An update of molecular pathology and shifting systems of classification in tumours of the female genital tract

Open AccessPublished:April 13, 2020DOI:https://doi.org/10.1016/j.mpdhp.2020.03.007

      Abstract

      The decreasing costs of next generation sequencing technologies and greater acceptance of molecular and biologic findings into the pathology domain, have shifted our paradigms of classification for many gynecologic tumors. This review focuses on major molecular developments within the last 5 years in endometrial carcinoma, endocervical adenocarcinoma, vulvar squamous cell carcinoma and uterine sarcoma, and the emergence of molecular subgroups within each family of tumors.

      Keywords

      Molecular information is increasingly used for typing of neoplasms, risk assessment and directing cancer treatment. This review highlights recent developments in the molecular stratification of endometrial carcinoma, endocervical adenocarcinoma, vulvar carcinoma and selected uterine sarcomas.

      Endometrial carcinoma

      Endometrial carcinoma (EC) is the most common gynecological malignancy in the developed world with increasing annual incidence and mortality rates in North America. Similar to the progress made in breast cancer, where subtyping integrates molecular information for stratification, molecular subtyping of EC has emerged as a priority in the gynecological oncology sphere.

       Recent molecular findings

      The Cancer Genome Atlas (TCGA): in 2013, the Cancer Genome Atlas (TGCA) published a comprehensive genomic analysis of EC (endometrioid, serous and mixed histotypes, n = 373). The TCGA described four prognostically distinct groups, characterized by tumour mutational burden and somatic copy number alterations: i) ultra-mutated EC with DNA polymerase epsilon (POLE) mutations in the exonuclease domain (POLE EDM), ii) Hypermutated EC with microsatellite instability (MSI), iii) low mutation rate EC with low frequency of DNA copy-number alterations (CN-L), and iv) low mutation rate EC but with high-frequency of DNA copy-number alterations (CN–H).
      • Kandoth C.
      • Schultz N.
      • et al.
      Cancer Genome Atlas Research Network
      Integrated genomic characterization of endometrial carcinoma.
      In terms of somatic mutations, ultramutated EC were enriched in ARID1A (>70%), FBXW7 (>80%), KRAS (>50%), and PI3K pathway (>70%) mutations, hypermutated EC had the highest RPL22 (>40%), CN-L EC had the highest CTNNB1 (>50%) and CN–H EC had the highest TP53 (>90%) and lowest frequency of PTEN (<10%) mutations.
      • Kandoth C.
      • Schultz N.
      • et al.
      Cancer Genome Atlas Research Network
      Integrated genomic characterization of endometrial carcinoma.
      The TCGA also revealed that molecularly distinct ECs exhibited overlapping histologic features, as well as vice versa, that biologically similar EC can have varied morphologic appearances.
      • Kandoth C.
      • Schultz N.
      • et al.
      Cancer Genome Atlas Research Network
      Integrated genomic characterization of endometrial carcinoma.
      This served as a catalyst for the development of a pragmatic molecular-based classification strategy that could be adopted in everyday practice.
      Emergence of pragmatic risk classifiers for EC: using immunohistochemistry (IHC), targeted sequencing and MSI testing, two different molecular classification schemes emerged. Both classifiers produced results that emulated the four TCGA based molecular subtypes.
      ProMisE, developed by Talhouk et al. in 2015
      • Talhouk A.
      • McConechy M.K.
      • Leung S.
      • et al.
      A clinically applicable molecular-based classification for endometrial cancers.
      recapitulated the four TGCA risk groups by using IHC for p53 and mismatch repair (MMR) proteins, together with sequencing for POLE exonuclease domain mutations (EDM). In the ProMisE classification system, four groups, serving as corollaries to the TGCA groups described above, were i) POLE EDM ii) MMR-D iii) p53 wt and iv) p53 abn. (Figure 1, Table 1). This iterative classifier has been confirmed in multiple cohorts.
      • Talhouk A.
      • McConechy M.K.
      • Leung S.
      • et al.
      A clinically applicable molecular-based classification for endometrial cancers.
      • Talhouk A.
      • McConechy M.K.
      • Leung S.
      • et al.
      Confirmation of ProMisE: a simple, genomics-based clinical classifier for endometrial cancer.
      • Kommoss S.
      • McConechy M.K.
      • Kommoss F.
      • et al.
      Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series.
      Figure 1
      Figure 1Endometrial carcinomas (EC) represent 4 different molecular subgroups. A) EC exhibiting morphologic ambiguity and high grade nuclear features, harboring a POLE exonuclease domain mutation. B) EC showing dense peritumoral lymphocytic inflammation, harboring deficient of mismatch repair proteins. C) EC with low-grade features, exhibiting no specific mutation profile (NSMP, p53 wild-type). D) EC with serous morphology, harbouring a TP53 mutation.
      Table 1Major molecular subtypes of endometrial carcinoma
      POLE EDMMMR-Dp53 wtp53 abn
      Alternate namesUltramutated

      POLE-mut
      Hypermutated

      MMRd
      Copy number low

      NSMP
      Copy number high p53-mut
      Salient molecular alterationsMutation in POLE exonuclease domain

      High mutational burden (>100 mutations/Mb)

      Low copy number alterations

      Mutations in PI3K pathway
      Microsatellite instability high, deficiency in mismatch repair proteins

      Intermediate mutational burden

      Low copy number alterations
      TP53 wild type

      Low mutational burden (<10/Mb)

      High copy number alterations

      Mutations in PI3K and Wnt/β-catenin pathways
      TP53 mutated

      Low mutational burden (<10/Mb)

      Low copy number alterations

      Rare mutations in ERBB2 and BRCA
      Proportion5%25%45%25%
      Clinical and prognostic featuresAge ∼50-60

      Pre/postmenopausal

      Low BMI

      Early stage and excellent outcomes
      Age ∼60

      Perimenopausal

      High BMI

      Intermediate outcomes
      Age ∼60

      Perimenopausal

      High BMI

      Intermediate outcomes
      Age ∼70

      Postmenopausal

      Low BMI

      High-stage and poor outcomes
      Histologic featuresMix of low-grade and high-grade endometrioid histology

      Ambiguous morphology, peri/intratumoral lymphocytes

      Can be associated with subclonal p53 patterns
      Mix of low-grade and high-grade endometrioid histology

      Ambiguous morphology, peri/intratumoral lymphocytes, substantial lymphovascular invasion

      Can be associated with subclonal p53 and MMR IHC patterns
      Mostly low-grade endometrioid histology

      Tend to express ER and PR
      Mostly serous histology

      Destructive growth patterns and lymphovascular invasion
      Treatment implicationsImmune checkpoint inhibitionImmune checkpoint inhibition

      Referral to Hereditary Cancer Program for suspected Lynch Syndrome
      Hormonal management

      Fertility sparing management may be considered
      Possible role for HER2 and PARP inhibitors
      The other, by Stelloo et al., was based on a comprehensive molecular analysis of high risk EC from PORTEC (Post Operative Radiation Therapy in Endometrial Carcinoma). They performed MSI testing, targeted mutational testing (including POLE) and IHC (including p53). Their results independently confirmed the four prognostic groups.
      • Stelloo E.
      • Bosse T.
      • Nout R.A.
      • et al.
      Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; A TransPORTEC initiative.

       Pathologic and clinical relevance

      POLE EDM EC presented in younger patients with lower body mass index (BMI) and early stage disease.
      • Talhouk A.
      • McConechy M.K.
      • Leung S.
      • et al.
      A clinically applicable molecular-based classification for endometrial cancers.
      • Talhouk A.
      • McConechy M.K.
      • Leung S.
      • et al.
      Confirmation of ProMisE: a simple, genomics-based clinical classifier for endometrial cancer.
      • Kommoss S.
      • McConechy M.K.
      • Kommoss F.
      • et al.
      Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series.
      Despite high-grade histologic features (high FIGO grade, nuclear grade, mitotic index), these patients experienced excellent clinical outcomes regardless of grade or stage at presentation.
      • Bakhsh S.
      • Kinloch M.
      • Hoang L.N.
      • et al.
      Histopathological features of endometrial carcinomas associated with POLE mutations: implications for decisions about adjuvant therapy.
      Theoretically, POLE EDM EC may be susceptible to immune checkpoint inhibition, but excellent outcomes for these patients may not necessitate this expensive therapeutic option.
      By contrast, p53 abn ECs, presented in older postmenopausal women, typically those with normal BMI. Histology is mostly serous or ‘serous-like’, with lymphovascular invasion and destructive growth patterns. These patients had poor clinical outcomes regardless of grade or stage at presentation.
      • Talhouk A.
      • McConechy M.K.
      • Leung S.
      • et al.
      A clinically applicable molecular-based classification for endometrial cancers.
      • Talhouk A.
      • McConechy M.K.
      • Leung S.
      • et al.
      Confirmation of ProMisE: a simple, genomics-based clinical classifier for endometrial cancer.
      • Kommoss S.
      • McConechy M.K.
      • Kommoss F.
      • et al.
      Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series.
      • Stelloo E.
      • Bosse T.
      • Nout R.A.
      • et al.
      Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; A TransPORTEC initiative.
      ,
      • Wortman B.G.
      • Bosse T.
      • Nout R.A.
      • et al.
      Molecular-integrated risk profile to determine adjuvant radiotherapy in endometrial cancer: evaluation of the pilot phase of the PORTEC-4a trial.
      MMR-D EC presented in middle-aged women with high BMI. They showed a tendency for extensive lymphovascular invasion and lymph node involvement. Pathologic clues to MMR-D status include lower uterine segment tumour location, tumour infiltrating lymphocytes, morphologic ambiguity and microcystic elongated fragmented (MELF) pattern of invasion.
      • Talhouk A.
      • McConechy M.K.
      • Leung S.
      • et al.
      A clinically applicable molecular-based classification for endometrial cancers.
      ,
      • Stelloo E.
      • Bosse T.
      • Nout R.A.
      • et al.
      Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; A TransPORTEC initiative.
      Given that 5–10% of ECs (all histotypes) are Lynch Syndrome related, routine MMR IHC evaluation in EC is recommended to triage patients to familial cancer screening programs.
      • Mills A.M.
      • Liou S.
      • Ford J.M.
      • Berek J.S.
      • Pai R.K.
      • Longacre T.A.
      Lynch syndrome screening should Be considered for all patients with newly diagnosed endometrial cancer.
      MMR-D patients are also candidates for immune checkpoint inhibition.
      Lastly, p53 wt or NSMP EC, represents almost half of all EC. Typically they are diagnosed in middle-aged women with obesity or those with high endogenous or exogenous estrogen exposures. The majority of these EC are low grade, low stage and many are treated with surgery alone. In general, outcomes for this group are favourable.
      • Talhouk A.
      • McConechy M.K.
      • Leung S.
      • et al.
      A clinically applicable molecular-based classification for endometrial cancers.
      • Talhouk A.
      • McConechy M.K.
      • Leung S.
      • et al.
      Confirmation of ProMisE: a simple, genomics-based clinical classifier for endometrial cancer.
      • Kommoss S.
      • McConechy M.K.
      • Kommoss F.
      • et al.
      Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series.
      • Stelloo E.
      • Bosse T.
      • Nout R.A.
      • et al.
      Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; A TransPORTEC initiative.
      ,
      • Wortman B.G.
      • Bosse T.
      • Nout R.A.
      • et al.
      Molecular-integrated risk profile to determine adjuvant radiotherapy in endometrial cancer: evaluation of the pilot phase of the PORTEC-4a trial.

       Translation to practice and barriers to implementation

      Excellent concordance in molecular subtyping between biopsy and hysterectomy specimens has been independently demonstrated by both the ProMisE and TransPORTEC investigators.
      • Talhouk A.
      • Hoang L.N.
      • McConechy M.K.
      • et al.
      Molecular classification of endometrial carcinoma on diagnostic specimens is highly concordant with final hysterectomy: earlier prognostic information to guide treatment.
      ,
      • Stelloo E.
      • Nout R.A.
      • Naves L.C.L.M.
      • et al.
      High concordance of molecular tumor alterations between pre-operative curettage and hysterectomy specimens in patients with endometrial carcinoma.
      The benefits for upfront triaging includes improved accuracy of IHC interpretation due to improved fixation in biopsy specimens and the provision of prognostic and predictive information for subsequent treatment planning.
      Multiple classifier EC is defined as a tumour harbouring more than one molecular classifying feature. It has been found in 3% of EC. A recent comprehensive analysis of >3500 molecularly-defined ECs showed that outcomes for cases containing multiple classifier cases, corresponded to those predicted by the driver molecular subtype. For example, MMRd-p53abn EC outcomes corresponded to those in MMRd, POLEmut-p53abn were consistent with POLEmut EC.
      • León-Castillo A.
      • Gilvazquez E.
      • Nout R.
      • et al.
      Clinicopathological and molecular characterisation of ‘multiple-classifier’ endometrial carcinomas.
      The interpretation of p53 and MMR IHC can pose challenges. A detailed review is included in this issue by Wong et al. and therefore we will keep our comments on these issues brief. Subclonal MMR loss is seen in 7% of EC, which occurs predominantly in the context of MLH1 hypermethylation.
      • Watkins J.C.
      • Nucci M.R.
      • Ritterhouse L.L.
      • Howitt B.E.
      • Sholl L.M.
      Unusual mismatch repair immunohistochemical patterns in endometrial carcinoma.
      Subclonal p53 is frequently encountered in multiple classifier cases (64% of MMRd-p53abn multiple classifier ECs, 31% of POLEmut-p53abn EC). Thus, a substantial proportion of subclonal p53 expression can be attributed to an epigenetic mechanism (MLH1 hypermethylation) or POLE mutations.
      • León-Castillo A.
      • Gilvazquez E.
      • Nout R.
      • et al.
      Clinicopathological and molecular characterisation of ‘multiple-classifier’ endometrial carcinomas.
      By design, both the ProMisE and TransPORTEC molecular classifiers are straightforward as p53 and MMR IHC are already in routine use in many pathology laboratories. The detection of POLE EDM mutations however, is still reliant on DNA sequencing, which may be inaccessible in many centers.
      Questions that still remain unanswered are the application of these classifiers to rare histotypes beyond endometrioid and serous carcinomas (ie. clear cell, dedifferentiated carcinoma), and whether any additional biomarkers (ie. CTNNB1, L1CAM) should be incorporated.

         Practice points

      • Molecular subtyping in EC is poised to become ‘standard of care’ in the diagnosis of EC
      • Pragmatic molecular classifiers for EC based of the TCGA have been developed, which strategy EC into four groups - POLE mutated, MMR-D/MSI, p53 mutated and p53 wild type (no specific mutation profile)
      • These four molecular subgroups confer clinical and prognostic information; tailored treatment strategies are very likely to follow upon results of upcoming clinical trials stratifying EC patients by molecular group
      • Multiple classifier cases are still defined by their truncal molecular subtype
      • EC with subclonal MMR loss should undergo testing for MLH1 hypermethylation testing, as the majority are due to epigenetic MLH1 gene silencing
      • EC with subclonal p53 IHC should prompt evaluation by MMR IHC and POLE mutation testing to achieve accurate risk stratification

      Endocervical adenocarcinoma

      Cervical carcinoma is a significant cause of worldwide mortality and morbidity. Almost all cervical squamous cell carcinoma (SCC), and the majority of endocervical adenocarcinomas (EDAC), are etiologically associated with human-papilloma virus (HPV). However, in the developed world, due to prophylactic anti-HPV vaccine campaigns, the incidence of HPV associated cervical adenocarcinoma is expected to decrease, and the relative incidence of non-HPV associated adenocarcinoma can be expected to rise.

       Recent molecular findings

      HPV-associated endocervical adenocarcinomas: approximately 80% of EDAC are associated with HPV infection.
      • Stolnicu S.
      • Barsan I.
      • Hoang L.
      • et al.
      International endocervical adenocarcinoma Criteria and classification (IECC): a new pathogenetic classification for invasive adenocarcinomas of the endocervix.
      The etiologic role of HPV in cervical adenocarcinomas is well established. Through the oncogenic viral proteins E6 and E7, DNA from high-risk HPV viruses integrates into the host genome. HPV inactivates tumor suppressors TP53 and RB, and it increases expression of Telomerase Reverse Transcriptase (TERT), and as well as cell cycle checkpoint inhibitor p21, immortalizing infected cells, and leading to increased cell cycle proliferation.
      Several somatic mutations have been identified in HPV associated EDAC. The most common genetic alterations are PIK3CA and KRAS, but mutations in TP53, MET, RB, GNAS, ERBB2 and IDH2 have also been reported, among others.
      • Hodgson A.
      • Amemiya Y.
      • Seth A.
      • Cesari M.
      • Djordjevic B.
      • Parra-Herran C.
      Genomic abnormalities in invasive endocervical adenocarcinoma correlate with pattern of invasion: biologic and clinical implications.
      • Lou H.
      • Villagran G.
      • Boland J.F.
      • et al.
      Genome analysis of Latin American cervical cancer: frequent activation of the PIK3CA pathway.
      • Hodgson A.
      • Howitt B.E.
      • Park K.J.
      • Lindeman N.
      • Nucci M.R.
      • Parra-Herran C.
      Genomic characterization of HPV-related and gastric-type endocervical adenocarcinoma: correlation with subtype and clinical behavior.
      In one study, HPV associated adenocarcinomas with PIK3CA, KRAS, MET, and RB had greater presentation at advanced stage, lymph node metastases, and mortality
      • Hodgson A.
      • Amemiya Y.
      • Seth A.
      • Cesari M.
      • Djordjevic B.
      • Parra-Herran C.
      Genomic abnormalities in invasive endocervical adenocarcinoma correlate with pattern of invasion: biologic and clinical implications.
      and, in another study, KRAS and GNAS were associated with disease recurrence and mortality.
      • Hodgson A.
      • Howitt B.E.
      • Park K.J.
      • Lindeman N.
      • Nucci M.R.
      • Parra-Herran C.
      Genomic characterization of HPV-related and gastric-type endocervical adenocarcinoma: correlation with subtype and clinical behavior.
      Particular subtypes of HPV associated EDAC may harbor distinct mutations. For example, STK11, was recently reported in the tumors of two patients with invasive stratified mucin producing lesion (iSMILE).
      • Hodgson A.
      • Howitt B.E.
      • Park K.J.
      • Lindeman N.
      • Nucci M.R.
      • Parra-Herran C.
      Genomic characterization of HPV-related and gastric-type endocervical adenocarcinoma: correlation with subtype and clinical behavior.
      Non-HPV-associated endocervical adenocarcinomas: EDACs which are not associated with HPV infection comprizes of a wider variety of neoplasms. Their molecular alterations are highlighted individually for each entity.
      Gastric-type endocervical adenocarcinoma – gastric type cervical adenocarcinoma (GAS) accounts for 10% of all EDAC and is the most common EDAC in the non-HPV related category.
      • Stolnicu S.
      • Barsan I.
      • Hoang L.
      • et al.
      International endocervical adenocarcinoma Criteria and classification (IECC): a new pathogenetic classification for invasive adenocarcinomas of the endocervix.
      GAS encompasses the histologic spectrum of the very well differentiated minimal deviation adenocarcinoma (MDA) and the poorly differentiated gastric-type adenocarcinoma. The clonal association between MDA and GAS has been confirmed in one case report by McCluggage et al. in a patient with Peutz-Jeghers syndrome who had a composite GAS and MDA, in which both components exhibited the same molecular alteration of an extra copy of chromosome 7.
      • McCluggage W.G.
      • Harley I.
      • Houghton J.P.
      • Geyer F.C.
      • MacKay A.
      • Reis-Filho J.S.
      Composite cervical adenocarcinoma composed of adenoma malignum and gastric type adenocarcinoma (dedifferentiated adenoma malignum) in a patient with Peutz Jeghers syndrome.
      GAS is associated with Peutz-Jegher Syndrome in up to 10% of cases and may also arise sporadically. These sporadic tumors have a heterogenous genetic profile where TP53 is the most frequently mutated gene.
      • Hodgson A.
      • Howitt B.E.
      • Park K.J.
      • Lindeman N.
      • Nucci M.R.
      • Parra-Herran C.
      Genomic characterization of HPV-related and gastric-type endocervical adenocarcinoma: correlation with subtype and clinical behavior.
      ,
      • Garg S.
      • Nagaria T.S.
      • Clarke B.
      • et al.
      Molecular characterization of gastric-type endocervical adenocarcinoma using next-generation sequencing.
      Interestingly, some sporadic cases of GAS have been shown to harbor somatic mutations STK11, the tumor suppressor gene responsible for Peutz-Jeghers syndrome.
      • Garg S.
      • Nagaria T.S.
      • Clarke B.
      • et al.
      Molecular characterization of gastric-type endocervical adenocarcinoma using next-generation sequencing.
      ,
      • Kuragaki C.
      • Enomoto T.
      • Ueno Y.
      • et al.
      Mutations in the STK11 gene characterize minimal deviation adenocarcinoma of the uterine cervix.
      Other molecular alterations seen in GAS include KRAS, ERBB2, MSH6, CDKN2A/B, POLE, SLX4, ARID1A, BRCA2, ATM, NTRK3, and MSH2.
      • Hodgson A.
      • Howitt B.E.
      • Park K.J.
      • Lindeman N.
      • Nucci M.R.
      • Parra-Herran C.
      Genomic characterization of HPV-related and gastric-type endocervical adenocarcinoma: correlation with subtype and clinical behavior.
      ,
      • Garg S.
      • Nagaria T.S.
      • Clarke B.
      • et al.
      Molecular characterization of gastric-type endocervical adenocarcinoma using next-generation sequencing.
      Additionally, HER2 amplification was recently reported in a subset of patients with GAS.
      • Garg S.
      • Nagaria T.S.
      • Clarke B.
      • et al.
      Molecular characterization of gastric-type endocervical adenocarcinoma using next-generation sequencing.
      Although there is no targeted molecular therapy for GAS, the molecular findings suggest that anti-HER2 therapy, PARP inhibitors and cell cycle inhibitors may be therapeutic options.
      Clear cell carcinoma – clear cell adenocarcinoma of the cervix is a rare neoplasm, accounting for 3% of all cervical adenocarcinomas.
      • Stolnicu S.
      • Barsan I.
      • Hoang L.
      • et al.
      International endocervical adenocarcinoma Criteria and classification (IECC): a new pathogenetic classification for invasive adenocarcinomas of the endocervix.
      This tumor is historically associated with intrauterine exposure to diethylstilbestrol (DES) or with cervical endometriosis.
      Causal mutations have not been identified in clear cell carcinoma of the cervix. A subset exhibit microsatellite instability.
      • Boyd J.
      • Takahashi H.
      • Waggoner S.E.
      • et al.
      Molecular genetic analysis of clear cell adenocarcinomas of the vagina and cervix associated and unassociated with diethylstilbestrol exposure in utero.
      Although p53 IHC overexpression has been observed, TP53 gene mutations have not been detected.
      • Boyd J.
      • Takahashi H.
      • Waggoner S.E.
      • et al.
      Molecular genetic analysis of clear cell adenocarcinomas of the vagina and cervix associated and unassociated with diethylstilbestrol exposure in utero.
      ,
      • Waggoner S.E.
      • Anderson S.M.
      • Luce M.C.
      • Takahashi H.
      • Boyd J.
      p53 protein expression and gene analysis in clear cell adenocarcinoma of the vagina and cervix.
      Mesonephric carcinoma – mesonephric carcinomas are rare, non-HPV associated cervical neoplasms thought to arise from mesonephric remnants. They account for <1% of all cervical adenocarcinomas.
      • Stolnicu S.
      • Barsan I.
      • Hoang L.
      • et al.
      International endocervical adenocarcinoma Criteria and classification (IECC): a new pathogenetic classification for invasive adenocarcinomas of the endocervix.
      The majority of mesonephric carcinomas are associated with mutations in KRAS.
      • Mirkovic J.
      • Sholl L.M.
      • Garcia E.
      • et al.
      Targeted genomic profiling reveals recurrent KRAS mutations and gain of chromosome 1q in mesonephric carcinomas of the female genital tract.
      ,
      • Pors J.
      • Ho J.
      • Prentice L.
      • et al.
      c-KIT analysis and targeted molecular sequencing of mesonephric carcinomas of the female genital tract.
      Mutations in NRAS, chromatin remodeling genes, BCOR, TP53, and CTNNB1 have also been described.
      • Mirkovic J.
      • Sholl L.M.
      • Garcia E.
      • et al.
      Targeted genomic profiling reveals recurrent KRAS mutations and gain of chromosome 1q in mesonephric carcinomas of the female genital tract.
      ,
      • Pors J.
      • Ho J.
      • Prentice L.
      • et al.
      c-KIT analysis and targeted molecular sequencing of mesonephric carcinomas of the female genital tract.
      Mesonephric hyperplasia does not appear to harbour KRAS or NRAS mutations,
      • Pors J.
      • Ho J.
      • Prentice L.
      • et al.
      c-KIT analysis and targeted molecular sequencing of mesonephric carcinomas of the female genital tract.
      a finding which may be helpful in distinguishing mesonephric hyperplasia from mesonephric carcinoma.
      No targeted molecular therapies have been identified for mesonephric carcinoma. Positive c-kit IHC is frequently seen in mesonephric carcinomas, but as mutations in KIT have not been detected, imatinib therapy is unlikely to be of clinical benefit.
      • Pors J.
      • Ho J.
      • Prentice L.
      • et al.
      c-KIT analysis and targeted molecular sequencing of mesonephric carcinomas of the female genital tract.

       Pathologic and clinical relevance

      In 2017, the International Endocervical Adenocarcinoma Criteria and Classification (IECC) proposed a new classification for invasive cervical adenocarcinoma,
      • Stolnicu S.
      • Barsan I.
      • Hoang L.
      • et al.
      International endocervical adenocarcinoma Criteria and classification (IECC): a new pathogenetic classification for invasive adenocarcinomas of the endocervix.
      which reflected biologic, molecular and morphologic lineaments (Table 2). The IECC separated cervical adenocarcinomas into two groups primarily based on its etiologic association with HPV, 1) HPV associated (HPVA) and 2) non-HPV associated (NHPVA) groups. THE HPVA EDACs included usual type (which encompassed villoglandular and micropapillary architectural variants) and mucinous types (NOS, intestinal, signet-ring and iSMILE). The NHPVA EDACs included gastric, clear cell, endometrioid and mesonephric types.
      • Stolnicu S.
      • Barsan I.
      • Hoang L.
      • et al.
      International endocervical adenocarcinoma Criteria and classification (IECC): a new pathogenetic classification for invasive adenocarcinomas of the endocervix.
      The NHPVA EDACs exhibited older age, larger tumor size, higher stage, and worse survival.
      • Stolnicu S.
      • Barsan I.
      • Hoang L.
      • et al.
      International endocervical adenocarcinoma Criteria and classification (IECC): a new pathogenetic classification for invasive adenocarcinomas of the endocervix.
      ,
      • Stolnicu S.
      • Hoang L.
      • Chiu D.
      • et al.
      Clinical outcomes of HPV-associated and unassociated endocervical adenocarcinomas categorized by the international endocervical adenocarcinoma Criteria and classification (IECC).
      ,
      • Hodgson A.
      • Olkhov-Mitsel E.
      • Howitt B.E.
      • Nucci M.R.
      • Parra-Herran C.
      International Endocervical Adenocarcinoma Criteria and Classification (IECC): correlation with adverse clinicopathological features and patient outcome.
      This classification system will be adopted by the next edition of the WHO Classification of Tumors of the Female Reproductive System, and it has been identified as one of the most important developments in gynecologic pathology in the past 50 years.
      Table 2Major molecular subtypes of endocervical adenocarcinoma
      HPV-associated (HPVA)Non-HPV-associated (NHPVA)
      HPV statusPositiveNegative
      Molecular alterationsMutations in PIK3CA and KRASMutations in TP53, KRAS, ERBB2, STK11
      Proportion80%20%
      Clinical and prognostic featuresYounger patients (4th decade)

      Smaller tumor size

      Lower stage disease

      Negative margins

      Better prognosis
      Older patients (5th decade or higher)

      Larger tumor size

      Higher stage disease

      Propensity for positive margins

      Poor prognosis
      Histologic featuresFloating mitotic figures and apoptotic bodies visible on scanning magnification

      Histotypes:

      Usual type

      Mucinous types (NOS, intestinal, signet ring)

      Villoglandular type or pattern iSMILE

      Silva patterns are relevant for predicting lymph node involvement

      Positive for p16 IHC and HPV ISH
      Lack of floating mitotic figures and apoptotic bodies on scanning magnification

      Histotypes:

      Gastric type

      Mesonephric

      Clear Cell

      Endometrioid

      Possibly serous

      NOS

      Silva patterns are not relevant

      Usually negative for p16 IHC and HPV ISH
      Treatment implicationsHPV vaccination and role for HPV testing in clinical follow-upReferral to Hereditary Cancer Program for suspected Peutz-Jegher Syndrome

       Translation to practice and barriers to implementation

      The incorporation of IECC into daily surgical practice is feasible, because identification of the HPVA group can be done accurately by histologic assessment alone in 93% of cases.
      • Stolnicu S.
      • Barsan I.
      • Hoang L.
      • et al.
      International endocervical adenocarcinoma Criteria and classification (IECC): a new pathogenetic classification for invasive adenocarcinomas of the endocervix.
      HPVA can be assigned based on the presence of apical mitotic figures and apoptotic bodies present at scanning magnification (Figure 2). Challenging cases can be adjudicated by p16 IHC, HPV in-situ hybridization or other biomarkers.
      Figure 2
      Figure 2Endocervical adenocarcinomas (EDAC) from 2 major etiologic groups. A) HPV-associated (HPVA) EDAC showing apical mitotic figures and apoptotic debris. B) Non-HPV-associated (NHPVA) EDAC showing absence of apical mitotic figure and apoptotic debris, and features of gastric-type adenocarcinoma.
      As with the development of any new system, there will be ongoing revisions and shifts in classification. The enigmatic ‘endometrioid’ carcinoma has now been removed and now only includes biologic endometrioid carcinoma (ie. those associated with cervical endometriosis). The micropapillary EDAC, once a separate entity in the WHO, is now considered an architectural pattern of usual-type EDAC. The ‘serous’ category under NHPVA still remains contested, as some tumors denoted as serous carcinomas of the cervix, actually represent HPV-associated tumors.
      • Togami S.
      • Sasajima Y.
      • Kasamatsu T.
      • et al.
      Immunophenotype and human papillomavirus status of serous adenocarcinoma of the uterine cervix.
      The IECC has been referenced in the most recent NCCN (National Comprehensive Cancer Network) guidelines for the treatment of cervical adenocarcinoma, but the surgical and adjuvant treatment approaches for these two major groups of tumors remains the same.

      National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology [Internet]. [cited 2020 Feb 1]. Available from: https://www.nccn.org/professionals/physician_gls/default.aspx.

         Practice points

      • The IECC proposed a new stratification for endocervical carcinomas based on HPV status (HPV-associated [HPVA] and non-NHPVA associated [NHPVA]), which confers biologic, clinical and prognostic relevance
      • Compared to HPVA, the NHPVA exhibited worse progression-free and overall survival
      • The mutations found in HPVA and NHPVA endocervical adenocarcinomas can overlap (ie. PIK3CA, KRAS, TP53, STK11), and clinical separation is based most importantly on HPV status
      • The major histotypes of HPVA are usual and mucinous types; NHPVA are gastric, clear cell and mesonephric carcinomas
      • HPVA and NHPVA classification can be achieved by histology alone in the vast majority of cases

      Vulvar squamous cell carcinoma

      Vulvar squamous cell carcinoma (VSCC) accounts for 80–90% of vulvar malignancies. The high-risk of severe morbidity with treatment escalation is a major challenge in managing vulvar carcinoma. There is a clear need for better prognostic stratification tools to limit treatment-associated morbidity.

       Recent molecular findings

      VSCC are separated in two broad categories based on their pathophysiology: HPV-associated VSCC and HPV-independent-VSCC (Table 3).
      Table 3Major molecular subtypes of vulvar squamous cell carcinoma
      HPV-associatedHPV-independent TP53 mutatedHPV-independent TP53 wildtype
      Salient molecular alterationsHPV associatedNot associated with HPV

      Mutations in TP53
      Not associated with HPV

      No mutations in TP53
      Proportion60%30%10%
      Clinical and prognostic featuresPremenopausal

      Smokers, immunosuppression

      Multifocal, multicentric

      Progression from in-situ to invasive cancer is slow

      Low propensity for recurrences

      Good outcomes
      Postmenopausal

      Inflammatory dermatoses and lichen sclerosus

      Unifocal, unicentric, but ‘field effect’ is often present

      Progression from in-situ to invasive cancer is fast

      High propensity for recurrences

      Poor outcomes
      Postmenopausal

      Risk factors are poorly defined

      Unifocal, unicentric

      Progression from in-situ to invasive cancer is intermediate

      Intermediate propensity for recurrences

      Intermediate outcomes
      Histologic featuresPrecursor lesion is HSIL or usual type VIN

      Invasive squamous cell carcinoma is basaloid or warty p16 IHC and HPV ISH are positive

      p53 IHC expression is reduced (mid-epithelial and markedly reduced staining patterns)
      Precursor lesion is differentiated VIN

      Invasive squamous cell carcinoma is usually keratinizing p16 IHC and HPV ISH are negative

      p53 IHC shows a mutant pattern of expression (basal/parabasal overexpression, absent[null], cytoplasmic staining patterns)
      Precursor lesion is VAAD or deVIL

      Invasive squamous cell carcinoma is usually well-differentiated (verrucous carcinoma) p16 IHC and HPV ISH are negative

      p53 IHC shows a scattered (wild-type) pattern of expression
      Treatment implicationsImiquimod and other antiviral treatments

      HPV vaccination and role for HPV testing in clinical follow-up
      Possible role for immune checkpoint inhibition
      To date, Han et al. is the only group to have performed whole exome sequencing on VSCC. In their series, the somatic mutational load was higher in the HPV-independent group, but overall copy number alterations and mutation signatures did not differ.
      • Han M.-R.
      • Shin S.
      • Park H.-C.
      • et al.
      Mutational signatures and chromosome alteration profiles of squamous cell carcinomas of the vulva.
      Both groups harboured FBXW7 and BRCA2 mutations, the HPV-associated VSCC harboured mutations in PIK3CA, while the HPV-independent group harbored mutations in TP53, FAT1, HRAS, APC and CDKN2A.
      • Han M.-R.
      • Shin S.
      • Park H.-C.
      • et al.
      Mutational signatures and chromosome alteration profiles of squamous cell carcinomas of the vulva.
      Zieba et al. examined 81 VSCC and found TP53 mutations (46% and 41%) and CDKN2A mutations (25% and 21%) in HPV-associated and HPV-independent VSCC respectively.
      • Zięba S.
      • Kowalik A.
      • Zalewski K.
      • et al.
      Somatic mutation profiling of vulvar cancer: exploring therapeutic targets.
      They also identified mutations in PIK3CA, HRAS, FBXW7 in both groups at low frequencies (<10%) and rare (1%) PTEN, SMAD4, STK11, FGFR3 mutations only in the HPV-associated group. Trietsch et al. reported similar findings. TP53 mutations were enriched in the HPV-independent VSCC (62% vs 17%). However, mutations in CDK2NA, HRAS, KRAS, PIK3CA, PPP3R1A and PTEN were found in the HPV-independent tumors.
      • Trietsch M.D.
      • Spaans V.M.
      • ter Haar N.T.
      • et al.
      CDKN2A(p16) and HRAS are frequently mutated in vulvar squamous cell carcinoma.
      Nooij et al. proposed stratifying VSCC into three prognostically relevant groups based on HPV and TP53 mutation status. They proposed 3 VSCC groups, i) HPV+, ii) HPV-/p53abn and iii) HPV-/p53wt. In contrast to the preceding studies, they reported NOTCH1 mutations in 41% of HPV-independent and none of the HPV-associated VSCC (Figure 3).
      • Nooij L.S.
      • Ter Haar N.T.
      • Ruano D.
      • et al.
      Genomic characterization of vulvar (Pre)cancers identifies distinct molecular subtypes with prognostic significance.
      Figure 3
      Figure 3Vulvar squamous cell carcinoma (VSCC) representing 3 different molecular subgroups. A) VSCC exhibiting basaloid features, positive for HPV. B) VSCC with keratinization and nuclear atypia, negative for HPV and positive for a TP53 mutation. C) VSCC with broad invasive nests, negative for HPV and negative for a TP53 mutation (p53 wild-type).
      Recent studies revealed that HPV-independent p53 wild-type VSCC show recurrent mutations in PIK3CA and ARID1A. In a study of atypical verruciform lesions, a precursor to VSCC, 73% harboured mutations in PIK3CA and 55% in ARID1A. None had TP53 mutations, although some acquired TP53 mutations upon progression to VSCC.
      • Watkins J.C.
      • Howitt B.E.
      • Horowitz N.S.
      • et al.
      Differentiated exophytic vulvar intraepithelial lesions are genetically distinct from keratinizing squamous cell carcinomas and contain mutations in PIK3CA.
      While some mutations appear to be enriched in one VSCC group or the other, there remains substantial overlap and mutation status alone does not reliably differentiate between HPV-associated and HPV-independent VSCC.

       Pathologic and clinical relevance

      HPV-associated (HPVA) VSCC is associated with high grade squamous intraepithelial lesion/usual vulvar intraepithelial neoplasia (HSIL/uVIN). These lesions are typically seen in younger women. Characteristically, HPVA squamous neoplasia (invasive and pre-invasive) shows basaloid or warty morphology, although morphologic overlap with NHPVA has been demonstrated in up to 20% of cases.
      • Dong F.
      • Kojiro S.
      • Borger D.R.
      • Growdon W.B.
      • Oliva E.
      Squamous cell carcinoma of the vulva A subclassification of 97 cases by clinicopathologic, immunohistochemical, and molecular features (p16, p53, and EGFR).
      By contrast, HPV-independent VSCC most commonly occurs in older women, often in association with chronic vulvar dermatoses and typically lichen sclerosus. Our understanding of HPV-independent pre-invasive neoplasia is evolving and these entities remain diagnostically challenging for both clinicians and pathologists alike. HPV-independent VSCCs usually arise from differentiated vulvar intraepithelial lesion (dVIN), vulvar acanthosis with altered differentiation (VAAD)
      • Nascimento A.F.
      • Granter S.R.
      • Cviko A.
      • Yuan L.
      • Hecht J.L.
      • Crum C.P.
      Vulvar acanthosis with altered differentiation: a precursor to verrucous carcinoma?.
      and differentiated exophytic vulvar intraepithelial lesion (DEVIL).
      • Watkins J.C.
      • Howitt B.E.
      • Horowitz N.S.
      • et al.
      Differentiated exophytic vulvar intraepithelial lesions are genetically distinct from keratinizing squamous cell carcinomas and contain mutations in PIK3CA.
      The histomorphologic features for these entities can be subtle and difficult to categorize in a background of chronic inflammatory changes or in limited biopsy specimens. Assessment of the transition between the lesional and background normal epithelium and ancillary IHC use, is often very helpful.
      • Singh N.
      • Leen S.L.
      • Han G.
      • et al.
      Expanding the morphologic spectrum of differentiated VIN (dVIN) through detailed mapping of cases with p53 loss.
      There is increasing recognition that HPV status is of prognostic value because most studies have demonstrated better outcomes in HPV-associated neoplasia.
      • Allo G.
      • Yap M.
      • Cuartero J.
      • et al.
      HPV-independent vulvar squamous cell carcinoma is associated with significantly worse prognosis compared with HPV-associated tumors.
      ,
      • McAlpine J.N.
      • Leung S.C.Y.
      • Cheng A.
      • et al.
      Human papillomavirus (HPV)-independent vulvar squamous cell carcinoma has a worse prognosis than HPV-associated disease: a retrospective cohort study.
      Clinical progression from HPV-independent pre-invasive neoplasia to invasive VSCC is also accelerated as compared to HPVA disease. dVIN is 6-times more likely to progress to VSCC compared with uVIN, and progresses almost twice as fast (23 months versus 41 months).
      • Van De Nieuwenhof H.P.
      • Van Kempen L.C.L.T.
      • De Hullu J.A.
      • et al.
      The etiologic role of HPV in vulvar squamous cell carcinoma fine tuned.
      In the proposed framework by Nooij et al., the HPV-/p53wt had an intermediate prognosis, better than the HPV-/p53abn group and worse than the HPV + group. The 5-year progression free survival for each of the 3 groups has been reported to be 5.3%, 22.6% and 16.3% (p = 0.044) and 5-year overall survival was 75%, 56.3% and 67.2% (p = 0.296) respectively.
      • Nooij L.S.
      • Ter Haar N.T.
      • Ruano D.
      • et al.
      Genomic characterization of vulvar (Pre)cancers identifies distinct molecular subtypes with prognostic significance.

       Translation to practice and barriers to implementation

      Immunohistochemistry for p16 is commonly used in clinical settings to segregate VSCC into HPV-associated and HPV-independent categories. This is discussed by Wong et al. in this issue.
      As discussed above, HPV-independent VSCCs can be further subdivided by TP53 mutation status. Tessier-Cloutier et al. have recently demonstrated concordance between TP53 mutation status and p53 IHC expression and have proposed a pattern-based approach to p53 IHC interpretation.
      • Tessier-Cloutier B.
      • Kortekaas K.
      • Thompson E.
      • et al.
      Major p53 immunohistochemical patterns in in-situ and invasive squamous cell carcinomas of the vulva and correlation with TP53 mutation status.
      In this pattern-based framework, there were two wild type patterns: 1) scattered, and 2) mid-epithelial expression (with basal sparing) and four mutant patterns: 3) basal overexpression, 4) parabasal/diffuse overexpression, 5) absent and 6) cytoplasmic expression. These IHC patterns were consistent with TP53 mutation status in 58/61 (95%) VSCC and 39/42 (93%) in-situ lesions.
      • Tessier-Cloutier B.
      • Kortekaas K.
      • Thompson E.
      • et al.
      Major p53 immunohistochemical patterns in in-situ and invasive squamous cell carcinomas of the vulva and correlation with TP53 mutation status.
      A follow-up study by Thompson et al. (unpublished) expands on the mid-epithelial pattern and describes a markedly reduced p53 staining pattern, which are HPV-associated patterns where p53 is easily mistaken for missense or nonsense IHC patterns. Recognition of these patterns and interpretation alongside p16 is helpful to avoid inaccurate assignment of TP53 mutation status.
      The morphologic overlap with benign and banal-appearing pre-invasive neoplasias (ie. VAAD and deVIL) and lack of ancillary biomarkers for their diagnosis, still remains a significant challenge.
      As in the case of EDAC, the NCCN guidelines for vulvar carcinoma recognize two groups (HPV-associated and non HPV-associated). However, the treatment approach to vulvar carcinoma remains the same regardless of etiology, unlike the adoption of stratified treatment in head and neck oropharyngeal carcinomas.

      National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology [Internet]. [cited 2020 Feb 1]. Available from: https://www.nccn.org/professionals/physician_gls/default.aspx.

         Practice points

      • Vulvar squamous cell carcinoma can be stratified into HPV-associated and HPV -independent groups, which are clinically and prognostically important
      • There is recent evidence to show that the HPV-independent group may be further stratified by TP53 mutation status
      • p53 IHC can be used as a surrogate for TP53 mutation status in vulvar squamous cell carcinoma and squamous precursor lesions using a pattern-based framework for interpretation

      Uterine sarcomas

      The incorporation of RNA-sequencing technologies in advanced clinical laboratories have resulted in a fusillade of findings in the realm of uterine sarcomas. Many sarcomas have shifted out of the undifferentiated uterine sarcoma (UUS) basket into more specific tumor types.

       High-grade endometrial stromal sarcoma (HG-ESS)

      The features of YWHAE-NUTM2 HG-ESS have been described extensively elsewhere. Here we focus on HG-ESS which BCOR genetic rearrangements.

       Molecular findings

      These tumors are characterized by genetic fusions involving BCOR and ZC3H7B.
      • Lewis N.
      • Soslow R.A.
      • Delair D.F.
      • et al.
      ZC3H7B-BCOR high-grade endometrial stromal sarcomas: a report of 17 cases of a newly defined entity.
      ,
      • Cotzia P.
      • Benayed R.
      • Mullaney K.
      • et al.
      Undifferentiated uterine sarcomas represent under-recognized high-grade endometrial stromal sarcomas.
      BCOR internal tandem duplications (ITD) within exon 15 have also been described.
      • Lewis N.
      • Soslow R.A.
      • Delair D.F.
      • et al.
      ZC3H7B-BCOR high-grade endometrial stromal sarcomas: a report of 17 cases of a newly defined entity.
      ,
      • Mariño-Enriquez A.
      • Lauria A.
      • Przybyl J.
      • et al.
      BCOR internal tandem duplication in high-grade uterine sarcomas.
      ,
      • Juckett L.T.
      • Lin D.I.
      • Madison R.
      • Ross J.S.
      • Schrock A.B.
      • Ali S.
      A pan-cancer landscape analysis reveals a subset of endometrial stromal and pediatric tumors defined by internal tandem duplications of BCOR.
      BCOR (BCL-6 interacting co-repressor) is responsible for epigenetic regulation and cellular differentiation. HG-ESS with YWHAE-NUTM2 rearrangements, also show increased mRNA expression of BCOR, illustrating the related nature of these two tumors.
      • Kao Y.C.
      • Sung Y.S.
      • Zhang L.
      • et al.
      Recurrent BCOR internal tandem duplication and YWHAE - NUTM2B fusions in soft tissue undifferentiated round cell sarcoma of infancy: overlapping genetic features with clear cell sarcoma of kidney.

       Pathologic and clinical relevance

      HG-ESS with BCOR rearrangements occur in women in their 5th decade of life, while BCOR ITD thus far has been reported to occur in women of a slightly younger age (4th decade of life).
      • Lewis N.
      • Soslow R.A.
      • Delair D.F.
      • et al.
      ZC3H7B-BCOR high-grade endometrial stromal sarcomas: a report of 17 cases of a newly defined entity.
      ,
      • Mariño-Enriquez A.
      • Lauria A.
      • Przybyl J.
      • et al.
      BCOR internal tandem duplication in high-grade uterine sarcomas.
      ,
      • Juckett L.T.
      • Lin D.I.
      • Madison R.
      • Ross J.S.
      • Schrock A.B.
      • Ali S.
      A pan-cancer landscape analysis reveals a subset of endometrial stromal and pediatric tumors defined by internal tandem duplications of BCOR.
      More than half of patients present with high-stage disease and approximately half will experience recurrences or metastatic disease.
      • Lewis N.
      • Soslow R.A.
      • Delair D.F.
      • et al.
      ZC3H7B-BCOR high-grade endometrial stromal sarcomas: a report of 17 cases of a newly defined entity.
      ,
      • Juckett L.T.
      • Lin D.I.
      • Madison R.
      • Ross J.S.
      • Schrock A.B.
      • Ali S.
      A pan-cancer landscape analysis reveals a subset of endometrial stromal and pediatric tumors defined by internal tandem duplications of BCOR.
      Like the family of ESS, these tumors show tongue-like growth patterns. They comprize of haphazard fascicles of monotonous spindled cells with blue-grey myxoid stroma, a feature which had led to their notorious confusion with myxoid leiomyosarcoma. The cells have ovoid/spindled nuclei and variable mitotic activity.
      • Lewis N.
      • Soslow R.A.
      • Delair D.F.
      • et al.
      ZC3H7B-BCOR high-grade endometrial stromal sarcomas: a report of 17 cases of a newly defined entity.
      ESS with BCOR ITD also exhibit variable amounts of myxoid matrix, however they can also encompass a high-grade round cell component.
      • Cotzia P.
      • Benayed R.
      • Mullaney K.
      • et al.
      Undifferentiated uterine sarcomas represent under-recognized high-grade endometrial stromal sarcomas.
      • Mariño-Enriquez A.
      • Lauria A.
      • Przybyl J.
      • et al.
      BCOR internal tandem duplication in high-grade uterine sarcomas.
      • Juckett L.T.
      • Lin D.I.
      • Madison R.
      • Ross J.S.
      • Schrock A.B.
      • Ali S.
      A pan-cancer landscape analysis reveals a subset of endometrial stromal and pediatric tumors defined by internal tandem duplications of BCOR.
      The majority of ESS with BCOR-rearrangements are CD10 positive, cyclin-D1 positive, show absence of desmin, variable ER/PR expression and half are BCOR positive by IHC.
      • Lewis N.
      • Soslow R.A.
      • Delair D.F.
      • et al.
      ZC3H7B-BCOR high-grade endometrial stromal sarcomas: a report of 17 cases of a newly defined entity.

       Translational considerations and nuances

      BCOR IHC expression is not specific to BCOR altered ESS, and have also been reported in YWHAE-NUTM2 HGESS and uterine adenosarcomas.
      • Chiang S.
      • Lee C.H.
      • Stewart C.J.R.
      • et al.
      BCOR is a robust diagnostic immunohistochemical marker of genetically diverse high-grade endometrial stromal sarcoma, including tumors exhibiting variant morphology.
      ,
      • Muthukumarana V.
      • Fix D.J.
      • Stolnicu S.
      • et al.
      BCOR expression in mullerian adenosarcoma A potential diagnostic pitfall.
      While the number of diagnostic entities within the HG-ESS category continues to grow, the treatment approach for these tumors remains the same and no targeted molecular therapies have emerged. Therefore, it is unclear whether expensive molecular tests need to be performed when the management strategy remains unchanged.

       Fibrosarcoma-like tumors of the uterus

      In the last two years, fibrosarcoma-like tumors harbouring Neurotrophic Tyrosine Kinase Receptor (NTRK) and Platelet Derived Growth Factor beta chain (PDGFB) rearrangements have been described in the cervix, and to a lesser extent, in the uterine corpus.
      • Chiang S.
      • Cotzia P.
      • Hyman D.M.
      • et al.
      NTRK fusions define a novel uterine sarcoma subtype with features of fibrosarcoma.
      • Croce S.
      • Hostein I.
      • Longacre T.A.
      • et al.
      Uterine and vaginal sarcomas resembling fibrosarcoma: a clinicopathological and molecular analysis of 13 cases showing common NTRK-rearrangements and the description of a COL1A1-PDGFB fusion novel to uterine neoplasms.
      • Rabban J.T.
      • Devine P.
      • Sangoi A.R.
      • et al.
      NTRK fusion cervical sarcoma: a report of 3 cases, emphasizing morphological and immunohistochemical distinction from other uterine sarcomas, including adenosarcoma.

       Recent molecular findings

      NTRK1, NTRK2 and NTRK3 encode for various tropomyosin receptor kinase (Trk) proteins (TrkA, TrkB, TrkC), which activate well-known signalling pathways, leading to increased cellular proliferation. The 3′ tyrosine kinase domain of NTRK can be fused to the 5’ region of various partners (TPM3, TPR, LMNA, RBPMS, EML4, SPECC1L), resulting in a chimeric protein receptor with constitutive activation of the tyrosine kinase domain. NTRK fusions have been found in fibrosarcoma-like tumors of the uterine cervix and uterine corpus, with TPM3 being the most common fusion partner.
      • Chiang S.
      • Cotzia P.
      • Hyman D.M.
      • et al.
      NTRK fusions define a novel uterine sarcoma subtype with features of fibrosarcoma.
      • Croce S.
      • Hostein I.
      • Longacre T.A.
      • et al.
      Uterine and vaginal sarcomas resembling fibrosarcoma: a clinicopathological and molecular analysis of 13 cases showing common NTRK-rearrangements and the description of a COL1A1-PDGFB fusion novel to uterine neoplasms.
      • Rabban J.T.
      • Devine P.
      • Sangoi A.R.
      • et al.
      NTRK fusion cervical sarcoma: a report of 3 cases, emphasizing morphological and immunohistochemical distinction from other uterine sarcomas, including adenosarcoma.
      PDGFB is a potent mitogen for mesenchymal cells such as fibroblasts and myofibroblasts. Fusion of COL1A1-PDGFB results in overproduction of PDGFB which binds to PDGFB receptors, causing autocrine stimulation that results in cellular proliferation. To date, COL1A1-PDGFB has been reported in 3 cases of fibrosarcoma-like tumors of the cervix and uterine corpus.
      • Croce S.
      • Hostein I.
      • Longacre T.A.
      • et al.
      Uterine and vaginal sarcomas resembling fibrosarcoma: a clinicopathological and molecular analysis of 13 cases showing common NTRK-rearrangements and the description of a COL1A1-PDGFB fusion novel to uterine neoplasms.

       Pathologic and clinical relevance

      Patients with NTRK rearranged fibrosarcoma-like sarcoma are usually in their 4th decade of life. Most patients present with stage I disease. Approximately half of patients develop recurrences (vaginal/pelvic) or metastases (lung, omentum, liver, brain).
      • Chiang S.
      • Cotzia P.
      • Hyman D.M.
      • et al.
      NTRK fusions define a novel uterine sarcoma subtype with features of fibrosarcoma.
      • Croce S.
      • Hostein I.
      • Longacre T.A.
      • et al.
      Uterine and vaginal sarcomas resembling fibrosarcoma: a clinicopathological and molecular analysis of 13 cases showing common NTRK-rearrangements and the description of a COL1A1-PDGFB fusion novel to uterine neoplasms.
      • Rabban J.T.
      • Devine P.
      • Sangoi A.R.
      • et al.
      NTRK fusion cervical sarcoma: a report of 3 cases, emphasizing morphological and immunohistochemical distinction from other uterine sarcomas, including adenosarcoma.
      The number of patients with PDGFB fusions is limited. Patient ages were 48, 60 and 82 years, and of the two patients with clinical follow up, one experienced pelvic recurrence (bladder and rectum) and died of disease.
      • Croce S.
      • Hostein I.
      • Longacre T.A.
      • et al.
      Uterine and vaginal sarcomas resembling fibrosarcoma: a clinicopathological and molecular analysis of 13 cases showing common NTRK-rearrangements and the description of a COL1A1-PDGFB fusion novel to uterine neoplasms.
      NTRK-rearranged tumors are characterized by fascicles of spindled cells arranged in patternless or fascicular, herringbone or storiform patterns. The spindled cells have mild to moderate cytologic atypia, ovoid nuclei and inconspicuous nucleoli and variable mitotic activity. The majority are negative for lymphovascular invasion and one-third exhibit hemangiopericytoma-like vasculature. These features can cause confusion with solitary fibrous tumor and inflammatory myofibroblastic tumor (ancillary testing for STAT6 and ALK1 can be helpful to in this regard). Entrapped glands can mimic the appearance of adenosarcoma.
      • Rabban J.T.
      • Devine P.
      • Sangoi A.R.
      • et al.
      NTRK fusion cervical sarcoma: a report of 3 cases, emphasizing morphological and immunohistochemical distinction from other uterine sarcomas, including adenosarcoma.
      The histologic features of PDGFB-rearranged tumors are very similar, except they do not tend to show lymphocytic inflammation.
      • Croce S.
      • Hostein I.
      • Longacre T.A.
      • et al.
      Uterine and vaginal sarcomas resembling fibrosarcoma: a clinicopathological and molecular analysis of 13 cases showing common NTRK-rearrangements and the description of a COL1A1-PDGFB fusion novel to uterine neoplasms.
      Almost all NTRK-rearranged tumors are positive for S100 (in variable proportions) immunohistochemistry and negative for desmin, ER, PR and SOX10. CD34 has shown discrepant expression.
      • Chiang S.
      • Cotzia P.
      • Hyman D.M.
      • et al.
      NTRK fusions define a novel uterine sarcoma subtype with features of fibrosarcoma.
      ,
      • Rabban J.T.
      • Devine P.
      • Sangoi A.R.
      • et al.
      NTRK fusion cervical sarcoma: a report of 3 cases, emphasizing morphological and immunohistochemical distinction from other uterine sarcomas, including adenosarcoma.
      Trk staining was strong and diffuse in all tumors with NTRK-rearrangements, and exhibiting variable patterns depending on the fusion.
      • Chiang S.
      • Cotzia P.
      • Hyman D.M.
      • et al.
      NTRK fusions define a novel uterine sarcoma subtype with features of fibrosarcoma.
      • Croce S.
      • Hostein I.
      • Longacre T.A.
      • et al.
      Uterine and vaginal sarcomas resembling fibrosarcoma: a clinicopathological and molecular analysis of 13 cases showing common NTRK-rearrangements and the description of a COL1A1-PDGFB fusion novel to uterine neoplasms.
      • Rabban J.T.
      • Devine P.
      • Sangoi A.R.
      • et al.
      NTRK fusion cervical sarcoma: a report of 3 cases, emphasizing morphological and immunohistochemical distinction from other uterine sarcomas, including adenosarcoma.
      The immunoprofile of the PDGFB-rearranged tumors, were similar, except they did not express S100 or Trk.
      • Croce S.
      • Hostein I.
      • Longacre T.A.
      • et al.
      Uterine and vaginal sarcomas resembling fibrosarcoma: a clinicopathological and molecular analysis of 13 cases showing common NTRK-rearrangements and the description of a COL1A1-PDGFB fusion novel to uterine neoplasms.

       Translational considerations and nuances

      Trk immunohistochemical expression is not unique to uterine sarcomas with NTRK-rearrangements and have been reported in YWHAE and BCOR rearranged uterine sarcomas.
      • Mohammad N.
      • Wolber R.
      • Yip S.
      • et al.
      Frequent NTRK expression in high-grade endometrial stromal sarcoma harboring BCOR/BCORL1 genetic alterations (abs1156). In “abstracts from USCAP 2020: gynecologic and obstetric pathology.
      The discovery of NTRK-rearranged tumors is important as it opens the door to Trk inhibitors, such as entrectinib and larotrectinib. The same applies for COL1A1-PDGFB and the therapeutic use of imatinib. Whether tumors with COL1A1-PDGFB should be called fibrosarcoma-like or a variant DFSP can be debated. Croce et al. argued that the more aggressive clinical behavior of these tumors warrants their classification as a separate entity.

         Practice points

      • Uterine sarcomas harboring BCOR-ZC3H7B or BCOR internal tandem repeats exhibit aggressive clinical behavior and are best classified under the high-grade endometrial stromal sarcoma category
      • Fibrosarcoma-like sarcomas of the uterus and cervix can harbor rearrangements involving NTRK or PDFGR, therefore opening the possibility for targeted molecular therapy (ie. Trk inhibitors and imatinib)
      • There is often morphologic overlap between many types of uterine mesenchymal tumors which warrant further ancillary testing for accurate classification

      Uterine tumor resembling sex-cord stromal tumor (UTROSCT)

      In a review of the major molecular findings in gynecologic pathology, we would be remiss not to mention the recent molecular findings in UTROSCT, at least briefly. It has not shifted classification paradigms but can be used to accurately delineate UTROSCT from its mimics (ie. low-grade endometrial stromal sarcoma with sex-cord differentiation). UTROSCT often display fusions between NCOA (Nuclear Receptor Coactivator) and estrogen receptor 1 (ESR1) or growth regulation by estrogen in breast cancer 1 (GREB1) (ESR1-NCOA3, ESR1-NCOA2 and GREB1-NCOA1/2).
      • Goebel E.A.
      • Hernandez Bonilla S.
      • Dong F.
      • et al.
      Uterine tumor resembling ovarian sex cord tumor (UTROSCT): a morphologic and molecular study of 26 cases confirms recurrent NCOA1-3 rearrangement.
      A recent study found that only 1 of 4 uterine sarcomas with GREB1 rearrangements exhibited convincing sex-cord elements and they behaved more aggressively than ESR1-rearranged UTROSCT, raising the possibility of a need for further sub-stratification of these tumors which likely exist on a disease spectrum.
      • Lee C.-H.
      • Kao Y.-C.
      • Lee W.-R.
      • et al.
      Clinicopathologic characterization of GREB1-rearranged uterine sarcomas with variable sex-cord differentiation.

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