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Pathology of the Corpus: Case Reports

Endometrial Carcinoma as the Presenting Malignancy in a Teenager With a Pathogenic TP53 Germline Mutation: A Case Report and Literature Review

Irshaid, Lina M.D.; Clark, Mitchell M.D.; Fadare, Oluwole M.D.; Finberg, Karin E. M.D., Ph.D.; Parkash, Vinita M.B.B.S., M.P.H.

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International Journal of Gynecological Pathology: May 2022 - Volume 41 - Issue 3 - p 258-267
doi: 10.1097/PGP.0000000000000792
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Patients with germline TP53 mutations are characterized by the occurrence of multiple early-onset malignancies. The characteristic syndrome is that of Li-Fraumeni syndrome (LFS, OMIM # 151623), an autosomal dominant disorder typified by premenopausal breast carcinoma, adrenal cortical tumors, bone, and soft tissue sarcomas, leukemias, and tumors of the brain and spinal cord. However, a number of other tumors also occur in such families, including lung carcinoma, gastrointestinal carcinoma (colorectal and pancreatic), melanoma, and prostate cancer 1. The specific spectra of tumors in a patient or family are dependent on multiple variables, including the type of mutation, its specific effects, and penetrance characteristics 1. Gynecologic malignancies are uncommonly reported in families harboring TP53 mutations, and the predominant tumor type reported is ovarian. Uterine carcinoma has been reported only a handful of times in patients with germline TP53 mutations, none as a presenting tumor in a teenager. We report on an 18-year-old patient with a germline mutation in TP53 who presented with endometrial carcinoma.


An 18-year-old gravida 0 Hispanic female presented with the complaint of abnormal uterine bleeding for 1 year. Her medical history was significant for irritable bowel syndrome, bipolar disorder, and anxiety. Transvaginal ultrasound showed a thickened endometrial lining of 2.3 cm as well as multiple solid pelvic masses suspicious for malignancy. A dilation and curettage revealed a high-grade endometrial carcinoma (Fig. 1). The patient underwent a laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy with optimal tumor debulking. Colonoscopy was performed to assess for coexistent colonic adenocarcinoma, under the consideration that the patient might have Lynch syndrome. The patient also underwent a formal genetic consultation with a 4-generation pedigree analysis, which was negative for uterine, ovarian, colon, thyroid, and other cancers. The patient’s father was deceased in his mid-fifties of apparent nonmalignant causes and her mother was alive and well. She had no siblings.

FIG. 1:
Dilation and curettage reveals a high-grade endometrial carcinoma with foci of solid growth (×20).

Grossly a 4.5 cm tumor mass filled the endometrial cavity and extended towards the cervix (Fig. 2A). Both ovaries were enlarged to 7 and 8 cm. The omentum was infiltrated by a tumor and formed an omental cake. Tumor nodules were present on the liver and peritoneum. Microscopically, the endometrium showed a high-grade endometrioid carcinoma with focal gland formation (Fig. 2B). The poorly differentiated areas were varied in their appearance and ranged from areas of cohesive solid growth with monomorphic nuclei (Fig. 2C) and geographic necrosis to areas with cytoplasmic clearing and anaplastic nuclei. The tumor deeply invaded the myometrium and was metastatic to the ovaries, omentum, lymph nodes, and liver. Immunohistochemically, the tumor showed abnormal mutation-type p53 overexpression (Fig. 2D), and patchy expression of p16 2. It was focally positive for estrogen and progesterone receptors. Mismatch repair protein (MLH1, MSH2, MSH6, and PMS2) expression was retained. ERBB2 (HER2) expression was negative. Bilateral fallopian tubes were grossly and microscopically unremarkable. In addition, p53 stains showed wild-type expression. Three colonic polyps, the largest in the rectum measuring 1.4 cm, were removed. Two were tubular adenomas. The rectal polyp revealed a tubulovillous adenoma with high-grade dysplasia, which showed abnormal mutation-type p53 overexpression.

FIG. 2:
(A) Grossly, the tumor fills the endometrial cavity and extends towards the lower uterine segment. (B) Microscopically, the tumor shows distinct foci of gland formation, solid growth, and squamous differentiation (×40). (C) Poorly differentiated areas show cohesive solid growth with abundant mitotic figures (×100). (D) Immunohistochemically, the tumor is diffusely and strongly positive for p53.

DNA from the uterine tumor was evaluated for genetic variants in exonic regions of 409 cancer-related genes using a modification of the Ion AmpliSeq Comprehensive Cancer Panel (ThermoFisher Scientific). DNA was extracted after enrichment for malignant cells by manual microdissection of formalin-fixed paraffin-embedded tissue sections. Amplicon sequencing was performed on an Ion Torrent PGM next-generation sequencer. The raw data was analyzed in Torrent Suite v3.4.2 with variants identified by the Ion Reporter v1.6 and custom software developed by the YNHH Tumor Profiling Laboratory. DNA isolated from a pelvic lymph node that was negative for carcinoma was analyzed in parallel to serve as the germline reference.

A single-nucleotide substitution in the TP53 gene (NM_000546.6:c.818G>A), encoding the missense substitution p.Arg273His (R273H) was detected in both the tumor and benign lymph node (Fig. 3) 3. The variant, an established pathogenic variant associated with LFS when present in the germline (ClinVar Accession VCV000012366.11), was detected in 51% of the sequencing reads obtained from the lymph node, compatible with a heterozygous germline mutation, while the variant was present at a higher allelic fraction (81%) in the tumor. Given that the tumor tissue analyzed was estimated visually to contain 80% malignant cells, the frequency of the TP53 mutation DNA isolated from the tumor was compatible with loss of the wild-type allele (ie, loss of heterozygosity) at the TP53 locus. DNA isolated from the lymph node also showed that the patient was homozygous for the minor (Arg) allele at TP53 codon 72, a common polymorphism (dbSNP rs1042522).

FIG. 3:
Visualization of the TP53 c.818G>A variant in DNA sequencing reads obtained from the tumor (top track) and a benign lymph node (bottom track). Reads are colored red for the positive rightward (5′–3′) DNA strand and blue for the negative leftward (reverse-complement) DNA strand. The reference sequence for TP53 exon 8 and its amino acid translation are shown below. The arrow at the lower left indicates that TP53 is encoded on the negative DNA strand, and the nucleotide and protein reference sequences run from right to left. Thus, the red “T” shown between the center lines corresponds to a G>A substitution in the TP53 coding sequence. Coverage tracks show the distribution of wild-type (blue) and variant (red) nucleotides at position 818 in the corresponding .bam files. The lymph node showed 81 mutant reads (of 157 total), compatible with a heterozygous germline variant, while a higher proportion of mutant reads (417 mutant of 511 total) was detected in the tumor, consistent with loss of heterozygosity. Aligned sequencing reads were viewed in the Integrative Genome Viewer (IGV) 3.

Four somatic variants were also identified in the uterine tumor. A deletion of 12 nucleotides was detected in PTEN (NM_000314.8: c.729_740delCCCTCAGCCGTT), resulting in an in-frame deletion (p.F243_P246del) in the C2 tensin-type domain involved in lipid membrane binding. The PTEN variant was detected at an allelic fraction of 60%, suggestive of loss of heterozygosity, and is predicted by the PROVEAN software tool to have a deleterious effect on protein function. Missense variants of uncertain significance were present at lower allelic fractions in TSC2 (NM_000548.5: c.2904G>C, p.E968D, 34%), TAF1L (NM_153809.2: c.1614G>C, p.E538D, 19%) and ITGB2 (NM_000211.5: c.658G>C, p.E220Q, 13%). In addition, copy number analysis revealed high-level amplification (copy number ≥10) of both CCND1 (11q13.3) and NUMA1 (11q13.4) as well as an estimated copy number of 6 at MEN1 (11q13.1).

Following surgery, the patient attempted multiple therapeutic regimens including chemotherapy (cisplatin, paclitaxel, and doxorubicin for 6 cycles), hormonal therapy (Arimidex and Megace), and 2 clinical trial drugs: LEE011 (ribociclib), a selective CDK4/CDK6 inhibitor administered to target the CCND1 (cyclin D1) amplification, and MPDL3280A (atezolizumab), a monoclonal antibody recognizing PD-L1. Unfortunately, the patient’s tumor rapidly progressed despite all treatments attempts and she succumbed to her disease 2 years following diagnosis.


Endometrial carcinoma in young patients is uncommon and typically reported in 2 circumstances 4. In the first and more common circumstance, the patient has unopposed hyperestrinism and develops a low-grade endometrioid carcinoma that is often amenable to progestin therapy. Most patients are in their thirties, although rare cases have been reported as early as 15 years of age 5. In the second scenario, the patient has a cancer predisposition syndrome, most commonly Lynch syndrome, and may present with a higher grade, aggressive, dedifferentiated carcinoma 4. Although our patient was found to have 3 colonic tumors, in addition to her primary endometrial carcinoma, all tumors demonstrated retained expression of mismatch repair proteins, making Lynch syndrome unlikely.

However, genomic sequencing detected a TP53 mutation (R273H) in the tumor and germline. The endometrial tumor demonstrated strong staining for p53, compatible with a pathogenic TP53 missense mutation 2,6. As exemplified by the present case, TP53 is unusual among tumor suppressor genes associated with hereditary cancer syndromes, as the pathogenic variants are typically missense variants, rather than deletions. These missense variants occur at a number of mutational hotspots, and the spectrum of germline missense variants detected in individuals with LFS is similar to the spectrum of somatic missense variants detected in cancers 1.

Indeed, the R273H mutation detected in this case is one of the most common germline TP53 mutations reported in the IARC TP53 Database (version R20, July 2019) 7. In addition, in the Catalogue of Somatic Mutations in Cancer (COSMIC) Database, codon 273 is the most frequently mutated TP53 codon in tumors, with R273H and R273C comprising the majority of missense variants at this residue 8. An estimate of the frequency of TP53 R273H in the general population is provided by the Genome Aggregation Database (gnomAD), a large collection of exome and whole-genome sequencing data obtained from population studies of common adult-onset diseases (eg, cardiovascular disease, type 2 diabetes); TP53 R273H is a rare variant observed in 4 of 251,054 alleles (allele frequency 0.00001593) 9.

The p53 protein, a 393 amino acid protein known as the “Guardian of the Genome,” is activated under conditions of cellular stress and upregulates the expression of genes involved in biologic processes such as cell cycle arrest, DNA repair, and apoptosis 10. The protein is comprised of an N-terminal transcriptional activation domain, a proline-rich domain, a DNA binding domain (also known as the core domain), a tetramerization domain, and a C-terminal regulatory domain. TP53 missense mutations have been classified into 2 categories: (1) those that markedly disrupt the 3-dimensional structure of the protein (i.e. conformational mutations) and (2) those that affect amino acids involved in DNA contacts, which block wild-type p53 transcriptional activity without markedly altering the conformation of the mutant p53 protein (i.e. contact mutations) 11. R273 lies within the DNA binding domain and participates in an extended network of interactions involving the DNA phosphate backbone as well as the side chains of several other amino acids 12. The crystal structure of the p53 R273H shows that this mutation impairs DNA binding without significantly impacting the thermodynamic stability of the core domain, leading to the classification of R273H as a DNA contact mutation 13.

R273H is one of several TP53 missense variants that not only show a loss of wild-type p53 function but also exhibit additional novel, oncogenic properties in experimental systems 14. Mice heterozygous for an endogenous p53 point mutation analogous to the human R273H substitution (Tp53R270H/+), which serve as a model for LFS, develop a spectrum of tumors distinct from mice that are heterozygous for a null p53 allele (Tp53+/−), supporting the hypothesis that R273H confers novel p53 functions 15. Compared with wild-type TP53 control lymphocytes, lymphocytes from heterozygote carriers of R273H show a reduction in DNA sites bound by p53 after exposure to the chemotherapy agent doxorubicin. Because the active form of p53 functions as a tetramer, this suggests that R273 has the capacity to act as a dominant-negative allele that disrupts wild-type p53 function, likely by forming inactive heterotetramers 16. In the case presented in this report, however, the TP53 R273H germline mutation was detected in the tumor DNA at a variant allelic fraction compatible with loss of heterozygosity, supporting the notion that some of the pathogenic consequences of the R273H allele result from loss-of-function effects.

In a large study of 415 carriers of germline TP53 mutations, the mean age of tumor onset was significantly lower in those with dominant-negative missense mutations (mutations defined as the ability to inhibit the activity of the wild-type p53 protein; 23.8 yr) compared with those with loss-of-function mutations (frameshift or in-frame deletions/insertions, nonsense mutations, and genomic rearrangements; 28.5 yr) 17. In that study, 41% of mutation carriers had developed a tumor by age 18, the age of endometrial carcinoma diagnosis in our patient. In addition, several genetic modifiers have been described to lower mean age at tumor onset in patients with LFS. These include polymorphisms within the TP53 gene as well as polymorphisms in genes encoding key regulators of p53, such as MDM2 and miR-605, a micro-RNA that disrupts the p53-MDM2 feedback loop 18. Of note, our patient was a homozygote for TP53 p.Arg72, a common polymorphism that enhances the metastatic potential of mutant forms of p53, while having a limited effect on the activity of wild-type p53 19.

Endometrial carcinomas in patients or families with germline TP53 mutations are distinctly uncommon; reported cases of all uterine carcinomas in patients or families with germline TP53 mutations are presented in Table 120–38. A total of 23 cases are documented to date (13 endometrial, 7 cervical, and 3 uterine cancer, not other specified); however, 4 cases (marked with an asterisk) would not be classified by current standards as having pathogenic TP53 mutations. Further, reported cases demonstrate that endometrial cancer in Lynch syndrome may be a relatively late-developing malignancy. Of 8 patients with pathogenic germline TP53 mutations and whose age is reported (Table 1), only 2 were below 46 years (the cutoff age used in the modified “Chompret Criteria” for screening probands with a TP53 core tumor) 39. Our patient’s 4-generation pedigree analysis was negative for cancers, mitigating against an inherited cancer syndrome, and suggesting a possible de novo germline TP53 mutation as is seen in 7% to 20% of LFS patients 1. An absence of family history could also be related to issues of nonpaternity that may not be known to the proband. At the same time, it should be noted that LFS pedigrees are exceedingly hard to characterize, especially in small families, due to the wide variety of tumor types and age of presentation seen in different members of the same family.

TABLE 1 - Uterine carcinomas in patients or families with germline TP53 variants: molecular, pathologic, and clinical data review
Proband germline TP53 variant
References Exon cDNA nomenclature Protein nomenclature Patient relationship to proband Site and histology of uterine tumor Age at diagnosis (yr) Stage Other tumors (age at diagnosis) History of malignancy in patient’s first-degree relatives (relationship to patient, age at diagnosis, or death from diagnosis) Familial variant (diagnosis of malignancy, age at follow-up)
Prosser et al. 20 8 c.800G>A p.R267Q Mother Cervical cancer 62 NA Lung cancer (53) Breast cancer (daughter, 49), breast cancer (mother, 42) Same variant detected in proband’s sister (no cancer history, 37) and first cousin of the mother (no cancer history, 74)
Eeles et al. 21 8 c.817C>T p.R273C Proband Endometrial cancer 51 NA Trichilemmoma (19), malignant fibrous histiocytoma of thigh (22), ovarian osteosarcoma (32), trichoepitheliomata (40), bilateral breast carcinoma (37 and 51) Osteosarcoma of bone and breast cancer (sister, 12 and 32, respectively), gallbladder cancer (mother, 70) Same variant detected in proband’s mother and sister
Bardeesy et al. 22 7 c.736A>G p.M246V Mother Cervical cancer 30 NA Glioma (35) Wilms tumor (daughter, 2), adrenal carcinoma (daughter, 1), ovarian cancer (sister, 28), Wilms tumor (half-sister, 18 mo) Same variant detected in proband’s mother (this patient)
Dockhorn-Dworniczak et al. 23 6 c.638G>C p.R213P Aunt Endometrial cancer 48 NA None Brain tumor (son, 13), soft tissue sarcoma (sister, 43), breast cancer (sister, 48) Same variant detected in proband’s brother (no cancer history, 23), sister (no cancer history, 21), mother (breast cancer at 48), and aunt (this patient)
Varley et al. 24 Intron 3 splice acceptor c.97-1G>A NA Great great grandmother Uterine cancer, NOS 50 NA NA Breast cancer (daughter, 57), fibrosarcoma (son, 35), sarcoma of breast and thigh (daughter, 45 and 52, respectively) Same variant detected in proband’s mother (no cancer history) and proband’s aunt (meningeal sarcoma at 29)
Esteller et al. 25* NA NA NA Proband Endometrial cancer—endometrioid type with papillary differentiation NA NA NA NA NA
Nichols et al. 26* NA NA NA Proband Endometrial cancer 48 NA NA Endometrial carcinoma (35) NA
NA NA NA Proband Endometrial cancer 51 NA NA NA
NA NA NA Proband Cervical cancer 30 NA NA Cervical cancer (33, 33 and 62) NA
Nogales et al. 27 10 c.1006G>T p.E336Ter Proband Endometrial cancer—endometrioid type 25 IA Osteosarcoma (10), fibroadenoma (15), bilateral phyllodes tumors (18), reticulohistiocytoma (21), DCIS of breast (23), granulosa cell tumor of ovary (23), IDC (24), liposarcoma (24), leiomyosarcoma (25) None None
Senzer et al. 28 4 c.151delG p.E51NfsTer72 Aunt Uterine cancer, NOS 34 NA None Sarcoma (brother, 24), breast cancer (brother, 52), malignancy of unknown etiology (father, 38) NA
Gonzalez et al. 29 NA NA NA Relative, NOS Cervical cancer <50 NA NA NA NA
NA NA NA Relative, NOS Uterine cancer, NOS <50 NA NA NA NA
Ruijs et al. 30 7 c.733G>A p.G245S Relative, NOS Cervical cancer 43 NA NA Brain tumor (27), esophageal cancer (37), breast cancer (28, 34, and 44); exact relationship of relatives to patient unknown NA
Melhem-Bertrandt et al. 31 5 c.438G>A p.W146Ter Proband Endometrial cancer NA NA Sarcoma, renal cell carcinoma NA NA
Raymond et al. 32* NA NA NA Aunt Endometrial cancer 53 NA None Lung cancer (brother, 70), bone cancer (sister, 65), ovarian cancer (sister, 55) NA
Pennington et al. 33 8 c.869G>A p.R290H Proband Endometrial cancer—mixed endometrioid and serous types 48 IIIC1 None Lymphoma (father, 39) NA
8 c.818G>A p.R273H Proband Endometrial cancer—serous type 77 IVA NA NA NA
Heitzer et al. 34 Intron 6 splice acceptor c.673-1G>A NA Proband Endometrial cancer—endometrioid type 43 IA Bilateral breast carcinoma (IDC at 38 and carcinoma with mixed ductal and lobular features at 44); patient also harbored a germline CDH1 variant Brain tumor (son, 17), breast carcinoma (sister, 26), gastric cancer (father, 63) NA
Chao et al. 35* 4 c.215C>G p.Pro72Arg Proband Endometrial cancer—endometrioid type 54 IIIC Mesothelioma (54) Hepatocellular carcinoma (father, 70) Same variant detected in proband’s son (no cancer history, 30)
Huang et al. 36* 10 c.1010G>A p.R337H Proband Cervical cancer—squamous cell carcinoma 44 NA NA NA NA
Intron 4 splice acceptor c.376-2dup NA Proband Endometrial cancer—endometrioid type 69 NA NA NA NA
Ferreira et al. 37 10 c.1010G>A p.R337H Proband Cervical cancer 44 NA Adrenocortical carcinoma NA NA
Exon (introns for splice site variants) and cDNA nomenclature are reported per NCBI reference transcript NM_000546.6. Case reports marked with an asterisk (*) include TP53 variants for which the contribution to hereditary cancer predisposition has not been firmly established. Esteller et al. 25 report a 16 bp insertion in intron 3 described as the “p53PIN3 variant”; while previously described in dbSNP under rs17878362, this accession no longer has any supporting observations in the current build of dbSNP. Raymond et al. 32 report a variant described as “c.G>T 207 bp upstream from exon 1”; this was classified as a variant of uncertain significance by the authors. Chao et al. 35 report on a case with TP53 Pro72Arg; this is a common polymorphism (rs1042522) present on about a third of the TP53 alleles in the general population 38. Huang et al. 36 intron 4 splice acceptor variant is classified as a variant of uncertain significance in ClinVar.
cDNA indicates coding DNA; DCIS, ductal carcinoma in situ; dbSNP, single-nucleotide polymorphism database; IDC, invasive ductal carcinoma; NA, not applicable/not available; NOS, not otherwise specified.

The low number of patients with endometrial carcinoma and germline TP53 mutations may reflect selection bias deriving from a focus on early-onset cancers as the sentinel events for patients with germline TP53 mutations, the rarity of genomic testing until recently, or the reduced life expectancy of patients with germline TP53 mutations. To date, germline genomic testing of unselected cohorts of patients with endometrial cancer show a low prevalence of germline TP53 mutations (0.17%), although it is somewhat higher in patients with uterine serous tumors (0.74%–1.3%) 33,40. Increased germline genomic testing in patients with tumors is identifying a higher prevalence of kindreds with TP53 mutations, expanding the spectrum of cancers associated with germline mutations and identifying kindreds with primary late-onset cancers 41,42. This has led to the expansion of the LFS into a wider cancer syndrome designated the heritable TP53-related cancer (hTP53rc) syndrome 39. However, the traditional age and/or pedigree-based triggers for germline mutation testing remain, and may limit the ability to identify patients with late-onset and/or de novo hereditary cancer syndromes. Screening of all endometrial cancers with p53 immunohistochemistry is an intriguing possible approach to consider, to identify patients with late-onset hTP53rc. About 30% of endometrial cancers show aberrant p53 expression and would triage to further genetic counseling/genetic testing 43. A similar approach (screening for mismatch protein repair expression) has been successfully applied to screen endometrial cancer patients for Lynch syndrome. The cost-effectiveness of this approach for LFS remains to be determined.

In summary, our paper reports the first case of a teenager who presented with endometrioid endometrial carcinoma and was found to have a TP53 R273H germline missense mutation.


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Li-Fraumeni; Endometrial carcinoma; TP53; R273H mutation

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