Appendix 1: Surgical Cut up of Cervical Specimens

Appendix 1: Surgical Cut Up of Cervical Specimens

Naveena Singh and Lars-Christian Horn

Introduction • Size of each fragment in three dimensions, measured in millimeters, or the range of the A variety of specimens are received as part of diag- largest and smallest dimensions: for mucoid nosis and surgical treatment of precancerous lesions samples and/or those with immeasurably and malignant cervical pathology. Specimen han- small tissue fragments, an aggregate measure- dling is crucial for accurate diagnosis, staging, and ment may be given in three dimensions or a reporting, to enable optimal patient management. volume dimension in milliliters. Handling, sampling, and processing of different specimen types are outlined below [1–4]. Specimen Dissection and Block Selection Cervical Punch/Wedge Biopsies • Process all tissue, including mucoid material. Cervical biopsies are usually colposcopically • If fragments are very small, wrap in tissue or directed and carried out as a diagnostic proce- process in mesh bags/wire cages to prevent dure, generally after an abnormal smear. These loss during processing. are usually received in formalin and are 4–7 mm • For easier visibility and handling during in their greatest dimension and 2–4 mm thick. embedding and cutting, the tissue may be Wedge biopsies are larger than punch biopsies inked using eosin before transfer to cassettes. but smaller than excision specimens and are car- • Specimens greater than 5 × 5 mm may be ried out colposcopically as an alternative diag- bisected along the mucosal surface or sliced nostic procedure to a punch biopsy to confirm perpendicular to this surface; if sectioned, this neoplasia before definitive treatment. should be recorded. • For wedge biopsies, identify the squamocolumnar Macroscopic Description junction where possible, and slice perpendicularly to this; if sectioned, this should be recorded. The following should be recorded: • Number of fragments. Processing/Staining • Color and consistency of the biopsies. • Use standard H&E. N. Singh • A minimum of three levels should be exam- Department of Cellular Pathology, ined in each case. Barts Health NHS Trust, London, UK • Further levels, with a minimum of three addi- L.-C. Horn tional levels, should be examined if there is a Division of Breast, Gynecologic and Perinatal Pathology, Pathology, Institute of Pathology, discrepancy between cytology and histology University Hospital of Leipzig, Leipzig, Germany or to visualize the epithelium if this is not seen.

© Springer International Publishing AG 2017 C.S. Herrington (ed.), Pathology of the Cervix, Essentials of Diagnostic Gynecological Pathology 3, 237 DOI 10.1007/978-3-319-51257-0 238 Appendix 1: Surgical Cut Up of Cervical Specimens

Excision Specimens: Cervical Cone • Measurements of flat/opened loop biopsy in Biopsy and Large Loop Excision three dimensions (noting which dimension is of the Transformation Zone (LLETZ; being measured). Also Known as Loop Electrosurgical • In practice there tends to be variation in what Excision Procedure, LEEP) is considered “depth”; to be relevant clinically [5] and to allow for standard measurements to Cone/LLETZ biopsies are carried out on women be recorded, the description should clearly with abnormal cytology samples as a “see and treat” indicate the following three dimensions: procedure, or following a positive punch biopsy. –– Length of the mucosal surface, i.e., a radial The biopsy can be diagnostic or therapeutic. Large measure of distance from endocervical to loop diathermy is most commonly used and favored ectocervical (EE) edges because of reduced levels of bleeding, improved –– Maximum thickness of tissue healing and preservation of cervical anatomy, and –– Circumference or perpendicular diameters ability to be performed as an outpatient procedure, of tissue, for open and intact specimens, without general anesthetic. Electrothermal artefact respectively. can, however, impair histological diagnosis and • For multiple loop biopsies, the number of render the assessment of excision margins difficult, pieces, with the smallest and largest measured especially in cases of glandular neoplasia. Cone in the maximum dimension where the sample biopsies are performed using a scalpel (“cold is small or in three dimensions where it is knife”). This is carried out as an in-patient proce- larger. dure under general anesthetic. A “cold knife” cone • The color, consistency, and presence of any biopsy is traditionally a preferred procedure for surface lesions. assessing glandular lesions of the cervix, especially after a diagnostic biopsy, to enable excision of a greater length of the endocervical canal ensuring Specimen Dissection and Block complete excision and to avoid difficulties in diag- Selection nostic interpretation due to diathermy artefact. Intact cone or loop biopsies are roughly coni- • For all loop/cone biopsies, all slices must be cal in shape. The specimen may arrive free in the blocked sequentially and not in random order. specimen pot, or it may be orientated and/or • All of the tissue should be processed. pinned to a corkboard. It may be open at one end • Consider the use of ink where the identifica- (giving a U-shape) or opened and drawn out into tion of margins is difficult. For example, ink- a flattened, curved specimen. Alternatively, it ing the ectocervical rim can be useful when may be received as multiple loop fragments, e.g., orientating individual slices in the presence of superficial, deeper/“top-hat” or marginal frag- a large ectropion. However, this is not always ments. Marking the specimen with a suture by the necessary. clinician (e.g., at 12 o’clock position) may be help- • Note that opening or probing an intact loop/cone ful for orientation of the specimen during cutting. biopsy may damage the surface epithelium. • When sectioning intact central loop/cone biopsies, two possible methods can be employed: Macroscopic Description –– Slicing serially parallel to the sagittal plane at 2–3 mm intervals, from one edge to the The following should be recorded: other (beginning at the 3 or 9 o’clock edge), perpendicular to the transverse axis of the • It is customary to record the measurements of external os. The curved lateral ends may be the intact central loop/cone biopsy in three processed with the flat or curved side down- dimensions (anteroposterior, side to side, and ward; a useful alternative is to cut these thickness). slices perpendicular to the longest axis of Appendix 1: Surgical Cut Up of Cervical Specimens 239

the slice so that the entire curved edge can Macroscopic Description be examined at 2–3 mm intervals. –– Sampling radially, in wedge-shaped slices. The following should be recorded: • Opened loop biopsies should be processed in sequential transverse slices, with the same • Size of the specimen surface facing down so that successive blocks • Size of the cervix (in hysterectomy allow examination of tissue at 2–3 mm inter- specimens) vals rather than of contiguous planes or of • Presence or absence of attached adnexal opposite surfaces which would be 4–6 mm structures apart. • Presence or absence of parametrial tissues and • Fragments (e.g., superficial, deep/“top-hat,” vagina or marginal) should be processed in desig- nated sequential cassettes. • Only one slice should be processed in one cas- Specimen Dissection and Block sette; this may contain more than one piece of Selection tissue as when transverse slices are made parallel to the sagittal plane or when the curved • When the uterus has already been opened and lateral edges are submitted in multiple slices sampled before the cervical lesion was parallel to the longest axis of the slices. detected, two standard cervical blocks may already have been taken. • In all cases, block all cervical tissue to examine Processing/Staining the entire transformation zone. This will ensure that the whole lesion has been processed, exclude • Use standard H&E. A single full-face section an invasive component, and allow assessment of is sufficient from each block. the inferior (vaginal) excision margin. • Examine further levels if the full epithelial surface is not evident, if there is cytohistologi- cal discrepancy, or if invasive disease is sus- Processing/Staining pected on the basis of the cytological, colposcopic, or histological features. • Use standard H&E. • Cut a full-face single section from each block. • If the surface epithelium is missing, sections Simple Hysterectomy/ are incomplete, or invasion is suspected con- Trachelectomy sider cutting further levels.

This may be performed in cases where persistent abnormal cytology has been reported, after thera- Radical Trachelectomy peutic conization or loop excision of an earlier cervical lesion, or for persistent cytological This procedure is performed for low-stage cervical changes where the transformation zone cannot be cancers, where surgical treatment with preserva- visualized colposcopically (because of cervical tion of fertility is desired. The following structures stenosis or scarring from previous cervical loop are included in radical trachelectomy specimens: biopsies or conization). This may also be carried out in women as an option instead of conization • Cervix when the family is complete. In some instances, • Parametrium CIN may be an incidental finding when simple • Vaginal cuff hysterectomy has been performed for other clini- • Pelvic lymphadenectomy (this may be carried cal reasons. out as a separate surgical procedure) 240 Appendix 1: Surgical Cut Up of Cervical Specimens

Macroscopic Description color to mark the anterior and posterior aspects. The following should be recorded: • The specimen should be blocked in its entirety. Block taking will vary according to local pref- • Structures included and whether the specimen erences and the nature of the individual speci- can be orientated. In most cases, the surgeon men (see below). will place a suture at the 12 o’clock position to • There is often a large central circumferential assist orientation; this should be encouraged. biopsy defect and no macroscopically visible The peritoneum is present posteriorly, often residual tumor, while in some instances, there taking a triangular shape with the apex point- is macroscopic evidence of residual tumor: ing downward. There is usually no peritoneum –– Where residual tumor is clearly visible, the over the anterior surface of vaginal trachelec- blocks should be taken in such a way that it tomies, but a small amount may be present in is possible to measure tumor position and specimens excised abdominally. Where the distance relative to margins (proximal, anterior and posterior aspects of a specimen vaginal, cervical stromal (tumor-free stro- are difficult to identify, this should be clearly mal rim), and parametrial). recorded. –– Blocks should be taken in a standard way • Height/length, lateral, and anteroposterior for all other cases (i.e., when there is no dimensions in millimeters. residual visible tumor) and should also be • Length of vaginal cuff as a range (with maxi- taken to sample the remaining tissue after mum and minimum dimensions, as this usu- the tumor has been assessed. ally varies around the circumference); also, • Recommended method: the positions of the maximum and minimum –– Slice in parallel, horizontal slices of lengths. 2–3 mm thickness, including cervix and • Dimensions of resected parametrial/mesome- attached parametrial tissues in continuity, trial tissues in three dimensions recorded sep- starting from the upper end and stopping arately for anterior, posterior, left, and right. 10–15 mm above the external os, taking • Presence of any macroscopic abnormality: care not to slice through the vaginal residual tumor, biopsy defect/scar or other fornices. lesions. –– Slice the lower part of the specimen, com- • Measurement of residual tumor, biopsy defect, prising the ectocervix and attached vaginal or other lesion(s) cuff, radially. • Residual tumor should be measured in three –– Each slice is processed in a separate dimensions, and the number of quadrants cassette. involved should be recorded. –– The proximal/upper margin (first slice) is • Position of residual tumor as clock face posi- embedded to allow examination of the tion and distance from the proximal, distal, superior surface. and radial resection margins. –– All transverse slices are embedded simi- larly, with the superior surface forming the cutting face of the block. Specimen Dissection and Block –– Each slice may have to be bisected, or cut Selection into three or four pieces, to fit into a cassette in a way that preserves all surgical • Parametrial margins should be inked. Using a margins. The cassettes must not be >80% standard protocol of right (Red or gReen) and filled with tissue. Large blocks can be used left (bLue or yeLlow) helps to maintain orien- if preferred. No tissue should be trimmed tation after slicing, as does use of a different or discarded. Appendix 1: Surgical Cut Up of Cervical Specimens 241

• Alternative method: • Length of vaginal cuff as a range (with maxi- –– Take one sagittal slice through the length of mum and minimum dimensions, as this usu- the trachelectomy, leaving right and left ally varies around the circumference); also, hemicervices with parametrial and vaginal the positions of the maximum and minimum tissues attached. The vertical slice is pro- lengths cessed as anterior and posterior portions of • Dimensions of resected parametrial/mesome- cervix and vagina trial tissues in three dimensions recorded sep- –– The remaining specimen is then handled as arately for anterior, posterior, left, and right above, in horizontal slices for the upper • Presence of any macroscopic abnormality: portion and radial slices for the lower with residual tumor, biopsy defect/scar, or other vaginal cuff. lesions • For specimens that are smaller than 10–15 mm • Dimensions of residual tumor, biopsy defect, in their vertical dimension, processing as a or other lesion(s) cone or LLETZ may be preferable. • Position of residual tumor as clock face position and distance from the proximal, distal, and radial resection margins Processing/Staining

• Use standard H&E. Specimen Dissection and Block • Cut a full-face single section from each block. Selection (Fig. A1.1a and b) • If the surface epithelium is missing or sections are incomplete, consider cutting further levels. • Parametrial margins should be inked. Using a standard protocol of right (Red or gReen) and left (bLue or yeLlow) helps to maintain orien- Radical Hysterectomy tation after slicing, as does use of a different color to mark the anterior and posterior Traditionally this has been the standard treatment aspects. for cases of cervical carcinoma at stage IA2, IB, and • The cervix should be separated with the vagi- IIA. With the greater use and equivalent survival nal cuff and parametrial tissues attached. results using radical chemoradiotherapy, this proce- • There may be a large central circumferential dure is becoming more infrequent, particularly in biopsy defect and no macroscopically visible countries with a successful cervical screening pro- residual tumor, while in some instances, there gram. This is carried out in cases where there is a is macroscopically evidence residual tumor very low chance of adjuvant therapy being indi- seen: cated. The surgical specimen includes the parame- –– Where residual tumor is clearly visible, the tria, vaginal cuff, and pelvic+/- para-aortic lymph blocks should be taken in such a way that it node dissection. The adnexa are usually included is possible to measure tumor position and but, in younger women, the ovaries may be con- distance relative to margins (proximal, served to prevent premature menopause. vaginal, cervical stromal (tumor-free stromal rim), and parametrial). –– Blocks should be taken in a standard way Macroscopic Description for all other cases (i.e., when there is no residual visible tumor) and should also be The following should be recorded: taken to sample the remaining tissue after the tumor has been assessed. • Structures included • Recommended method: • Height/length, lateral, and anteroposterior –– Slice in parallel, horizontal slices of dimensions in millimeters 2–3 mm thickness, including cervix and 242 Appendix 1: Surgical Cut Up of Cervical Specimens

b Appendix 1: Surgical Cut Up of Cervical Specimens 243

attached parametrial tissues in continuity, Pelvic Exenteration (Figs. A1.2 starting from the upper end and stopping and A1.3) 10–15 mm above the external os, taking care not to slice through the vaginal forni- Pelvic exenteration may be performed for ces, as above for trachelectomy advanced cervical carcinoma or central recurrent specimens. disease, sometimes after treatment with chemo- –– The lower part of the specimen, comprising radiation. Because of the highly individual surgi- the ectocervix and attached vaginal cuff, is cal approach in a given patient, the following radially sliced, as above for trachelectomy recommendations must be carefully adapted to specimens. the specimen. The hysterectomy specimen will • Examine each slice carefully for residual be accompanied by adjacent or adherent organs, tumor. e.g., bladder, large bowel, and (in rare cases) pel- • Where there is no macroscopically evidence vic sidewall and/or bone. Prior chemoradiation residual tumor, sample all the tissue in the may obscure the primary tumor and also the same way as described for radical extent of macroscopic tumor spread. Appropriate trachelectomy. fixation is mandatory in these generally large • In the presence of residual tumor, at least one specimens to ensure adequate handling and block of tumor per centimeter of its maximum microscopic examination. It may be necessary to dimension should be taken. fix the specimen for 24–48 h. Tamponade of the • Blocks should enable measurement of the bladder, large bowel, and vagina with cellulose deepest portion of the tumor to the external may be helpful to improve fixation and keep the rim of cervix and to the nearest parametrial organs in shape before cutting. margin. Dissection of adherent or adjacent organs • For tumors positioned low in the cervix, should be carried out in a way that does not com- blocks should enable measurement to the vag- promise assessment of resection margins; a neat inal margin. sagittal slice through all structures is helpful to • All vaginal tissue should be sampled to detect/ assist fixation, demonstrate relationship of tumor exclude microscopic vaginal involvement. to different structures and surgical margins and • All parametrial tissue should be sampled to allow for block selection (Figs. A1.2 and A1.3). exclude microscopic parametrial invasion. A photographic record of the specimen may be • Representative sections should be taken of useful. Consider painting resection margins with remaining structures, i.e., uterine corpus and different colors of ink/dye and inflating the uri- adnexa. nary bladder with formalin prior to specimen opening. Open adherent or adjacent organs to allow fixation without compromising resection Processing/Staining margins. Block selection will vary according to the position of the tumor, but, broadly speaking, • Use standard H&E. perpendicular sections are favored over tangen- • Cut a full-face single section from each block. tial sections for evaluating the resection margins • If the surface epithelium is missing or sections and enabling measurement of the distance are incomplete, consider cutting further levels. between the tumor and the given margin.

Fig. A1.1 Figure A1.1: Embedding sites for a radical ding sites. Notes: Block codes 3 and 4 contain the transi- hysterectomy in a case of cervical carcinoma (a) tion between the tumor and the most proximal parametrial Schematic description of embedding sites with block tissue (paracervix) for the examination for tiny foci of codes. (b) Radical hysterectomy after appropriate fixation extrauterine disease. Block codes 6 and 7 - the parametrial and coronal sectioning of the specimen, showing embed- tissue should be embedded completely 244 Appendix 1: Surgical Cut Up of Cervical Specimens

Fig. A1.2 Exenteration specimen from locally advanced tion (see text). The uterus was previously opened at the 6 cervical carcinoma containing urinary bladder and the o’clock position during frozen section examination, and uterus with sagittal cutting. Note the well-preserved shape then the specimen was fixed for 48 h in buffered formalin of the urinary bladder after previous tamponade and fixa-

Fig. A1.3 Exenteration specimen from a patient with central pelvic recurrence of a squamous cell carcinoma of the uterine cervix, cut in the sagittal plane Appendix 1: Surgical Cut Up of Cervical Specimens 245

Macroscopic Description perpendicular to the mucosa directly overly- ing the cervical tumor. The following should be recorded: • Sample the closest circumferential resection margins. Inking may be helpful in determin- • Height/length, lateral, and anteroposterior ing the status and distance of the resection dimensions in millimeters. margins. • Record and measure the specimen compo- • Consider using oversized tissue blocks when nents, their gross appearances, and any macro- examining cervical tumors in exenteration scopic lesions, capturing relevant information specimens, in order to retain anatomical rela- on the relationship of the tumor to the bowel tionships and assess resection margins. (usually the rectum) and urinary bladder. Process additional standard-sized blocks of • Describe the presence, and the extent of tumor to allow immunohistochemistry or involvement, of any tumor in the vaginal forni- other special stains to be undertaken if ces, parametria, urinary bladder, and rectum. necessary. • Measure the distance from the tumor to the resection margins. • Record the number and site of lymph nodes Processing/Staining recovered from the specimen; note macroscopic involvement and dimensions of involved nodes. • Use standard H&E. • Cut a full-face single section from each block. • If sections are incomplete, consider cutting Specimen Dissection and Block further levels. Selection

• Hemisect the entire specimen in the sagittal Lymph Node Specimens plane through the uterus and neoplasm. This allows detailed evaluation of the relationship Lymph nodes are usually sent in separate pots, of the tumor to adjacent anatomical structures labeled according to the site of origin. In exen- and facilitates block selection. teration specimens, process nodes that are • Consider taking blocks of the vaginal resec- recovered from the mesocolon/mesorectum tion margin, in continuity with the tumor, and parametria separately. The earliest site of where the vaginal cuff is short. nodal metastasis is the subcapsular sinus, and • Take separate blocks of the trimmed circum- sectioning of lymph nodes should be such that ferential vaginal resection margin. examination of this space is maximized. • Block the parametrial and paracervical tissues Sentinel lymph nodes should be processed the in their entirety, recording laterality. same way as non-sentinel nodes with addi- • To assess infiltration of the rectum and blad- tional procedures for ultra staging according to der, sample the rectum and bladder local protocols. 246 Appendix 1: Surgical Cut Up of Cervical Specimens

Macroscopic Description surrounding such nodes to determine the presence of extracapsular extension. The following should be recorded for each speci- • Nodes that are not macroscopically involved men site: should be processed entirely: –– Nodes >5 mm in largest diameter should be • Total amount of tissue bisected or serially sliced at 2 mm intervals • Number of macroscopically identifiable nodes perpendicular to the longest axis. Large • Range of sizes in three dimensions lymph nodes may require processing in • Macroscopic evidence of metastasis more than one block. • Macroscopic evidence of extranodal spread –– Nodes <5 mm should be processed whole. • Ideally all remaining adipose tissue should be processed. If this amounts to an unusually Specimen Dissection and Block large number of cassettes (>4 additional Selection blocks), and the node yield is high, only representative sections may be taken at the discre- • Large lymph nodes should be sampled in sep- tion of the pathologist. arate cassettes. • Small nodes, which are being processed without cutting, can be placed as multiple in one Processing/Staining cassette. • Block details should be carefully recorded, as • Use standard H&E. it may not be possible to distinguish between • Cut a full-face single section from each block. a single node processed in several slices and • If sections are incomplete, consider cutting multiple separate nodes in a single cassette. further levels. • Only one block is necessary from any grossly • Procedures for sentinel node processing involved node. It is recommended to leave a should be followed according to local small rim of surrounding fatty tissue protocols. Appendix 2: Dataset for Reporting Cervical Neoplasia

Naveena Singh and Lars-Christian Horn

The dataset presented here is based on the recom- Previous therapy: mendations of the International Collaboration on • Administered Cancer Reporting (ICCR, http://www.iccr-cancer. –– Chemotherapy org/datasets) [6]. The ICCR is an alliance between –– Radiation the Royal College of Pathologists of Australasia, –– Chemoradiation the Royal College of Pathologists of the United • No prior therapy Kingdom, the College of American Pathologists, • Information not provided and the Canadian Partnership Against Cancer. This was formed with a view to standardizing can- Element name: Specimen(s) submitted cer reporting worldwide by developing evidence- REQUIRED based datasets for each cancer site and reducing Response type: Value list (multi-select, i.e., the effort involved in cancer dataset development more than one option can be chosen)/text: by different international institutions. • Not specified The following elements may be recorded in • Loop excision* pathology reports on cervical neoplasia; in each • Cone biopsy it is indicated whether these are required or • Trachelectomy recommended. • Hysterectomy: –– Simple Element name: Prior treatment –– Radical RECOMMENDED –– Part of exenteration Response type: Value list (single and multi- –– Type not specified select)/text: • Left tube Previous procedure performed: • Right tube • Loop • Left ovary • Cone • Right ovary • Trachelectomy • Left parametrium • No prior procedure • Right parametrium • Information not provided • Vaginal cuff • Pelvic exenteration: N. Singh –– Urinary bladder Department of Cellular Pathology, –– Rectum Barts Health NHS Trust, London, UK –– Vagina L.-C. Horn –– Sigmoid colon Division of Breast, Gynecologic and Perinatal –– Others (specify) Pathology, Pathology, Institute of Pathology, • Lymphadenectomy specimen(s) University Hospital of Leipzig, Leipzig, Germany

© Springer International Publishing AG 2017 C.S. Herrington (ed.), Pathology of the Cervix, Essentials of Diagnostic Gynecological Pathology 3, 247 DOI 10.1007/978-3-319-51257-0 248 Appendix 2: Dataset for Reporting Cervical Neoplasia

–– Left: Element name: Macroscopic tumor site(s) • Sentinel node(s) RECOMMENDED • Regional nodes: pelvic Response type: Value list (multi-select, i.e., • Non-regional nodes: inguinal more than one option can be chosen)/text: –– Right: • No macroscopically visible tumor • Sentinel node(s) • Indeterminate • Regional nodes: pelvic • Anterior cervix • Non-regional nodes: inguinal • Posterior cervix –– Non-regional: para-aortic • Left lateral cervix –– Other node groups (specify) • Right lateral cervix • Others (specify) • Circumference of cervix • Extension to the vaginal cuff *Loop excision includes loop electrosurgical • Extension to the isthmus of the uterus or excision procedure (LEEP) and large loop exci- the uterine body sion of the transformation zone (LLETZ) • Left parametrium • Right parametrium Element name: Specimen dimensions • Other organs or tissues (if additional tissue REQUIRED was resected, e.g. the urinary bladder meso- Response type: Numeric in mm/value list: thelium, the rectum or the bladder wall) Number of tissue pieces: *___ Tissue piece dimensions: *___×___×___mm Element name: Macroscopic appearance of tumor(s) (record for each RECOMMENDED piece) Response type: Value list (multi-select, i.e., Cervix: ** Diameter of more than one option can be chosen)/text: ectocervix • No macroscopically visible tumor ___×___mm • Exophytic/polypoid Depth of specimen • Flat ___mm • Ulcerated Vaginal cuff***: Minimum length • Circumferential/barrel shaped cervix ___mm • Others (specify) Maximum length ___mm Element name: Block identification key Not applicable RECOMMENDED Left parametrium: Length ___mm or Response type:Text not applicable (RECOMMENDED) Element name: Tumor dimensions* Right parametrium: Length ___mm or REQUIRED not applicable Response type: Value list/numeric mm: (RECOMMENDED) • Horizontal extent ___×___mm • Depth of invasion ___mm OR not assessable *Applicable to loop/cone biopsies only –– If not assessable record **Applicable to loop/cone biopsies and trache- Thickness ___mm lectomy specimens only ***Applicable to loop/cone biopsies, trachelec- *If separate tumors specify the dimensions for tomy, and hysterectomy specimens each tumor Appendix 2: Dataset for Reporting Cervical Neoplasia 249

Element name: Histological tumor type • Not identified REQUIRED • Present Response type: Value list (multi-select, i.e., more than one option can be chosen)/text: Element name 3: Stratified mucin-producing • WHO 2014 listed tumors intraepithelial lesion (SMILE) Response type: Value list: Element name: Histological tumor grade • Not identified RECOMMENDED NO • Present Response type: Value list: • G1: Well differentiated Element name 4: Other possible precursor • G2: Moderately differentiated lesions • G3: Poorly differentiated RECOMMENDED • GX: Cannot be graded Response type: Value list: • Not graded • Not identified • Present: Element name: Lymphovascular invasion –– Lobular endocervical glandular REQUIRED hyperplasia Response type: Value list/text: –– Adenocarcinoma in situ of gastric • Not identified type • Indeterminate –– Others (specify) • Present Element name: Extent of invasion Element name: Perineural involvement REQUIRED RECOMMENDED Response type: Value list/text:x Response type: Value list (multi-select, i.e., • Not applicable more than one option can be chosen)/text • Vagina: –– Involved: • Upper two thirds Coexistent Pathology • Lower third –– Not involved ELEMENTS 1, 2 AND 3 REQUIRED FOR • Endometrium: LOOP/CONE EXCISIONS/TRACHELEC –– Involved TOMIES ONLY; RECOMMENDED FOR –– Not involved OTHER SPECIMENS • Myometrium: –– Involved Element name 1: Squamous intraepithelial –– Not involved lesion (SIL) (CIN) • Parametrium: Response type: Value list: –– Involved: • Not identified • Left • Present • Right –– Grade: –– Not involved • Low-grade SIL (LSIL) (CIN 1) • Fallopian tube: • High-grade SIL (HSIL) (CIN 2/3) –– Involved: • Left Element name 2: Adenocarcinoma in situ • Right (AIS)/high-grade cervical glandular intraepi –– Not involved thelial neoplasia (HG CGIN) Response type: Value list: 250 Appendix 2: Dataset for Reporting Cervical Neoplasia

• Ovary: For Carcinoma –– Involved: • Left Hysterectomy/Trachelectomy • Right Specimen –– Not involved • Bladder: Not Distance from –– Involved: Margin Involved involved tumor (mm)# • Specify compartment Radial/stromal –– Not involved margin • Rectum: Ectocervical/ –– Involved: vaginal cuff margin • Specify compartment Closest lateral Right –– Not involved margin Left • Other organs or tissues: Endocervical –– Involved: margin* • Specify –– Not involved Loop/Cone Element name: Margin status REQUIRED Distance Not from tumor Response type: Value list/numeric in mm/text Margin Involved involved (mm)# • Margins cannot be assessed Ectocervical OR complete the following: margin Endocervical margin Radial/stromal margin Unspecified margin**

For Preinvasive Disease

Margin is not applicable to Margin HSIL AIS/SMILE specimen Involved Not Distance Involved Not Distance of involved of margin involved margin (mm)# (mm)# Ectocervical/ vaginal cuff margin Endocervical margin Radial/stromal margin Unspecified margin

#Complete only if not involved and if less than 10 mm *These measurements are required only for trachelectomy specimens **Use for loop/cone biopsies where it is not possible to say whether the margin is ectocervical or endocervical Appendix 2: Dataset for Reporting Cervical Neoplasia 251

Element name: Lymph node status • Not performed REQUIRED • Performed: Response type: Value list/numeric/text –– Human papillomavirus (HPV) testing • Not submitted (specify details) • Not involved –– Immunohistochemistry (specify details) • Involved –– Others (specify details) • Left: –– Sentinel node(s): Element name: Pathologically confirmed distant • Number of lymph nodes examined** __ metastases • Number of positive lymph nodes** __ REQUIRED –– Regional nodes – pelvic: Response type: Value list (single select)/text • Number of lymph nodes examined** __ • Not identified • Number of positive lymph nodes** __ • Present (specify site(s)) –– Non-regional nodes – inguinal: • Number of lymph nodes examined** __ • Number of positive lymph nodes** __ Provisional Pathological Staging • Right: Pre-Multidisciplinary Team Meeting –– Sentinel node(s): (MDTM) • Number of lymph nodes examined** __ • Number of positive lymph nodes** __ Element name 1: FIGO 2009 EDITION –– Regional nodes – pelvic: REQUIRED • Number of lymph nodes examined** __ Response type: FIGO list of values • Number of positive lymph nodes** __ –– Non-regional nodes – inguinal: Element name 2: TNM descriptors (UICC 8th • Number of lymph nodes examined** __ Edition, 2016) • Number of positive lymph nodes** __ RECOMMENDED • Non-regional – para-aortic: Response type: • Number of lymph nodes examined** __ • m (multiple primary tumors) • Number of positive lymph nodes** __ • r (recurrent) • Other node group (specify): • y (post treatment) • Number of lymph nodes examined** __ • Number of positive lymph nodes** __ Element name 3: Primary tumor T category (UICC 8th Edition, 2016) **In some cases, it may not be possible to record REQUIRED the actual number of nodes due to fragmentation Response type: TNM pT value list of the specimen Element name 4: Regional lymph nodes N Element name: Ancillary studies category (UICC 8th Edition, 2016) REQUIRED REQUIRED Response type: Value list: Response type: • No nodes submitted or found • TNM pN value list Appendix 3: TNM and FIGO Staging of Cervical Carcinoma (ICD-O C53)

Naveena Singh and Lars-Christian Horn

The definitions of the T and M categories corre- TNM FIGO spond to the FIGO stages [7, 8]. FIGO staging does category stage Definition not take nodal involvement into account. Both sys- T1b2 IB2 Clinically visible lesion >4.0 cm in greatest dimension tems are presented below for comparison. T2 II Tumor invades beyond the uterus but not to pelvic wall or to TNM FIGO lower third of vagina category stage Definition T2a IIA Without parametrial invasion T – primary tumor T2a1 IIA1 Clinically visible lesion 4.0 cm in TX – Primary tumor cannot be assessed ≤ greatest dimension T0 – No evidence of primary tumor T2a2 IIA2 Clinically visible lesion >4.0 cm in Tis – Carcinoma in situ (preinvasive greatest dimension carcinoma) T2b IIB Tumor with parametrial invasion T1 I Cervical carcinoma confined to T3 III Tumor extends to pelvic wall the uterus and/or involves lower third of (extension to corpus should be vagina and/or causes disregarded) hydronephrosis or T1a IA Invasive carcinoma, diagnosed nonfunctioning kidney* only by microscopy, T3a IIIA Tumor involves lower third of with deepest invasion 5.0 mm ≤ vagina, with no extension to pelvic and largest extension 7.0 mm ≤ wall T1a1 IA1 Measured stromal invasion T3b IIIB Extension to pelvic wall and/or 3.0 mm in depth and 7.0 mm in ≤ ≤ hydronephrosis or nonfunctioning horizontal spread kidney T1a2 IA2 Measured stromal invasion of T4 IV Tumor has extended beyond the >3.0 mm and not >5.0 mm, and true pelvis or has involved 7.0 mm in horizontal spread ≤ (biopsy proven) the mucosa of T1b IB Clinically visible lesion limited to the bladder or rectum. Bullous the cervix uteri or preclinical edema does not permit a case to cancers greater than stage T1a/IA be allocated to stage IV T1b1 IB1 Clinically visible lesion ≤4.0 cm in T4 I VA Spread to adjacent organs greatest dimension N – regional lymph nodes NX – Regional lymph nodes cannot be assessed N. Singh N0 – No regional lymph node Department of Cellular Pathology, metastasis** Barts Health NHS Trust, London, UK N1 – Regional lymph node metastasis*** L.-C. Horn M – distant metastasis Division of Breast, Gynecologic and Perinatal M0 – No distant metastasis Pathology, Pathology, Institute of Pathology, M1 IVB Spread to distant organs**** University Hospital of Leipzig, Leipzig, Germany

© Springer International Publishing AG 2017 C.S. Herrington (ed.), Pathology of the Cervix, Essentials of Diagnostic Gynecological Pathology 3, 253 DOI 10.1007/978-3-319-51257-0 254 Appendix 3: TNM and FIGO Staging of Cervical Carcinoma (ICD-O C53)

Notes: TNM stage T N M Stage II T2 N0 M0 • Depth of invasion should be taken from the Stage IIA T2a N0 M0 base of the epithelium, either surface or glan- Stage IIA1 T2a1 N0 M0 dular, from which it originates. The depth of Stage IIA2 T2a2 N0 M0 invasion is defined as the measurement of the Stage IIB T2b N0 M0 tumor from the epithelial-stromal junction of Stage III T3 N0 M0 the adjacent most superficial papillae to the Stage IIIA T3a N0 M0 deepest point of invasion Stage IIIB T3b Any N M0 • Vascular space involvement, venous or lym- Stage IIIB T1, T2, T3 N1 M0 phatic, does not affect stage classification Stage IVA T4 Any N M0 • FIGO no longer includes stage 0 (Tis) Stage IVB Any T Any N M1 • All macroscopically visible lesions, even with FIGO stage Ia dimensions, are T1b/IB • Bullous edema is not sufficient to classify a tumor as T4 Additional/Optional Descriptors • *On rectal examination, there is no cancer-free in the TNM Classification space between the tumor and the pelvic wall. All cases with hydronephrosis or nonfunction- Sentinel Lymph Node ing kidney are included, unless they are known to be due to another cause The following designations are applicable for • **Histological examination of a pelvic lymph- sentinel lymph node assessment: adenectomy specimen will ordinarily include six or more lymph nodes. If the lymph nodes pNX(sn) Sentinel lymph node could not be are negative, but the number ordinarily exam- assessed. ined is not met, classify as pN0 pN0(sn) No sentinel lymph node metastasis. • ***Regional lymph nodes include paracervical, pN0(sn) Sentinel lymph node metastasis. parametrial, and hypogastric (internal iliac, obturator); common and external iliac; and presacral and lateral sacral nodes. Para-aortic Isolated Tumor Cells nodes are not regional • ****Distant metastasis includes inguinal lymph Isolated tumor cells (ITCs) are single tumor cells or nodes and intraperitoneal disease except small clusters of cells no more than 0.2 mm in great- metastasis to pelvic serosa. It excludes metas- est dimension detected by routine H&E stains or tasis to vagina, pelvic serosa, and adnexa immunohistochemistry. Cases with ITC in lymph nodes or distant metastatic sites should be classified as N0 or M0, respectively. This also applies to find- TNM Stage Grouping ings suggestive of tumor cells or tumor cell compo- nents detected by non-morphological techniques TNM stage T N M such as flow cytometry or DNA analysis. Stage 0 Tis N0 M0 The following designations are applicable to ITC Stage I T1 N0 M0 in regional lymph nodes:pN0 N o Stage IA T1a N0 M0 regional lymph node metastasis Stage IA1 T1a1 N0 M0 histologically; no examination for Stage IA2 T1a2 N0 M0 ITCs Stage IB T1b N0 M0 pN0(i-) No regional lymph node metasta- Stage IB1 T1b1 N0 M0 sis histologically; negative mor- Stage IB2 T1b2 N0 M0 phological findings for ITCs Appendix 3: TNM and FIGO Staging of Cervical Carcinoma (ICD-O C53) 255 pN0(i+) No regional lymph node metasta- that examination and is not an estimate of the sis histologically; positive mor- extent of tumor prior to multimodality therapy. phological findings for ITCs pN0(mol-) No regional lymph node metastasis histologically; negative non- Recurrent Tumors morphological findings for ITCs pN0(mol+) No regional lymph node metasta- Recurrent tumors classified after a disease-free sis histologically; positive non- interval are identified by the “r” prefix. morphological findings for ITCs The following designations are applicable to ITCs in sentinel lymph nodes: Classification at Autopsy pN0(i-)(sn) No sentinel lymph node metastasis histologically; negative The prefix “a” indicates that classification is first morphological findings for ITCs determined at autopsy. pN0(i+)(sn) No sentinel lymph node metastasis histologically; positive morphological findings for ITCs Lymphatic Invasion: L pN0(mol-)(sn) No sentinel lymph node metastasis histologically; negative LX Lymphatic invasion cannot be assessed. non-morphological findings L0 No lymphatic invasion. for ITCs L1 Lymphatic invasion. pN0(mol+)(sn) No sentinel lymph node metastasis histologically; positive non- morphological findings for ITCs Venous Invasion: V

VX Venous invasion cannot be assessed. Multiple Primary Tumors V0 No venous invasion. V1 Microscopic venous invasion. The suffix “m,” in parentheses, is used to indicate V2 Macroscopic venous invasion. the presence of multiple primary tumors at a sin- Note: Macroscopic involvement of the wall of gle site. veins (with no tumor within the lumen of the veins) is classified as V2.

Classification Following Multimodality Therapy Perineural Invasion: Pn

The prefix “y” is used to categorize tumors exam- PnX Perineural invasion cannot be assessed. ined following multimodality therapy. This indi- Pn0 No perineural invasion. cates the extent of tumor present at the time of Pn1 Perineural invasion. Appendix 4: Frozen Section Analysis in Cervical Carcinoma

Naveena Singh and Lars-Christian Horn

In certain instances, surgical specimens in patients men may be entirely submitted as radial sections with cervical carcinoma may require intraoperative aided by inking the endocervical and ectocervical assessment by frozen section (FS) analysis. Here margins with different colors, performing one or we will briefly review the approach and results of two sections per slide [12]. An accuracy of FS analyses in conization specimens, simple and 75–100% in distinguishing dysplasia from inva- radical trachelectomies and radical hysterectomies, sive carcinoma and for the diagnosis of microinva- as well as lymph node specimens. sive carcinoma has been reported [9–13]. Other institutions examine only the endocervical margin by transverse (en face) section on Conization Specimens FS to guide additional surgery in cases of involvement [13, 14]. The reported accuracy ranges There may be two scenarios for FS analyses in between 87 and 100%. conization specimens:

1. To diagnose the lesion Trachelectomy Specimens 2. To examine the excision margins Simple or radical trachelectomy (TE) is the fertil- In patients with non-visible lesions, a loop elec- ity preserving approach in patients with cervical trosurgical excisional procedure (LEEP) or cone cancer of FIGO stage IA2/IB1 or more. One biopsy must be performed to make a definitive important parameter of successful treatment is diagnosis of invasive cancer and to evaluate the the absence of disease at surgical margins [15], in size of the carcinoma and its depth of invasion. To particular the isthmic/endocervical margin. At reduce the time for establishing the definitive diag- present, there is no consensus regarding the best nosis and for reduction of the waiting time for the approach for FS [16, 17]. Performing a transverse patient in case of additional surgery, some institu- or en face section tangential to the endocervical tions offer FS to determine lesion size and depth of margin allows the examination of the entire mar- invasion followed by simple or radical hysterec- gin surface. The disadvantage may be that the tomy with or without lymphadenectomy performed exact distance between the invasive growing at the same surgery [9-12]. For FS, the cone speci- tumor and the endocervical margin cannot be given. Longitudinal section(s) from the (inked) N. Singh endocervical margin in the direction of the inva- Department of Cellular Pathology, sive growing tumor (to the ectocervix) allows the Barts Health NHS Trust, London, UK exact measurement of the distance between the L.-C. Horn tumor edge and the endocervical margin. But the Division of Breast, Gynecologic and Perinatal Pathology, Pathology, Institute of Pathology, whole circumference of the endocervical margin University Hospital of Leipzig, Leipzig, Germany will not be covered by this method [16, 18]. Some

© Springer International Publishing AG 2017 C.S. Herrington (ed.), Pathology of the Cervix, Essentials of Diagnostic Gynecological Pathology 3, 257 DOI 10.1007/978-3-319-51257-0 258 Appendix 4: Frozen Section Analysis in Cervical Carcinoma studies examine the margin by longitudinal sec- completely [27]. Two to three step sections from tions with complete embedding as radial sections the frozen block should be performed to increase aided by inking [19]. the detection of small metastatic deposits. The best way may be the combination of both approaches [17, 20] by performing a transverse section of about 0.2–0.3 cm thickness and an References additional perpendicular section from the leading edge of the tumor in the direction of the endocer- Appendix 1 : Surgical Cut Up of vical margin to measure the distance between the Cervical Specimens tumor and the margin. The final distance between the invasive front and the endocervical margin is 1. Hirschowitz L, Ganesan R, Singh N, McCluggage calculated by adding the distance from the tumor WG. Dataset for histological reporting of cervical neoplasia. 3rd ed. London: The Royal College of to the edge of the perpendicular section to the Pathologists; 2011. thickness of the tangential section. An accuracy 2. NHS Cancer Screening Programmes. Histopathology of up to 100% has been reported for combined reporting in cervical screening : an integrated transverse and perpendicular sections [17]. approach. 2nd ed. Sheffield: NHS Cancer Screening Programmes; 2012. 3. Pecorelli S, Zigliani L, Odicino F. Revised FIGO staging for carcinoma of the cervix. Int J Gynaecol Radical Hysterectomies Obstet. 2009;105(2):107–8. 4. Sobin LH, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumours. 7th ed. Oxford: Intraoperative examination of radical hysterec- Wiley-Blackwell; 2010. tomy for cervical cancer is rarely indicated [21, 22]. 5. Castanon A, Landy R, Brocklehurst P, Evans H, The distal vaginal resection margin may be exam- Peebles D, Singh N, et al. Risk of preterm delivery ined using tangential sections. Additionally, cases with increasing depth of excision for cervical intraepithelial neoplasia in England: nested case-control with close posterior, anterior, or parametrial study. BMJ. 2014;349:g6223. resection margins (i.e., in the direction of the mesorectum, urinary bladder, or site of parametrial infiltration) may be examined using perpendicular Appendix 2 : Dataset for Reporting sectioning with inking of the margins. Very rarely, Cervical Neoplasia assessment of involvement of the lower uterine segment/uterine corpus may be requested [23]. 6. McCluggage WG, Hirschowitz L, Rous B, AlvaradoCabrero I, Duggan MA, Horn LC, Hui P, Ordi J, Otis CN, Park KJ, Plante M, Stewart CJR, Wiredu EK. Carcinoma of the Cervix. Histopathology Reporting Guide. International Collaboration on Lymph Nodes Cancer Reporting. http://www.iccrcancer.org/datasets/publisheddatasets/femalereproductiveorgans/cer- Frozen section examination of pelvic (and rarely vicalcarcinoma. Accession date 22 April 2017. para-aortic) lymph nodes may be requested intra- operatively. The examination of lymph nodes in Appendix 3 : TNM AND FIGO Staging cervical cancer may be challenging, and accuracy of Cervical Carcinoma (ICD-O C53) of up to 33% has been reported [24-26]. The tissue received should be measured and carefully dis- 7. Brierley JD; Gospodarowicz MK; Wittekind C. TNM sected and palpated to identify small lymph nodes. Classification of Malignant Tumours. 8th ed: Wiley Lymph nodes up to 0.3 cm may be embedded Blackwell; 2016. 8. Pecorelli S. Revised FIGO staging for carcinoma of completely; larger nodes should ideally be sliced the vulva, cervix, and endometrium. Int J Gynaecol perpendicular to their longest axis and processed Obstet. 2009;105(2):103–4. Appendix 4: Frozen Section Analysis in Cervical Carcinoma 259

Appendix 4 : Frozen Section Analysis 18. Chênevert J, Têtu B, Plante M, Roy M, Renaud MC, in Cervical Carcinoma Grégoire J, Grondin K, Dubé V. Indication and method of frozen section in vaginal radical trachelectomy. Int J Gynecol Pathol. 2009;28(5):480–8. 9. Giuntoli 2nd RL, Winburn KA, Silverman MB, 19. Ismiil N, Ghorab Z, Covens A, Nofech-Mozes S, Saad Keeney GL, Cliby WA. Frozen section evaluation of R, Dubé V, Khalifa MA. Intraoperative margin assess- cervical cold knife cone specimens is accurate in the ment of the radical trachelectomy specimen. Gynecol diagnosis of microinvasive squamous cell carcinoma. Oncol. 2008;110(3):316–23. Gynecol Oncol. 2003;91(2):280–4. 20. Park KJ, Soslow RA, Sonoda Y, Barakat RR, Abu- 10. Gu M, Lin F. Efficacy of cone biopsy of the uterine Rustum NR. Frozen-section evaluation of cervical cervix during frozen section for the evaluation of cer- adenocarcinoma at time of radical trachelectomy: vical intraepithelial neoplasia grade 3. Am J Clin pathologic pitfalls and the application of an objec- Pathol. 2004;122(3):383–8. tive scoring system. Gynecol Oncol. 2009;113(1): 11. Hasanzadeh M, Sharifi N, Yusefi Z, Saghafe N, 42–6. Moghiman T, Tetedeg V. Role of frozen sections in the 21. Baker P, Oliva E. A practical approach to intraopera- evaluation of moderate to severe dysplasia during tive consultation in gynecological pathology. Int J uterine cervix conization. Asian Pac J Cancer Prev. Gynecol Pathol. 2008;27(3):353–65. 2010;11(3):731–4. 22. Horn LC, Wagner S. Frozen section analysis of vul- 12. Martinelli F, Schmeler KM, Johnson C, Brown J, vectomy specimens: results of a 5-year study period. Euscher ED, Ramirez PT, Frumovitz M. Utility of Int J Gynecol Pathol. 2010;29(2):165–72. conization with frozen section for intraoperative tri- 23. Höckel M, Hentschel B, Horn LC. Association age prior to definitive hysterectomy. Gynecol Oncol. between developmental steps in the organogenesis of 2012;127(2):307–11. the uterine cervix and locoregional progression of cer- 13. Rouzier R, Feyereisen E, Constancis E, Haddad B, vical cancer: a prospective clinicopathological analy- Dubois P, Paniel BJ. Frozen section examination of sis. Lancet Oncol. 2014;15(4):445–56. the endocervical margin of cervical conization speci- 24. Bjornsson BL, Nelson BE, Reale FR, Rose PG. mens. Gynecol Oncol. 2003;90(2):305–9. Accuracy of frozen section for lymph node metastasis 14. Behtash N, Karimi Zarchi M, Hamedi B, Azmoode in patients undergoing radical hysterectomy for carci- Ardalan F, Tehranian A. The value of frozen section- noma of the cervix. Gynecol Oncol. 1993;51(1): ing for the evaluation of resection margins in cases of 50–3. conization. Arch Gynecol Obstet. 2007;276(5): 25. Fader AN, Edwards RP, Cost M, Kanbour-Shakir A, 529–32. Kelley JL, Schwartz B, Sukumvanich P, Comerci J, 15. Schneider A, Erdemoglu E, Chiantera V, Reed N, Sumkin J, Elishaev E, Rohan LC. Sentinel lymph Morice P, Rodolakis A, Denschlag D, Kesic V. node biopsy in early-stage cervical cancer: utility of Clinical recommendation radical trachelectomy for intraoperative versus postoperative assessment. fertility preservation in patients with early-stage cer- Gynecol Oncol. 2008;111(1):13–7. vical cancer. Int J Gynecol Cancer. 2012;22(4): 26. Garg G, Shah JP, Toy EP, Field JB, Bryant CS, Liu JR, 659–66. Morris RT. Intra-operative detection of nodal metasta- 16. Tanguay C, Plante M, Renaud MC, Roy M, Têtu B. sis in early stage cervical cancer: a survey of the prac- Vaginal radical trachelectomy in the treatment of cer- tice patterns of SGO members. Gynecol Oncol. vical cancer: the role of frozen section. Int J Gynecol 2011;121(1):143–7. Pathol. 2004;23(2):170–5. 27. Rosai J, editor. Rosai and Ackerman’s Surgical 17. Zhang D, Ge H, Li J, Wu X. A new method of surgical Pathology. Edinburgh/London/New York/Oxford/ margin assuring for abdominal radical trachelectomy Philadelphia/St. Louis/Sydney/Toronto: Elsevier; in frozen section. Eur J Cancer. 2015;51(6):734–41. 2011. p. 2553–4, 2579–83, 2633–6. Index

A diffuse laminar endocervical hyperplasia, 85 Acute myeloid leukemia (AML), 236 ectopic prostate tissue, 94 Adenocarcinoma in situ (AIS) endocervical polyp, 85 characteristics, 16–18 endocervicosis, 87 usual type, 156–157 endometriosis, 94 Adenofibroma, 217–220 hyperplasia, 86–87 Adenoid basal carcinoma (ABC) LEGH, 85 clinical and gross features, 229 mesonephric remnants, 86–87 histogenesis, 231 microglandular hyperplasia, 94 histopathology, 229–231 Müllerian papilloma, 85 prognosis and management, 231 Nabothian cysts, 85 Adenoid cystic carcinoma (ACC) tubo-endometrioid metaplasia, 87, 90–94 clinical and gross features, 231 tunnel clusters, 85 histogenesis, 232 Benign squamous lesions histopathology, 231–232 condyloma acuminatum, 80–82 prognosis and management, 232 squamous metaplasia, 80 Adenosarcoma, 217–220 squamous papilloma, 82–83 Adenosquamous carcinoma transitional metaplasia, 83–84 clinical and gross features, 227 Bethesda system, 50–51 histogenesis, 228 Bivalent vaccines, 35 histopathology, 227–228 Blue nevus prognosis and management, 228 clinical and gross features, 232 Anogenital warts, 25–26 histogenesis, 233 Arias-Stella reaction histopathology, 232–233 benign glandular lesions, 87–89 prognosis and management, 233 in situ and invasive adenocarcinoma, 180–181 Atrophy, 110–111 Atypical endocervical cells (AEC), 181–182 C Atypical glandular cells (AGC) Carcinogenesis, 1 AEC, 181–182 Carcinosarcomas, 216–217 direct sample endometrium, 183–185 Cervical cancer HSIL, 186–189 adenocarcinoma vs. squamous cell carcinoma, 68–69 reactive changes management, recurrence of, 75 endocervical polyps, 185–187 metastatic disease, 75 intrauterine device, 185, 186 nonsurgical management tubal metaplasia, 182–183 adjuvant chemotherapy, 74–75 Atypical squamous cells (ASC), 109 chemoradiotherapy, 72 neoadjuvant chemotherapy, 74 radiation, 72–74 B stage IA carcinoma, 67–69 Basal cell hyperplasia, 110 stage IB carcinoma, 69–70 Basaloid SCC, 127–128 treatment Benign glandular lesions future directions, 71 Arias-Stella reaction, 87–89 reduce risk of, 70–71

Cervical glandular intraepithelial neoplasia (CGIN), 56 E Cervical infections, 94–95 Embryonal rhabdomyosarcoma, 137, 210–213 Cervical intraepithelial neoplasia (CIN), 48. See also Endocervical adenocarcinoma (EACA) Cervical squamous intraepithelial lesions epidemiology, 155–156 Cervical screening HG-CGIN/AIS, 156–157 automation, 58–59 cytopathology, 160–163 cytology and histology, UK terminology, 49–52 histopathology, 157–160 cytology-based population, 47–49 immunohistochemistry, 170–172 epidemiology, 47 invasive NHS, 51, 53–54 cytopathology, 167–170 NHSCSP histopathology, 165–167 HPV testing, 55–56, 60–61 prognosis, 164 HPV vaccination, 59–60 usual type, 163–164 LBC, 54–55 pathobiology, 156 test of cure, 56, 57 Endocervical adenomyoma, 220–221 triage of low-grade abnormality, 56, 57 Endocervical gland hyperplasias, 176 principles, 45 Endocervical neoplasia, immunohistochemistry of, program, 46–47 170–172 test, 46 Endocervicosis, 87, 176 treatment, 46 Endometrioid carcinoma, 197–198 in UK, 49 Endometriosis, 94, 174–175 Cervical squamous intraepithelial lesions Endosalpingiosis, 176 atypical squamous cells, 109 Epithelioid trophoblastic tumor (ETT), 135–136 biomarkers E7 protein, 28 HPV molecular assays, 116 Equivocal lesions, 181 immunohistochemistry, 112–115 in situ hybridization, 115–116 clinical course and management, 116–117 F cone biopsy, 100 Fetal squamocolumnar junction cytological specimens, 99–100 BCL2, 4, 5 endocervical gland extension, 108 (cyto)keratins, 4 epidemiology and risk factors, 99 hierarchical model, for cell lineages, 7–8 genetic features, 116 immunomarker profile, 5 gross/colposcopic features, 101 immunophenotyping study, 7–8 history and terminology, 97–98 molecular markers, 4 hysterectomy, 101 p63, 5–7 LEEP, 100–101 reserve cells, 4 microscopic mimics solid cord, 5 atrophy, 110–111 spatiotemporal distribution, 4–5 basal cell hyperplasia, 110 reactive atypia, 109 squamous cell carcinoma, 111–112 G squamous metaplasia, 110 Gastric-type adenocarcinoma (GAS), 195–197 morphological manifestations Germ cell tumors, 235–236 HSIL, 104–108 Gestational trophoblastic disease, 135 LSIL, 102–104 Glassy cell carcinoma, 134 LSIL/CIN1, 102–103 clinical and gross features, 228–229 normal squamous epithelium, 101–102 histogenesis, 229 surgical biopsy, 100 histopathology, 229 Chemoradiotherapy, 72 prognosis and management, 229 Chemotherapy, neoadjuvant, 74 Gynecological cytopathology, 51 Clear cell carcinoma, 199–200, 204 Condyloma acuminatum, 80–82 Cytokeratin 7 (CK7), 115 H High-grade cervical glandular intraepithelial neoplasia (HG-CGIN) D AIS, 156–157 Dendritic cells (DC), 33 cytopathology, 160–163 Department of Health (DoH), 54 histopathology, 157–160 Diffuse laminar endocervical hyperplasia, 85, 179 High-grade neuroendocrine carcinoma, 224 Index 263

High-grade squamous intraepithelial lesion (HSIL), Intensity-modulated radiotherapy (IMRT), 73, 74 14–16 Intramuscular (IM) injection, 34 CIN2, 104–105 Intrauterine device (IUD), 185, 186 CIN3, 105–107 Invasive endocervical adenocarcinoma endocervical glands, 186–189 cytopathology, 167–170 management, 117 histopathology, 165–167 variants, 108 prognosis, 164 Human papillomaviruses (HPVs) usual type, 163–164 classification, 22–26 DNA, 115 epidemiology K clearance and risk, 30–31 Keratinizing SCC, 125, 127 cytological, prevalence in disease, 32 Ki67, 115 general population, prevalence in, 28–30 histological, prevalence in disease, 31–32 genome organization and life cycle, 26–28 L high-risk, 193 Langerhans cell histiocytosis (LCH), 226 host defences Langerhans cells, 33 basal keratinocytes, 33 Large cell neuroendocrine carcinoma (LCNEC), dendritic cells, 33 134, 135, 225, 226 Langerhans cells, 33 Liquid-based cytology (LBC), 54–55 NK cells, 33 Lobular endocervical glandular hyperplasia (LEGH) role, 32 characteristics, 179–180 TLR, 33 histogenesis and precursors, 201–204 VLP, 34 Loop electrosurgical excision procedure (LEEP), immunization 100–101 delivery and immunogenicity, 34–35 Lower female reproductive tract prophylactic vaccines, 34, 36 embryonic and fetal development, 2 therapeutic vaccines, 35–36 mesenchymal signals, 4 infection, 12–13, 22 Müllerian ducts, 2 molecular assays, 116 p63, 3–4 NHSCSP squamocolumnar junction, 4 testing, 55–56, 60–61 transformation zone, 4 vaccination, 59–60 urogenital sinus, 3 RNA, 116 Low-grade squamous intraepithelial lesion (LSIL), testing 14, 56 advantages, 37–38 CIN1, 102–103 biospecimens, 39–40 clinical management, 117 detection and management, 36–37 cytology, 103–104 disadvantages, 37–38 histology, 103 in immunized populations, 40 Lymphoepithelioma-like SCC, 130 indications, 37–38 Lymphoid tumors, 236, 237 molecular, 36–37 Lymphovascular space involvement (LVSI), screening and management, 37 68, 143–144 targets and types, 38 tools and biomarkers, for risk stratification, 39 Hyperplasia, 205 M Hysterectomy, 101 Malignant melanoma (MM), 134, 135 MAVARIC study, 59 Melanoma I clinical and gross features, 233 Immunohistochemistry histogenesis, 234 cervical squamous intraepithelial lesions, histopathology, 233–234 112–115 prognosis and management, 234 diagnosis, squamous cell carcinomas, 137 Mesenchymal neoplasms endocervical adenocarcinoma, 170–172 embryonal rhabdomyosarcoma, 210–213 Inflammation, 85 myofibroblastoma, of lower female genital tract, In situ hybridization (ISH) 213–215 HPV DNA, 115 pseudoneoplastic myxoid change, 215 HPV RNA, 116 smooth muscle, 209–210 264 Index

Mesonephric carcinoma, 200 Placental site nodule (PSN), 132 Mesonephric duct remnants, 86–87, 205 ProExC, 115 Metastatic disease, 75 Prophylactic vaccines, 36 Metastatic ductal carcinoma, 135 Pseudoneoplastic myxoid change, 215 Microglandular hyperplasia, 94, 177–179 Pyloric gland metaplasia (PGM), 201–202 Mixed epithelial and mesenchymal neoplasms adenofibroma and adenosarcoma, 217–220 carcinosarcomas, 216–217 Q endocervical adenomyoma, 220–221 Quadrivalent vaccine, 35 Myeloid tumors, 226 Myofibroblastoma, of lower female genital tract, 213–215 R Radiotherapy, 72–75 N Retinoblastoma (RB), 28 National Health Service Cervical Screening Programme (NHSCSP) HPV testing, 55–56, 60–61 S HPV vaccination, 59–60 SCC. See Squamous cell carcinoma (SCC) LBC, 54–55 Secondary malignancy, 239 test of cure, 56, 57 Sentinel node surgery, 71 triage of low-grade abnormality, 56, 57 Serous carcinoma, 198–199 Natural killer cells (NK cells), 33 Serous carcinoma in situ, 204–205 Neoadjuvant chemotherapy (NACT) Small cell neuroendocrine carcinoma (SCNEC), SCC, 149 136–137, 224 surgical treatments, 71, 74 Smooth muscle neoplasms, 209–210 Neuroendocrine tumors (NETs) Squamocolumnar junctional (SCJ) markers, 115 histogenesis, 226–227 Squamotransitional/transitional SCC, 129 histopathology, 223–226 Squamous cell carcinoma (SCC), 111–112 macroscopic appearance, 223 clinical features, 122 prognosis and management, 227 definition, 121 NHSCSP. See National Health Service Cervical diagnosis immunohistochemistry, 137 Screening Programme (NHSCSP) differential diagnosis, 130–131 Non-human papillomavirus (HPV)-related carcinomas invasive disease, 133–136 clear cell carcinoma, 199–200 lesions mimicking invasive disease, 132–133 endometrioid carcinoma, 197–198 small round blue cell appearance, 136–137 gastric-type adenocarcinoma, 195–197 etiology, 122 histogenesis and precursors, 200–201 factors affecting prognosis and staging clear cell carcinoma, 204 adnexal involvement, 147 endometrioid carcinoma in situ, 205 depth of cervical stromal invasion, 145–146 hyperplasia, 205 diameter, 142 LEGH, 201–204 grade, 142 mesonephric duct remnants, 205 LVSI, 143–145 serous carcinoma in situ, 204–205 lymph node metastasis, 147–149 tuboendometrial metaplasia, 205 molecular biomarkers, 149 mesonephric carcinoma, 200 parametrial involvement, 146–147 serous carcinoma, 198–199 pattern of invasion, 144 Non-keratinizing SCC, 124–127 perineural involvement, 144 (chemo)radiation-induced changes, 149 stage, 141 O surgical margin status, 142–143 Oxyphilic metaplasia, 174, 175 uterine corpus, 147 volume, 142 macroscopic appearances, 122–124 P microscopic appearances, 122, 124 p16, 112–115 basaloid, 127–128 Papanicolaou classification system, 49–50 keratinizing, 125, 127 Papillary SCC, 129–130 lymphoepithelioma-like, 130 Pap smear/test, 99–100, 157 non-keratinizing, 124–127 Parametrial involvement, 146–147 papillary, 129–130 Perineural involvement (PNI), 144 squamotransitional/transitional, 129 Index 265

verrucous, 128 carcinogenesis, 1 warty/condylomatous, 128–129 development, 1 stromal invasion fetal squamocolumnar junction diagnosis, 138–139 BCL2, 4, 5 measurement, 139–141 hierarchical model, for cell lineages, 7–8 Squamous intraepithelial lesion (SIL), 80, 81. See immunomarker profile, 5 High-grade squamous intraepithelial lesion immunophenotyping study, 7–8 (HSIL) and Low-grade squamous keratins, 4 intraepithelial lesion (LSIL) molecular markers, 4 Squamous metaplasia, 80, 110 p63, 5–7 uterine cervix, 10–12 reserve cells, 4 Squamous papilloma, 82–83 solid cord, 5 Stem cells, 9 spatiotemporal distribution, 4–5 Stratified mucin-producing carcinoma, lower female reproductive tract 135, 136 embryonic and fetal development, 2 Superficially invasive squamous cell carcinoma mesenchymal signals, 4 (SISCCA), 138, 139 Müllerian ducts, 2 p63, 3–4 squamocolumnar junction, 4 T TZ, 4 Therapeutic vaccines, 35–36 urogenital sinus, 3 Toll-like receptor (TLR), 33 premalignant lesions Trachelectomy, 69–70 AIS, 16–18 Transitional cell carcinoma (TCC), 133 HSIL, 14–16 Transitional metaplasia, 83–84 LSIL, 14 Tubal metaplasia (TM) morphological distinction, 13 atypical glandular cells, 182–183 squamous metaplasia, 10–12 in situ and invasive adenocarcinoma, 172–174 TZ, 9–10 Tuboendometrioid metaplasia (TEM), 87, 90–94, 172, 173, 205 Tunnel clusters, 177 V Verrucous SCC, 128 Virus like particles (VLPs), 34 U Undifferentiated carcinoma, 229 Uterine cervix W adult squamocolumnar junction, progenitor cells, 8–9 Warty/condylomatous SCC, 128–129