Recurrent uterine adenofibroma revealed to be hyperparathyroidism-jaw tumor syndrome: Case report.

A 21-year-old woman (P 0) with chief complaints of fever and diarrhea presented to an internist, who ordered computed tomography (CT) that revealed a uterine tumor incidentally. The patient was then referred to the obstetrics and gynecology department of our hospital. Her menarche was at 12 years old, and her menstrual cycle was 25-30 days. Menstruation was hypermenorrhea and lasted 10 days. Serum cancer antigen (CA) 125 and CA 19-9 levels were 48.2 U/ml (normal range 0-35 U/ml) and 17.1 U/ml (normal range 0-35 U/ml), respectively. Magnetic resonance imaging (MRI) was performed at 3.0T for further examination. Sagittal T2-weighted imaging (WI) (repetition time [TR]/echo time [TE], 5808/90 ms) showed a large, heterogeneous high-intensity mass, approximately 95 × 54 × 78 mm 3 in size, without myometrial invasion, expanding across the uterine cavity and extending into the vagina through the cervical canal ( Fig.1 A, arrow). The uterus was enlarged to 130 × 97× 84 mm 3 . The mass contained multiple cysts ( Fig.1 B, arrows) that showed low intensity, with some cysts showing high intensity on fat-suppressed enhanced T1 high resolution isotropic volume excitation (eTHRIVE) (Gradient Echo; TE, 4.0/2.0 ms) ( Fig. 1 C, °). The solid component, with the exception of cystic changes of variable sizes, showed contrast enhancement similar to the uterine wall from the arterial phase (35 sec) through the equilibrium phase (130 sec) on the dynamic contrast enhanced study ( Fig. 1 D), high intensity on diffusion-weighted imaging (DWI) (b = 1000 s/mm2, TR/TE, 6799/72 ms) ( Fig. 1 E) and low intensity (1.26 × 10 −3 mm 2 /s) on apparent diffusion coefficient (ADC) maps. Fig. 1 (A) Sagittal T2-weighted imaging (WI) (repetition time [TR]/echo time [TE], 5808/90 ms) showed a large, heterogeneous high-intensity mass (arrow), approximately 95 × 54 × 78 mm 3 in size, without myometrial invasion, expanding across the uterine cavity and extending into the vagina through the cervical canal. (B) The mass contained multiple cysts showing high-intensity in them on T2WI (arrows). (C) Some of those cysts showed low intensity and the others showed high intensity on fat-suppressed enhanced T1 high resolution isotropic volume excitation (eTHRIVE) (Gradient Echo; TE, 4.0/2.0 ms). A bone cystic lesion in the right hip bone was indicated (△). (D) The solid component, with the exception of cystic changes of variable sizes, showed contrast enhancement similar to the uterine wall from the arterial phase (35 sec) through the equilibrium phase (130 sec) on the dynamic contrast enhanced study and (E) high intensity on diffusion-weighted imaging (DWI) (b = 1000 s/mm 2 , TR/TE, 6799/72 ms) and low intensity (1.26 × 10 −3 mm 2 /s) on apparent diffusion coefficient (ADC) maps (not shown). Fig 1 (A) Sagittal T2-weighted imaging (WI) (repetition time [TR]/echo time [TE], 5808/90 ms) showed a large, heterogeneous high-intensity mass (arrow), approximately 95 × 54 × 78 mm 3 in size, without myometrial invasion, expanding across the uterine cavity and extending into the vagina through the cervical canal. (B) The mass contained multiple cysts showing high-intensity in them on T2WI (arrows). (C) Some of those cysts showed low intensity and the others showed high intensity on fat-suppressed enhanced T1 high resolution isotropic volume excitation (eTHRIVE) (Gradient Echo; TE, 4.0/2.0 ms). A bone cystic lesion in the right hip bone was indicated (△). (D) The solid component, with the exception of cystic changes of variable sizes, showed contrast enhancement similar to the uterine wall from the arterial phase (35 sec) through the equilibrium phase (130 sec) on the dynamic contrast enhanced study and (E) high intensity on diffusion-weighted imaging (DWI) (b = 1000 s/mm 2 , TR/TE, 6799/72 ms) and low intensity (1.26 × 10 −3 mm 2 /s) on apparent diffusion coefficient (ADC) maps (not shown). Although biopsy results indicated adenofibroma pathologically, the possibility of adenosarcoma could not be totally ruled out because the diagnosis referred to just a portion of the tumor. Two months before the patient saw the internist, she visited an orthopedist because of bilateral knee and heel pain. Knee CT revealed a thin bone cortex and heterogeneous bone trabeculae. Therefore, abnormal bone metabolism was suspected and she was referred to an endocrinologist. A blood test performed by the endocrinologist showed high serum parathyroid hormone (PTH) greater than 3200 pg/ml (normal range; 8.3-38.7 pg/ml), high serum calcium level of 11.2 mg/dL (normal range 8.5-10.2 mg/dL), low-normal plasma phosphorus of 2.4 mg/dL (normal range 2.4-4.3 mg/dL) and high bone-type alkaline phosphatase of 818 U/L (normal range 2.9-14.5 U/L), indicating hyperparathyroidism due to high serum PTH. Quantitative bone mineral analysis showed her bone density was low for her age, at 68%. On cervical ultrasonography, a tumor with a diameter of 37.5 mm was detected behind the inferior pole of the right thyroid lobe. On 99mTc-methoxy-isobutyl-isonitrile (MIBI) single photon emission CT (SPECT)/CT fusion imaging, the tumor appeared as focal areas of increased uptake on early images with fixed uptake that persisted on delayed images. Additionally, diffuse bone uptake was observed and many bone cystic lesions were detected on CT as well as MRI ( Fig.1 B, △). Those findings were deemed to be caused by bone hypermetabolism due to high serum PTH. Given the patient’s very high serum PTH and relatively large parathyroid tumor, parathyroid cancer was considered as a differential diagnosis for parathyroid adenoma. During treatment for prevention of hungry bone syndrome, the patient broke her left femur and right humerus by falling at home, probably due to decreased bone mineral content, and underwent surgery for these injuries. Whole-body 18F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) showed weak FDG uptake (maximum standardized uptake value [SUVmax]: 2.3) in the uterine tumor ( Fig. 2 A, △) and diffuse increased uptake in bone throughout the body (SUVmax: 7.5) ( Fig. 2 A, arrows), and weak FDG uptake (SUVmax: 1.2) in the right lower parathyroid tumor ( Fig. 2 B, arrow). Weak FDG uptake in the uterine tumor suggested a benign uterine tumor like adenomyoma and adenofibroma rather than a malignant tumor such as adenosarcoma, in line with the pathological result of the biopsied specimen. The diffuse increased uptake in bone was deemed to be caused by bone hypermetabolic status due to high serum PTH. Weak FDG uptake in the parathyroid tumor suggested adenoma rather than carcinoma. Fig. 2 (A) Whole-body 18F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) showed weak FDG uptake (maximum standardized uptake value [SUVmax]: 2.3) in the uterine tumor (△) and diffuse increased uptake in bone throughout the body (SUVmax: 7.5) (arrows), and (B) weak FDG uptake (SUVmax: 1.2) in the right lower parathyroid tumor (arrow). Fig 2 (A) Whole-body 18F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) showed weak FDG uptake (maximum standardized uptake value [SUVmax]: 2.3) in the uterine tumor (△) and diffuse increased uptake in bone throughout the body (SUVmax: 7.5) (arrows), and (B) weak FDG uptake (SUVmax: 1.2) in the right lower parathyroid tumor (arrow). Although the patient’s family history included a father with a history of hypertension and a maternal grandmother with laryngeal cancer, none of her relatives had hyperparathyroidism. Two months after MRI, transcervical resection (TCR) for the uterine tumor was performed. Multiple smooth surface polypoid masses without atypical vessels were observed in the uterus and cervix through rigid endoscope ( Fig. 3 A). The masses were removed by using placental forceps so as not to hurt uterine endometrium. Intracervical polyps were divided by twisting with placental forceps and bleeding was stopped by bipolar scissors. Macroscopically the resected specimen appeared whitish smooth polypoid tumors ( Fig. 3 B). The pathological diagnosis was adenofibroma, just as it was for the previous biopsied specimen. Therefore, the patient was monitored over time. Fig. 3 (A) Multiple smooth surface polypoid masses without atypical vessels were observed in uterine cavity through rigid endoscope. (B) Macroscopically the resected specimen appeared whitish smooth polypoid tumors. Fig 3 (A) Multiple smooth surface polypoid masses without atypical vessels were observed in uterine cavity through rigid endoscope. (B) Macroscopically the resected specimen appeared whitish smooth polypoid tumors. Six months after she visited the orthopedist for the first time, parathyroidectomy for the right enlarged parathyroid tumor with right thyroid lobectomy was performed. At the time of surgery, a tiny left lower parathyroid nodule was incidentally found and resected at the same time. Pathologically, both the right lower parathyroid tumor and left upper parathyroid nodule were diagnosed as parathyroid adenoma. Subsequent course of the uterine tumor and treatments ( Fig. 4 ). Fig. 4 On the second MRI, the volume of the intrauterine tumor has decreased by the first TCR, but numerous residual tumors are observed. Two years after the second MRI, a uterine polypoid tumor extended into the vagina through the cervical canal again and analysis of a biopsied specimen of the tumor protruding from the external os of the uterus indicated adenofibroma. The third MRI, performed 3 mo after the biopsy, showed the recurrent uterine tumor had grown almost as large as the tumor observed on the first MRI, leading to a second TCR 8 mo after the third MRI. The resected specimen was diagnosed as adenofibroma pathologically. The last MRI was performed 3 mo after the second TCR, and showed a recurrent intrauterine tumor with a diameter of 45 mm at the internal os (arrow). Fig 4 On the second MRI, the volume of the intrauterine tumor has decreased by the first TCR, but numerous residual tumors are observed. Two years after the second MRI, a uterine polypoid tumor extended into the vagina through the cervical canal again and analysis of a biopsied specimen of the tumor protruding from the external os of the uterus indicated adenofibroma. The third MRI, performed 3 mo after the biopsy, showed the recurrent uterine tumor had grown almost as large as the tumor observed on the first MRI, leading to a second TCR 8 mo after the third MRI. The resected specimen was diagnosed as adenofibroma pathologically. The last MRI was performed 3 mo after the second TCR, and showed a recurrent intrauterine tumor with a diameter of 45 mm at the internal os (arrow). A second MRI scan performed just 1 month after the first TCR showed decrease in volume of intrauterine tumors but there were still numerous residual tumors. Two years after the second MRI, a uterine polypoid tumor extending into the vagina through the cervical canal was observed once again, and pathology results from a biopsied specimen of the protruded tumor from the external os of the uterus indicated adenofibroma. The third MRI performed 3 months after the biopsy showed the recurrent uterine tumor had grown almost as large as the tumor observed on the first MRI, leading to a second TCR 8 months after the third MRI. The resected specimen was diagnosed as adenofibroma pathologically. The last MRI was performed 3 months after the second TCR, and showed a recurrent intrauterine tumor with a diameter of 45 mm at the internal os ( Fig. 4 , arrow). Eventually, the patient hoped to undergo hysterectomy because she no longer wished fertility-sparing treatment and frequent surgeries for recurrent uterine tumors. Thus, abdominal modified radical hysterectomy with bilateral salpingectomy and partial omentectomy were subsequently performed in case the uterine tumor was ultimately diagnosed as malignant. On gross examination, a smooth polypoid tumor recurred from the level of the internal os to the endocervix ( Fig. 5 , arrows). Benign glandular epithelial components surrounded by stromal cells without atypia were observed on pathological examination, and thus the tumor was finally diagnosed as adenofibroma. Fig. 5 On gross examination, a smooth polypoid tumor with a diameter of 45 mm recurred from the level of the internal os to the endocervix (arrows). Fig 5 On gross examination, a smooth polypoid tumor with a diameter of 45 mm recurred from the level of the internal os to the endocervix (arrows). Proof that the uterine tumor was caused by a genetic disorder. It was unusual that a benign uterine tumor such as adenofibroma recurred so frequently, requiring repeated TCR. Therefore, we suspected some genetic factors might be associated with the course. Considering that the patient had primary hyperparathyroidism at a very young age, familial primary hyperparathyroidism (FPHPT) was a possibility. HPT-JT is the only syndrome among FPHPT cases that is associated with uterine tumors, and it is caused by germline mutations in HRPT2/CDC73. The immunohistochemical method to suggest that the adenofibroma was associated with a germline HRPT2/CDC73 mutation is to demonstrate loss of nuclear expression of parafibromin, the protein encoded by HRPT2/CDC73. Although sporadic uterine polyps show nuclear parafibromin immunostaining in stromal and epithelial cells ( Fig. 6 A), tumors such as parathyroid adenoma or uterine tumor in HPT-JT patients do not show nuclear parafibromin expression. Therefore, we performed immunohistochemical analysis of parafibromin expression in the adenofibroma and proved lack of nuclear parafibromin expression ( Fig. 6 B). Fig. 6 Immunohistochemical analysis of parafibromin expression in a uterine polyp. (A) A sporadic uterine polyp in another patient shows nuclear parafibromin immunostaining in stromal and epithelial cells. (B) The uterine adenofibromas in this case lacked nuclear parafibromin expression, which proved that the adenofibroma arose due to germ-line HRPT2/CDC73 mutation. Fig 6 Immunohistochemical analysis of parafibromin expression in a uterine polyp. (A) A sporadic uterine polyp in another patient shows nuclear parafibromin immunostaining in stromal and epithelial cells. (B) The uterine adenofibromas in this case lacked nuclear parafibromin expression, which proved that the adenofibroma arose due to germ-line HRPT2/CDC73 mutation.

Go Nakai: Writing - original draft; Conceptualization; Data curation. Takashi Yamada: Investigation; Formal analysis; Methodology; Supervision. Tomohito Tanaka: Formal analysis; Data curation. Kazuhiro Yamamoto: Data curation. Keigo Osuga: Writing - review & editing; Supervision.

Written, informed consent for publication of this case was obtained from the patient.

When investigating recurrent uterine polypoid lesions in young patients, it is essential to consider genetic conditions such as HPT-JT in the differential diagnosis, as this enables appropriate surveillance for associated neoplasms in the parathyroid glands, jaw, and kidneys.

Adenofibromas, which were formerly categorized as mixed epithelial and mesenchymal tumors, comprise a benign glandular and a benign stromal component. In contrast, adenosarcomas, which fall in the same classification, comprise a benign glandular but a low-grade malignant stromal component in most cases. The low-grade malignant stromal component in adenosarcoma can be difficult to differentiate from the benign stromal component observed in adenofibroma from a biopsied specimen alone. However, differentiation between them matters, especially when the tumor recurs frequently even after TCR in women of reproductive age, given the previous report that uterine cervical adenosarcoma initially diagnosed as a cervical polyp pathologically can present as a recurrent cervical polyp [ 2 ]. Furthermore, adenofibroma was eliminated from the fifth edition of the World Health Organization (WHO) classification [ 1 ] because the majority of tumors previously diagnosed as adenofibromas are simply low grade adenosarcomas or benign polyps with unusual morphology. Thus, it was crucial in this case to determine whether the uterine polypoid tumors were adenosarcomas or benign polyps to decide on the future course of treatment. However, the possibility of adenosarcoma could not be completely ruled out until hysterectomy was performed. Even on MRI, the findings of uterine adenofibroma in this case were similar to those of adenosarcoma described in previous reports [ 3 , 4 ]. Both adenofibroma and adenosarcoma can appear as an intrauterine polypoid mass with intratumoral cysts. The mass shows heterogeneous high intensity on T2WI, with some intratumoral cysts showing high intensity on fat-saturated T1WI. MRI findings might also be similar to those of uterine polypoid adenomyoma [ 5 , 6 ]. Thus, it was difficult to differentiate benign tumors such as adenofibroma or adenomyoma from adenosarcoma by MRI alone. Moreover, the adenofibroma showed high SI on DWI and low SI on ADC mapping, and the ADC value was as low as that reported in adenosarcoma with sarcomatous overgrowth using 1.5T MRI [ 3 ]. Considering these facts, DWI may not be useful to differentiate benign fibromatous component from malignant sarcomatous component in mixed epithelial and mesenchymal tumors. On the other hand, 18F-FDG PET-CT may be useful to differentiate them because it showed weak FDG uptake (SUVmax: 2.3) in the adenofibroma implying benignity, while adenosarcoma with sarcomatous overgrowth (SUVmax: 8.2) [ 3 ] or its recurrent lesions showed intense FDG uptake in previous reports [ 7 ]. However, FDG uptake has never been reported in low grade adenosarcoma. Our case represents the first report to describe the MRI and PET-CT findings of recurrent uterine adenofibromas in a patient with HPT-JT in detail. Hyperparathyroidism is common in middle-aged women over 40 years of age, and the most common cause is a solitary parathyroid adenoma (85%), while cancer is rare (1%) [ 8 ]. The possibility of familial hyperparathyroidism should be kept in mind given the young age of the patient in this case, but there was no family history of hyperparathyroidism. Familial hyperparathyroidism accounts for about 2%-5% of primary hyperparathyroidism and is relatively rare, mostly due to multiple endocrine neoplasia (MEN). However, there are other syndromes besides MEN: HPT-JT, familial solitary hyperparathyroidism and familial hypocalcemic hypercalcemia. In particular, HPT-JT is known to be frequently associated with uterine tumors [ 9 ]. HPT-JT is a rare inherited disease in which neoplastic lesions arise in combination with parathyroid adenomas or carcinomas and jaw tumors [ 10 ]. The frequency of parathyroid carcinoma is 15%, which is higher than in sporadic cases. It is caused by an abnormality in the HRPT2/CDC73 gene located on chromosome 1q31.2, which also functions as a tumor suppressor gene [ 11 ]. It is inherited in an autosomal-dominant manner and is associated with renal tumors (e.g. multiple cysts, malignant tumors, mixed epithelial-stromal tumors) in 20% of cases, as well as uterine tumors in women. Uterine tumors occur in 61.5% of cases [ 12 ], which is higher than the 30% incidence of jaw tumors included in the disease name, and adenosarcomas, adenofibromas, leiomyomas, adenomyosis, and endometrial hyperplasia have been reported as histological types [ 9 ]. High rates of recurrent polyps that required hysterectomy [ 12 ] and hypermenorrhea that required hysterectomy were also reported [ 9 ], consistent with a condition that could explain the frequent recurrences of a benign tumor, as in the present case. Alexandra Arfi et al. [ 13 ] reported the case of a 32-year-old patient with known HPT-JT who presented with a polypoid adenomyomatous endometrium without malignancy. The uterine polyp was removed via hysteroscopic resection, but recurrence was confirmed endoscopically 1 month later. This case demonstrated an early tendency toward recurrence despite its benign histology, a clinical behavior similar to that observed in our patient. Although the present patient had no family history of hyperparathyroidism, the HRPT2/CDC73 gene is incompletely penetrant and is often not recognized as phenotypic (i.e. apparently normal) despite the presence of genetic abnormalities. There are also reports of no association between genotype and phenotype [ 9 ]. Furthermore, there are many cases in which the blood calcium level does not exceed the symptomatic level of 12 mg/dL even when PTH is high, and in fact, in the present case, PTH was abnormally high at more than 3200 pg/ml, but the serum calcium level was only slightly above the threshold at 11.2 mg/dL. In addition, signs of hypercalcemia such as malaise, loss of appetite, thirst and polyposia are nonspecific, and even patients with hyperparathyroidism notice no symptoms as long as their serum calcium level is less than 12 mg/dL. Therefore, familial hyperparathyroidism cannot be easily ruled out even if there is no family history of hyperparathyroidism or neoplasia [ 14 ]. One of the methods to prove that the patient has HPT-JT is to prove that the amino acid protein called parafibromin encoded by the HRPT2/CDC73 gene is not expressed in tumors of the uterus or parathyroid adenomas, which can be done by staining with an anti-parafibromin antibody [ 12 ]. Staining of this patient's polyps with anti-parafibromin antibodies proved that the tumor was a uterine tumor due to an abnormality in the HRPT2/CDC73 gene, as the nuclei of the tumor's glandular cells were not stained. Therefore, this patient is at risk of developing new parathyroid, jaw, or renal tumors in the future. Therefore, proving HPT-JT may be useful for prophylactic screening for these tumors [ 15 ]. Because HPT-JT is a rare disorder, no formal guidelines exist regarding follow-up after diagnosis. However, several surveillance strategies have been proposed as measures that may facilitate the early detection of conditions that could develop over time [ 9 , 14 ], including: (1) annual measurement of serum calcium, parathyroid hormone, and vitamin D; (2) periodic ultrasound examination of the parathyroid glands; (3) panoramic dental X-ray imaging (with neck shielding) at least every 5 years; (4) renal imaging (ultrasound, MRI, or CT) at least every 5 years; and (5) regular gynecological evaluation, including at minimum pelvic ultrasound. annual measurement of serum calcium, parathyroid hormone, and vitamin D; periodic ultrasound examination of the parathyroid glands; panoramic dental X-ray imaging (with neck shielding) at least every 5 years; renal imaging (ultrasound, MRI, or CT) at least every 5 years; and regular gynecological evaluation, including at minimum pelvic ultrasound.

Uterine adenofibroma was formerly categorized as a benign mixed epithelial and mesenchymal tumor, but was eliminated from the fifth edition of the World Health Organization (WHO) classification [ 1 ] because the majority of tumors previously diagnosed as adenofibromas are simply low grade adenosarcoma or benign polyps with unusual morphology. Furthermore, it is not easy to diagnose adenosarcoma based on tissue biopsy alone because the malignant mesenchymal component sometimes shows low grade pathological features such as low mitotic activity or mild nuclear atypia, leading to difficulty in differentiating it from adenofibroma. Since uterine cervical polyps that continued to recur despite repeated resection were revealed to be adenosarcoma in a previous report [ 2 ], follow-up of a patient with recurrent uterine adenofibroma requires special care. We treated a woman with recurrent uterine adenofibroma who had been diagnosed with hyperparathyroidism. Although biopsy results indicated adenofibroma pathologically, the possibility of adenosarcoma could not be totally ruled out. However, the uterine tumor was finally diagnosed as adenofibroma by hysterectomy. This report presents a case of recurrent uterine adenofibroma ultimately diagnosed as hyperparathyroidism–jaw tumor syndrome (HPT-JT).

The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.