Morphological, imaging and surgical aspects in a complex case of uterine leiomyosarcoma [304984]

[anonimizat] a complex case of uterine leiomyosarcoma

AIDA PETCA1,2), SIMONA VLĂDĂREANU2,3), DAN – CRISTIAN RADU1), MIHAELA BOȚ1,2), COSTIN BERCEANU4), [anonimizat]2,5), COSMIN MEDAR2,6), RĂZVAN – COSMIN PETCA2,7)

1) [anonimizat], Bucharest, Romania

2) „Carol Davila” of and Pharmacy, , Romania

3) [anonimizat], Bucharest, Romania

4) [anonimizat], Romania

5) [anonimizat], Bucharest, Romania

6) [anonimizat],

7) [anonimizat]. Th. [anonimizat], [anonimizat], PhD, [anonimizat], 17 Marasti Boulevard, 011461, Bucharest, Romania; Phone +40721-200461, e-mail: [anonimizat]

Abstract

Leiomyosarcoma is a rare condition so there are relatively few and small case series and no prospective studies to provide clear guidelines regarding management. We report on a case that presents some particularities that further underline diagnostic and treatment difficulties posed by the affliction of such a rare tumor. This is the case of a 43-year-old woman who had a [anonimizat] a spectacular growth rate over a short period. [anonimizat], came for belly enlargement with rapid increase in size over the previous two months. Physical exam and ultrasound lead to the conclusion of a large abdominal mass. A computed tomography scan showed a mass arising from the pelvis and a large amount of ascites. An exploratory laparotomy was performed and the histopathology report confirmed the diagnosis of uterine leiomyosarcoma. [anonimizat], real surgical difficulties. Final diagnosis is done by histopathologic examination after surgical excision. Frequently it is late diagnosed when complete removal of the tumor is often impossible.

Key words: leiomyosarcoma, [anonimizat] a malignant smooth muscle tumor of the uterus responsible for 30 to 40% [anonimizat] 1-2 % of all uterine malignances [1]. Uterine sarcomas (US) [anonimizat] 3–5% of all malignant uterine tumors. The overall annual incidence is approximately 17 per million [2,3]. In studies and systematic reviews hysterectomies or myomectomies performed for a [anonimizat] 0.20 percent (1 in 500) [anonimizat] 0.05 (1 in 2000) to 0.28 percent (1 in 352) depending upon the included studies [4-7]. [anonimizat], uterine sarcomas are generally characterized by a [anonimizat] a high rate of local recurrences and a high rate of metastases [8,9]. It is a rare condition so there are relatively few and small case series and no prospective studies to provide clear guidelines regarding treatment or long time management.

Smooth muscle tumors constitute basically a group composed of benign leiomyomas and malignant leiomyosarcomas. Smooth muscle tumors with both atypia and mitotic activity are usually diagnosed leiomyosarcomas on their potential for metastasis but there are lesions that cannot be easily integrated in either category. Extrauterine leiomyosarcomas can occur at any site, although are more frequent in the retroperitoneum and proximal extremities and they are characterized by likeness to smooth muscle but may suffer pleomorphic evolution [10]. Presence of smooth muscle actin is nearly uniform and desmin-positivity frequent. This and the lack of KIT expression separate leiomyosarcoma from GIST (gastrointestinal stromal tumor) [11]. Leiomyosarcomas are known to be genetically complex, often found to have chaotic karyotypes including aneuploidy or polyploidy. Recent studies have shown that uterine Leiomyosarcomas present frequent mutations in TP53, ATRX, and MED12 [12].

The gross majority of uterine leiomyosarcomas are sufficiently differentiated, at least focally, to allow recognition although they appear malignant on microscopic examination [10]. The diagnostic strategy includes a search for the mitotic index, presence of atypia, and coagulative tumor-cell necrosis [13]. Uterine leiomyosarcomas are to be diagnosed apart from mitotically active or atypical leiomyomas and uterine smooth-muscle neoplasms with low malignant potential [14]. Presence of coagulative tumour-cell necrosis is decisive and should be distinguished from hyaline and ulcerative necrosis [9]. Usual investigation in leiomyosarcoma histologic examination include immune-peroxidase staining is positive for muscle markers SMA (smooth muscle actin), HHF35 (pan muscle actin), h-caldesmon and desmin. A rare number of cases have demonstrated cytokeratin or EMA (epithelial membrane antigen) staining [15]. Histological variants of leiomyosarcoma include atypical leiomyoma that covers a spectrum between leiomyoma and leiomyosarcoma. A mitotically active leiomyoma describes a lesion lacking significant nuclear atypia or tumour necrosis, but with between 5 and 15 mitoses per HPF [16].

Uterine sarcomas have been classified into three main histologic subgroups, in order of decreasing incidence: malignant mixed mullerian tumor (carcinosarcoma [MMMT]), leiomyosarcoma (LMS), and endometrial stromal sarcoma (ESS). Each group of tumors exhibits a different pattern of spread, as well pathologic features, prognostic factors, and response to treatment. There are in use two grading systems: FNCLCC (Fédération Nationale des Centres de Lutte Contre le Cancer) and the NCI (National Cancer Institute) one.

The prognosis of these tumors following surgery varies, with ESS (endometrial stromal sarcoma) benefiting of a better prognosis compared to leiomyosarcoma or undifferentiated endometrial sarcoma [17]. For aggressive sarcomas, there is expressed interest in adjuvant treatment, which has been centered on the evaluation of systemic agents. However, the rarity of these tumors makes the conduct of prospective trials difficult and no consensus adjuvant regimen has been reached.

Case presentation

A 43-year-old woman (nullipara, virgo) uncooperative, oligophrenic, with congenital spastic tetraparesis and hydrocephalus came at the emergency ward of Elias Emergency University Hospital, Bucharest for gastrointestinal complaints, dyspnea and a mass in her abdomen with rapid increase in size over a period of two months. The patient had amenorrhea for 2 months, with no history of genital bleeding.

At physical examination, the patient was in a generally altered condition, pallor was present, but the patient's vital signs were normal. A pelvic examination could not be done because of the spastic position of the patient, who was on her right lateral decubitus with both hips flexed. Abdominally, there was a palpable mass arising from the pelvis to the epigastrium, the upper and lateral borders of the mass could not be made out, the lower margin could not be ascertained, the mass was firm to hard, with restricted mobility and nontender. CT scan examination (figure 1) described a large, macronodular, hypodense, approximately 237x222mm mass arising from the pelvis to the epigastric level, probably concerning the uterus-adnexal area. There was also described hepatomegaly, a single metastatic pulmonary nodule and left hip dislocation. The patient was anemic with Hb-7,7g/dl, Ht-29,2%.

The patient was proposed for an exploratory laparotomy. Intraoperatively clear ascites was present in approximative 1L, a giant uterine tumor, with irregular surface, lobulated, with multiple nodules: 20/15/10cm, (3,3kg) and 4 smaller myomas, (cumulative size of 7/6/5cm). The mass had close adhesion to the epiploon, which at that level was edematous; the uterus was globally increased in volume 25/25/15cm, the ovaries were both polycystic. Total abdominal hysterectomy (along with the tumor) with bilateral salpingo-oophorectomy was performed with the complete removal of the tumor mass. (figures 2 and 3)

The histology exam comprised 29 paraffin tissue blocks ID No. from 281354 to 281383. One block – 281355 was sent for second opinion and specialized immunohistochemistry exam. Histopathologic examination revealed: lax, edematous, pauci-cellular areas, intermixed with dense cellular ones, dense proliferation with fascicular growth pattern (bundles intersect at different angles) composed of large, spindle cells with hypertrophic, cigar-shaped nuclei, some large, irregular, bizzare nuclei with granular chromatin and small basophilic nucleoli, abundant eosinophilic fibrillary cytoplasm. (figures 4,5,6) There were found relatively frequent atypical mitosis – 15/10HPF, rare multinucleate tumor cells and areas of tumor necrosis. Numerous capillary vessels could be seen, some of them dilated with branched or anastomotic rami. There was noted reticulin and collagen meshwork surrounding each tumor cell on Gömöri staining. Tumor cells were intensely positive for smooth muscle actin (imunohistochemical assay for SMA), CD34 was positive in endothelial cells and negative in tumor cells highlighting the dense capillary network, estrogen receptor diffusely positive in 60 % of tumor cells nuclei, Ki67 (marker of cell proliferation) positive in numerous tumor cells (Ki67 index 40%). (figures 7,8, 9)

The histology exam diagnosis was: Leiomyosarcoma with mixed areas, grade 2 (FNCLCC score 4 – differentiation 1, mitotic index 2, necrosis 1) ICD-O 8890/3 (figures 10, 11, 12)

Post-surgery evolution of the patient was favorable, as was the general health condition at the 1 month visit. Regrettably, we lost the patient at follow-up as there were no further visits and we failed to track the patient probably due to the difficult socio-economic status of the patient.

Discussion

We had the case of a 43-year-old patient with hydrocephalus, spastic tetraparesis, and impaired cognitive abilities that presented with a greatly distended abdomen and that could only lie in right lateral decubitus. That posed great technical difficulties regarding clinical and imagistic examination, though the patient was largely compliant. Imaging was led by ultrasound exam that found an inhomogeneous aspect with mixed echogenic and poor echogenic areas and irregular vessel distribution within the tumor at color Doppler. The characteristics and the fast rate of growth brought to attention the possibility of a malignant uterine lump. But there were, also, ascites and the ovaries were enlarged with a cystic aspect that was not dissimilar to an ovarian malignancy. There was poor evidence of the tumor limits on ultrasound and a subsequent CT scan was done that showed the real extent of the tumor and the presence of a pulmonary nodule, without underlining suspicion of LMS. MRI scan, though not highly specific, is the recommended mode of uLMS imaging [18,19] but we had no means of achieving it. Also, a future diagnostic tool may be18F-FDG PET, but current data are limited [20].

As we arose to the decision of surgical intervention, mainly to achieve abdominal decompression, became evident that the team of surgeons and the accompanying anesthesiologists would face a great challenge due to the real difficulty of positioning the patient on the operating table. As myorelaxation was achieved the operators could further concentrate on the tumor resection. It is important for clinicians to try to resect a tumor as completely as possible as this appears to be the only way to achieve a favorable outcome. Cure rates for patients with disease limited to the uterus range from 20 to 60% depending on the success of the primary resection [21,22]. We performed total abdominal hysterectomy en bloc with the tumor with bilateral salpingo-oophorectomy completely excising the tumor. The tumor presented intimate adhesion to the epiploon which was edematous and the adnexa were, also, closely bound to the tumor and with edema and inflammation. The histology exam did not find any adnexal spread of the malignancy. Adnexal or lymphatic spread is only present in about 3% of early stage uterine leiomyosarcomas [23,24]. In a series of 1396 patients, adnexectomy and lymphadenectomy failed to be independent prognostic factors for survival [25]. However, the ovaries are frequently removed in account of age, the small percentage of ovarian metastasis, and the potential for a low-grade hormone-sensitive uterine leiomyosarcoma. A simple hysterectomy with oophorectomy, but without lymphadenectomy, represents standard treatment for early stage uterine leiomyosarcomas. In premenopausal women, a simple hysterectomy (without oophorectomy) can be considered [22]. Histology essays highlighted the presence of SMA markers, the high mitotic rate and necrosis that are specific for uLMS. Tumor cell necrosis is only seen in LMSs [26]. Our histology exam revealed necrosis as defined for LMS showing an marked transition from necrotic to nonnecrotic tumor, without interposed granulation tissue or fibrous tissue and necrotic areas frequently exhibiting preserved nuclei with marked pleomorphism and hyperchromasia and nuclear debris without inflammatory signs [16]. It is very important for the postoperative management of the patient to realize a histological differential diagnosis with leiomyoma. Usually, spindle cell LMS presents elongated cells with eosinophilic fibrillary cytoplasm and elongated blunt-ended nuclei and cells form long intersecting fascicles and frequently display an infiltrative growth into the surrounding myometrium [27]. The lax, edematous, pauci-cellular areas, alternating with dense cellular ones, the fascicular growth pattern (bundles intersecting at different angles) composed of large, spindle cells with hypertrophic, cigar-shaped nuclei, and large, bizzare nuclei with granular chromatin and small basophilic nucleoli and abundant eosinophilic fibrillary cytoplasm that we found at histo-pathology examination support the spindle cell LMS diagnostic. Also, there were found relatively frequent atypical mitosis – 15/10HPF. Rarely we have to distinguish LMS of LM with bizarre nuclei. Features that can be seen in LM with bizarre nuclei include large atypical mononucleated or multinucleated cells, karyorrhectic nuclei, prominent nucleoli, nuclear pseudo-inclusions, coarse chromatin, or even increased mitotic activity by the highest count (up to 7 mitoses per 10 HPFs). Leiomyomas do not have tumor cell necrosis and they present minimal or no cytologic atypia in background non–bizarre smooth muscle cells [28,29]. It has also revealed positive estrogen receptor in 60% of tumor cells suggesting that would have made the patient susceptible for aromatase inhibitors treatment for consolidation of the surgical achievement. However, a 2010 study failed to demonstrate any real benefits for the outcome [30]. A recently published retrospective study on the use of the aromatase inhibitor letrozole in 16 ER/PR positive uLMS (uterine leiomyosarcoma) patients revealed clinical benefit in 10/16 patients (partial response in 2/16 and stable disease in 8/16 patients). Also, the use of the aromatase inhibitor exemestane as second line treatment resulted in clinical benefit in 50% of patients. However, no prospective trials testing hormonal therapy in uLMS have been performed [31,32]. Usual first line chemo-therapy is fixed-dose rate gemcitabine plus docetaxel, and adding the angiogenesis inhibitor bevacizumab showed no benefit [33,34].

Although we recommended oncologic follow-up the patient failed to comply mainly due to poor socio-economic condition with the only one known relative being her stepmother.

An interesting aspect of this case is represented by the possibility of an x-linked congenital condition such as the ATRX – Alpha thalassaemia-mental retardation syndrome [35] that could explain the anemia in the absence of vaginal bleeding and the mental impairment of the patient. A very recent study established by exome sequencing of uterine leiomyosarcomas there are frequent mutations in TP53, ATRX, and MED12 [12]. It presents itself as an interesting theory the possibility of an X-linked mutation that both could promote leiomyosarcoma and, also, explain anemia, spastic tetraplegia and mental retardation. Other mutations on the X chromosome are, also, related to hydrocephalus. The vast majority of described cases of ATR-X syndrome affect male patients and are extremely rare and usually milder in women.

Conclusion

Leiomyosarcoma poses challenging problems regarding histological diagnosis and, due to its growth rate, real surgical difficulties. Imaging investigations like ultrasound, MRI and CT are not consistent with leiomyoma differential diagnosis, leaving to the histology exam the leiomyosarcoma diagnosis. Frequently it is late diagnosed when complete removal of the tumor is often impossible. Owing to advancing science in the complex genetics of the tumor and the future promise of targeted molecular treatment we may hope for a less bleak outcome for the leiomyosarcoma patients.

Conflict of interests

The authors declare that they have no conflict of interests.

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Received:

Accepted:

Figure 1 CT Scan Image

Figure 2 Intraoperative aspect of the tumor

Figure 3 Sectioned tumor

Figure 4 Lax, edematous, pauci-cellular areas, intermixed

with dense cellular ones. Hematoxylin-eosin 40x

Figure 5 Dense proliferation with fascicular growth pattern

composed of large, spindle cells with hypertrophic, cigar-like nuclei.

Hematoxylin-eosin, 100x

Figure 6 Tumor cells with large, irregular nuclei

and abundant eosinophilic fibrillary cytoplasm.

Hematoxylin-eosin, 200x

Figure 7 Fascicles of tumor cells intersecting at different angles and planes.

Note numerous capillary vessels, some of them dilated and branched.

Masson 100x

Figure 8 Note reticulin and collagen meshwork surrounding

each tumoral cell. Gömöri 200x

Figure 9 Tumoral cells are intensely positive for smooth muscle actin

(imunohistochemical assay for SMA)

Figure 10 CD34 positive in endothelial cells, negative in tumor cells.

It highlights the dense capillary network with dilated and branched vessels

Figure 11 Estrogen receptor diffusely positive in tumor cells nuclei

Figure 12Ki67 (marker of cell proliferation) positive in

numerous tumor cells (Ki67 index 40%)