Introduction

Leiomyomas and leiomyosarcomas are the benign and malignant proliferations of smooth muscle tissues. Although smooth muscle tumours can arise anywhere in our body, like the gastrointestinal tract, retroperitoneum, skin and blood vessels, the uterus is the most common site for the occurrence of leiomyomas and leiomyosarcomas. The benign leiomyomas, which arise in the uterine wall are called fibroids.

Leiomyomas proliferate under the influence of oestrogen and progesterone. Their size increases during reproductive years, especially during pregnancy, and regresses after menopause. They are comprised of proliferating smooth muscles and excess extracellular fibrous supporting tissue.⁷

These tumours range from benign to malignant, i.e., leiomyoma, leiomyoma variants, smooth muscle tumours of uncertain malignant potential (STUMP), and malignant leiomyosarcoma.¹

This article provides an overview of the clinical presentation of leiomyoma and its malignant counterpart, leiomyosarcoma. It highlights the importance of distinguishing between the two, explores the potential consequences of misdiagnosis, discusses the diagnostic challenges and pitfalls commonly encountered, and outlines strategies to overcome these challenges.

Age group: Leiomyomas mostly occur in the reproductive and perimenopausal age groups, whereas leiomyosarcomas occur in older patients (45 years and above).⁵

Prevalence and Incidence: The prevalence of uterine smooth muscle tumours ranges from 4.5% to 68.6%, with a lifetime risk of around 70%.¹ Leiomyosarcomas are the most common uterine sarcomas, with an incidence of 41-60%. Leiomyosarcomas are extremely aggressive tumours with poor prognosis.³

Risk factors

• Advancing age
• Multiparity
• Polycystic Ovarian Syndrome
• Hormone replacement therapy
• Dietary factors like high consumption of red meat, reduced intake of vegetables, fruits and vitamin D
• Genetic factors like hereditary leiomyomatosis syndrome associated with renal cell carcinoma⁷ 
• Mechanical pressure during pregnancy and delivery may contribute to chromosomal damage to uterine muscles, increasing the risk of leiomyomas and sarcomas¹

Clinical presentation

 Both leiomyoma and leiomyosarcoma present with similar signs and symptoms.

• Heavy menstrual bleeding
• Anemia
• Abdominal mass
• Increased urinary frequency or incontinence
• Constipation
• Painful sex
• Pregnancy complications^1,5

Radiological findings 

Leiomyoma appears as a well-circumscribed mass with shadows inside and at the edge of the lesion. It shows circumferential flow on colour doppler imaging. On the other hand, leiomyosarcomas are seen typically as single large tumours, with a regular or irregular outline, frequent irregular anechoic areas due to necrosis and irregular vascularisation.³

Histopathology

Diagnosis of leiomyosarcomas is made if two out of the three criteria are met:

• Coagulative tumour cell necrosis
• Severe nuclear atypia
• High mitotic count (more than 15 mitotic figures per 10 high power fields) ^5,6

Diagnosis 

Transvaginal ultrasound (TVS) is the first-line imaging technique employed for uterine mass evaluation. It is cheap, convenient, and safe, but its sensitivity to diagnose leiomyosarcoma is low.²

Computed Tomography (CT scan) is used pre-operatively for staging of leiomyosarcomas, but its sensitivity and specificity for detection is low.²

Magnetic resonance imaging (MRI) with intravenous contrast is the gold standard technique for evaluation of uterine masses. Due to high cost, it has limited availability in low-resource settings.^2,3,7

18F-FDG-PET-CT (Fludeoxyglucose-18 Positron Emission Tomography-Computed Tomography) can be employed to distinguish uterine sarcomas from leiomyomas. Leiomyosarcomas show greater 18F-FDG uptake on PET-CT in comparison to leiomyomas.⁵

A new tracer, 3’-deoxy-3'-18F-fluorothymidine PET (18F-FLT- PET), has been found to be superior to 18F-FDG-PET-CT. It has the advantage that it can assess tumour proliferation without its uptake by inflammatory tissues.⁷

Why do these two entities need differentiation? 

For designing the optimal treatment and selecting the appropriate surgical approach tailored to an individual, distinction between leiomyoma and leiomyosarcoma is of utmost importance. 

Conservative approaches using medical treatments like the administration of gonadotrophin-releasing hormone analogues, uterine artery embolisation, and laparoscopic uterine artery occlusion or fertility-sparing surgery (myomectomy) are opted for leiomyomas, whereas hysterectomy is performed in leiomyosarcomas. The surgical approach also varies, i.e. laparotomy in leiomyosarcomas and minimally invasive surgery in leiomyomas.^1,2

Leiomyosarcomas can only be accurately diagnosed by histopathological examination of surgically excised specimens because the core biopsies and radiological modalities like ultrasound, CT or MRI can’t distinguish leiomyoma from leiomyosarcomas pre-operatively.² 

There are high chances, with a reported prevalence of 0.01% to 0.28%, that the uterine masses which are presumed to be leiomyomas based on imaging studies turn out to be leiomyosarcoma histopathologically.^2.3

That’s why accurate and timely diagnosis preoperatively can benefit patients and clinicians to decide optimal management, which can reduce the financial burden on patients by avoiding unnecessary surgeries.¹

Implications of misdiagnosis 

Leiomyosarcomas are highly aggressive tumours with great potential to spread to other organs. The consequences can be devastating if there is underdiagnosis of leiomyosarcomas leading to delayed and inappropriate treatment. On the other hand, benign masses, if overdiagnosed as malignant, mean the patient undergoes surgery with uterine loss that could otherwise have been avoided.⁷

As discussed above, leiomyosarcomas are incidental findings on histopathological examination of radiologically presumed leiomyoma. Morcellators are instruments used to cut tissue into small pieces in minimally invasive surgery done for leiomyoma. This can disrupt the uterine mass, which may lead to the dissemination of malignant cells in the abdominal cavity.¹

Pitfalls in the diagnosis

The diagnostic challenges arise both histopathologically andradiologically which are discussed below:

1. A biopsy of the suspected mass enables us to directly evaluate the tumor tissues. However, the biopsy samples are very small and may not reflect the true representative areas required for pathological diagnosis of leiomyosarcoma, leading to the possibility of underdiagnosis. The high heterogeneity of the tumours and the risk of neoplastic dissemination during biopsy procedures restrict their use.²
2. Coagulative tumour cell necrosis is often confused with ischaemic-type necrosis; hence, its diagnosis is difficult.⁶
3. Serum levels of total LDH are usually assessed in these patients. The levels are often abnormally high in patients with leiomyosarcoma, but the levels are also often elevated in patients with degenerated myoma and certain types of leiomyoma.⁶
4. Leiomyoma with bizarre nuclei (LM-BN), a rare variant of leiomyoma, can resemble leiomyosarcoma histopathologically, as it shows diffuse nuclear atypia and 5-9 mitoses/10 high power fields (HPFs). Genomic profiling is needed to differentiate between LM-BN and LMS.⁴
5. Epithelioid and myxoid LMS, which are rare but aggressive variants with mild atypia, low mitotic rate and frequent absence of necrosis, are diagnosed as smooth muscle tumours of uncertain malignant potential (STUMP). STUMP generally have a favourable prognosis.⁵
6. Hyaline degeneration, a secondary change that occurs due to ischaemia because of rapid growth of the tumour, should be differentiated from coagulative necrosis, which is an important diagnostic feature of leiomyosarcoma.⁸
7. The differential diagnosis of myxoid leiomyosarcoma is myxoid leiomyoma. Myxoid leiomyomas are small, well-circumscribed, with no cytologic atypia and 1-2 mitosis/10 high‑power fields (HPFs). The tumour may be partially myxoid; hence, extensive sampling of the excised specimen is recommended. Sometimes, the non‑myxoid areas are misinterpreted as myometrium, and the tumour gives a false impression of having infiltrative margins, like a myxoid leiomyosarcoma.⁸
8. Microscopically, bizarre leiomyoma (symplastic) reveals spindle cells with scattered multinucleated bizarre cells with prominent nucleoli that may mimic atypical cells, which need differentiation from leiomyosarcoma.⁸
9. The misdiagnosis of these two entities can occur due to errors at the time of tissue processing. For example, due to inadequate fixation, autolytic changes can occur in the specimen, which mask the visibility of mitotic figures and can lead to a wrong diagnosis.⁸
10. Leiomyosarcomas appear as large heterogeneous masses that present with haemorrhage or cystic necrosis on MRI. Similar findings can be seen in cases of cellular leiomyoma, degenerated leiomyoma, and atypical leiomyoma.⁶
11. The soft tissue tumours which show elongated cells with serpentine nuclei, morphologically resembling smooth muscle cells, can mimic leiomyosarcoma histologically. For example, cellular schwannoma, also called malignant peripheral nerve sheath tumour, malignant fibrous histiocytoma, monophasic synovial sarcoma, spindle cell rhabdomyosarcoma, extragastrointestinal stromal tumour, inflammatory myofibroblastic tumour, and fibrosarcoma. The immunohistochemical markers like SMA, desmin, and h-caldesmon, which are positive for smooth muscle tissue differentiation, can help differentiate between these entities and leiomyosarcomas.⁹

Strategies to avoid error

Ancillary techniques such as immunohistochemistry (IHC) carried out on the biopsy samples, can be employed for the preoperative diagnosis of LMS and leiomyomas using markers like Ki-67 and low-molecular-mass polypeptide 2 (LMP2). LMP2 deficiency and higher Ki-67 expression is reported in LMS.⁶

Summary

Leiomyosarcomas are rare, highly aggressive tumours. Their accurate preoperative diagnosis is crucial for timely surgical planning. The variants of its benign counterpart, i.e. leiomyoma, exhibit features, histopathologically and radiologically, that pose diagnostic challenges. Biopsy samples from representative areas, proper grossing, adequate fixation and staining can overcome these hurdles. MRI is the gold standard technique for the distinction between the two entities, but high cost is a limiting factor in low-resource settings. In doubtful cases, PET-CT and immunohistochemistry can act as complementary tests for diagnosis.