Ebook Sarcoma of the female genitalia (Vol 1): Part 1

The book provides a description at length of the epidemiology, etiology, pathological anatomy, prognosis, diagnosis, differential diagnosis, imaging and comprehensive therapy of each primary, relapsed, and metastasized tumor including surgery, chemo-, hormone- and radio- and targeted therapy.

Philipp-Andreas Hessler, Lars Kaderali,

Hanka Lehnhoff, Lisa Linke

Medicine Greifswald and German Clinical Center of

Excellence for Genital Sarcomas and Mixed Tumors

Ferdinand-Sauerbruch-Straße

17475 Greifswald, Germany

e-mail: koehlerg@uni-greifswald.de

Prof Dr Marek Zygmunt

Department of Obstetrics and Gynecology, University

Medicine Greifswald and German Clinical Center of

Excellence for Genital Sarcomas and Mixed Tumors

Dr Katja Evert Institute of Pathology, University Hospital Regensburg and German Clinical Center of Excellence for Genital Sarcomas and Mixed Tumors, Greifswald

Franz-Josef-Strauß-Allee 11

93053 Regensburg, Deutschland e-mail: katja.evert@ukr.de

Collaborators

Dr Philipp-Andreas Hessler

Department of Gynecologic Surgery, Center of

Minimal-Invasive Surgery, Sachsenhausen,

Frankfurt/Main/Germany

Prof Dr Lars Kaderali

Institute for Bioinformatics, University Medicine

Greifswald/Germany

Hanka Lehnhoff Department of Obstetrics and Gynecology University Medicine Greifswald, Germany and German Clinical Center of Excellence for Genital Sarcomas and Mixed Tumors, Greifswald/Germany

Lisa Linke Department of Obstetrics and Gynecology University Medicine Greifswald and German Clinical Center of Excellence for Genital Sarcomas and Mixed Tumors, Greifswald/Germany

ISBN 978-3-11-035141-5

e-ISBN (PDF) 978-3-11-035197-2

e-ISBN (EPUB) 978-3-11-038763-6

The publisher, together with the authors and editors, has taken great pains to ensure that all information

presented in this work (programs, applications, amounts, dosages, etc.) reflects the standard of knowledge at the time of publication Despite careful manuscript preparation and proof correction, errors can nevertheless occur Authors, editors and publisher disclaim all responsibility and for any errors or omissions or liability for the results obtained from use of the information, or parts thereof, contained in this work.

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© 2017 Walter de Gruyter GmbH, Berlin/Boston

Cover image: Hackelöer HJ, Kreiselmaier P Facharzt-Zentrum für Kinderwunsch Pränatale Medizin, Endokrinologie u Osteologie, Amedes Experts Hamburg, Hamburg, Germany

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This monograph, comprising two volumes, discusses typical sarcomas of the femalegenitalia, including angiosarcoma, liposarcoma and rhabdomyosarcoma as well asthe different types of mixed tumors Other rare mesenchymal genital tumors are alsocomprehensively presented, such as the different variants of leiomyoma, smoothmuscle tumors with uncertain malignant potential, endometrial stromal nodules,endometrial stromal tumors with sex cord-like elements (ESTSCLE), uterine tumorresembling ovarian sex-cord/stromal tumor (UTROCST) and PEComas The behavior

of the aforementioned neoplasms in relation to, and in the context of fertility andpregnancy is covered in a separate chapter Another chapter is devoted to the preven-tion of subjecting sarcomas to inadequate surgical therapeutic measures under theassumed diagnosis of leiomyoma, and includes a diagnostic-therapeutic flowchartwith a diagnostic score The following subsections are provided for each of the tumorentities listed above: epidemiology, etiology, macroscopy and microscopy, clinicalpresentation, diagnostics, imaging, differential diagnostics, prognosis, surgical andradiation therapy for the primary tumor or recurrences and metastases includingprimary, adjuvant and palliative chemotherapy, hormone therapy, targeted therapyand aftercare

The substantial basis for this monograph comprises 1,681 fully documented coma consultation cases of the German Clinical Center of Excellence for GenitalSarcomas and Mixed Tumors (“Deutsches klinisches Kompetenzzentrum für geni-tale Sarkome und Mischtumoren”, DKSM), University Medicine Greifswald/Germany,and the data kindly provided by our cooperation partners “Velener Working Group onAmbulatory Surgery” (“Velener Arbeitsgemeinschaft Ambulantes Operieren Deutsch-land”, VAAO) and the Department Gynecologic Surgery, Center of Minimal-InvasiveSurgery, Sachsenhausen/Frankfurt Main/Germany

sar-The overriding aim of this monograph is to identify and provide therapeutic ance on the basis of evaluation of the DKSM data performed by the DKSM doctoralresearch group “uterine sarcomas”, as well as on 2,025 literature sources, recommen-dations and studies published up to the end of May 2016 Particular attention hasbeen devoted to determining, as far as possible, which measures can currently not

guid-be defined as standard practice In total, 576 figures and illustrations have guid-been porated and are comprehensively described

incor-The listed tumor entities also constitute a particular diagnostic challenge forpathologists that is beset with numerous pitfalls and difficulties This monograph,therefore, addresses gynecologists and pathologists in both clinical and private prac-tice, but also surgeons and hemato-oncologists

Sincere thanks must be extended to a total of 112 gynecologists, pathologists, diologists, hemato-oncologists and medical practitioners in clinical and private prac-tice, but also affected patients, who kindly provided figures, images and data for use

ra-in this monograph

Greifswald and Regensburg, June 2016

Prof Dr G Köhler, Prof Dr M Zygmunt,

Department of Obstetrics and Gynecology, University Medicine Greifswald

and German Clinical Center of Excellence for Sarcomas and Mixed Tumors,

Greifswald

Prof Dr M Evert, Dr Katja Evert

Institute of Pathology, University Hospital Regensburg

and German Clinical Center of Excellence for Genital Sarcomas and Mixed Tumors,Greifswald

sarcoma surgery (ISBN: 978-3-11-035141-5)

Volume 2: Other rare sarcomas, mixed tumors, genital sarcomas and pregnancy

(ISBN: 978-3-11-045921-0)

List of abbreviations|XXI

Definition of cytoreduction, NCCN-Guidelines|XXV

Immunohistochemistry table|XXVI

Volume 1

Günter Köhler, Katja Evert, Marek Zygmunt and Matthias Evert

1 Variants of leiomyoma (angio- and lipoleiomyoma, cotyledonoid and

cellular leiomyoma, leiomyoma with bizarre nuclei, mitotically active, epithelioid and myxoid leiomyoma), smooth muscle tumors with uncertain malignant potential (atypical smooth muscle tumors), disseminated peritoneal leiomyomatosis, benign metastasizing leiomyoma, intravenous

1.1 Angioleiomyoma (Angiomyoma, vascular leiomyoma)|1

1.1.1 General, epidemiology, etiology, pathogenesis,

1.2.1 General, pathogenesis, pathological-anatomical findings|6

1.2.2 Clinical presentation, diagnostics, imaging, differential

diagnostics|7

1.2.3 Course, prognosis, primary surgery, systemic and radiogenic

therapy|8

1.3 Cotyledonoid dissecting leiomyoma|8

1.3.1 General, pathogenesis, pathological-anatomical findings|8

1.3.2 Clinical presentation, diagnostics, imaging, differential

diagnostics|9

1.3.3 Course, prognosis, primary surgery, systemic and radiogenic

therapy|9

1.4 Cellular leiomyoma|10

1.4.1 General, pathogenesis, pathological-anatomical findings|10

1.4.2 Clinical presentation, diagnostics, imaging, differential

diagnostics|13

1.4.3 Course, prognosis, primary surgery, systemic and radiogenic

therapy|19

1.4.4 Aftercare, recurrences, metastases|22

1.5 Leiomyoma with bizarre nuclei|23

1.5.1 General, pathogenesis, pathological-anatomical findings|23

1.5.2 Clinical presentation, diagnostics, imaging, differential

diagnostics|26

1.5.3 Course, prognosis, primary surgery, systemic and radiogenic

therapy|26

1.6 Mitotically active leiomyoma|27

1.6.1 General, pathogenesis, pathological-anatomical findings|27

1.6.2 Clinical presentation, diagnostics, imaging, differential

diagnostics|28

1.6.3 Course, prognosis, primary surgery, systemic and radiogenic

therapy|30

1.7 Epithelioid leiomyoma|30

1.7.1 General, pathogenesis, pathological-anatomical findings|30

1.7.2 Clinical presentation, diagnostics, imaging, differential

diagnostics|32

1.7.3 Course, prognosis, primary surgery, systemic and radiogenic

therapy|33

1.8 Myxoid leiomyoma|33

1.8.1 General, pathogenesis, pathological-anatomical findings|33

1.8.2 Clinical presentation, diagnostics, imaging, differential

diagnostics|35

1.8.3 Course, prognosis, primary surgery, systemic and radiogenic

therapy|35

1.9 Atypical smooth muscle tumors (smooth muscle tumors with uncertain

malignant potential – STUMP), epithelioid and myxoid leiomyoma withuncertain malignant potential|36

1.9.1 General, pathogenesis, pathological-anatomical findings|36

1.9.2 Clinical presentation, diagnostics, imaging, differential

1.10 Leiomyoma, its variants and smooth muscle tumors with uncertain

malignant potential of the vulva|56

1.10.1 General, pathogenesis, pathological-anatomical findings|56

1.10.2 Clinical presentation, diagnostics, imaging, differential

diagnostics|57

1.10.3 Course, prognosis, primary surgery, systemic and radiogenic

therapy|58

1.11 Ovarian and tubal leiomyomas, their variants and smooth muscle

tumors with uncertain malignant potential|59

1.11.1 General, pathogenesis, pathological-anatomical findings|59

1.11.2 Clinical presentation, diagnostics, imaging, differential

diagnostics|60

1.11.3 Course, prognosis, primary surgery, systemic and radiogenic

therapy|61

1.12 Retroperitoneal and vaginal pelvic leiomyomas, their variants and

smooth muscle tumors with uncertain malignant potential|62

1.12.1 General, pathogenesis, pathological-anatomical findings|62

1.12.2 Clinical presentation, diagnostics, imaging, differential

diagnostics|62

1.12.3 Course, prognosis, primary surgery, systemic and radiogenic

therapy|65

1.13 Disseminated (diffuse) peritoneal leiomyomatosis (Leiomyomatosis

peritonealis disseminata) and parasitic leiomyoma|65

1.13.1 General, pathogenesis, pathological-anatomical findings|65

1.13.2 Clinical features, diagnostics, imaging, differential diagnostics|72

1.13.3 Course, prognosis, primary surgery, systemic and radiogenic

therapy|76

1.13.4 Aftercare, recurrences, metastases, surgical management and

postoperative additive therapy for recurrences and metastatic

disease|79

1.14 Benign metastasizing leiomyoma (MLM)|81

1.14.1 General, pathogenesis, pathological-anatomical findings|81

1.14.2 Clinical presentation, diagnostics, imaging, differential

diagnostics|84

1.14.3 Course, prognosis, primary surgery, systemic and radiogenic

therapy|88

1.14.4 Aftercare, recurrences, metastases, surgical management and

postoperative additive therapy for recurrences and metastatic

disease|92

1.15 Intravenous (intravascular) leiomyomatosis (IVLM)|92

1.15.1 General, pathogenesis, pathological-anatomical findings|92

1.15.2 Clinical presentation, diagnostics, imaging, differential

diagnostic|95

1.15.3 Course, prognosis, primary surgery, systemic and radiogenic

therapy|98

1.15.4 Aftercare, recurrences, metastases, surgical management and

postoperative additive therapy for recurrences and metastaticdisease|101

Günter Köhler, Katja Evert, Marek Zygmunt and Matthias Evert

2.1 Uterine leiomyosarcoma|119

2.1.1 General, epidemiology, etiology, pathogenesis, staging|119

2.1.2 Macroscopic and microscopic features|124

2.1.3 Clinical presentation, diagnostics, screening|134

2.1.4 Imaging|139

2.1.5 Differential diagnostics|150

2.1.6 Course, prognosis|155

2.1.7 Primary surgery|161

2.1.8 Adjuvant and additive radio-, chemo- and hormone therapy|166

2.1.9 Primary radio-, chemo- and hormone therapy, approach in cases

of general inoperability|170

2.1.10 Aftercare, recurrences, metastases|172

2.1.11 Surgical management and postoperative additive therapy for

recurrences and metastatic disease|177

2.1.12 Palliative radio-, chemo- and hormone therapy, treatment

with small molecules, supportive therapy|184

2.2 Leiomyosarcoma of the ovary|192

2.2.1 General, epidemiology, etiology, pathogenesis, staging,

2.3 Leiomyosarcoma of the fallopian tube|196

2.3.1 General, pathogenesis, pathological-anatomical findings|196

2.3.2 Clinical presentation, diagnostics, imaging, differential

diagnostics|196

2.3.3 Course, prognosis, primary surgery, systemic and radiogenic

therapy|196

2.4 Leiomyosarcoma of the uterine, pelvic and ovarian veins|197

2.4.1 General, pathogenesis, staging, pathological-anatomical

findings|197

2.4.2 Clinical presentation, diagnostics, imaging, differential

diagnostics|197

2.4.3 Course, prognosis, primary surgery, systemic and radiogenic

therapy|198

2.5 Leiomyosarcoma of the vagina|199

2.5.1 General, pathogenesis, staging, pathological-anatomical

2.6 Leiomyosarcoma of the vulva|203

2.6.1 General, pathogenesis, pathologic-anatomical features|203

2.6.2 Clinical presentation, diagnostics, imaging, differential

diagnostics|205

2.6.3 Course, prognosis, primary surgery, systemic and radiogenic

therapy|206

Günter Köhler, Katja Evert, Marek Zygmunt and Matthias Evert

3 Endometrial stromal tumors – endometrial stromal nodule, endometrial

stromal tumor with sex cord-like elements (ESTSCLE), uterine tumor resembling ovarian sex-cord tumor (UTROSCT) and similar tumors|231

3.1 Endometrial stromal nodule|231

3.1.1 Uterine endometrial stromal nodule|231

3.1.2 Extrauterine endometrial stromal nodules|243

3.2 Special variants of endometrial stromal tumors|243

3.2.1 Endometrial stromal tumor with endometrioid glands|243

3.2.2 Mixed endometrial stromal and smooth muscle tumor,

combined stromal-smooth muscle|243

3.2.3 Uterine tumor with sex cord-like elements type I

(ESTSCLE, endometrial stromal tumor with sex cord-like

elements)|244

3.2.4 Uterine tumors with sex cord-like elements type II (UTROSCT, uterine

tumors resembling ovarian sex-cord tumors)|247

Günter Köhler, Katja Evert, Marek Zygmunt and Matthias Evert

4.1 Uterine low-grade endometrial stromal sarcoma|257

4.1.1 General, epidemiology, etiology, pathogenesis, staging|257

4.1.2 Macroscopic and microscopic features|260

4.1.3 Clinical presentation, diagnostics, screening|267

4.1.4 Imaging|270

4.1.5 Differential diagnostics|279

4.1.6 Course, prognosis|282

4.1.7 Primary surgery|288

4.1.8 Adjuvant and additive radio-, chemo- and hormone therapy|291

4.1.9 Primary radio-, chemo- and hormone therapy, approach in cases

of general inoperability|296

4.1.10 Aftercare, recurrences, metastases|298

4.1.11 Surgical management and postoperative additive therapy for

recurrences and metastatic disease|301

4.1.12 Palliative radio-, chemo- and hormone therapy, treatment

with small molecules, supportive therapy|304

4.2 Extrauterine endometrial stromal sarcomas|309

Günter Köhler, Katja Evert, Marek Zygmunt and Matthias Evert

5 High-grade endometrial stromal sarcoma and undifferentiated uterine

5.1 Uterine high-grade endometrial stromal sarcoma and undifferentiated

uterine sarcoma|327

5.1.1 General, epidemiology, etiology, pathogenesis, staging|327

5.1.2 Macroscopic and microscopic features|329

5.1.3 Clinical presentation, diagnostics, screening|335

5.1.4 Imaging|336

5.1.5 Differential diagnostics|343

5.1.6 Course, prognosis|346

5.1.7 Primary surgery|349

5.1.8 Adjuvant and additive radio, chemo and hormone therapy|351

5.1.9 Primary radio-, chemo- and hormone therapy, approach in cases

of general inoperability|354

5.1.10 Aftercare, recurrences, metastases|356

5.1.11 Surgical management and postoperative additive therapy for

recurrences and metastatic disease|358

5.1.12 Palliative radio-, chemo- and hormone therapy, treatment

with small molecules, supportive therapy|361

5.2 Extrauterine high-grade endometrial stromal sarcomas

and undifferentiated uterine sarcomas|365

Günter Köhler, Lars Kaderali, Matthias Evert and Marek Zygmunt

6.1 Inadequate surgical treatment of uterine sarcomas in leiomyoma

surgery|373

6.2 Inadequate surgical treatment of sarcomas and STUMP – impact on

prognosis|373

6.3 Prevalence of uterine sarcomas in hysterectomies and surgery

performed under the indication of leiomyoma|380

6.4 Anamnestic and clinical criteria suggestive of uterine sarcoma in cases

of supposed leiomyoma|382

6.5 Further, extended diagnostics when there are findings suggestive of

uterine sarcoma in cases of assumed leiomyoma|388

6.6 Diagnostic flowchart for preventing the performance of inadequate

surgery on sarcomas under an assumed indication of

leiomyoma|395

6.7 Risk assessment as a decision-making aid when surgery is planned

under an indication of leiomyoma|398

6.8 Measures to be applied when sarcoma have been subjected

to inadequate surgery under an indication of leiomyoma|400

1.1.1 General, epidemiology, etiology, pathogenesis, staging|1

1.1.2 Macroscopic and microscopic features|2

1.1.3 Clinical presentation, diagnostics, screening|4

1.1.4 Imaging|4

1.1.5 Differential diagnostics|5

1.1.6 Course, prognosis|6

1.1.7 Primary surgery|6

1.1.8 Adjuvant and additive radio-, chemo- and hormone therapy|8

1.1.9 Primary radio-, chemo- and hormone therapy, approach in cases

of general inoperability|9

1.1.10 Aftercare, recurrences, metastases|10

1.1.11 Surgery and postoperative additive therapy for recurrences

and metastases|10

1.1.12 Palliative radio-, chemo- and hormone therapy, small molecule therapy,

supportive therapy|12

1.2 Extrauterine angiosarcomas|14

1.2.1 Angiosarcomas of the vulva and the vagina|14

1.2.2 Angiosarcoma of the ovary and the tuba uterina|18

Günter Köhler, Katja Evert, Marek Zygmunt and Matthias Evert

2.1 Uterine liposarcoma|29

2.1.1 General, epidemiology, etiology, pathogenesis, staging|29

2.1.2 Macroscopic and microscopic features|31

2.1.3 Clinical presentation, diagnostics, screening|35

2.1.4 Imaging|35

2.1.5 Differential diagnostics|40

2.1.6 Course, prognosis|40

2.1.7 Primary surgery|42

2.1.8 Adjuvant and additive radio-, chemo- and hormone therapy|43

2.1.9 Primary radio-, chemo- and hormone therapy, approach in cases

of general inoperability|45

2.1.10 Aftercare, recurrences, metastases|46

2.1.11 Surgical management of and postoperative additive therapy

for recurrences and metastatic disease|48

2.1.12 Palliative radio-, chemo- and hormone therapy, therapy

with small molecules, supportive therapy|49

3.1.1 General, epidemiology, etiology, pathogenesis, staging|64

3.1.2 Macroscopic and microscopic features|70

3.1.3 Clinical presentation, diagnostics, screening|73

3.1.4 Imaging|75

3.1.5 Differential diagnostics|77

3.1.6 Course, prognosis|78

3.1.7 Primary surgery|83

3.1.8 Adjuvant and additive radio-, chemo- and hormone therapy|87

3.1.9 Primary radiation, hormone and chemotherapy, approach in cases

of general inoperability|91

3.1.10 Aftercare, recurrences, metastases|94

3.1.11 Surgical management and postoperative additive therapy

for recurrences and metastatic disease|95

3.1.12 Palliative radiotherapy, chemotherapy and hormone therapy,

therapy with small molecules|96

3.2 Extrauterine rhabdomyosarcoma|98

3.2.1 Rhabdomyosarcoma of the ovary and the fallopian tube|98

3.2.2 Rhabdomyosarcomas of the vulva and the vagina|102

Günter Köhler, Katja Evert, Marek Zygmunt and Matthias Evert

4 Perivascular epithelioid cell tumor (PEComa)|117

4.1 PEComa of the uterus|117

4.1.1 General, epidemiology, etiology, pathogenesis, staging|117

4.1.2 Macroscopic and microscopic features|119

4.1.3 Clinical presentation, diagnostics, screening|122

4.1.4 Imaging|123

4.1.5 Differential diagnostics|125

4.1.6 Course, prognosis|128

4.1.7 Primary surgery|128

4.1.8 Adjuvant and additive radio-, chemo- and hormone therapy|129

4.1.9 Primary radio-, chemo- and hormone therapy, approach in cases

of general inoperability|130

4.1.10 Aftercare, recurrences, metastases|131

4.1.11 Surgical management and postoperative additive treatment

for recurrences and metastatic disease|132

4.1.12 Palliative radio-, chemo- and hormone therapy, therapy with small

molecules, supportive therapy|133

4.2 Extrauterine and extragenital PEComas|135

4.2.1 General, pathogenesis, pathologic-anatomical features|135

4.2.2 Clinical presentation, diagnostics, imaging, differential

diagnostics|136

4.2.3 Course, prognosis, operative, systemic and radiogenic therapy|138

Günter Köhler, Katja Evert, Marek Zygmunt and Matthias Evert

5.1 Uterine adenofibroma|143

5.1.1 General, pathogenesis, pathologico-anatomical features|143

5.1.2 Clinical presentation, diagnostics, imaging, differential diagnostics,

screening|146

5.1.3 Course, prognosis, operative, systemic and radiogenic therapy|148

5.1.4 Aftercare, recurrences, metastases and their treatment|150

5.2 Extrauterine adenofibromas|151

5.2.1 Adenofibromas of the ovary and the fallopian tube|151

Günter Köhler, Katja Evert, Marek Zygmunt and Matthias Evert

6.1 Uterine adenosarcoma|157

6.1.1 General, epidemiology, etiology, pathogenesis, staging|157

6.1.2 Macroscopic and microscopic features|159

6.1.3 Clinical presentation, diagnostics, screening|165

6.1.4 Imaging|166

6.1.5 Differential diagnostics|171

6.1.6 Course, prognosis|173

6.1.7 Primary surgery|176

6.1.8 Adjuvant and additive radio-, chemo- and hormone therapy|180

6.1.9 Primary radio-, chemo- and hormone therapy, approach in cases

of general inoperability|184

6.1.10 Aftercare, recurrences, metastases|186

6.1.11 Surgical management and postoperative additive therapy

for recurrences and metastatic disease|188

6.1.12 Palliative radio-, chemo- and hormone therapy,

treatment with small molecules, supportive therapy|190

6.2 Extrauterine and extragenital adenosarcomas|194

6.2.1 Adenosarcomas of the ovary and the fallopian tube|194

6.2.2 Adenosarcoma of the vagina|196

6.2.3 Extragenital adenosarcomas|196

Günter Köhler, Katja Evert, Marek Zygmunt and Matthias Evert

7.1 Uterine carcinosarcoma|205

7.1.1 General, epidemiology, etiology, pathogenesis, staging|205

7.1.2 Macroscopic and microscopic features|209

7.1.3 Clinical presentation, diagnostics, screening|217

7.1.4 Imaging|219

7.1.5 Differential diagnostics|226

7.1.6 Course, prognosis|230

7.1.7 Primary surgery|234

7.1.8 Adjuvant and additive radio-, chemo- and hormone therapy|239

7.1.9 Primary radio-, chemo- and hormone therapy, approach in case

of general inoperability|248

7.1.10 Aftercare, recurrences, metastases|250

7.1.11 Surgical and postoperative additive treatment for recurrences

and metastatic disease|252

7.1.12 Palliative radio-, chemo- and hormone therapy,

therapy with small molecules, supportive therapy|254

7.2 Extrauterine carcinosarcoma|261

7.2.1 Carcinosarcoma of the ovary|261

7.2.2 Carcinosarcoma of the fallopian tube|276

7.2.3 Peritoneal carcinosarcoma|277

7.2.4 Extraperitoneal carcinosarcoma|278

Marek Zygmunt, Matthias Evert, Katja Evert and Günter Köhler

8 Fertility and pregnancy and variants of leiomyoma, smooth muscle tumors

of unclear malignant potential, stromal tumors, genital sarcomas, PEComas

8.1 General, symptoms, clinical presentation, diagnostics,

differential diagnostics, prognosis|297

8.2 Disseminated (diffuse) peritoneal leiomyomatosis|300

8.3 Intravenous (intravascular) leiomyomatosis|301

8.4 Benign metastasizing leiomyomas|302

8.5 Leiomyoma and its variants|303

8.6 Smooth muscle tumors of uncertain malignant potential|304

8.8 Endometrial stromal nodules and uterine tumors with sex cord-like

elements type I and II (ESTSCLE and UTROSCT)|308

8.9 Low-grade endometrial stromal sarcoma|309

8.10 High-grade endometrial stromal sarcomas and undifferentiated

AAGL American Association of Gynecologic Laparoscopists

AUB Abnormal uterine bleeding(s)

BSO Bilateral Salpingo-oophorectomy

DFS Disease free survival

DKSM Deutsches klinisches Kompetenzzentrum für genitale Sarkome und Mischtumoren

Universitätsmedizin Greifswald (German Clinical Center of Excellence for Genital Sarcomas and Mixed Tumors, University Medicine Greifswald)

DPLM Disseminated (diffuse) peritoneal leiomyomatosis

DSS Disease specific survival

DW-MRI Diffusion-weighted magnetic resonance imaging

EGF(R) Epithelial growth factor (receptor)

ERMS Embryonal rhabdomyosarcoma

ERT External (percutaneous) radiotherapy

ESN Endometrial stromal nodule

EST Endometrial stromal tumor

ESTSCLE Endometrial stromal tumor with sex cord-like elements

FDG-PET F-FDG-PET ( 18 F-2-Fluor-2-deoxy-D-glucose-PET) FES-PET F-FES-PET (16α- 18 F-fluoro-17β estradiol-PET)

GCIG Gynecologic Cancer InterGroup

GIST Gastrointestinal stromal tumors

GnRH Gonadotropin-releasing hormone

HE-stain Hematoxylin and eosin stain

HG-ESS High-grade endometrial stromal sarcoma HMB45 Human melanoma black 45

HPF High power field (400× magnification)

Lig Ligamentum, ligament

LG-ESS Low-grade endometrial stromal sarcoma LITT Laser-induced thermotherapy

LVI Lymphovascular invasion

M/10 HPF Counted mitoses per 10 HPF

MLM Benign metastasizing leiomyoma

MPA Medroxyprogesterone acetate

MRI Magnetic resonance imaging

MRT Magnetic resonance tomography

mTOR Mammalian target of rapamycin

N/L-ratio Neutrophil/lymphocyte ratio

NOS Not otherwise specified

NPV Negative predictive value

PDGF(R) Platelet-derived growth factor (receptors)

PEComa Perivascular epithelioid cell tumor

PET-CT Positron emission tomography

PFI Progression free interval

PFS Progression free survival

RAH Radical abdominal hysterectomy

RFA Radiofrequency ablation

RFI Relapse free interval

RFS Relapse free survival

RT Radiation therapy, radiotherapy, ERT with and without VBT

RVH Radical vaginal hysterectomy

SAH Supracervical abdominal hysterectomy

SEER Surveillance, Epidemiology and End Results

SERM Selective estrogen receptor modulator

SHE Supracervical hysterectomy

SI Signal intensity (in MRI)

SIRT Selective internal radiation therapy

SLH Supracervical laparoscopic hysterectomy

STS Soft tissue sarcoma

STUMP Smooth muscle tumor with uncertain malignant potential

SUV Standardized uptake value

T1W, T2W T1/T2 weighted MRI

T1WC T1 weighted contrast MRI

T1W-FS T1 or T2 weighted MRI with fat suppression, occasionally also T1/2W STIR

T2W-FS see T1W-FS

TAH Total abdominal hysterectomy

TCN Tumor cell necrosis

TKI Tyrosine kinase inhibitor

TLH Total laparoscopic hysterectomy

TVH Total vaginal hysterectomy

TVS Transvaginal sonography

UCS Uterine carcinosarcoma

UES Undifferentiated endometrial sarcoma

UPA Ulipristal acetate

UTROSCT Uterine tumor resembling ovarian sex-cord stromal tumor UUS Undifferentiated uterine sarcoma

VA Vincristine plus actinomycin

VAC Vincristine plus actinomycin D plus cyclophosphamide VAI Vincristine plus actinomycin D plus ifosfamide

VBT Vaginal brachytherapy

VEGF(R) Vascular endothelial growth factor (receptor)

WT-1 Wilms tumor Gen 1

Cytoreduction (debulking)

– Maximal cytoreduction (debulking): no macroscopically visible residual disease,

patient clinically tumor-free

– Optimal cytoreduction (debulking): only residual disease with a diameter or height of < 1 cm (< 2 cm according to some sources)

– Suboptimal cytoreduction (debulking): residual disease > 1 cm (> 2 cm according to

1 Variants of leiomyoma (angio- and lipoleiomyoma, cotyledonoid and cellular leiomyoma, leiomyoma with bizarre nuclei, mitotically active, epithelioid and myxoid leiomyoma), smooth muscle tumors with uncertain malignant potential (atypical

smooth muscle tumors), disseminated peritoneal leiomyomatosis, benign metastasizing leiomyoma, intravenous leiomyomatosis

1.1 Angioleiomyoma (Angiomyoma, vascular leiomyoma)

1.1.1 General, epidemiology, etiology, pathogenesis, pathological-anatomical findings

The current WHO Classification (183) does not list uterine ALM as a variant of LM.However, the clinical features of ALM justify that they are discussed in the context

of LM ALM is a smooth muscle tumor and is thus deemed a soft tissue tumor (261).Most ALM arise in the skin of the extremities (89 %) and in the vicinity of the head(9 %) (82) Women are noticeably more frequently affected than men are One strikingfeature of ALM is its ample degree of vascularization Furthermore, ALM have clinicalfeatures that are suggestive of malignant behavior, but do not fulfill the malignancycriteria This applies to the frequent localization of such tumors in the lower extrem-ity in particular These suspicious clinical findings can lead to (even intraoperative)confusion with a malignant mesenchymal tumor

Uterine and other genital ALM are very rare and are almost always an unexpecteddiagnosis There is one account of a large ALM in the ligamentum latum in a 52-year-old woman (44) The uterine variant typically arises during pubescence The few avail-able data suggest that extrauterine forms occur slightly later, in the 5th and 6th decade

of life (260), though there is a known case of an enormous ALM in a 19-year-old woman(222) Very little is known about this unusual LM in terms of pathogenesis and etiology

It appears to develop from the smooth musculature of the veins

The strong degree of vascularity lends such tumors a brownish-red to deepred/blueish-red (Fig 1.1.1 (A)), sometimes pink to yellowish macroscopic appear-ance The presence of ample dilated vessels renders ALM relatively soft compared

to ordinary uterine LM, and elastic like rubber The so-called solid type can also berelatively coarse in comparison ALM often have a lobulated appearance, but cannonetheless be clearly delineated from surrounding tissues Both solid and cystic

structures as well as opened vessels and hemorrhages can be visible on the cut face Very large tumors often exhibit necrosis An abundance of larger vessels canalso give the cut-surface a sponge-like look (88) These macroscopic features oftengive the impression of a malignant tumor Like ordinary LM, multiple ALM can arisesynchronously Furthermore, ALM can be submucously, intramurally and subseros-ally localized Subserosal ALM can develop extraperitoneally into the ligamentumlatum or the abdominal cavity via pedicular growth, and clinically mimic a solid,relatively soft adnexal tumor (36, 84) There are reports of tumors reaching diameters

sur-of up to 28 cm (100) ALM easily bleed when touched Since the definitive diagnosiscannot be made on the basis of clinical criteria alone, the unusual appearance of ALMshould give rise to intraoperative histologic clarification via frozen section

ALM are also microscopically well-delineated from their surroundings They ically have noticeably elevated numbers of large, thick-walled, arteriole-like vessels.The uniform spindle-like smooth muscle cells are often swirled around the vessels(36) ALM are histologically differentiated into the solid/capillary, cavernous andvenous subtypes Cavernous and venous ALM are characterized by strongly dilatatedvascular spaces with narrow media and the ample presence of vessels with thickmuscular walls (82, 117) Necroses, mitoses and atypia are usually not observed, andwhen they are, they do not account for a substantial share of the tumor’s total volume(Fig 1.1.1 (B))

render-The spindle cells are positive for SMA, desmin, vimentin, caldesmon, ER and PGR(36, 58, 84, 91, 154) Cytokeratins are not expressed The vascular component is im-munoreactive for CD34 (84), though there are also reports of CD34 negative tumors(58) Immunostaining for CD10 and HMB45 is negative in ALM.

Angioleiomyoma is a benign variant of leiomyoma and is very rare Little is known about such tumors in terms of etiology and pathogenesis Macroscopically speaking, angioleiomyomas are well-delineated tumors with a rubber-like consistency on palpation, and can appear solid and cys- tic Angioleiomyomas exhibit a huge degree of vascularization Histologic appearance resembles ordinary leiomyoma, but with numerous capillary or cavernously dilated vessels and thick-walled veins.

1.1.2 Clinical presentation, diagnostics, imaging, differential diagnostics

ALM largely correspond to LM in terms of clinical symptomatology and findings,though there are some noteworthy particularities Bleeding, predominantly as heavymenstrual bleeding, is often severe and can swiftly result in anemia On palpa-tion, ALM seem softer and more elastic than ordinary LM, and the uterus can bediffusely/irregularly enlarged Like ordinary LM, ALM can reach enormous dimen-sions They can literally fill the entire lower abdomen, and occasionally be equivalent

in size to 40 weeks’ gestation (84, 88, 129, 222) Rapid growth is not uncommon.Large cavernous ALM can contain ample amounts of blood In one case, a cavernousALM weighed 5.1 kg and contained 2 liters of blood (129) Intratumoral bleeding withclotting occasionally results in consumptive coagulopathy (88) The large amount

of blood can “mimic” rapid growth, cause pains in the lower pelvis and justify asuspected diagnosis of sarcoma Otherwise, pains are rather the exception in patientswith genital ALM, and more frequently occur when the tumor is localized in theextremities Curettage indicated for AUB as well as twisting off pedunculated submu-cosal ALM can result in severe bleeding that can be difficult to arrest, if need be via HE.There are accounts in which tumors have spontaneously ruptured, causing massivebleeding and hemoperitoneum (51) They can mimic a ruptured ectopic pregnancy.Taking all of the presented findings and features together should suffice to at leastsuspect ALM However, the proper diagnosis is only rarely reached preoperatively,even when there are typical symptoms

In the majority of cases, ALM are subjected to further diagnostics because of per)menorrhagia or a “rapidly growing uterus” Besides palpatory examination, curet-tage and HSC appear to be the primary methods of choice in practice due to the AUB.However, the correct diagnosis can often not be reached on the basis of curettage,unless myometrium could also be retrieved via very sharp or “vigorous” curettage, orunless the tumor is submucosal

(hy-Ordinary LM is the most important DD A rubbery consistency should be deemedsuggestive of ALM On occasion, soft DLM can masquerade as ALM Pedunculated

subserosal ALM can reach considerable dimensions and are barely discernible frommobile ovarian tumors on palpation (84) Compared to malignant ovarian tumors,however, ascites is absent and CA-125 values are not elevated in ALM (22, 84, 102).Sonography reveals a well-circumscribed uterine mass with heterogeneous echo-genicity, solid components and numerous anechoic voids that correspond to vessels(58, 91, 100) These voids are noticeably larger in cavernous ALM, and can achievethe size of small cysts Doppler sonography shows a diffuse distribution of vesselsthroughout the entire tumor Blood flow speed is elevated and the resistant index islow Ultimately, LM with pronounced vascularity should be deemed suspicious of be-ing ALM Sarcoma would be a justifiable differential diagnostic consideration in thesecases Strongly vascularized tumors also clearly present as such in sonography whenlocalized in the ligamentum latum (44).

ALM often appear as heterogeneous lobulated tumors in CT They can also appear

to be multicystic, or contain both solid and cystic components The borders betweenthese two components can be irregular, i.e the components can exhibit a certain de-gree of “blending” (84, 91, 100) In CECT, the presence of prominent, wound, vessel-like enhancing structures in tissue masses that are well-delineated from the uterinewall should be regarded as being suggestive of ALM

T2W-MRI reveals a tumor with both hyperintense fluid-filled and solid intense areas that correspond to the smooth musculature These two structuresirregularly blend into each other The solid components show strong enhancement inT1WC (91) The solid structures thus correspond to the MRI picture of LM However,neither DLM nor a malignant tumor can be properly ruled out via diagnostic imaging(187) Larger, mixed solid and multicystic ALM are sometimes not discernible fromovarian tumors in MRI (80) The PET-CT shows no increase of activity (91) It is veryeffective in differentiating ALM from malignant tumors

hypo-In summary, the simultaneous presence of cystic and solid structures is the sive feature in imaging diagnostics The solid structures exhibit the MRI characteris-tics of LM The combined context of medical history, clinical findings and diagnosticimaging justifies at least a suspicion of ALM

deci-The symptoms of and findings for uterine angioleiomyoma largely correspond to those of ordinary leiomyoma However, angioleiomyomas are noticeably softer and often exhibit rapid growth Ab- normal uterine bleeding is usually more pronounced Severe bleeding can occur during curettage.

In sonography, angioleiomyomas are well-delineated, exhibit ample vascularity, contain numerous anechoic voids, and possibly cystic sections Angioleiomyomas have marked strong central vas- cularity in Doppler sonography CT often reveals a heterogeneous lobulated mass that can contain both solid and cystic components T2W-MRI shows a coincidence of hypointense solid sections and numerous fluid-filled spaces The solid components show strong enhancement in contrast MRI.

The coincidence of a uterine tumor and rapid growth can arouse a suspicion of uterinesarcoma, not least because the latter also have a softer consistency than ordinary LM

In contrast to the very rare uterine ANS (see also ANS, Vol 2, Chapter 1), ALM do notexpress CD34 (58) The implications of a rapidly growing uterus are discussed at length

in the chapter on LMS (Chapter 2) DLM can bear close gross resemblance to ALM interms of consistency and color From a clinical perspective, very rare uterine heman-gioma is another differential diagnostic possibility However, hemangiomas and ALMdiffer in that the former is usually not well-delineated from its surroundings, neithermacroscopically nor microscopically Arteriovenous malformations have similar fea-tures and appearance to hemangiomas (84) PEComa can be ruled out on the basis ofHMB45 negativity (58)

While the cystic components revealed in diagnostic imaging are suggestive ofALM, they are usually a sign of LM degeneration Such findings sometimes also con-stitute a cystic adenomyoma, or innate intrauterine cysts (204)

Endometrial stromal sarcomas are also highly vascular in microscopy, but theirvessels are not thick-walled The very rare uterine ANS macroscopically differ fromALM in that they are poorly circumscribed, while microscopy reveals pronounced cel-lular pleomorphism and positive immunostaining for ERG and CD31 In contrast to thesuspicious clinical and macroscopic findings, the risk of mistaking ALM with sarcoma

in histology is low

Ordinary leiomyoma is the pivotal clinical differential diagnosis Rapid growth, tumor softness and suspicious sonography can be suggestive of sarcoma.

1.1.3 Course, prognosis, primary surgery, systemic and radiogenic therapy

ALM are without doubt benign Clinical course can be complicated by heavy bleeding,pain and potential tumor rupture ALM subjected to surgery have an excellent prog-nosis that corresponds to that for LM ALM have a Ki67 index of between 0 und 25 %(mean 2 %) (156) Only two cases have been reported in which local recurrence devel-oped after surgery on extragenital ALM, though no mention is made of the surgicalprocedures applied (82)

The (usually strong) menorrhagia and the risk of tumor rupture require that thethreshold for surgery be set more generously than for ordinary LM Once the proper di-agnosis has been reached, further surgical treatment should be performed according

to the criteria for LM surgery THE is the standard surgical procedure Bleeding can beample in the course of surgery, rendering endoscopic procedures rather inadequate.There is no indication for BSO Whether or not it is opted for BSO will thus depend

on the desire of the patient, her menopausal status, or on the presence of anotherindication for the procedure Since ALM are without doubt benign, patients can alsoundergo conservative, uterus-sparing surgery The large volumes of blood involvedcan complicate tumor enucleation or morcellation procedures

Adjuvant or additive therapy is not indicated, because ALM are without doubtbenign.

There is no indication for primary RT or CHT No data have been published onthe treatment of ALM with progestins, antiprogestins, GnRH analogues and UPA Inthe event that a certain amount of time needs to be bridged until surgery can be per-formed, analogous to ordinary LM, there is currently no reason not to administer GnRHanalogues or UPA as a means of symptom control, i.e stopping bleeding Due to itsgood adverse effect profile, UPA might be particularly adequate for treating stronghypermenorrhea In a recent study, applying the AI letrozole (2.5 mg over 3 mo) topremenopausal LM patients (aged 30–55 years) achieved a tumor volume reduction of

> 50 % and significant symptomatology improvements (63) AI apparently inhibits matases and, subsequently, the production of estradiol within LM (63) Administering

aro-10 mg mifepristone vaginally daily achieved similar clinical results in a comparablesample (273) In Germany, AI and mifepristone are only eligible for off-label use

No data are available regarding the application of invasive-conservative dures like embolization and high-frequency ultrasound therapy, not least becauseALM are so uncommon

proce-Like ordinary leiomyoma, angioleiomyoma is a benign tumor Hysterectomy is the standard cal method, though strong intraoperative bleeding must be reckoned with There is no indication for any type of adjuvant therapy GnRH analogues or ulipristal acetate can be applied in order to bridge time until surgery and as a means for controlling symptoms.

surgi-1.1.4 Aftercare, recurrences, metastases and their treatment

No special follow-up strategy is necessary HRT can be applied in cases in which theovaries have been removed, under consideration of the general indications and con-traindications

Angioleiomyomas do not require special aftercare or follow-up.

1.2 Lipoleiomyoma

1.2.1 General, pathogenesis, pathological-anatomical findings

Under WHO Classification, LLM is regarded as an independent variant of LM (183).LLM contain a mixture of mature adipocytes and smooth muscle cells They appear

to predominantly arise in postmenopausal women (259) Chromosomal aberrationshave been observed in a number of LLM (175) LLM account for 0.28 % of all LM It

is suspected that the shortage of estrogen in postmenopausal women might inducetransformation of smooth muscle cells and facilitate the build-up of fat deposits (141)

The results provided by a working group of the DKSM reveal that LLM account for0.98 % of LM (126) Affected women frequently have disorders in their fat-relatedmetabolism and are often heavy by comparison LLM are relatively soft tumors with

a whitish-yellowish color on the cut surface Purely adipocytic areas appear yellowand are very soft LLM have an average diameter of 4.6 cm Fat tissue can account forstrongly varying shares of total tumor volume (Fig 1.2.1), ranging from microscopicamounts to almost the entire tumor (43) Lipoblasts, mitoses and atypia are absent(see also Tab 1.9.1)

Fig 1.2.1:Histologic aspect of a lipoleiomyoma The tumor is characterized by a stroma with mediate collagen levels Small fascicles of leiomyocytes and small groups of univacuolar fat cells, all without atypia, are embedded in the stroma.

Tumors with a pronounced vascular component consisting of arteries, veins or finable vessels are referred to as angiolipoleiomyoma (275) The latter has nothing to

unde-do with angiomyolipoma from the PEComa family (cf PEComa, Vol 2, Chapter 4) LLMcan also arise in the vicinity of the ligamentum latum (260)

Lipoleiomyomas contain a mixture of mature adipocytes and smooth muscle cells and nantly arise in postmenopausal women.

predomi-1.2.2 Clinical presentation, diagnostics, imaging, differential diagnostics

LLM exhibit the symptoms of ordinary LM, but are usually asymptomatic LLM are ally only diagnosed as such after surgery, if prior diagnostic imaging reveals nothingsuspicious

usu-As is the case for all adipocytic tumors, sonography reveals more or less sive hyperechoic areas in an otherwise hypoechoic uterine mass (191) In native CTand CECT, the adipocytic accumulations are recognizable, both natively and withinthe enhancing LM, on the basis of their weaker attenuation (191) T1 and T2W-MRIreveal high SI that is typically encountered in fat tissue (191) Hypointense sectionscorrespond to the smooth muscle component A diagnosis of an adipocytic tumor can

expan-be secured via fat suppression (13, 149) Malignant uterine and extrauterine genitaladipocytic sarcomas are the most important DD in diagnostic imaging

Lipoleiomyoma corresponds to ordinary leiomyoma in terms of clinical features and behavior agnostic imaging can produce suspicions of lipoleiomyoma on the basis of the hyperechoic sono- graphic findings and high signal intensity in T1W and T2W-MRI.

Di-1.2.3 Course, prognosis, primary surgery, systemic and radiogenic therapy

LLM is a benign tumor Constituting a variant of LM, the “International Classification

of Diseases for Oncology” deems LLM benign and codes it with “0” (183) However,malignant transformation appears to be generally possible (182) HE constitutes thetherapeutic measure of choice Conservative, organ-sparing surgery is also possible.There is no indication for adjuvant or additive RT, CHT or HT The same appliesfor primary or neoadjuvant CHT and/or RT in generally inoperable cases

Lipoleiomyomas are benign Hysterectomy is the procedure of choice, organ-sparing surgery is possible There is no indication for systemic or radiogenic therapy.

1.3 Cotyledonoid dissecting leiomyoma

1.3.1 General, pathogenesis, pathological-anatomical findings

Cotyledonoid LM is listed as an independent variant of LM in the current WHO cation (183) Cotyledonoid dissecting LM (or Sternberg tumor) exhibits benign smoothmuscle proliferation with tongue-like spread This tumor thus belongs to the group of

Classifi-LM with unusual growth patterns Affected women are aged between 23 and 73 years(mean 44, median 46) Atypia, mitoses and tumor necrosis are not present in cotyle-donoid dissecting LM (121, 224) Growth beyond the uterus into the ligamentum la-tum is frequently observed (121, 187, 204) Cotyledonoid dissecting LM can also fillthe entire pelvis (75) There are also known accounts of entirely extrauterine growth(152, 215) Adhesions with neighboring organs without infiltration are not uncommon(224) Intravascular involvement is observed in 21 % of cases (152, 224) Accordingly, tu-mors vary considerably in size, ranging from 4 to 41 cm, with a mean widest diameter

of 14.2 cm Cotyledonoid LM generally exhibit prominent vessels and strong ponic change Combined with the edemas and vessels, the tumor’s dark-red color andsponge-like structure render it similar to placental cotyledons when it has spread be-yond the uterus (hence the name) Based on their appearance, cotyledonoid LM aresometimes also referred to as grape-like tumors (182, 211, 275) Epithelioid variantshave been described (32) Despite the tumor’s “threatening” macroscopic and micro-scopic spread characteristics, including VI, it remains benign and can be discernedfrom STUMP and LMS (see below) on the basis of its macroscopy and the defined his-tologic criteria (absence of TCN, atypia and mitoses) (see also Tab 1.9.1)

hydro-Cotyledonoid dissecting leiomyoma is characterized by benign smooth muscle proliferation with tongue-like extension within the myometrium Prominent vessels, hydropic changes and extension beyond the uterus are common They give the tumor a placenta-like appearance.

1.3.2 Clinical presentation, diagnostics, imaging, differential diagnostics

Symptoms most closely resemble those of LM Cotyledonoid dissecting LM has a ticeable rubbery consistency on palpation Severe pelvic pain can arise when there isspread within the pelvis Cotyledonoid LM is largely identical to ordinary LM in sonog-raphy (121) and MRI (152) The tumor is homogeneously isointense to surroundingmyometrium and neighboring LM in T1W-MRI T2W shows moderate heterogeneous SIthat is higher than that of neighboring LM, but lower than that of normal myometrium

no-In T1WC, cotyledonoid dissecting LM shows strong enhancement with minimal erogeneity, as do neighboring LM However, SI is slightly higher than in ordinary LM(152, 224) There are ample noticeable signal voids that correspond to the high de-gree of vascularity (203) Cotyledonoid LM can be clinically mistaken with adnexaltumors The macroscopic, placenta-like appearance might be deemed suggestive ofmalignancy or sarcoma (32, 121, 187) DPLM, IVLM or parasitic LM are further possibleDD

het-Cotyledonoid dissecting leiomyoma is accompanied by symptoms comparable to those of ordinary leiomyoma They have a noticeably rubbery consistency on palpation Their outer appearance of- ten gives rise to suspicions of sarcoma In diagnostic imaging, both sonography and MRI reveal numerous voids, which correspond to vessels, within the typical leiomyoma picture.

1.3.3 Course, prognosis, primary surgery, systemic and radiogenic therapy

Cotyledonoid LM are without doubt benign As a variant of LM, the “InternationalClassification of Diseases for Oncology” deems such tumors benign and codes themwith “0” (183) THE is the therapeutic measure of choice In general, given the un-usual growth pattern of these tumors, recurrences need to be reckoned with whenconservative surgery is opted for Organ-sparing operations should, therefore, only beperformed upon critical deliberation, and should leave no microscopic residual dis-ease There are two reports of cases in which recurrences arose, reportedly as a result

of residual disease (211, 237) Continuous growth with uncontrollable AUB were served in a case of a patient who underwent incomplete surgery (210) However, thereare also reports of cases in which there was no recurrence despite R1 resection andthe presence of LVI (81, 224) In one case, a patient in whom a superficial tumor hadbeen incompletely resected gave birth via cesarean section after an uneventful preg-nancy No residual tumor was found (215) In another case, a cotyledonoid LM wasexcised completely at 14 weeks of gestation, and cesarean section to term revealed

ob-that the uterus was disease-free (152) Judging by the presented experiences, it pears as though recurrences only occur in patients with at least microscopic residualdisease Reresection/completion surgery should, therefore, be considered in cases inwhich there is microscopic or macroscopic residual tumor.

ap-There is no indication for adjuvant or additive RT, CHT or HT The same appliesfor primary and neoadjuvant CHT and/or RT in generally inoperable cases

In one case report, applying GnRH analogues achieved a (albeit minor) sion (215) Temporary treatment with GnRH analogues can, therefore, be adequate forbridging the time until surgery or impending menopause

remis-Cotyledonoid leiomyoma is a benign tumor Total hysterectomy is the measure of choice R0 section is the method of choice when there is extrauterine spread Uterus-sparing surgery can be adequate if it leaves no microscopic residual disease There is no indication for systemic or radio- genic therapy Short-term therapy with GnRH analogues can be considered in inoperable cases.

re-1.4 Cellular leiomyoma

1.4.1 General, pathogenesis, pathological-anatomical findings

The current WHO Classification (183) categorizes CLM as a variant of benign LM Atumor is classified as CLM if it is significantly more cellular than normal myometrium,but exhibits no nuclear atypia or TCN, and has fewer than 4 M/10 HPF (43) Highly cel-lular leiomyomas can achieve levels of cellularity comparable to ESN or LG-ESS (178).Around 0.7 to 5 % of LM are deemed cellular, roughly equivalent to the frequency ofatypical LM, mitotically active LM and LMS combined (207) According to calcula-tions by the DKSM (126), CLM account for 1.2 % (1 in 83 cases) of all myoma operations(n = 2,500) Affected patients are aged between 27 and 72 years (median 46, mean

44.7–45.3) (78, 178, 239) CLM is without doubt morphologically benign However,chromosome 1p deletions were observed in 23 % of CLM in more recent molecular-genetic studies (96) CLM with 1p deletions more frequently occur in postmenopausalpatients and are larger than tumors without this defect CLM with 1p deletions havecharacteristics that bear resemblance to those of LMS (96, 239) From a clinical andprognostic perspective, CLM should be classified as STUMP (see prognosis) Notwith-standing, CLM do not exhibit the elevated MI or the moderate-to-severe atypia thatare typically present in STUMP

The rate of simultaneous adenomyosis and endometriosis is significantly lower inwomen with CLM than such with ordinary LM (239) These findings suggest that CLMand LM harbor etiologic and pathogenetic differences

CLM range in size from 2–10 cm (mean 6.1–7.5 cm, median 8.5 cm) (78, 212, 239).They are smaller than or roughly equal in size to LMS, for which a case-control study(78) and the DKSM data reveal median sizes of 10.7 cm and 8 cm, respectively CLM

are, however, considerably larger than ordinary LM, and can reach enormous sions (Fig 1.4.1 (A)) (231) CLM arise as solitary tumors in 53.6 % of cases, and consti-tute the largest lesion among numerous coinciding LM in 96 % of cases (239) Inter-estingly, CLM with 1p deletions are larger than tumors without this defect CLM areusually noticeably softer than ordinary LM as a result of their pronounced cellular-ity and the sparsity of connective tissue structures (Fig 1.4.1 (A), (C)) CLM lack thewhorled structure typically found on the cut surface of LM, and can thus appear to

dimen-be fleshier than ordinary LM The cut surface is gray to pink or brownish-yellowish

in color (Fig 1.4.1 (D), 1.4.3 (E)) Cystic structures (Fig 1.4.1 (B)), hemorrhages and/ornecroses are common (96), and are signs of the tumor’s rapid growth, that proves to

be too fast for vascularization to keep pace with

CLM show intense blue coloration in HE staining as a result of the ample presence

of spindle cells and the resulting high degree of nuclear density with only scant plasm (Fig 1.4.2 (A), (B)) As a result, delineation from the surroundings appears to besharper than is the case with ordinary LM More than 50 % of highly cellular LM haveirregular borders to the myometrium (see also ESN Fig 3.1.1 (B)) (178) The cells are ar-ranged more diffusely at the center, and in a more fascicular fashion in the peripheralregions of the tumor The tumor cells vary in terms of their shape, which is sometimesround, oval or typically spindle-shaped

cyto-Spindle cells account for the largest proportion of total tumor volume, but are dominantly located at the periphery of the tumor (178) The nuclei exhibit no or onlymild atypia (178) No mitoses can be verified in roughly one third of cases MI does notexceed 2 M/10 HPF in 56.4 % of CLM, while 5.1 % of CLM have an MI of 3–5 M/10 HPF(see also Tab 1.9.1) (78) In another source, an MI of 5–10 M/10 HPF was observed in2.4 % of CLM (212) CLM typically have ample thick-walled, in part hyalinized muscu-lar blood vessels that are sometimes dilatated The microscopic features of the bloodvessels are a helpful criterion for discerning CLM from LG-ESS and ESN, which arecharacterized by spiral artery-like vessels (178) Hemorrhages and infarct-like necrosesare often observed CLM with 1p deletions are more commonly highly cellular andmore frequently exhibit hyaline necroses (96) Hemorrhagic CLM with multifocal hem-orrhages are also referred to as “apoplectic LM” They appear to occur more frequently

pre-in pregnant women and women who take oral contraceptives (172)

CLM differ from LMS in that they show strong and diffuse staining for ER and PGR(275)

The Ki67 index is elevated in 76.7 % of CLM (78) Ki67 index in CLM ranges from0–10 % (mean 3 %), while the figures for atypical LM and LMS are 0 to 25 % (mean 2 %)and 6 to 50 % (mean 25 %), respectively In a different study (276), a mean of 63, 136 and2,425 Ki67 positive cells was found per 10 HPF in CLM, STUMP and LMS, respectively.However, this proliferation marker should always be interpreted with caution whendifferentiating between these three tumor types Furthermore, the Ki67 index does notappear to be suitable for predicting recurrence (156)

A leiomyoma is a cellular leiomyoma if it exhibits significantly higher cellularity than normal ometrium Cellular leiomyoma is a benign tumor when such assessment is based on microscopic criteria However, it appears to differ from ordinary leiomyoma in terms of etiology and pathogen- esis Tumors with chromosome 1p deletions show clinical characteristics reminiscent of leiomyo- sarcoma Cellular leiomyomas are larger than ordinary leiomyomas on average, have a fleshier appearance on the cut surface, and occasionally have cystic areas Thick-walled blood vessels are

my-a pmy-articulmy-arly conspicuous femy-ature of cellulmy-ar leiomyommy-a Focmy-al minor my-atypimy-a cmy-an occur, the number

of mitoses generally does not exceed 2 M/10 HPF in most cases.

(A) (B)

Fig 1.4.2:Cellular leiomyoma in microscopy (A) its high cellular density makes cellular leiomyoma difficult to histologically discern from stromal nodules or low-grade endometrial stromal sarcomas under weak magnification (compare to Fig 3.1.1 (A) ESN and Fig 4.1.7 (A) LG-ESS); (B) even under stronger magnification, the cells often more closely resemble those of endometrial stromal tu- mors (compare to Fig 4.1.4 (A) LG-ESS) than those of conventional leiomyoma This is a result of the sparse cytoplasm and the low density of myofilaments, which give the tumor a less eosinophilic appearance than that of ordinary LM.

1.4.2 Clinical presentation, diagnostics, imaging, differential diagnostics

CLM do not differ from “ordinary LM” in terms of symptomatology Irregular menstrualbleeding, mostly in form of heavy menstrual bleeding, is the common symptom Due

to their cellularity, CLM are usually soft or rubbery (178) on palpation, another featuremore suggestive of LG-ESS than of ordinary LM It is not rare for CLM to become no-ticeable due to their rapid growth, both in pre- and in postmenopausal patients (78).Nutritional problems can arise because vascularization cannot keep pace with the tu-mor’s rapid growth, and can consequently induce degenerative processes in the form

of cysts and hyaline necroses (Fig 1.4.1 (B)) that find their equivalents in sonography

as well (Fig 1.4.7 (A)) Rapid growth usually causes sensations of pressure, lower dominal pain and increased urinary urge (78) Rapid growth constitutes the indication

ab-on which surgery is performed in 39.5 % of cases, which is more frequent than amab-ongordinary LM (96, 212, 240) Rapid growth is observed in tumors with 1p deletions inparticular The described features notwithstanding, CLM can often not be clinicallydiscerned from ordinary LM

DD for CLM is identical with that for LM from a clinical perspective The dence of rapid growth and symptoms could be suggestive of LMS in perimenopausaland postmenopausal women, and of STUMP in patients aged younger than 25 Theissue “rapid growth” is addressed in detail in the chapter on LMS and also in Chap-ter 6 Transcervical core needle biopsy can be performed in order to differentiate CLMfrom LMS in exceptional cases (e.g when conservative surgery is planned despitesuspicious clinical or imaging diagnostic findings) More details, also regarding the