Benign metastasising leiomyoma with endometrial carcinoma, with a differential diagnosis of metastatic lung cancer

Abstract

Benign metastasising leiomyoma (BML) is a rare disease in which histologically benign uterine fibroids spread throughout the body. It is thought to originate from the hematogenous metastasis of myoma cells following myomectomy. To date, BML has been noted in patients with respiratory symptoms, even during regular checkups. There are few case reports of co-occurrence with gynaecological cancer. We report the case of a suspected stage IVb carcinoma based on preoperative examination for endometrial cancer, that indicated lung metastasis. However, postoperative pathology revealed a grade 1, pT1a pN0 tumour. We suspected BML based on the discrepant findings and history of myomectomy, and this was confirmed by lung biopsy. In metastatic lesions of a carcinoma patient with a history of myomectomy, the co-occurrence of BML should be considered when there is discrepancy between the preoperative suspected stage and postoperative pathology.

Background

Benign metastasising leiomyoma (BML), first described by Steiner¹, is a rare form of leiomyoma in which a histologically benign uterine fibroid metastasises to the lungs and other deep tissues, bones, lymph nodes and heart.²

Most cases have a history of myomectomy and are thought to develop in association with surgical procedures.³ In recent years, the number of myomectomies for fertility preservation in uterine leiomyoma has been on the rise, reflecting a trend toward late delivery.⁴ Similar to the risks of medical endometriosis, parasitic myoma and disseminated peritoneal leiomyomatosis, BML cases are expected to increase in prevalence in the future.

To date, there have been many reports of BML cases observed in medical examinations,⁵ detected through respiratory symptoms⁶ and even one case complicated by lung cancer,⁷ but there have been few reports of co-occurrence with gynaecological cancers. We report here a case of BML that was complicated by endometrioid carcinoma and required differentiation from metastatic lung cancer.

Case presentation

A 53-year-old nulliparous woman with a history of myomectomy at age 33 presented with atypical genital bleeding and chronic coughing. She was noted to have endometrial thickening of 7–8 mm after undergoing transvaginal ultrasonography during a regular check-up. The size and movement of her uterus were normal in her pelvic examination findings, her inguinal lymph node showed no swelling in her physical examination findings, and her auscultatory examination showed no abnormal findings such as crackle. Endometrial cytology revealed grade 1 endometrioid carcinoma. Tumour markers were within normal limits (CA125: 33.6 U/mL and Ca19-9: 14.2 U/mL). A preoperative MRI scan showed endometrial thickening, but it was estimated that the tumour did not invade more than half of the myometrium or the stromal connective tissue of the cervix. A preoperative CT scan showed cavernous nodules in the bilateral peripheral and basal parts of the lung (figure 1), and lung metastasis was suspected even though no lymph nodes swelled. Although positron emission tomography-CT did not show any obvious abnormal accumulation in the lungs, metastatic lesion could not be ruled out due to the possibility of limited accumulation from the small size of the lung nodules. Hence, FIGO (The International Federation of Gynecology and Obstetrics) stage IVb was preoperatively suspected.

Figure 1.

Axial simple pulmonary CT: scattered cavernous nodules (white arrow) are found in the bilateral lung periphery. Some nodules are not hollowed out at the base of the lung.

Abdominal total hysterectomy, bilateral salpingo-oophorectomy and pelvic lymph node dissection were performed. The pathological results revealed endometrioid carcinoma grade 1 was localised and growing within the endometrium. There was some local myometrial infiltration of 5/17 mm in the right uterine fundus, but no invasion of more than half of the myometrium was observed in any of them. Furthermore, no metastatic tissue was found in the pelvic lymph nodes. (pT1a pN0 (vascular invasion (−), margin invasion (−))). There was a discrepancy between the postoperative pathology results and the preoperative suspected stage. Due to this discrepancy and history of myomectomy, BML was suspected and a biopsy was performed via thoracoscopic partial resection of the right middle lobe. The pathological examination showed a bundled, spindle-shaped cell proliferation with prominent internal adipose tissue inclusions, no nuclear atypia and nuclear division less than 1/10 High power field (HPF). Immunostaining results were oestrogen receptor (+), progesterone receptor (+), low Ki-67 index, alpha-smooth muscle actin (+), desmin (+), caldesmon (+), melan A (−), HMB45 (−), CD10(−) and TTF-1(−), which is typical of BML (figure 2).

Figure 2.

Pathology of the middle lobe of the right lung: the pathology shows a bundled, spindle-shaped cell proliferation image with prominent internal adipose tissue inclusions, no nuclear atypia and nuclear division less than 1/10 HPF.

Outcome and follow-up

The final diagnosis was FIGO stage IA uterine endometrial cancer with concurrent symptomatic BML. It was decided that the patient should be followed up without adjuvant chemotherapy. Four years have passed since surgery without recurrence.

Discussion

We discovered two important clinical issues: (1) BML can occur with gynaecological cancer, and may mimic a metastatic tumour regardless of whether or not it is a benign disease. (2) A biopsy is crucial to its diagnosis.

To the best of our knowledge, to date, there have been only three published case reports of BML associated with gynaecological tumours (two cases of ovarian cancer and one case of endometrioid cancer) (see table 1).

Table 1.

Gynaecological cancer with BML: table sheet

Author	Patient /symptom	Cancer	History of operation	Imaging study (lung)	Pathology	Immunostaining
Tsukasa (present case)	53 years/ respiratory symptom +	Endometrial cancer *Stage IA	Myomectomy (+: 20 years ago) Hysterectomy (−)	CT：Bilateral multiple nodule shadow (⌀5 mm) FDG-PET：negative	Spindle-shaped cell proliferation no nuclear atypia nuclear division less than 1/10 HPF	Low Ki-67 index, α-SMA (+), desmin (+), caldesmon (+), ER (+), PR (+) cytokeratin AE1/AE3 (−), melan A (−), HMB45 (−) CD10 (−), TTF-1 (−)
Akar et al8	50 year/ none	Endometrial cancer *Stage IA	Myomectomy (−) Hysterectomy (−)	CT：Bilateral multiple nodule shadow (⌀7–9 mm) FDG-PET：not given	Not given	Low Ki-67 index, α-SMA (+), smooth muscle myosin heavy chain (+), ER (+), PR (+), p53 (+) CD68 (−), S-100 (−), Pancytokeratin (−), EMA (−), HMB45 (−)
Gan and Lu9	46 years/ respiratory symptom +	Ovarian cancer stage unexplained	Myomectomy (−) Hysterectomy (+: 8 years ago)	CT：bilateral multiple nodule shadow (⌀1–2 mm) FDG-PET：not given	Spindle-shaped cell proliferation no nuclear atypia nuclear division less than 1/10 HPF	α-SMA (+), desmin (+), cytokeratin (+), TTF-1 (+) ER (+), PR (+) CD10 (−), HMB45 (−)
Wu et al10	51 years/ respiratory symptom +	Ovarian cancer †Stage IIB	Myomectomy (−) Hysterectomy (−)	CT：not given FDG-PET：not given	No nuclear atypia nuclear division less than 1/10 HPF	ER (+), PR (+)

*FIGO 2008.

†FIGO 2014.

BML, benign metastasising leiomyoma; CT, computer tomography; EMA, epithelial membrane antigen; ER, oestrogen receptor; FDG-PET, Fluorodeoxyglucose-position emission tomography; HMB, human melanin black; PR, progesterone receptor; SMA, smooth muscle actin; TTF, thyroid transcription factor.

Regarding the case of endometrioid cancer,⁸ the pathological and immunostaining findings of lymph node dissection resulted in an incidental diagnosis of BML, and the patient was followed up without invasive postoperative therapy. The first case of ovarian cancer presented with serous borderline malignancy and a history of total hysterectomy for uterine myoma. BML was suspected due to poorly elevated tumour markers for metastatic lesion, and the diagnosis was established by lung biopsy.⁹ The other case was an incidental diagnosis of BML due to postoperative pathological examination of a lymph node from a patient with serous adenocarcinoma.¹⁰ A history of myomectomy and the dissociation of staging and other examination findings (eg, postoperative pathology and tumour markers) led to the diagnosis of BML by aggressive biopsy.

Histopathological diagnosis, such as a lung biopsy, is most important. Generally, the main tools leading to BML diagnosis are imaging and pathological findings. On imaging, BML is typically characterised by multiple nodules of a few millimetres to a few centimetres in length in both lung fields.¹¹ In contrast, 35%–37% of gynaecological distant metastases have been reported to be pulmonary metastases.¹² In particular, bilateral multiple lesions account for 72% of pulmonary metastases in endometrial cancer.¹³ Therefore, it may be difficult to differentiate metastatic lung cancer in endometrial cancer from BML, which is also commonly found in both lung fields based on CT images alone. Preoperative diagnosis by PET-CT is difficult because, similar to the present case, some reports show no FDG accumulation while others show FDG accumulation in oestrogen receptor-positive patients at an age when oestrogen exposure is high.^{14 15}

However, the diagnosis of BML is relatively easy to make after biopsy of the lesion and immunostaining. Pathological results are characterised by the presence of spindle-shaped cell proliferation, almost no nuclear atypia and fission and the absence of coagulation necrosis. In addition, immunostaining is positive for α-smooth muscle actin, HHF-35, desmin and caldesmon, similar to smooth muscle cells.¹⁶ Approximately 70%–80% of BMLs have been reported to be positive for oestrogen and progesterone receptors,¹⁵ suggesting that these also help in the diagnosis.

The most widely proposed hypothesis for the origin of BML is the hematogenous dissemination theory.¹⁷ It states that myoma cells are surgically extruded into the blood vessels, leading to metastasis. Our case supports this hypothesis. However, there have also been cases wherein the disease developed without a history of surgical procedures,³ suggesting that other mechanisms may be involved. Among them is the hormonal hypothesis,¹⁸ which suggests that oestrogen metabolites induce mutagenesis in a probability-dependent manner. If the hormonal hypothesis is considered, it is necessary to keep in mind that endometrial cancer may be more likely to develop with BML, as is thought in the unopposed oestrogen hypothesis.¹⁹

BML can be associated with gynaecological cancers, and histopathological diagnosis was found to be the most important strategy for accurate identification. If there is a discrepancy between postoperative pathology and preoperative suspected stage, a biopsy should be performed to consider the possibility of BML. The development of a co-occurrence of BML with endometrial cancer, based on the theory of hormonal hypothesis, requires further cases to be analysed.

Learning points.

• Benign metastasising leiomyoma (BML) can occur with gynecological cancer, and it may mimic the image of a metastatic tumor.

• In cases of previous surgery for a myoma-associated uterus and a discrepancy between postoperative pathology and preoperative suspected staging, the possibility of BML should be considered.

• Diagnosis using preoperative imaging alone is difficult; pathological examination and immunostaining are necessary when BML is suspected.