy name. I will not abandon them, neither in
heaven, nor upon earth.” And the Holy Virgin said: “Where is Moses,
the prophet? Where are all the prophets? And you, fathers, who
have never committed a sin? Where is Paul, God’s favourite? Where
is the Sunday, the pride of the Christian? And where is the power of
the worshipful cross through which Adam and Eve were delivered
from their curse?” Then Michael the archistrategos and all the angels
spoke: “Have mercy, O Master, upon the sinners!” And Moses wept
loud and said: “Have mercy upon them, O Lord! For I have given
them Thy Law!” And John wept and said: “Have mercy, O Master! I
preached Thy gospel to them.” And Paul wept and said: “Have
mercy, O Master! For I carried Thine epistles to the churches.”
And those that were in the darkness heard of this, and they all
wept with one voice and said: “Have mercy upon us, Son of God!
Have mercy upon us, King of all eternity!” And the Master said: “Hear
all! I have planted paradise, and created man according to my
image, and made him lord over paradise, and gave him eternal life.
But they have disobeyed me and sinned in their selfishness and
delivered themselves to death.... You became Christians only in
words, and did not keep my commands; for this you find yourselves
now in the fire everlasting, and I ought not to have mercy upon you!
But to-day, through the goodness of my Father who sent me to you,
and through the intercession of my Mother who wept much for you,
and through Michael, the archistrategos of the gospel, and through
the multitude of my martyrs who have laboured much in your behalf,
I give you from Good Thursday to the holy Pentecost, day and night,
for a rest, and you praise the Father and the Son and the Holy
Ghost!” And they all answered: “Glory be to Thy goodness! Glory to
the Father and the Son and the Holy Ghost, now and for ever!”

FOOTNOTES:

[99] The slope of the mountain near Kíev, where to-day is the
suburb of Podól.
[100] Pagan divinities. For Troyán, see note on p. 82; Khors,
the god of the sun (cf. note on p. 93); Velés, the god of
abundance (cf. note on p. 83); Perún, the god of thunder (see p.
70).
Daniel the Prisoner. (XIII. century.)
For some unknown reason Daniel had been imprisoned in
an island in the Lake of Lach, in the Government of Olónetsk.
He seems to have belonged to the druzhína of Yarosláv
Vsévolodovich of Pereyáslavl, who died in 1247 as Grand
Prince of Vladímir. That is all that is known about the life of
this layman, one of the few in the old period whose writing
has come down to our times. The begging letter which he
addressed to the Prince is composed of incorrectly quoted
biblical passages and popular saws and proverbs; many of
these he drew from an ancient collection, The Bee, in which
moral subjects are arranged in chapters. In their turn, Daniel’s
saws have largely entered into the composition of a very
popular collection of the same kind, The Emerald.

LETTER TO PRINCE YAROSLÁV VSÉVOLODOVICH

We will blare forth, O brothers, on the reasoning of our mind, as on


a trumpet forged of gold. We will strike the silver organs, and will
proclaim our wisdom, and will strike the thoughts of our mind, playing
on the God-inspired reeds, that our soul-saving thoughts might weep
loud. Arise, my glory! Arise, psalter and cymbals, that I may unfold
my meaning in proverbs, and that I may announce my glory in
words.... Knowing, O lord, your good disposition, I take refuge in
your customary kindness, for the Holy Writ says: Ask and you shall
receive. David has said: There is no speech nor language, where
their voice is not heard. Neither will we be silent, but will speak out to
our master, the most gracious Yarosláv Vsévolodovich.
Prince my lord! Remember me in your reign, for I, your slave, and
son of your slave, see all men warmed by your mercy as by the sun;
only I alone walk in darkness, deprived of the light from your eyes,
like the grass growing behind a wall, upon which neither the sun
shineth nor the rain falleth. So, my lord, incline your ears to the
words of my lips, and deliver me from all my sorrow.
Prince my lord! All get their fill from the abundance of your house;
but I alone thirst for your mercy, like a stag for a spring of water. I
was like a tree that stands in the road and that all passers-by strike;
—even thus I am insulted by all, for I am not protected by the terror
of your wrath, as by a firm palisade.
Prince my lord! The rich man is known everywhere, even in a
strange city, while the poor man walketh unseen in his own. The rich
man speaketh and all are silent, and his words are elated to the
clouds; but let the poor man speak out, and all will call out to him, for
the discourse of those is honoured whose garments are bright. But
you, my lord, look not at my outer garb, but consider my inner
thoughts, for my apparel is scanty, and I am young in years, but old
in mind, and I have soared in thought like an eagle in the air.
Prince my lord! Let me behold your fair face and form. Your lips
drop honey; your utterances are like paradise with its fruit; your
hands are filled with gold of Tharsos; your cheeks are a vessel of
spices; your throat is like a lily dropping myrrh—your mercy; your
look is as the choice Lebanon; your eyes are like a well of living
water; your belly is like an heap of wheat, feeding many; your head
riseth above my head....
Prince my lord! Look not at me as a wolf at a lamb; but look at me
as a mother at her babe. Look, O lord, at the birds of the air, that
neither plough, nor sow, nor gather into granaries, but rely upon
God’s kindness. Let not your hand be closed against giving alms to
the needy. For it is written: Give to him who asketh of you, open to
him who knocketh, that you may not forfeit the kingdom of heaven.
For it is also written: Confide your sorrow to the Lord, and He will
nurture you until eternity. Deprive not the needy wise man of his
bread, but extol him to the clouds, like pure gold in a dirty vessel; but
the silly rich man is like a silken pillow-case stuffed full of straw.
Prince my lord! Though I am not a valiant man in war, yet am I
strong in words, and I cull the sweetness of words, mixing them, as
sea-water in a leather bottle, and wind them and adorn them with
cunning parables, and I am glib of speech and ... my lips are
pleasing, like a stream of the river rapids.
Prince my lord! As an oak is strong by the multitude of its roots,
thus is our city under your domination. The helmsman is the head of
the vessel, and you, Prince, are the head of your people. I have seen
an army without a prince;—you might say: a big beast without its
head. Men are the heads of women, and princes—of men, and God
—of the prince. As the pillow-case that is adorned with silk makes a
pleasant appearance, even thus you, our Prince, are glorified and
honoured in many lands through the multitude of your men. As the
net does not hold the water, but keeps a multitude of fish, even thus
you, our Prince, keep not the wealth, but distribute it among the
strong, making them brave, for you will gain gold and cities through
them. Hezekiah, the King of the Jews, boasted before the
messengers of the King of Babylon, when he showed them the
treasure of his gold. But they answered: “Our kings are richer than
you, not with the treasure of gold, but with a multitude of brave and
wise men.” (For men will gain gold, but gold will not gain men.) Water
is the mother of the fish, and you are Prince of your people. Spring
adorns the earth with flowers, and you, Prince, adorn us with your
mercy. The sun alone warms with its rays, and you, Prince, adorn
and revive with your mercy.
Prince my lord! I have been in great distress, and have suffered
under the yoke of work: I have experienced all that is evil. Rather
would I see my foot in bast shoes in your house than in crimson
boots in the court of a boyár. Rather would I serve you in homespun
than in purple in the court of a boyár. Improper is a golden ring in the
nose of a swine, and a good garment upon a peasant. Even if a
kettle were to have golden rings in its handles, its bottom would not
escape blackness and burning. Even thus a peasant: let him be ever
so haughty and insolent, he will not escape his blemish, the name of
a peasant. Rather would I drink water in your house, than mead in
the court of a boyár; rather would I receive a roasted sparrow from
your hand than a shoulder of mutton from the hand of a bad master.
Often has my bread, earned by work, tasted as wormwood in my
mouth, and my drink I have mingled with tears. Serving a good
master, you gain your liberty in the end, but serving a bad master,
you only gain an increase of your labour. Solomon has said: Better is
one wise man than ten brave men without understanding; better is
one clever man than ten rulers of cities. Daniel has said: A brave
man, O Prince, you will easily acquire, but a wise man is dear; for
the counsel of the wise is good, and their armies are strong, and
their cities safe. The armies of others are strong, but without
understanding, and they suffer defeat. Many, arming themselves
against large cities, start out from smaller towns; as Svyatosláv, the
son of Ólga, said on his way to Constantinople to his small druzhína:
“We do not know, O brothers, whether the city is to be taken by us,
or whether we are to perish from the city: for if God is with us, who is
against us?”...
Not the sea draweth the ships, but the winds; even thus you, O
Prince, fall not yourself into grieving, but counsellors lead you into it.
Not the fire causeth the iron to be heated, but the blowing of the
bellows. A wise man is not generally valiant in war, but strong in
counsel; so it is good to gather wise men around you. It is good to
pasture horses in a fertile field (and to fight for a good prince). Often
armies perish through lack of order. If the armies are strongly placed,
they will, though they be defeated, make a good running fight; thus
Svyatopólk, who was guilty of killing his brothers, was so fortified,
that Yarosláv barely overcame him at night. Similarly Bonyák the
Scurfy through cunning routed the Hungarians at Gálich: when the
latter fortified themselves behind ramparts, the first scattered like
hunting men over the land; thus they routed the Hungarians, and
badly defeated them.
Prince my lord! I have not been brought up in Athens, nor have I
studied with the philosophers, but I have pored over books, like a
bee over all kinds of flowers: from them have I gathered sweetness
of speech, mingling wisdom with it, as sea-water in a leather bottle....
Serapión, Bishop of Vladímir. (XIII. century.)
Serapión had been abbot of the monastery of the Grottoes
in Kíev, and in 1274 he was made bishop of Vladímir and
Súzdal. He died in 1275. We have five of his sermons, which
are distinguished for a certain simple, stern eloquence. The
thirteenth century produced very few writers, and Serapión’s
sermons have an additional interest because they contain
references to the Tartar invasion.

A SERMON ON OMENS

The Lord’s blessing be with you!


You have heard, brothers, what the Lord Himself has said in the
gospel: in the last years there will be signs in the sun, in the moon,
and in the stars, and earthquakes in many places, and famine. What
had been foretold by the Lord then, is now fulfilled in our days.[101]
We have seen many times the sun perished, the moon darkened,
and the stars disturbed, and lately we have seen with our own eyes
the quaking of the earth. The earth, firm and immovable from the
beginning by the order of God, is in motion to-day, trembling on
account of our sins, being unable to bear our lawlessness. We did
not obey the gospel, did not obey the apostles, nor the prophets, nor
the great luminaries, I mean Basil and Gregory the theologues, John
Chrysostom, and the other holy fathers, by whom the faith was
confirmed, the heretics repelled, and God made known to all the
nations. They have taught us without interruption, but we are living in
lawlessness.
It is for this that God is punishing us with signs and earthquakes.
He does not speak with His lips, but chastises with deeds. God has
punished us with everything, but has not dispelled our evil habits:
now He shakes the earth and makes it tremble: He wants to shake
off our lawlessness and sins from the earth like leaves from a tree. If
any should say that there have been earthquakes before, I shall not
deny it. But what happened to us afterwards? Did we not have
famine, and plague, and many wars? But we did not repent, until
finally there came upon us a ruthless nation, at the instigation of
God, and laid waste our land, and took into captivity whole cities,
destroyed our holy churches, slew our fathers and brothers, violated
our mothers and sisters. Now, my brothers, having experienced that,
let us pray to our Lord, and make confession, lest we incur a greater
wrath of the Lord, and bring down upon us a greater punishment
than the first.
Much is still waiting for our repentance and for our conversion. If
we turn away from corrupt and ruthless judgments, if we do away
with bloody usury and all rapacity, thefts, robbery, blasphemy, lies,
calumny, oaths, and denunciations, and other satanic deeds,—if we
do away with all that, I know well that good things will come to us in
this life and in the future life. For He Himself hath said: Turn to me,
and I will turn to you. Keep away from everything, and I will withhold
your punishment. When will we, at last, turn away from our sins? Let
us spare ourselves and our children! At what time have we seen so
many sudden deaths? Many were taken away before they could care
for their houses; many lay down well in the evening and never arose
again. Have fear, I pray you, of this sudden parting! If we wander in
the will of the Lord, God will comfort us with many a comfort, will
cherish us as His sons, will take away from us earthly sorrow, will
give us a peaceful exit into the future life, where we shall enjoy
gladness, and endless happiness with those who do the will of the
Lord.
I have told you much, my brothers and children, but I see our
punishments will not be diminished, nor changed. Many take no
heed, as if they weened themselves to be immortal. I am afraid that
the word of God will come to pass with them: If I had not spoken to
them, they would not have sinned; but now they have no excuse for
their sin. And I repeat to you, if we do not change, we shall have no
excuse before the Lord. I, your sinful pastor, have done the
command of God in transmitting His word to you.
FOOTNOTES:

[101] These disturbances of nature are mentioned in the


Chronicle under the year 1230.
The Zadónshchina. (XIV. century.)
The Zadónshchina, i. e., The Exploits beyond the Don, has
come down in two versions, and is an interesting poetical
account of the battle at Kulikóvo (1380). The Word of Ígor’s
Armament had taken a strong hold on the author, who seems
to have been a certain Sofóniya of Ryazán. Not only are there
many parallels in the two poems, but whole passages are
bodily taken from the older text, with corruption of some
phrases, the meaning of which was not clear to the author of
the Zadónshchina.

THE ZADÓNSHCHINA

Let us go, O brothers, into the midnight country, the lot of Japheth,
[102] the son of Noah, from whom has risen the most glorious Russia;
let us there ascend the Kíev mountains, and look by the smooth
Dnieper over the whole Russian land, and hence to the Eastern land,
the lot of Shem, the son of Noah, from whom were born the Chinese,
[103] the pagan Tartars, the Mussulmans. They had defeated the race

of Japheth on the river Kayála.[104] And ever since, the Russian land
has been unhappy, and from the battle of the Kálka[105] up to
Mamáy’s defeat it has been covered with grief and sorrow, weeping
and lamenting its children. The Prince and the boyárs, and all the
brave men who had left all their homes, and wealth, and wives,
children, and cattle, having received honour and glory of this world,
have laid down their heads for the Russian land and the Christian
faith.
Let us come together, brothers and friends, sons of Russia! Let us
join word to word! Let us make the Russian land merry, and cast
sorrow on the eastern regions that are to the lot of Shem! Let us sing
about the victory over the heathen Mamáy, and an eulogy to the
Grand Prince Dmítri Ivánovich and his brother,[106] Prince Vladímir
Andréevich!... We shall sing as things have happened, and will not
race in thought, but will mention the times of the first years; we will
praise the wise Boyán,[107] the famous musician in Kíev town. That
wise Boyán put his golden fingers on the living strings, sang the
glory of the Russian princes, to the first Prince Rúrik, Ígor Rúrikovich
and Svyatosláv, Yaropólk, Vladímir Svyatoslávich, Yarosláv
Vladímirovich, praising them with songs and melodious musical
words.—But I shall mention Sofóniya of Ryazán, and shall praise in
songs and musical words the Prince Dmítri Ivánovich and his
brother, Prince Vladímir Andréevich, for their bravery and zeal was
for the Russian land and the Christian faith. For this, Grand Prince
Dmítri Ivánovich and his brother, Prince Vladímir Andréevich,
sharpened their hearts in bravery, arose in their strength, and
remembered their ancestor, Prince Vladímir of Kíev, the tsar of
Russia.
O lark, joy of beautiful days! Fly to the blue clouds, look towards
the strong city of Moscow, sing the glory of Grand Prince Dmítri
Andréevich! They have risen like falcons from the Russian land
against the fields of the Pólovtses. The horses neigh at the Moskvá;
the drums are beaten at the Kolómna; the trumpets blare at
Serpukhóv; the glory resounds over the whole Russian land.
Wonderfully the standards stand at the great Don; the embroidered
flags flutter in the wind; the gilded coats of mail glisten. The bells are
tolled in the vyéche[108] of Nóvgorod the Great. The men of
Nóvgorod stand in front of St. Sophia, and speak as follows: “We
shall not get in time to the aid of Grand Prince Dmítri Ivánovich.”
Then they flew together like eagles from the whole midnight country.
They were not eagles that flew together, but posádniks[109] that went
out with 7000 men from Nóvgorod the Great to Grand Prince Dmítri
Ivánovich and to his brother Vladímir Andréevich.
All the Russian princes came to the aid of Grand Prince Dmítri
Ivánovich, and they spoke as follows: “Lord Grand Prince! Already
do the pagan Tartars encroach upon our fields, and take away our
patrimony. They stand between the Don and Dnieper, on the river
Mechá.[110] But we, lord, will go beyond the swift river Don, will gain
glory in all the lands, will be an object of conversation for the old
men, and a memory for the young.”
Thus spoke Grand Prince Dmítri Ivánovich to his brothers, the
Russian princes: “My dear brothers, Russian princes! We are of the
same descent, from Grand Prince Iván Danílovich.[111] So far we
brothers have not been insulted either by falcon, or vulture, or white
gerfalcon, or this dog, pagan Mamáy.”
Nightingale! If you could only sing the glory of these two brothers,
Ólgerd’s sons,[112] Andréy of Pólotsk and Dmítri of Bryansk, for they
were born in Lithuania on a shield of the vanguard, swaddled under
trumpets, raised under helmets, fed at the point of the spear, and
given drink with the sharp sword. Spoke Andréy to his brother Dmítri:
“We are two brothers, sons of Ólgerd, grandchildren of Gedemín,
great-grandchildren of Skoldimér. Let us mount our swift steeds, let
us drink, O brother, with our helmets the water from the swift Don, let
us try our tempered swords.”
And Dmítri spoke to him: “Brother Andréy! We will not spare our
lives for the Russian land and Christian faith, and to avenge the
insult to Grand Prince Dmítri Ivánovich. Already, O brother, there is a
din and thunder in the famous city of Moscow. But, brother, it is not a
din or thunder: it is the noise made by the mighty army of Grand
Prince Dmítri Ivánovich and his brother Prince Vladímir Andréevich;
the brave fellows thunder with their gilded helmets and crimson
shields. Saddle, brother Andréy, your good swift steeds, for mine are
ready, having been saddled before. We will ride out, brother, into the
clear field, and will review our armies, as many brave men of
Lithuania as there are with us, but there are with us of the brave men
of Lithuania seven thousand mailed soldiers.”
Already there have arisen strong winds from the sea; they have
wafted a great cloud to the mouth of the Dnieper, against the
Russian land; bloody clouds have issued from it, and blue lightnings
flash through them. There will be a mighty din and thunder between
the Don and the Dnieper, and bodies of men will fall on the field of
Kulikóvo, and blood will flow on the river Nepryádva, for the carts
have already creaked between the Don and Dnieper, and the pagan
Tartars march against the Russian land. Grey wolves howl: they wish
at the river Mechá to invade the Russian land. Those are not grey
wolves: the infidel Tartars have come; they wish to cross the country
in war, and to conquer the Russian land. The geese have cackled
and the swans have flapped their wings,—pagan Mamáy has come
against the Russian land and has brought his generals....
What is that din and thunder so early before daybreak? Prince
Vladímir Andréevich has reviewed his army and is leading it to the
great Don. And he says to his brother, Grand Prince Dmítri
Ivánovich: “Slacken not, brother, against the pagan Tartars, for the
infidels are already in the Russian land, and are taking away our
patrimony!”...
The falcons and gerfalcons have swiftly flown across the Don, and
have swooped down on the many flocks of swans: the Russian
princes have attacked the Tartar might, and they strike with their
steel lances against the Tartar armour; the tempered swords thunder
against the Tartar helmets on the field of Kulikóvo, on the river
Nepryádva. Black is the earth under the hoofs, but they had sowed
the field with Tartar bones, and the earth was watered with their
blood, and mighty armies passed by and trampled down hills and
fields, and the rivers, springs and lakes were turbid. They uttered
mighty cries in the Russian land ... and they vanquished the Tartar
horde on the field of Kulikóvo, on the river Nepryádva.
On that field mighty clouds encountered, and in them lightnings
frequently flashed, and terrible thunders clapped: it is the Russian
brave warriors who were engaging the pagan Tartars for the great
insult, and their mighty gilded armour glistened, and the Russian
princes thundered with their tempered swords against the Tartar
helmets....
At that time neither soldiers nor shepherds called in the field near
the Don, in the land of Ryazán, but only ravens croaked for the sake
of the bodies of the dead, so that it was a terror and a pity to hear:
for the grass was watered with blood, and the trees were bent to the
ground with sorrow, and the birds sang pitiful songs. All princesses
and wives of the boyárs and generals wept for the slain. Fedósya,
the wife of Mikúla Vasílevich,[113] and Mary, the wife of Dmítri, wept
early in the morning at Moscow, standing on the city wall, and spoke
as follows: “Don, Don, you are a swift river, and have cut through
stone walls, and flow through the land of the Pólovtses! Bring back
my beloved one to me!”...
All over the Russian land there spread joy and merriment: the
Russian glory was borne through the land, but shame and
destruction came on the pagan Tartars, evil Mussulmans.... The
Grand Prince by his own bravery and with his druzhína vanquished
pagan Mamáy for the sake of the Russian land and the Christian
faith. The pagans deposited their own arms under the Russian
swords, and the trumpets were not sounded, their voices were silent.
Mamáy galloped away from his druzhína, howled like a grey wolf,
and ran away to the city of Khafest....[114]

FOOTNOTES:

[102] The Byzantine chronographers generally begin their


accounts with Noah; so does Néstor, who follows those sources.
[103] The original has a word derived from Khin, which seems
to be identical with “China,” and is used in general for Asiatics.
[104] See pp. 75 and 89.
[105] The battle with the Tartars at the river Kálka took place in
1224.
[106] Vladímir Andréevich was the cousin of Dmítri Donskóy,
the son of Iván II.
[107] In the text the word is boyarin, i. e., “boyár,” evidently a
corruption of Boyán, which is one of the proofs of the
Zadónshchina being a later imitation of the Word of Ígor’s
Armament.
[108] Popular assembly of Nóvgorod.
[109] Burgomasters or governors of Nóvgorod.
[110] Tributary of the Don.
[111] Iván Kalitá, 1328-1340.
[112] These Lithuanian Princes had acknowledged the
sovereignty of Moscow.
Afanási Nikítin. (XV. century.)
Nikítin set out about 1468 for India, whence he returned in
1474. He wrote out an account of his many adventures, which
is interesting for its sober though rather one-sided narration. It
stands alone in the old Russian literature as the writing of a
layman bent on a commercial enterprise. His Travel to India
has been translated by Count Wielhorsky for the Hakluyt
Society.

TRAVEL TO INDIA

I, poor sinner, brought a stallion to the land of India; with God’s


help I reached Junir all well, but it cost me a hundred roubles.
The winter began from Trinity day, and we wintered at Junir and
lived there two months; but day and night for four months there is but
rain and dirt. At this time of the year the people till the ground, sow
wheat, tuturegan (?), peas, and all sorts of vegetables. Wine is kept
in large skins (?) of Indian goats....
Horses are fed on peas; also on kichiris, boiled with sugar and oil;
early in the morning they get shishenivo. Horses are not born in that
country, but oxen and buffaloes; and these are used for riding,
conveying goods, and every other purpose.
Junir stands on a stony island; no human hand built it—God made
the town. A narrow road, which it takes a day to ascend, admitting of
only one man at a time, leads up a hill to it.
In the winter, the people put on the fata, and wear it around the
waist, on the shoulders, and on their head; but the princes and
nobles put trowsers on, a shirt and a caftan, wearing a fata on the
shoulders, another as a belt round the waist, and a third round their
head.
O God, true God, merciful God, gracious God!
At Junir the Khan took away my horse, and having heard that I
was no Mahommedan, but a Russian, he said: “I will give thee the
horse and a thousand pieces of gold, if thou wilt embrace our faith,
the Mahommedan faith; and if thou wilt not embrace our
Mahommedan faith, I shall keep the horse and take a thousand
pieces of gold upon thy head.” He gave me four days to consider,
and all this occurred during the fast of the Assumption of our Lady,
on the eve of our Saviour’s day (18th of August).
And the Lord took pity upon me because of His holy festival, and
did not withdraw His mercy from me, His simple servant, and allowed
me not to perish at Junir among the infidels. On the eve of our
Saviour’s day there came a man from Khorassan, Khozaiocha
Mahmet, and I implored him to pity me. He repaired to the Khan into
the town, and praying him delivered me from being converted, and
took from him my horse. Such was the Lord’s wonderful mercy on
the Saviour’s day.
Now, Christian brethren of Russia, whoever of you wishes to go to
the Indian country may leave his faith in Russia, confess Mahomet,
and then proceed to the land of Hindostan. Those Mussulman dogs
have lied to me, saying I should find plenty of our goods; but there is
nothing for our country. All goods for the land of Mussulmans, as
pepper and colours, and these are cheap.
The rulers and the nobles in the land of India are all
Khorassanians. The Hindoos walk all on foot and walk fast. They are
all naked and bare-footed, and carry a shield in one hand and a
sword in the other. Some of the servants are armed with straight
bows and arrows.
Elephants are greatly used in battle. The men on foot are sent
first, the Khorassanians being mounted in full armour, man as well as
horse. Large scythes are attached to the trunks and tusks of the
elephants, and the animals are clad in ornamental plates of steel.
They carry a citadel, and in the citadel twelve men in armour with
guns and arrows.
There is a place Shikhbaludin Peratyr, a bazaar Aladinand, and a
fair once a year, where people from all parts of India assemble and

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