Data Set for Reporting of Uterine Malignant and Potentially Malignant Mesenchymal Tumors: Recommendations From the International Collaboration on Cancer Reporting (ICCR) : International Journal of Gynecological Pathology

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Data Set for Reporting of Uterine Malignant and Potentially Malignant Mesenchymal Tumors: Recommendations From the International Collaboration on Cancer Reporting (ICCR)

Nucci, Marisa R. M.D.; Webster, Fleur M.Sc.; Croce, Sabrina M.D.; George, Suzanne M.D.; Howitt, Brooke E. M.D.; Ip, Philip P.C. F.R.C.Path.; Lee, Cheng-Han M.D.-Ph.D., F.R.C.P.C.; Rabban, Joseph T. M.D., M.P.H.; Soslow, Robert A. M.D.; van der Griend, Rachael F.R.C.P.A.; Lax, Sigurd F. M.D., Ph.D.; McCluggage, W. Glenn F.R.C.Path.

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International Journal of Gynecological Pathology 41():p S44-S63, November 2022. | DOI: 10.1097/PGP.0000000000000911
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Abstract

The International Collaboration on Cancer Reporting (ICCR), founded by the Canadian Association of Pathologists in collaboration with the Canadian Partnership Against Cancer (CPAC), the College of American Pathologists, and the United Kingdom and Australasian Colleges of Pathology, was established to develop internationally standardized and evidence-based cancer reporting protocols for surgical pathology specimens. In recent years, the ICCR has developed into a global alliance of an increasing number of sustaining pathology societies and cancer organizations. By performing a comprehensive review of currently published data sets, a thorough review of the literature, and utilizing the knowledge and experience of experts in the field, the ICCR seeks to ensure that all cancer reports generated worldwide will be of similar high quality and record consistent data. The ICCR has previously developed gynecological cancer data sets for the most common gynecologic malignancies; endometrial, ovarian/fallopian tube/primary peritoneal, and cervical carcinomas 1–3. These evidence-based data sets have been generated by a panel of internationally recognized expert gynecological pathologists and a single clinician with expertise in the area. The data sets have been subject to international open consultation and are freely available online from the ICCR website for worldwide use (http://www.iccr-cancer.org/datasets/published-datasets/female-reproductive). The process for the production of these datasets and their reporting elements have been published in peer-reviewed journals 1–3. This ICCR data set on uterine malignant and potentially malignant mesenchymal tumors is 1 of 4 recently produced contemporary data sets on more uncommon gynecological malignancies, the others covering vulval carcinomas, gestational trophoblastic neoplasia, and vaginal carcinomas; all of these are copublished in this special edition of the International Journal of Gynecological Pathology. These new evidence-based data sets, which include updates from the 5th edition of the World Health Organization (WHO) Classification of Tumors of the Female Genital Tract 4, provide recommendations for pathologists worldwide when handling resection specimens of these less common gynecological tumors.

MATERIALS AND METHODS

The ICCR has developed a set of standard operating procedures for the process of data set development (described in previous publications 1–3), and defined the selection process, roles and responsibilities of the chair, expert panel members, the ICCR Dataset Steering Committee representative on the panel, ICCR Series Champion, and the project manager. The ICCR Series Champion provided guidance and support to the Chair of the Dataset Authoring Committee (DAC) regarding ICCR standards and ensured harmonization across gynecological data sets. After the expert panel was established, the project manager collated existing international data sets for uterine malignant and potentially malignant mesenchymal tumors (CAP and RCPath) and scheduled a series of teleconferences to review and discuss each of the elements proposed to be included in the data set. In addition, the development process for the data set was also conducted by email correspondence.

The cancer data set comprises a scope and a series of elements which are considered important for clinical management, staging or prognosis of the neoplasm. Elements are included by consensus agreement of the DAC (the expert panel members). An element is designated as core (required) or noncore (recommended) by the DAC as described below.

Core elements are those which are agreed by the DAC to be essential for the clinical management, staging or prognosis of the cancer. These elements will either have evidentiary support at level III-2 or above (based on prognostic factors in the National Health and Medical Research Council (NHMRC) levels of evidence document 5. When level III-2 evidence is not available, an element may be designated as core where there is unanimous agreement by the DAC. The list of all core elements is the minimum reporting standard for the specific type of cancer.

Noncore elements are those to which the DAC unanimously agrees should be included in the data set but are not supported by level III-2 evidence. These elements may be clinically important and recommended as good practice but are not yet validated or regularly used in patient management.

Once the elements were agreed upon by the panel, the members then discussed and agreed on the value list of responses to each element. The Chair of the DAC then assigned the writing of a commentary for each element to members of the panel, based on a review of the current literature. The commentary comprises explanatory text and tables to clarify core and noncore elements, presents the relevant evidence for each element, and defines the way each element should be reported. The lists of core and noncore elements and the associated commentaries are presented below. Those data set items which include both core and noncore elements, are included in the core elements section in this paper.

The draft data set was subject to an international public consultation, from which all feedback received was reviewed by the DAC. The finalized data set was subsequently submitted to the ICCR Dataset Steering Committee for ratification and publication. All ICCR data sets, including this one on uterine malignant and potentially malignant mesenchymal tumors, are freely available worldwide at the ICCR website at www.iccr-cancer.org/datasets.

RESULTS

Scope

The data set has been developed for the pathology reporting of resection specimens of the uterus for sarcomas and mesenchymal tumors with potentially malignant behavior. The data set is applicable to tumors of the uterine corpus and the uterine cervix.

Carcinomas, other nonmesenchymal malignancies, and metastatic neoplasms are excluded from this data set. Carcinosarcoma is also excluded as it is considered to represent a malignant epithelial tumor with divergent mesenchymal differentiation based on clinicopathologic, immunohistochemical, and molecular analysis; as such, this entity is included in the ICCR Endometrial cancer data set.

Core Elements

A summary of the core elements is provided in Table 1 and each is described in further detail below.

TABLE 1 - Core and noncore elements for the pathology reporting of uterine malignant and potentially malignant mesenchymal tumors
Core Noncore
Operative procedure Clinical information
Specimen integrity Block identification key
Tumor site Extent of invasion
Maximum tumor dimension  Distance of tumor to uterine serosa
Histological tumor type Margin status
Mitotic count Extent of invasion  Distance of tumor from closest cervical or vaginal margin; specify closest margin, if possible
 Uterine serosa involvement
Lymphovascular invasion  Parametrial margin—specify laterality, if possible
Margin status Coexistent pathology
 Distal/cervical or vaginal Ancillary studies
 Parametrial
Lymph node status
Pathologically confirmed distant metastasis
Provisional pathologic staging

Operative Procedure

While a diagnosis of a uterine sarcoma or tumor of uncertain malignant potential may occur with limited sampling of disease (endometrial biopsy, curetting or core biopsy), a significant subset is clinically unsuspected and first diagnosed upon pathologic examination of a myomectomy or hysterectomy specimen. Hysterectomy, with or without bilateral salpingo-oophorectomy, and myomectomy can provide both diagnostic and complete surgical resection of disease, although myomectomy may be associated with residual tumor postresection. Laparoscopic myomectomy/ hysterectomy followed by in vivo fragmentation (morcellation) affects specimen integrity, discussed below, and may be suboptimal for diagnosis because of distortion of the organ’s anatomy. In general, surgical management is related to tumor site and wish for fertility preservation and the decision to perform salpingo-oophorectomy depends on the disease type and the patient’s age as ovarian preservation in young patients with uterine sarcoma may not impact overall survival 6,7. Nevertheless, hysterectomy with or without bilateral salpingo-oophorectomy is the most common and complete type of resection for malignant mesenchymal tumors. Since some sarcomas more frequently metastasize to lymph nodes than others, planning lymph node sampling or dissection is partly based on the sarcoma type (if known preoperatively), presence of clinically evident nodal disease at time of surgery, and surgeon’s preference.

Specimen Integrity

Documentation of specimen integrity is crucial for reporting of malignant and potentially malignant uterine mesenchymal tumors as integrity affects evaluation of margins and can impact staging and prognosis of uterine sarcomas 8–10. It is important to document morcellation, a surgical technique performed in vivo after laparoscopic myomectomy or hysterectomy to reduce the size of the specimen into fragments small enough to be removed from the patient through the laparoscopic incision sites. Documentation is important as recurrence of uterine sarcoma may occur when tumors are removed laparoscopically with morcellation 11. After this phenomenon was first documented in several series 11–13, certain protective measures were encouraged by the gynecology community regarding use of this particular surgical technique 14–16.

Specimen(s) Submitted

The presence of accompanying organs or tissues, other than the primary tumor site specimen (myomectomy or hysterectomy) is important because it contributes to the pathologic assessment of tumor extension, other than by imaging and staging. If peritoneal washings/peritoneal fluid are submitted, this should be documented along with the presence or absence of tumor cells.

Tumor Site

Uterine sarcomas can arise primarily in the cervix or corpus, and in most cases, the site can easily be assigned. If the origin of a sarcoma is equivocal and it is difficult to establish whether the tumor has arisen from the cervix or the corpus (including the isthmus), deference is typically given to a corpus origin 17. Some tumors cannot be assigned a site of origin; for example, if they are removed piecemeal, such as with morcellation, or when they efface normal anatomy and/or present at high stage. In this instance, the “other” category can be used with an explanatory note.

Maximum Tumor Dimension

Maximum tumor measurement requires an intact tumor as dimensions cannot be assessed on piecemeal or morcellated specimens. As such, evaluation of this element usually requires a hysterectomy or myomectomy specimen. Tumor size, which is the gross measurement across the largest dimension, is given in millimetres, although International Federation of Gynecology and Obstetrics (FIGO) and TNM staging parameters require conversion to centimetres. We recommend to sample at least one block per cm of maximum tumor dimension.

Measurement in 3 dimensions is not required, nevertheless, tumor size is an important quality measure. When a case is being reviewed, it allows the reviewing pathologist to assess whether the tumor has been “adequately” sampled. This may be particularly important in tumors with variable or undifferentiated morphology.

Tumor size is also critical for staging and may have prognostic significance. Leiomyosarcomas and endometrial stromal sarcomas confined to the uterus and measuring <50 mm may have a more favorable prognosis, which is reflected in the staging (FIGO Stage IA vs. IB) 18, although some studies have shown no association between size and outcome for Stage I leiomyosarcoma 19. Size ≥50 mm is one of the parameters used to assess malignant potential in perivascular epithelioid cell tumors (PEComa) of gynecological origin 20,21. For inflammatory myofibroblastic tumor (IMT), size >70 mm may be associated with an aggressive clinical course, although evidence is limited 22,23.

Histologic Tumor Type

Our knowledge of the different types of mesenchymal tumors that can occur in the uterus has expanded in the past decade, as underlying molecular abnormalities have helped define distinctive clinicopathologic entities. Proper classification of malignant and potentially malignant tumors is crucial as there are important differences in clinical management and outcome. In many instances, additional tumor sampling may be more useful than ancillary techniques; in particular, sampling of the border of tumors can be useful. Prediction of malignant behavior is sometimes based on small series with limited numbers of patients.

All mesenchymal tumors of the uterus should be typed according to the most recent edition of the WHO Classification of Female Genital Tumors, 5th edition, 2020 (Table 2) 4. The ICCR data set includes 5th edition Corrigenda, June 2021 24. The most commonly encountered sarcomas—leiomyosarcoma, endometrial stromal sarcoma and Müllerian adenosarcoma—will be discussed first.

TABLE 2 - World Health Organization classification of mesenchymal tumors of the uterine corpus 5.
Descriptor ICD-O codes*
Mesenchymal tumors specific to the uterus
 Smooth muscle tumor of uncertain malignant potential (STUMP) 8897/1
 Leiomyosarcoma 8890/3
 Endometrial stromal sarcoma, low grade 8931/3
 Endometrial stromal sarcoma, high grade 8930/3
 Undifferentiated uterine sarcoma 8805/3
 Uterine tumor resembling ovarian sex cord tumor (UTROSCT) 8590/1
 Perivascular epithelioid cell tumor (PEComa) 8714/3
 Inflammatory myofibroblastic tumor 8825/1
Mixed epithelial and mesenchymal tumors
 Adenosarcoma 8933/3
*These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2). Behavior is coded /0 for benign tumors; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumors, primary site; and /6 for malignant tumors, metastatic site. Behavior code /6 is not generally used by cancer registries. Incorporates all relevant changes from the 5th Edition Corrigenda June 2021.
Copyright World Health Organization/International Agency for Research on Cancer, Lyon, France. All permission requests for this image should be made to the copyright holder.

Smooth Muscle Tumors. Classification of smooth muscle tumors primarily relies on histologic assessment of several parameters. This assessment, however, can be challenging as benign, malignant, and tumors classified as of uncertain malignant potential can share overlapping morphologies. For example, a high degree of cellularity may be seen in both benign (cellular leiomyoma) and malignant (leiomyosarcoma) tumors. Nevertheless, using the most recent edition of the WHO Classification, most uterine smooth muscle neoplasms are readily diagnosed either as benign or malignant 25. The type of leiomyosarcoma (spindle, epithelioid, myxoid) should be included in the report.

Leiomyosarcoma with spindle cell differentiation is diagnosed when there are at least 2 of the following 3 histologic parameters: diffuse, moderate to severe nuclear atypia, mitotic count ≥10 per 2 mm2 [≥10 mitoses per 10 high power fields (HPF) if field diameter is 0.55 mm) and tumor cell necrosis 25. The criteria for diagnosis of malignancy in epithelioid and myxoid smooth muscle tumors are stricter. Epithelioid leiomyosarcoma usually contains ≥4 mitoses per 2 mm2 (≥4 mitoses per 10 HPFs if field diameter is 0.55 mm) moderate to severe nuclear atypia and/or tumor cell necrosis 26–29. Myxoid leiomyosarcomas usually have an infiltrative border, and either moderate to severe nuclear atypia, tumor cell necrosis, or >1 mitoses per 2 mm2 (>1 mitoses per 10 HPFs if field diameter is 0.55 mm) 30.

Tumors which show morphologic features that exceed the criteria for leiomyoma but fall below the threshold for leiomyosarcoma may be diagnosed as smooth muscle tumor of uncertain malignant potential (STUMP) 31,32. The category of STUMP should be used sparingly and before making a diagnosis of STUMP, every effort should be made to establish a diagnosis of either a leiomyoma subtype, leiomyosarcoma, or one of the recently described mesenchymal tumors with deceptively bland cytology as included in this data set [i.e. PEComa, IMT, and neurotrophic tyrosine receptor kinase (NTRK)-rearranged spindle cell sarcoma]. Besides epithelioid and myxoid neoplasms, the most common histologic subtypes of leiomyoma which may give rise to diagnostic difficulties are leiomyoma with bizarre nuclei and cellular leiomyoma. In order to make a distinction from leiomyosarcoma, accurate assessment of the number of mitoses in leiomyoma with bizarre nuclei is important but this is not straightforward because karyorrhectic nuclei may mimic mitoses 33,34. Fumarate hydratase (FH)-deficient morphology can be seen in leiomyoma with bizarre nuclei as well as conventional and cellular leiomyomata. In FH-deficient leiomyomata, the nuclei are often arranged in chains, have eosinophilic cytoplasmic inclusions, prominent eosinophilic nucleoli, and perinucleolar halos. The presence of these features, often accompanied by staghorn blood vessels and alveolar-pattern edema, particularly in a smooth muscle tumor occurring in a young woman, should prompt consideration of association with FH deficiency. Loss of FH staining by immunohistochemistry supports the diagnosis. Of note, a subset of these tumors are characterized by intact expression of FH (corresponding to the presence of FH protein that is nonfunctional). With either loss or a nonfunctional FH protein, accumulation of 2-SC and a positive 2-SC stain confirms the diagnosis. Although the majority of these cases seems to be sporadic, hereditary leiomyoma and renal cell carcinoma syndrome needs to be excluded in the appropriate clinical setting 35–38. As high cellularity may be observed in benign and malignant smooth muscle tumors, as well as endometrial stromal neoplasms, tumors considered cellular leiomyoma should not contain microscopic features which exceed the WHO criteria for leiomyoma 25.

According to the 5th edition WHO corrigenda 24, STUMP is an applicable diagnosis if a spindle cell smooth muscle tumor has focal/multifocal or diffuse nuclear atypia, 5 to 9 mitoses per 2 mm2 (5–9 mitoses per 10 HPFs if field diameter is 0.55 mm) and lacks tumor cell necrosis. Approximately 12% to 17% of such tumors have recurred. The STUMP diagnosis is also applicable to any bland smooth muscle tumor with tumor cell necrosis or necrosis of an uncertain type. Approximately 28% of such tumors have recurred. Tumors lacking cytologic atypia and tumor cell necrosis, but with ≥15 mitoses per 2 mm2 (≥15 mitoses per 10 HPFs if field diameter is 0.55 mm) are also considered STUMPs. Although none of such cases has recurred, the experience with these tumors is limited 32,39. In addition to the Stanford criteria 39, other helpful parameters that may be included in the assessment of recurrent potential in smooth muscle neoplasms are atypical mitoses, vascular involvement, and infiltrative/irregular margins 40. Epithelioid and myxoid STUMPs are rare, and it is important to exclude their respective benign and malignant variants by integrating gross, microscopic, and molecular findings 29,41.

Endometrial Stromal Sarcoma. The classification of endometrial stromal sarcoma has evolved over time due to a better understanding of its morphologic spectrum and underlying recurrent molecular abnormalities. While it was historically separated into low and high grade categories based on mitotic count, the category of high-grade endometrial stromal sarcoma was removed from the 2003 WHO Classification as there was a lack of clinical relevance in separating tumors that morphologically resembled proliferative phase endometrial stroma into low and high grade categories based on mitotic count alone 42. It is worth noting that the category of high-grade endometrial stromal sarcoma at that time represented a heterogeneous group of tumors including those that resembled endometrial stroma and those with more nuclear pleomorphism. Currently, 2 categories of endometrial stromal sarcoma are recognized by the most recent WHO Classification 4. While they maintain the same lexicon used in the past—low-grade and high-grade endometrial stromal sarcoma—they represent 2 distinct clinicopathologic entities with differing morphology, biologic behavior, and molecular findings 42–48.

Low-grade endometrial stromal sarcoma is composed of cells which morphologically resemble proliferative-phase endometrial stroma, that is, cells have uniform round to ovoid nuclei and scant cytoplasm, and they are associated with a delicate spiral arteriole-like network. This tumor has a characteristic growth pattern as it typically permeates the myometrium in a “finger-like” or “tongue-like” manner; lymphovascular invasion (LVI) is frequent and sometimes prominent. Smooth muscle, sex cord-like, fibrous and myxoid variant morphology is not uncommon. Most, but not all tumors, harbor gene fusions most commonly JAZF1-SUZ12. Tumors with sex cord-like differentiation often harbor fusions involving PHF1. Patients with low-grade endometrial stromal sarcoma typically have an indolent and protracted course.

Some low-grade endometrial stromal tumors are classified as having “limited” infiltration. These represent tumors that lack overt myometrial permeation but have more margin irregularity than allowed for designation as an endometrial stromal nodule 49,50. Although most behave in a benign fashion, a subset of tumors classified as such have metastasized. Thus, these tumors should be regarded as potentially malignant and be classified as low-grade endometrial stromal sarcomas with limited infiltration 51.

High-grade endometrial stromal sarcoma encompasses tumors that have distinctive clinical, histologic and molecular findings that differs from low-grade endometrial stromal sarcoma 46,48,52–54. This tumor type occurs over a wide age range and shows a variable morphology but typically contains at least a focal characteristic round cell component (if associated with YWHAE-rearrangement), or myxoid spindle cell component (if associated with BCOR-rearrangement, most commonly ZC3H7B-BCOR, or internal tandem duplications). Patients with high-grade endometrial stromal sarcoma more commonly present at higher stage in comparison to patients with low-grade endometrial stromal sarcoma. Histologically, they can show expansile, permeative, or more commonly destructive infiltration of the myometrium; LVI can also be prominent. Tumors associated with YWHAE-rearrangement often, but not always, have a morphologically low-grade component often akin to the fibromyxoid variant of low-grade endometrial sarcoma. BCOR-associated tumors can closely mimic the appearance of myxoid leiomyosarcoma as tumor cells are often spindled with mild to moderate nuclear atypia and set in a prominent myxoid stroma. Limited clinical data suggest that high-grade endometrial stromal sarcomas, regardless of the underlying genetic abnormality, are more likely to pursue an aggressive clinical course with earlier recurrences and metastasis, in comparison to low-grade endometrial stromal sarcoma 46,48,52,54.

Although rare, a scenario worth mentioning is the potential for low-grade endometrial stromal sarcoma to “transform” to a high-grade tumor. In this scenario, the tumor may have the appearance of a high-grade endometrial stromal sarcoma or undifferentiated uterine sarcoma but harbor translocations characteristic of conventional low-grade endometrial stromal sarcoma 55.

Müllerian Adenosarcoma. Müllerian adenosarcoma is a biphasic neoplasm composed of a benign, non-neoplastic Müllerian epithelial component and a malignant sarcomatous component which is usually, but not always, morphologically low grade 56. These tumors are uncommon, representing <1% of all uterine malignancies and ~10% of uterine sarcomas. Gross examination may show multiple large, soft polypoid masses filling the uterine cavity; tumors may invade the myometrium or cervical stroma, a finding more commonly associated with sarcomatous overgrowth. Characteristic histologic findings include a leaf-like growth pattern (also often described as phyllodes-like as the appearance is akin to a phyllodes tumor of the breast), with intraglandular stromal polypoid projections, and cuffing of the glands by hypercellular stroma. However, not all adenosarcomas show phylloidiform growth with some being composed of variably sized rounded glands surrounded by hypercellular stroma (rigid cysts); a combination of these appearances is not uncommon. The stromal cells may show variable amounts of nuclear atypia in the form of nuclear enlargement with irregular nuclear contour or nuclear hyperchromasia. Mitoses are typically identified [usually >1 per 2 mm2 (>1 mitosis per 10 HPFs if field diameter is 0.55 mm)] but may be sparse or, in rare cases, absent. The stromal component is most commonly homologous, that is, it has the appearance of endometrial or cervical stroma, but may also show heterologous differentiation, most commonly rhabdomyosarcoma. Sex cord-like differentiation may also occur. Sarcomatous overgrowth is defined as the presence of >25% of the tumor composed solely of a neoplastic stromal component without epithelium; sex cord–like differentiation is not considered in the assessment of stromal overgrowth 57,58. Sarcomatous overgrowth often shows aberrant p53 immunoreactivity and loss of hormone receptor positivity 59,60. It is important to note that the non-neoplastic epithelial component typically has a banal appearance, sometimes with various types of epithelia (tubal, endometrioid, mucinous, squamous); occasionally the epithelial component may show some cytologic atypia in the form of nuclear enlargement and hyperchromasia. In this latter scenario, additional sampling may be prudent to exclude carcinosarcoma. Features associated with an unfavorable outcome include sarcomatous overgrowth, deep myometrial invasion, and extrauterine extension 61; morphologically high grade nuclear atypia (marked nuclear enlargement and hyperchromasia) that shows mutation-type staining pattern for p53 may also be an adverse prognostic feature 60.

Undifferentiated Uterine Sarcoma (Unclassifiable Sarcoma). Sarcomas which cannot be classified are considered undifferentiated uterine sarcoma. This is a diagnosis of exclusion after other malignancies, such as undifferentiated carcinoma, carcinosarcoma, leiomyosarcoma, and high-grade endometrial stromal sarcoma have been excluded. As many of the tumors in the differential diagnosis may have areas of morphologic overlap, the diagnosis of undifferentiated uterine sarcoma is best rendered on a complete excision specimen as a more limited specimen may lack the diagnostic features of other uterine malignancies. It is worth noting that undifferentiated uterine sarcoma can be separated into 2 different types based on their morphologic appearance: uniform and pleomorphic 62. With advanced molecular techniques and newly reported molecular abnormalities, the former are increasingly categorized as high-grade endometrial stromal sarcomas, whereas the pleomorphic type most likely represent sarcomas that are so poorly differentiated that they cannot be classified 63. Some of these tumors may represent carcinosarcomas in which only the sarcomatous component is seen, and thus before making a diagnosis of an undifferentiated uterine sarcoma, additional sampling should be considered which may reveal diagnostic areas. Indeed, before rendering the diagnosis of undifferentiated uterine sarcoma in an excision specimen, extensive tumor sampling, immunohistochemical staining, and if possible, molecular testing may be needed to exclude other neoplasms.

Potentially malignant mesenchymal tumors of the uterus are those in which prognostication requires assessment of various clinical and pathologic parameters to determine biologic potential. Tumors within this category include uterine tumor resembling ovarian sex cord tumor (UTROSCT), PEComa, and IMT.

UTROSCT. UTROSCT is an uncommon uterine neoplasm whose histologic features recapitulates the appearance of an ovarian sex cord tumor. Historically, the term UTROSCT included tumors entirely composed of sex cord elements as well as endometrial stromal tumors with extensive sex cord differentiation; the latter are no longer considered in this category based on morphologic as well as molecular differences. UTROSCT exhibit a wide range of morphologic appearances with diffuse, corded, trabecular, tubular, retiform and/or nested growth. Tumor cells have variable amounts of cytoplasm ranging from inconspicuous to abundant, which may be pale, foamy or eosinophilic; rhabdoid morphology may be seen and can be extensive. Nuclei are usually uniform with minimal cytologic atypia, and the mitotic count is low. Nuclear atypia in the form of nuclear enlargement and hyperchromasia, as well as brisk mitotic activity, may be seen. UTROSCT is characterized by recurrent gene fusions involving NCOA1-3, GREB1, and ESR164–67. These tumors are considered to be of uncertain malignant potential. Although data is limited, features that may be associated with aggressive behavior include a mitotic count >2 per 2 mm2 (>2 mitoses per 10 HPFs if field diameter is 0.55 mm), necrosis, extensive (>50%) rhabdoid morphology and potentially tumors with GREB1 rearrangement 65–68.

PEComa. PEComas are unusual mesenchymal neoplasms that are composed of a distinctive population of cells, termed perivascular epithelioid cells, which co-express smooth muscle and melanocytic markers. These tumors have a wide anatomic distribution, and the uterus is the most common site when they occur in the female genital tract 20,21,69–71. Most tumors occur sporadically with only a small subset being associated with tuberous sclerosis. Histologically, tumors most commonly are composed of epithelioid and spindle cells but can sometimes be solely or predominantly epithelioid or spindled. Tumors often, but not always, show a characteristic perivascular pattern of growth in which the tumor cells are radially arranged around the vasculature. The neoplastic cells also may be seen within the muscular wall of the vessel. Another distinctive aspect is their cytologic appearance; the cells are remarkable for abundant granular eosinophilic or clear cytoplasm although predominantly spindled tumors may show less abundant cytoplasm. When epithelioid, the tumor cells grow in sheets, nests and/or trabeculae that are surrounded by a delicate capillary vasculature. Spindled tumors often exhibit fascicular growth and can mimic smooth muscle neoplasia, the distinctive morphologic difference being the granular appearance of the cytoplasm. Of note, TFE3-associated PEComas often are composed of epithelioid cells that have predominantly clear cytoplasm; extensive melanin deposition may also occur. Assessment of potential malignant behavior for PEComa of the female genital tract is based on the following parameters: tumor size ≥50 mm, high nuclear grade, mitotic count of >1 mitosis per 12 mm2, presence of necrosis and presence of vascular invasion. If a tumor has 3 or more of these features, it is best classified as malignant. Only tumors that lack all features could potentially be considered benign. Any tumor with 1 or 2 features should be considered of uncertain malignant potential.

IMT. IMT is a myofibroblastic/fibroblastic neoplasm characterized by a variably myxoid stroma with an accompanying variably intense inflammatory infiltrate, primarily composed of lymphocytes and plasma cells. This tumor shows a wide anatomic distribution with the uterine corpus being the most common location in the female genital tract; less commonly it involves the cervix 22,72–74. Occasionally, IMT may be identified at the time of delivery and in some cases may be adherent to the maternal surface of the placenta or be associated with the placental membranes 75,76. Microscopically, the tumor borders can be well demarcated or irregular, either showing permeative (stromal sarcoma-like) or infiltrative margins. Several different morphologies may be seen and are often intermixed: myxoid, leiomyoma-like, or hyalinized. The myxoid pattern is characteristically hypocellular with individual cells dispersed in an abundant myxoid matrix, a feature that imparts a fasciitis-like appearance on low power magnification. The leiomyoma-like areas are composed of spindled cells in intersecting fascicles or showing storiform growth; the former closely mimics smooth muscle neoplasia. The hyalinized pattern is remarkable for an abundant hyalinized and collagenous stroma containing scattered spindled cells. The tumor cells in the fasciitis-like areas are spindled with eosinophilic to amphophilic cytoplasmic processes and ovoid to tapered nuclei with open dispersed chromatin, features that closely resemble the appearance of the spindled cells of nodular fasciitis. The spindled cells in the leiomyoma-like areas have features indistinguishable from smooth muscle neoplasia with eosinophilic cytoplasm and more oblong nuclei with blunt ends. The epithelioid variant of IMT, which typically occurs in the abdominal cavity and is characterized by a predominant component of epithelioid cells with eosinophilic cytoplasm and vesicular nuclei, has recently been described to occur in the uterus 77, and has also been reported in the ovary 78,79. An inflammatory infiltrate, often present at the periphery of the tumor but also dispersed throughout, is typically composed of lymphocytes and plasma cells although other inflammatory cells can be seen; the amount and distribution of inflammatory cells vary but inflammation is typically a reproducible finding and characteristic of IMT. Assessment of potential malignant behavior for IMT of the female genital tract is not well established. Some tumors present at high stage and should be considered malignant. Pathologic features which have been associated with aggressive behavior include large tumor size (>150 mm), marked nuclear atypia, LVI and tumors with high mitotic counts (>10 per 2 mm2 which corresponds to >10 mitoses per 10 HPFs if field diameter is 0.55 mm). These features are not invariably associated with adverse outcome and conversely tumors as small as 62 mm or with mitotic counts of only 1 per 2 mm2 (1 mitosis per 10 HPFs if field diameter is 0.55 mm) have recurred. Recurrence of IMT at all anatomic sites is estimated at 25% and is related to resectability 80. As complete resection is typically achieved with hysterectomy, this may partially explain the overall good outcome for most patients with uterine neoplasms.

Rhabdomyosarcoma. Less common uterine sarcomas include rhabdomyosarcoma and alveolar soft part sarcoma (ASPS). Different types of rhabdomyosarcoma have been described in the female genital tract; in the uterus, embryonal rhabdomyosarcoma (ERMS) and pleomorphic rhabdomyosarcoma are the most likely to be encountered 81–84. Histologically, ERMS characteristically shows alternating cellularity with hypocellular myxoid zones and hypercellular foci of spindled rhabdomyoblasts, often condensing underneath the overlying epithelium (cambium layer). Heterologous cartilaginous differentiation is commonly seen. Pleomorphic rhabdomyosarcoma is composed of sheets of highly atypical spindled, polygonal or rhabdoid cells with large irregular, frequently multinucleated cells, and eosinophilic cytoplasm. Mitoses are frequent and often atypical. Both subtypes of rhabdomyosarcoma are positive for desmin, myoD1, and myogenin. ERMS is associated with high frequency of DICER1 mutation which may be somatic or germline. Adult patients with ERMS have a less favorable prognosis than children 81. Patients with pleomorphic rhabdomyosarcoma have a poor prognosis 84. Some of these tumors may represent rhabdomyosarcomatous overgrowth in an adenosarcoma or carcinosarcoma; thus, extensive sampling should be undertaken to exclude an epithelial component before diagnosing a pleomorphic rhabdomyosarcoma.

ASPS. ASPS can occur at any location in the female genital tract; uterine tumors can occur in the corpus or cervix 85–88. Histologically, they are composed of nests of large, polygonal epithelioid cells with abundant eosinophilic granular cytoplasm containing an eccentric or centrally located nucleus with vesicular nuclei and prominent nucleolus. Characteristically, the nests are enveloped by a delicate sinusoidal vascular network and the cells often show dyscohesion resulting in an alveolar-like appearance. Cytoplasmic clearing and rhabdoid cells may be seen. Intracytoplasmic granules and/or rhomboid crystals may be apparent, which can be highlighted by periodic acid-Schiff stain and are diastase resistant. Mitoses are typically sparse. ASPS is characterized by TFE3 rearrangements as a result of chromosomal translocation t(x;17)(p11;q25). As a consequence, tumor cells typically show strong and diffuse nuclear staining for TFE3. The prognosis of ASPS at all anatomic sites appears to be related to resectability, which may explain the relative better prognosis for ASPS of the gynaecologic tract in comparison to those that arise elsewhere.

It is worth noting that many different types of sarcoma more commonly encountered in other anatomic locations can also rarely arise in the uterus, such as liposarcoma 89 and angiosarcoma 90–92. Before making the diagnosis of a pure unusual type of sarcoma of the uterus, additional sampling of the lesion should be performed to exclude the possibility that it represents the component of a more commonly encountered uterine neoplasm, such as sarcomatous overgrowth of an adenosarcoma or the mesenchymal component of a carcinosarcoma.

Emerging Entities. Emerging uterine mesenchymal entities include NTRK-rearranged sarcoma, PDGFB-rearranged sarcoma (and other tyrosine kinase fusion related sarcomas 93) and SMARCA4-deficient uterine sarcoma. NTRK-rearranged sarcoma has been recently described to occur in the uterine cervix and lower uterine segment 94–97. Histologically, NTRK-rearranged sarcomas typically have an infiltrative border and are composed of a proliferation of spindled cells exhibiting either a pattern-less architecture or showing (often haphazard) fascicular or herringbone growth. Entrapped endocervical glands may be encircled by the neoplastic cells, sometimes with polypoid projections simulating adenosarcoma; however, there is typically no periglandular stromal condensation. The spindle cells have eosinophilic cytoplasm and generally show mild to moderate nuclear enlargement with nuclei that are ovoid with dispersed chromatin and small nucleoli; epithelioid change and foci of marked atypia may be seen. The vascular component can be composed of delicate capillaries or vessels with variably thickened walls often with prominent hyalinization. The mitotic count is variable ranging from 0 to 50 per 2 mm2 (0–50 mitoses per 10 HPFs if field diameter is 0.55 mm) atypical mitotic figures and necrosis may be seen. Other findings that may be encountered include focal myxoid matrix, focal hemangiopericytoma-like vasculature, and a prominent lymphocytic infiltrate. These tumors show positivity for pan-TRK, but this marker is not specific for the gene fusion. Patients with NTRK-rearranged sarcoma typically present with Stage I disease; however, approximately one third have developed recurrence or metastasis94–97. Targeted therapy against tropomyosine kinase receptors has shown clinical benefit in patients with NTRK-associated sarcomas 98.

RET fusion positive neoplasms may also exhibit fibroblastic or neural-like differentiation and have phenotypic overlap with NTRK-related neoplasms 99. Recently a cervical sarcoma with a novel RET-SPECC1L fusion has been described 100. Rare spindle cell sarcomas with recurrent MEIS1-NCOA2 fusions have also been recently described 101.

COL1A1-PDGFB rearranged uterine sarcomas are rare and data is limited 96,102. These tumors are composed of a cellular proliferation of spindle cells that typically exhibit a storiform or herringbone growth pattern although one tumor has been described as showing fascicular “leiomyoma-like” growth. Overall, it is interesting to speculate that these tumors could be the uterine counterpart of dermatofibrosarcoma protuberans, as they show morphologic overlap (including fibrosarcomatous areas), a similar immunophenotype (focal loss of CD34 staining in “fibrosarcomatous areas”), as well as sharing the same gene fusion.

SMARCA4-deficient uterine sarcoma is a recently described entity that shares morphologic overlap with undifferentiated endometrial carcinoma but has distinctive clinicopathologic and molecular differences 103–105. Tumors characteristically show a diffuse growth of large epithelioid cells with round vesicular nuclei and exhibit prominent rhabdoid morphology; other features which may be focally present include phyllodiform architecture, vague cording or nesting associated with stromal hyalinization, small cell or spindled morphology, and focal myxoid stromal change. Brisk mitoses (usually >20 per 10 HPFs/0.24 mm2), necrosis and LVI are common. Patients with SMARCA4-deficient uterine sarcoma have a poor prognosis 103–105.

Mitotic Count

The clinical significance of mitotic activity depends on the specific tumor-type involved. Documentation of mitotic activity (highest mitotic count) is required for leiomyosarcoma, STUMP and PEComa, and strongly recommended for UTROSCT, IMT, solitary fibrous tumor and undifferentiated uterine sarcoma. It is optional for other sarcoma types. The 5th edition of the WHO Classification of Tumors 4 considers both HPFs and mm2 for counting of mitoses. In addition, the size of the objective field is mentioned.

For leiomyosarcoma and STUMP, mitotic activity constitutes part of the diagnostic definition together with other histologic features including nuclear atypia and tumor cell necrosis. Mitotic count ≥10 mitoses per 2 mm2 (≥10 mitoses per 10 HPFs if field diameter is 0.55 mm) is used for spindle cell smooth muscle tumors, whereas mitotic count ≥4 mitoses per 2 mm2 (≥4 mitoses per 10 HPFs if field diameter is 0.55 mm) and ≥2 mitoses per 2 mm2 (≥2 mitoses per 10 HPFs if field diameter is 0.55 mm) are used for epithelioid and myxoid smooth muscle tumors, respectively 4. For STUMP, mitotic activity forms part of the diagnostic definition under two scenarios based on the 2020 WHO Classification 4: (1) tumors with focal/multifocal or diffuse nuclear atypia, and 5-9 mitoses per 2 mm2 (5–9 mitoses per 10 HPFs if field diameter is 0.55 mm) but lacking tumor cell necrosis; and (2) tumors showing ≥15 mitoses per 2 mm2 (≥15 mitoses per 10 HPFs if field diameter is 0.55 mm) and lacking nuclear atypia and tumor cell necrosis. It is important to note that degenerative nuclear changes/karyorrhexis may mimic mitotic figures, particularly atypical mitotic figures. It is generally recommended that a formal mitotic count should rely predominantly if not exclusively on counting of typical bipolar mitoses. For PEComa, the presence of any mitotic activity, together with tumor size (≥50 mm), high grade atypia, necrosis and LVI form the criteria for malignancy in the gynaecologic tract 20,69,106. For other rare uterine sarcoma types in which mitotic count is part of the risk stratification (eg, solitary fibrous tumor), mitotic activity should also be documented.

For IMT, there is limited evidence that mitotic count and large tumor size may be associated with more aggressive clinical behavior 23,30. For UTROSCT, there is also limited evidence that elevated mitotic counts and necrosis are associated with malignant behavior 68. Mitotic activity is generally brisk for undifferentiated uterine sarcoma and mitotic count has been shown to be prognostically relevant in undifferentiated uterine sarcomas (lacking endometrial stromal sarcoma genetic fusions) with tumors showing a mitotic count of >25 mitoses per 2 mm2 (>25 mitoses per 10 HPFs if field diameter is 0.55 mm) being associated with decreased survival 107,108.

Most adenosarcomas demonstrate stromal mitoses [>1 mitosis per 2 mm2 (>1 mitosis per 10 HPFs if the field diameter is 0.55 mm)] but mitotic activity may be minimal or even absent in some cases 109,110. There is currently no evidence that mitotic count alone is prognostically significant, in contrast to the presence of sarcomatous overgrowth and/or deep myometrial invasion which are associated with worse prognosis 56. With regard to endometrial stromal sarcomas, while low-grade endometrial stromal sarcomas tend to exhibit lower mitotic counts than high-grade endometrial stromal sarcomas, there is overlap in the range of mitotic activity and thus the number of mitoses is not used for diagnostic classification. However, most low-grade endometrial stromal sarcomas display a mitotic rate of <5 mitoses per 2 mm2 (<5 mitoses per 10 HPF if field diameter is 0.55 mm) and a finding of high mitotic rate (particularly >10 mitoses) should prompt more thorough tumor sampling and careful histologic evaluation as well as consideration of ancillary studies to exclude high-grade endometrial stromal sarcoma or other tumor types. The degree of mitotic activity has no diagnostic or known prognostic significance for recently recognized entities including SMARCA4-deficient uterine sarcoma and NTRK-rearranged sarcoma. Mitotic activity is typically high in SMARCA4-deficient uterine sarcoma and is variable in NTRK-rearranged sarcoma.

Extent of Invasion

Most features relating to extent of invasion are core; there is 1 noncore feature (Table 1).

Myometrial or Cervical Stromal Invasion. The depth of myometrial invasion is an essential parameter in the staging of adenosarcomas located in the uterine corpus or cervix. According to the current FIGO Staging System 111, Stage IA adenosarcoma is limited to the endometrium/endocervix; Stage IB invades ≤50% of the myometrium or cervical stroma; and Stage IC invades >50% of the myometrium or cervical stroma 112,113. Myometrial infiltration is also an important prognostic factor in uterine adenosarcoma for overall survival and recurrence 18,60,114.

Because the staging of low and high-grade endometrial stromal sarcomas, leiomyosarcoma and undifferentiated uterine sarcoma (and other sarcomas) is not based currently on myometrial infiltration, the depth of myometrial infiltration is not relevant.

Uterine Serosa Involvement. Uterine serosal involvement should be documented as there is some evidence that it is an adverse prognostic factor in uterine leiomyosarcoma 115,116. Although evidence for clinical relevance for other uterine sarcomas is limited, the ICCR Uterine Sarcoma DAC considers it to represent a core element in reporting.

Tumor-free distance to uterine serosa refers to the distance between the deepest point of tumor within the myometrium and the nearest serosal surface and is considered a noncore element. Documentation of this parameter may be useful for future studies addressing its clinical relevance.

Parametrial Involvement. Parametrium is defined as the fibro-adipose connective tissue located laterally in the supracervical portion of the uterus. Most hysterectomies for uterine sarcoma will be simple hysterectomies without parametrial resections. If parametrial tissue is removed, the presence or absence of parametrial involvement should be documented as best practice. Although evidence for clinical relevance of parametrial involvement in uterine sarcomas is limited, the DAC considers it to represent a core element in reporting.

Omentum. Omental involvement should be documented as it contributes to the staging assessment. FIGO Stage IIIA equates to one site of abdominal involvement and IIIB to more than one site 111.

Vagina. A total hysterectomy can have a vaginal cuff which should be measured. The presence or absence of vaginal involvement in such cases should be documented on the report.

Fallopian Tube. The presence or absence of adnexal (ovarian/fallopian tube) involvement should be documented. Adnexal involvement affects the tumor stage (FIGO Stage IIA) which remains the most powerful prognostic factor for uterine sarcomas 18,113,117,118, and may occur as a result of direct extension or metastatic spread of tumor.

Ovary: The presence or absence of adnexal (ovarian/fallopian tube) involvement should be documented. Adnexal involvement affects the tumor stage (FIGO Stage IIA) which remains the most powerful prognostic factor for uterine sarcomas 18,113,117,118, and may occur as a result of direct extension or metastatic spread of tumor.

Peritoneal Biopsies: Peritoneal involvement should be documented as it contributes to the staging assessment. Pelvic peritoneal involvement equates to FIGO Stage IIB while abdominal peritoneal involvement equates to FIGO Stage IIIA or IIIB depending on the number of sites involved 111.

Peritoneal Washings/Peritoneal Fluid: The presence or absence of tumor cells in peritoneal fluid/washings should be documented if this specimen type is submitted. There is only limited data suggesting that positive peritoneal cytology may be an adverse prognostic factor in uterine sarcomas with one study suggesting that positive peritoneal cytology may be a prognostic factor for mortality in uterine sarcomas, particularly in leiomyosarcoma 119. Accrual of this data prospectively will facilitate future study regarding the prognostic significance of positive peritoneal fluid.

LVI

The presence or absence of LVI in uterine sarcomas should be documented. For some tumors, such as low-grade and high-grade endometrial stromal sarcoma, LVI is frequently encountered; in contrast, other tumors, such as adenosarcomas, uncommonly demonstrate LVI unless associated with deep myometrial invasion and/or sarcomatous overgrowth. The presence of LVI may carry prognostic significance in leiomyosarcoma, particularly when early stage 120,121, and in adenosarcoma 122–124.

One study evaluated specific patterns of vascular involvement by low-grade endometrial stromal sarcoma, high-grade endometrial stromal sarcoma, leiomyosarcoma, and undifferentiated uterine sarcoma and divided patterns into “true” vascular invasion versus “intrusion” into lymphovascular spaces 125. True LVI was characterized by dyscohesive clusters of tumors cells with irregular edges, lacking vasculature within the intravascular tumor and/or lack of immunohistochemically proven endothelial cells surrounding the intravascular tumor focus. Vascular intrusion, which was considered to be “pseudoinvasion,” was characterized by cohesive intravascular tumor with smooth contours and lined by endothelial cells. Pre-existing vascular spaces were frequently identified within the intravascular tumor in the cases of vascular intrusion and such foci were often in direct communication with the main tumor mass 125.

While usually straightforward, the assessment of LVI may be difficult in a minority of cases, for which the reasons may include (but are not limited to) suboptimal fixation or cauterization artefacts. In such cases, examination of multiple levels and/or immunostaining for endothelial or lymphatic markers (such as CD31, CD34, D2-40, and ERG) may be employed to assist with decision-making. Cases that are still equivocal after taking additional steps may be reported as “indeterminate” for LVI, but this designation should only be sparingly used, and it is useful to provide the reason in a comment in the report.

Margin Status

Most features relating to margin status are core, although there are some noncore features (Table 1). Margins of resection are an important parameter to include in reporting as they may guide postsurgical treatment with chemotherapy and/or radiation therapy depending on tumor type. In addition, positive margins have been shown to be a negative prognostic factor for a variety of different uterine sarcomas including low and high-grade endometrial stromal sarcoma 126, leiomyosarcoma 127, and Müllerian adenosarcoma 128. The most relevant margin is usually the distal cervicovaginal resection margin. However, the status of other surgical margins, such as the parametrium (when removed) including laterality, should also be documented. Recording the distance from the closest cervical or vaginal margin is a noncore element and documentation of this parameter may be useful for future studies addressing its clinical relevance.

Lymph Node Status

The anatomic location and number of lymph nodes dissected, the number containing tumor and the size of the largest tumor deposit should be accurately documented in the pathology report, if lymph nodes are resected. According to TNM8 129, nodal involvement should be recorded as the presence of isolated tumor cells (ITC, <0.2 mm), micrometastases (MIC, 0.2σ2 mm) or macrometastases (MAC, >2 mm). MAC are regarded as pN1, MIC as pN1 (mi) and ITCs are pN0 (i+); ITCs do not upstage a neoplasm. Involvement of pelvic and/or para-aortic lymph nodes by uterine sarcoma will upstage the sarcoma. The number of lymph nodes examined, and number of lymph nodes involved by tumor should be reported for regional lymphadenectomies, if performed.

Because of the low risk of metastatic disease in lymph nodes, routine lymph node dissection is typically not undertaken in low stage uterine leiomyosarcomas 130–132. Moreover, lymphadenectomy is not routinely undertaken for uterine leiomyosarcoma as it does not appear to impact overall survival 127,132,133. Nevertheless, lymph node resection should be performed if the lymph nodes appears enlarged or suspicious 134. The reported frequency of lymph node involvement in low-grade endometrial stromal sarcomas ranges from 3.6% to 10% 126,135,136, and from 10.2% to 44% for high-grade endometrial stromal sarcoma 126,137. The prognostic importance of lymphadenectomy for endometrial stromal sarcomas has been a subject of debate 117,135,138–140, although a recent meta-analysis concluded that for localized endometrial stromal sarcoma and leiomyosarcoma, lymphadenectomy is not recommended 133.

Lymph node metastasis is a significant prognostic factor in uterine adenosarcoma 141. However, lymphadenectomy is not typically performed unless lymph nodes appear enlarged and/or suspicious as the rate of nodal metastasis is low (6.5%) 142.

Pathologically Confirmed Distant Metastasis

Documentation of known metastatic disease is an important part of the pathology report. Such information, if available, should be recorded with as much detail as is available including the site, whether the specimen is a histopathology or cytopathology specimen and with reference to any relevant prior surgical pathology or cytopathology specimens.

Provisional Pathologic Staging

The pathologic staging must be provided on the pathology report and is therefore a core element. The term “provisional pathologic staging” is used in this data set to indicate that the stage that is provided may not represent the final tumor stage which should be determined at the multidisciplinary tumor board meeting where all the pathologic, clinical and radiologic features are available 111,129,143.

The latest version of either FIGO or TNM staging, or both, can be used depending on local preferences 111,129,143. The FIGO Staging System is in widespread use internationally and is the system used in most clinical trials and research studies. However, Union for International Cancer Control (UICC) or American Joint Committee on Cancer (AJCC) versions of TNM are used or mandated in many parts of the world 129,143. With regards to updating of staging systems, there is collaboration between FIGO and those agencies responsible for TNM with an agreement to adopt changes to FIGO staging. Following the introduction of a new FIGO Staging System, this is usually incorporated into TNM (both UICC and AJCC versions) at a later date. Apart from minor discrepancies in terminology, the UICC and AJCC systems are broadly concurrent.

There are 2 staging systems for uterine sarcomas. One is to be used specifically for adenosarcomas and the other is for leiomyosarcomas and endometrial stromal sarcomas 111. It is recommended that the latter staging system be used for other malignant uterine mesenchymal neoplasms, such as undifferentiated sarcoma and rhabdomyosarcoma; it is not recommended to provide a pathologic stage for STUMPs. It is controversial as to whether a pathologic stage should be applied to other mesenchymal tumors of uncertain malignant potential which are discussed in this data set, such as UTROSCT, PEComa, and IMT. However, a stage may be applied for those neoplasms which fulfil the criteria for malignancy in the individual tumor types, although this is not mandated.

A tumor should be staged following diagnosis using various appropriate modalities (clinical, radiologic, pathologic). While the original tumor stage should not be altered following treatment, TNM systems allow staging to be performed on a resection specimen following nonsurgical treatment (eg, chemotherapy, radiotherapy); in such cases, if a stage is being provided on the pathology report (this is optional), it should be prefixed by “y” to indicate that this is a posttherapy stage.

The reference document TNM Supplement: A commentary on uniform use, 5th Edition (Wittekind et al. 144 editors) may be of assistance when staging.

Noncore Elements

A summary of the noncore elements is provided in Table 1 and each is described below.

Clinical Information

Adequate clinical history is essential for accurate diagnoses and appropriate clinical care. It has been estimated that ~1% of diagnostic reports have been negatively impacted due to a lack of clinical information; in these instances, additional clinical information resulted in a change in diagnosis 145. A history of prior malignancy, radiation or hormonal therapy (which increases risk for sarcomas), and any prior excision are considered relevant.

Block Identification Key

The origin/designation of all tissue blocks should be recorded. This information should ideally be documented in the final pathology report and is particularly important should the need for internal or external review arise. The reviewer needs to be clear about the origin of each block in order to provide an informed specialist opinion. If this information is not included in the final pathology report, it should be available on the laboratory computer system and relayed to the reviewing pathologist. It may be useful to have a digital image of the specimen and record of the origin of the tumor blocks in some cases.

Recording the origin/designation of tissue blocks also facilitates retrieval of blocks for further immunohistochemical or molecular analysis, research studies or clinical trials.

Coexistent Pathology

There are no known precursor lesions of uterine sarcomas. Unrelated incidental conditions can be documented.

Ancillary Studies

Ancillary testing (chiefly immunohistochemistry and/or molecular testing) may be of value in the diagnosis of uterine malignant and potentially malignant mesenchymal tumors. The results of ancillary tests should be interpreted in the overall context of the clinical setting, macroscopic pathology, and microscopic pathology. The most recent WHO Classification 4 defines 2 potential roles for ancillary tests for certain tumors: (1) to serve as essential diagnostic criteria, required for establishing the diagnosis; or (2) to serve as supportive criteria that are desirable but not essential to establish the diagnosis. To harmonise with the latest WHO Classification 4, the DAC recommends adopting a similar strategy, acknowledging that some of these ancillary tests may not be available in all practice settings. Discussion of the detailed immunophenotype of the various uterine sarcomas or use of ancillary testing to resolve specific differential diagnoses is beyond the scope of these recommendations. Among the tumors with a defining molecular alteration, gene fusion is the main pathologic mechanism; thus, fluorescent in situ hybridisation or RNA sequencing are the primary types of molecular diagnostic tools, with a few rare exceptions of tumors characterized by inactivating mutations.

Leiomyosarcoma and STUMP are expected to exhibit a smooth muscle immunophenotype (positive for desmin, h-caldesmon, smooth muscle myosin and smooth muscle actin), although it is not uncommon for only some of the smooth muscle stains to be positive or for staining to be patchy, particularly in myxoid and epithelioid variants. While mutation of TP53, MED12, and/or ATRX occur in leiomyosarcomas, these alterations are not specific to leiomyosarcoma. A recent study has shown that p53 immunohistochemistry may be useful in distinguishing translocated associated sarcomas from other nontranslocated associated sarcomas with the former more often showing wild-type staining 146. A minority of myxoid leiomyosarcoma may exhibit PLAG1 immunoreactivity and PLAG1 fusion. Low-grade endometrial stromal sarcoma is expected to exhibit diffuse strong CD10 and estrogen receptor (ER) immunoreactivity The diagnosis can be supported by demonstrating a gene fusion involving JAZF1 and/or PHF1 but since only about two-thirds of these tumors harbor such a gene fusion, molecular testing is not essential for the diagnosis nor does a negative result exclude the diagnosis. High-grade endometrial stromal sarcoma encompasses a range of tumors that are subclassified by one of a variety of distinct gene fusions, thus often requiring molecular testing for the diagnosis. The high grade component of YWHAE-NUTM2A/B high-grade endometrial stromal sarcoma typically exhibits absent CD10 and ER immunoreactivity, positive cyclin D1, CD117, CD56, CD99, and BCOR immunoreactivity 147, and the YWHAE-NUTM2A/B gene fusion. ZC3H7B-BCOR high-grade endometrial stromal sarcoma retains CD10 immunoreactivity, exhibits variable ER immunoreactivity, positive cyclin D1 immunoreactivity, variable BCOR immunoreactivity, and ZC3H7B-BCOR gene fusion. High-grade endometrial stromal sarcoma with BCOR internal tandem duplication exhibit variable CD10 immunoreactivity, loss of ER immunoreactivity, positive cyclin D1 and BCOR immunoreactivity, and BCOR internal tandem duplication by molecular sequencing techniques.

SMARCA4-deficient uterine sarcoma is defined by loss of SMARCA4 (BRG1) immunoreactivity or, rarely, loss of SMARCB1 (INI1) immunoreactivity. The diagnosis can be supported by demonstrating inactivating mutation or deletion of SMARCA4. IMT is defined by positive ALK immunoreactivity; demonstration of ALK fusion by molecular testing can support the diagnosis but is not essential if the ALK immunostain is positive. PEComa is defined by dual melanocytic (HMB45, cathepsin K, melan A, MITF, and/or PNL2) and myoid (smooth muscle actin, desmin, h-caldesmon) immunoreactivity. It is recommended that at least two melanocytic markers be positive given the lack of specificity of any one marker for PEComa. The subset of PEComas that harbor a TFE3 fusion exhibits TFE3 immunoreactivity along with melanocytic marker immunoreactivity, although smooth muscle marker immunoreactivity may be limited or absent. The diagnosis of PEComa can be supported by demonstration of an inactivating mutation of TSC1 or TSC2 or by demonstrating TFE3 or RAD51B fusion 148. UTROSCT is characterized by polyphenotypic immunoreactivity of epithelial markers (keratin, epithelial membrane antigen), sex cord markers (FOXL2, SF1, calretinin, inhibin, WT1, and/or melan A), myoid markers (smooth muscle actin, desmin, and h-caldesmon) and hormone receptors (ER and progesterone receptor). The diagnosis can be supported by demonstrating ESR1 or GREB1 fusion; however, such alterations are not present in all cases, so a negative result does not exclude the diagnosis. NTRK uterine sarcoma is defined by a gene fusion involving NTRK1, NTRK2, or NTKR3. S100 and CD34 are usually positive, and immunoreactivity of these markers can be used as a screening tool to identify tumors that merit NTRK molecular testing; smooth muscle markers, CD10, and hormone receptors are usually negative. Pan-TRK immunoreactivity can also be used to triage testing for a NTRK fusion. However, high-grade endometrial stromal sarcoma may show pan-trk immunoreactivity in the absence of an NTRK fusion 149. Uterine adenosarcomas do not have a unique immunophenotype and so the diagnosis is mainly based on morphologic criteria. The tumor cells usually exhibit CD10 and ER immunoreactivity, but these markers may be absent in areas of high-grade stroma/sarcomatous overgrowth. Rhabdomyosarcoma is expected to exhibit immunoreactivity of desmin, myogenin, and/or myoD1. Both rhabdomyosarcoma and adenosarcoma with rhabdomyosarcomatous differentiation may harbor DICER1 mutations.

DISCUSSION

This data set includes several controversial issues that elicited a robust discussion as to whether they should be included in the data set and, if so, whether they were best considered core or noncore elements. In addition, it was debated whether to include tumors of uncertain malignant potential (eg, STUMPs) or to restrict the data set to uterine sarcomas. The expert panel agreed by consensus that tumors of uncertain malignant potential should be included as many uterine mesenchymal tumors exhibit a spectrum of behavior from indolent to aggressive, and the data elements which are used to risk stratify tumors (such as mitotic count) are applicable to certain tumor types in the data set. Including tumors of uncertain malignant potential will ensure the appropriate risk stratification for individual patients is performed. To reflect this change, the data set was entitled “Uterine Malignant and Potentially Malignant Mesenchymal Tumors.”

Another point of discussion concerned the number of entities listed under histologic tumor type. It was agreed that the list should reflect the updates from the recent 2020 edition of the WHO Classification of Female Genital Tumors 4 and that it should be comprehensive; nevertheless, the panel acknowledges that with the increasing use of molecular techniques new entities and types of uterine sarcoma continue to be described, and thus the current list is not exhaustive. As tumors are defined and before they become accepted lexicon, the “other” category can be utilized to address this issue.

The utility of histologic tumor grade as a standalone data set element was discussed and by consensus eliminated from the data set. The use of the term “grade” is a misnomer for certain tumor types; for example, low-grade and high-grade endometrial stromal sarcoma represent clinically, histologically, and molecularly distinct diseases and not a single tumor type with different differentiation states. While there is some literature on the potential diagnostic utility of grading Müllerian adenosarcoma in the absence of sarcomatous overgrowth into a low-grade and a high-grade category based on cytologic atypia, mitotic activity and presence/absence of p53 aberrant expression 60, this scenario is rare. Grading of leiomyosarcoma is also controversial. While the panel acknowledges that clinically indolent forms of low-grade uterine leiomyosarcoma exist 150, the majority of leiomyosarcomas are high grade by definition and recognition of low-grade leiomyosarcoma prospectively is difficult.

Mitotic count is an important parameter in the diagnosis and risk stratification for some, but not all, uterine mesenchymal tumors. As such, this element is considered a core value for leiomyosarcoma, STUMP, and PEComa. Nevertheless, including mitotic count is strongly encouraged for all tumors in this data set as collection of this data will be useful for future studies. The expert panel agreed by consensus that the highest count method is preferred. In WHO 2020, mitotic count is expressed per mm2 rather than the traditional denominator of per 10 HPFs. This takes into account that different microscopes have HPFs of different sizes; this approach will also be useful for reporting mitotic counts using digital systems. In this document, mitotic count is expressed per 2 mm2 since 10 HPFs is roughly equivalent to 2 mm2. This can easily be converted to mm2.

Finally, the data set element of ancillary studies (primarily referring to immunohistochemistry and molecular testing) elicited a variety of opinions regarding whether this should be considered core or noncore. The panel agreed to adopt the approach of the most recent WHO Classification 4 in which ancillary testing may either be needed to establish the diagnosis or may be used to support the diagnosis but is not required. To this end, this data set element is overall considered noncore, but is strongly encouraged depending on the tumor type. We also acknowledge that not all practice settings have access to these ancillary tests and, as such, requirement as a core element would be prohibitive.

CONCLUSIONS

This paper describes the development of the ICCR data set for the reporting of uterine malignant and potentially malignant mesenchymal tumors, which was developed by an international panel of expert gynecologic pathologists and a clinician with expertise in the field of sarcoma. This data set was created by review of the literature and other published datasets and by consensus opinion and incorporates the recent changes in the 2020 WHO Classification 4. It is our belief that worldwide implementation of this data set will result in uniformly high quality cancer reports leading to improved patient care. In addition, prospective collection of this data can be utilized for research and for informing best practices in the future.

Acknowledgments

The authors acknowledge the support of the International Society of Gynecological Pathologists (ISGyP) toward production of this data set.

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Keywords:

Uterus; Sarcoma; Mesenchymal tumor; Uncertain malignant potential; Data set; Protocol

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