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April 2005, Volume 55, Issue 4

Original Article

Malignant Smooth Muscle Tumours of Soft Tissue - a demographic and clinicopathological study at a tertiary care hospital

Hamidullah Shah  ( Department of Pathology and Microbiology, Aga Khan University Hospital, Karachi )
Yasmin Bhurgri  ( Department of Pathology and Microbiology, Aga Khan University Hospital, Karachi )
Shahid Pervez  ( Department of Pathology and Microbiology, Aga Khan University Hospital, Karachi )

Abstract

Objective: To determine the demographic characteristics and distribution of various reported prognostic factors of leiomyosarcoma (LMS) among subjects reporting to histopathology diagnostic centers of Aga Khan University (AKU) all over Pakistan between 2000-2004.

Methods: This study analyzed 205 consecutive confirmed cases of LMS received during a period of four years. The data regarding age, sex and size of tumor was obtained from the pathology medical records. Data on grade and positivity of immunohistochemical stains was assessed and all the variables analyzed using SPSS version 12.5.

Results: Of the 205 specimens of LMS, 31 were received as blocks for second opinion. A hundred specimens were multiple fragments, and 74 were intact masses. Of the latter, 40% had clear margins. The mean size of the tumor was 7.23 cms. (95% CI 6.1; 8.4). There were no cases of childhood LMS. Teenage LMS comprised 3% of all tumors. Grade 1 tumors were 16.6% of the total, 56.6% were grade 2, and 8.5% were grade 3. Vimentin positivity was observed in 97% of the tumors, desmin positivity in 56.7%, HHF35 positivity in 81.0%, s-100 positivity in 15.6% and cytokeratin positivity in 11% of the cases. The median age of LMS patients was 48.4 years, the mean age was 48.6 years (95% CI 45.9; 50.8) and male to female ratio was 1:1.2. The malignancy occurred a decade earlier in the females as compared to the males. The mean age of male cases was 52.3 years (95% CI 48.8; 55.8); and of females was 45.2 years (95% CI 41.8; 48.6). The mean age of teenage LMS was 17.2 years (95% CI 15.6; 18.7). The most common symptom was a painless swelling. The most common sites were lower limb (24.4%) and pelvis (24.4%) followed by abdomen (20.6%) and head and neck (12.7%). The least common sites were upper limb and chest (8.0% each). Seventy five percent of the tumors with involved margins were more than 5.0 cms. in size whereas 47% of tumors with free margins were above 5.0 cms. in size. Approximately half the tumors in the males were less than 5.0 cms, as compared with 31.0% in the females. LMS in the extremities was equally common in both genders, but trunk LMS was nearly twice as common in the females.

Conclusion: In our population, leiomyosarcoma occurs at a relatively younger age, has a late presentation; is more common in females as compared to males and usually excised incompletely. No genetic study for LMS has been published in Pakistan; these studies are recommended to determine the biological pattern of LMS in our population (JPMA 55:138;2005).

Introduction

Leiomyosarcoma (LMS) is a malignant neoplasm that originates from smooth muscle and presents as a mass anywhere in the body. LMS usually occurs in the female genital tract, however, these tumors can develop anywhere along the smooth muscle. This includes, all sites where smooth muscle is present such as the gastrointestinal tract, scrotum, nipple, skin, the supporting structures that connect various organs of the body, including the tendons, cartilage and synovial tissue that surrounds joints, soft fibrous tissues, blood vessels, soft fatty tissue, and the soft tissue of the nervous system. LMS are uncommon tumors and occur more frequently in females.

Grossly, the tumor appears as a soft, gray mass. Histologically LMS exhibit intersecting bundles of spindle-shaped cells showing nuclear pleomorphism and hyperchromasia. Occasionally, cell bundles of individual cells are separated by myxoid or fibrous intercellular matrix. Nuclear palisading and storiform pattern is a focal morphological presentation. Areas of tumor necrosis and hyalinization may be found. These cells typically have elongated nuclei with rounded ends.1 The standard criteria of diagnosis include histological confirmation and positivity for smooth muscle actin and vimentin.2-5

The history of sarcoma can be divided into two periods. The period before 1980 and after 1980, when immunohistochemical techniques were applied in the diagnosis of soft tissue sarcomas. Many studies thereafter carried out, examining previously diagnosed Malignant Fibrous Histiocytoma turned out to be LMS. It was after this period that the cumbersome diagnosis and further characterization of high-grade sarcomas was greatly facilitated.

The treatment of LMS is surgery, radiation therapy, and chemotherapy alone or in various combinations. If surgical margins are about 2 cm away from the tumor margin, the chance of tumor recurrence is almost negligible. It is therefore important to know the margin status of the tumor as a guideline for further treatment.

Our study included 205 cases of LMS, which were diagnosed, with the help of immunohistochemical stains using immunohistochemical techniques. The studies reported from Pakistan on this topic are limited to cases studies or data on small series.6-8

The objectives of this study were to determine the proportion of free margins, tumors with size less than five cms, and to describe the characteristics of this tumor by age, gender, site and grade. A secondary objective of the study was to compare proportions of free margins with the grade, size, and site, of the tumor and correlate with the age and gender of the patient and to determine the percentages of various immunohistochemical stains positivity in LMS.

Meterial and Methods

This descriptive study was carried out at Aga Khan University Hospital (AKUH) pathology department. The department receives surgical specimens from the AKUH, Karachi and through 59 pathology laboratory collection points in Pakistan. It covers a large geographical area, with collection points located in all major cities like Karachi, Hyderabad, Multan, Lahore, Quetta, Peshawar, Islamabad, Rawalpindi, Larkana and also many rural locations.

Quality control for diagnostic pathology is maintained through internal and external quality checks. External quality assurances for diagnostic pathology are maintained by the College of American Pathologists (CAP) surveys. Internal quality assurances are maintained by the use of histochemical stains and immunohistochemical techniques. Biological markers are used for malignancies, which necessitate cellular typing and sub-typing. The departmental consensus committee confirms diagnosis. Assistance and technical help of Armed Forces Institute of Pathology (AFIP) Washington DC was taken for confirmation of challenging cases until recently when the institute closed down. ISO 9002 certified the clinical pathology lab in 1999.

All the specimens for the present study were grossed and processed. Sections obtained from blocks of these specimens were stained with haematoxylin and eosin and examined microscopically. Immunohistochemical stains were used for further characterization of the tumor by envision systems. Immune markers used were vimentin, desmin, alpha smooth muscle actin (ASMA), S100, CD34 and CD68. Positive and negative controls were run in parallel with each new staining.9,10

Demographical variables recorded were the hospital patient-number, date of incidence, name, age, sex, address, ethnicity, topography, morphology, grading and staging. Tumors were categorized according to the UICC, TNM staging system and the FNCLL system (Table 1), to standardize with the staging systems in other parts of the world. The cases were categorized by tumor site and the age and sex of the patient.

The data obtained was analyzed using SPSS version 12.5. This included descriptive frequency analysis as well as mean, median, confidence intervals and standard deviation of patient age and specimen size. The percentages of grades and tumors with involved and free margins were also determined.

Results

We received 205 specimens of LMS, of which 31 were blocks for second opinion. Hundred specimens were multiple fragments, and 74 were received as intact masses. Of the latter 40% had clear margins. The mean size of the tumor was 7.23 cms. (95% CI 6.1; 8.4). There were no cases of childhood LMS. Teenage LMS comprised 3% of all tumors. Grade 1 tumors were 16.6% of the total, 56.6% were grade 2, and 8.5% were grade 3. Vimentin positivity was observed in 97% of the tumors, desmin positivity in 56.7%, HHF35 positivity in 81.0%, s-100 positivity in 15.6% and cytokeratin positivity in 11% of the cases.

Table 1. LMS histopathological grading system.22
 Tumor differentiation      
 Score 1 well differentiated sarcoma
 Score 1 moderately differentiated sarcoma
 Score 1 poorly differentiated sarcoma
Necrosis  
 Score 0 no necrosis
 Score 1 necrosis less than half
 Score 2 necrosis more than half.
Mitosis  
 Score 1 0-9 mitosis
 Score 2 10-19 mitosis
 Score 3 more than 20 mitosis

Grade 1 score of 3 ,4
 Grade 2 score of 4, 5
 Grade 3 score of 6, 7, 8

The median age of LMS patients was 48.4 years, the mean age was 48.6 years (95% CI 45.9; 50.8) and male to female ratio was 1:1.2. The malignancy occurred a decade earlier in the females as compared to the males. The mean age of male cases was 52.3 years (95% CI 48.8; 55.8); and of females was 45.2 years (95% CI 41.8; 48.6). The mean age of teenage LMS was 17.2 years (95% CI 15.6; 18.7) (Table 2).

The most common symptom was a painless swelling. The most common sites were lower limb (24.4%) and pelvis (24.4%) followed by abdomen (20.6%) and head and neck (12.7%). The least common sites were upper limb and chest (8.0% each). Seventy five percent of the tumors with involved margins were more than 5.0 cms. in size whereas 47% of tumors with free margins were above 5.0 cms. in size. Approximately hal

Table 2. Mean Values: age, grade site and correlations of LMS cases.
Ages Mean(years) Std.Deviation Median(years)
All ages, both genders 48.6 17.41 46.00
All ages, male gender
52.3 17.13 52.00
All ages, female gender 45.2 20.05 44.00
Teenage LMS
17.17 3.25 17.50
Grade Mean Age(years) Std.Deviation Median(years)
Grade 1 45.16 20.31 43.00
Grade 2 48.34 17.14 45.00
Grade 3 50.41 16.10 50.00
Ages Mean(Size) Std.Deviation Median(Size)
Grade 1 5.41 5.15 3.5
Grade 2 7.12 4.60 7.0
Grade 3 8.5 5.70 7.5
Site Mean(Size) Std.Deviation Median(Size)
Head and Neck
3.15
3.56 1.90
Upper Limb 6.38 3.89 6.05
Chest 10.00 6.48 10.00
Abdomen 7.61 6.84 6.00
Pelvis 8.75 3.95 9.00
Lower Limb 8.85 4.29 9.00
Total 7.41 5.05 7.00

the tumors in the males were less than 5.0 cms, as compared with 31.0% in the females. LMS in the extremities was equally common in both genders, but trunk LMS was nearly twice as common in the females. (Table 2) LMS limbs and pelvis were larger and with incomplete excision, however p-values were not calculated due to small sample sizes (Table 3).
Grade 1 tumors were 16.6% of the total, 56.6% were grade 2, and 8.5% were grade 3. Vimentin positivity was observed in 97% of the tumors, desmin positivity in 56.7%, HHF35 positivity in 81.0%, s-100 positivity in 15.6% and cytokeratin positivity in 11% of the cases.

Discussion

Sarcoma accounts for 1% of all the malignancies and LMS are 2-7% of all the sarcomas.9 This figure varies with different studies. In Pakistan published hospital and

Table 3. Distribution LMS cases by gender and tumour margin, stratified by site and size.
Size Margins (n=41) Gender (n=72)
  Involved Free   Male Female
  Cms. % Cms. % % %
<1.0 1 4.2 3 17.6 2 6.1 3 707
1.1-5.0 5 20.8 6 35.3 15 45.4 9 23.1
5.1-10.0 10 41.7 4 23.5 9 27.3 15 38.4
10.1-15.0 5 20.8 4 23.5 7 21.2 9 23.1
>15.0 3 12.5 0 0 0 0 3 23.1
Total 24 100 17 100 33 100 39 100
  Margins (n=41) Gender (n=207)
  Involved Free Male Female
Head and Neck
2 4 14 12
Upper Limb
2 2 7 7
Chest 1 - 5 10
Abdomen 5 2 15 22
Pelvis
6 5 17 27
Lower Limb 9 4 21 21
Unknown
- - 16 13
Total 24 17 93 110

pathology series have placed this figure closer to 13%, and a rare disease in children.6,7 Our study had no childhood LMS and 3% teenage LMS. Internationally, 10% of the total new cases occur in children and teenagers, though LMS is reported as a disease of adults, with age ranges from seven to 95 years and incidence peak in the sixth decade. The age range of our patients is a decade earlier with a peak in the fifth decade. The malignancy presented at an overall mean age of 48.6 years; male cases 52.3 years and females 45.2 years. This may be the natural pattern of disease or an underreporting or under diagnosis of LMS in our population or simply the shorter life expectancy. There is a reported predilection for females; LMS is relatively more common in females (53%) as compared to males (47%). This pattern was noted in our study too.9-14

The most common symptom in our study was a painless mass. Soft tissue sarcomas tend to be asymptomatic in the early stages. Often, malignancies of the smooth muscle cells are only detected when a large soft tissue sarcoma grows and begins to displace the normal tissue, typically of the intestine or blood or lymph systems. The most commonly experienced symptom is a painless swelling or mass arising from the smooth musclecells. Symptoms of a more advanced soft tissue sarcoma may include weight loss and pain as the tumor pushes against adjacent muscles and nerves.

Most studies report a higher distribution of LMS in extremities, about 50% of all soft tissue sarcomas occur in the smooth muscle cells of the body's extremities including arms, nipples, legs, hands and feet. In our study, only 32.4% occurred in the limbs. About 40% were located in the chest, back, hips, shoulders, gastrointestinal tract and abdomen. Studies have reported 10% of LMS in the head and neck, as against 12.7% in our study.

Regarding the histopathological diagnostic criteria for differentiation of LMS from leiomyoma (LM), the most reliable and reproducible measure in predicting malignancy is mitotic activity although several factors, such as size, cellularity, and necrosis correlate with malignancy to some extent.10-12 Unlike uterine lesions, more than two mitoses/10 high-power fields (HPFs) have been thought to warrant a finding of potential malignancy in external soft tissue LMS.10 However, even when these stringent criteria are applied, exceptions are not uncommon. In reality, histologically benign-looking LMSs occasionally metastasize after long latent periods, leading to the suspicion that the vast majority of LMSs with high cellularity are potentially malignant. As a result of these observations, a more strict criteria has beenrecently proposed, namely, greater than 1 mitosis per 10 HPFs for cutaneous LMS and greater than zero for that in deep soft tissue should be regarded as LMS.13-16

There is a late presentation of LMS in Pakistan, the diagnosis is based on haematoxylin and eosin stains. There is no existing data regarding the demographic characteristics of this tumor in our population. This is a prototype of all developing country malignancies, the tumors are reported and diagnosed late. In addition, incomplete tumor excision promotes recurrences and related mortality is high.

The use of immunohistochemical stains in diagnostic histopathology started in 1980 and still only a few institutes in Pakistan use these stains which are almost mandatory for confirmed diagnosis. The reason is primarily its expense. Most of these labs send the paraffin blocks to referral labs like the AKU pathology department.

The tumor size is one of the important predictor of poor prognosis in soft tissue sarcoma. A st.udy done by Miyajima et al showed that 43 (23.4%) of 184 cases were less than 5 cm and 141 (76.6%) of 184 cases are larger than 5 cm.18 Our study also revealed that 33% of cases were less than 5 cm while 66% of cases were more than 5cm.

Trojani et al19 developed a histological grading system for soft tissue sarcoma and various studies have reported the usefulness of this system. These studies have included many types of soft tissue sarcomas. The study done by Miyajima et al however showed no significant relationship between the prognosis and tumour grade.18 According to this study most of the cases were grade 2 while grade 1 and grade 3 were rare.

There is a well-known association between surgical margin and local recurrence and between local recurrence and tumor related death. In western studies, the percentage of lesions excised with wide and clear margins is almost 95% while in our study it was 40%.

Although research has yet to establish the cause or causes of LMS, risk factors may include: age, heredity and chemical exposure. LMS is more prevalent in adults over the age of fifty. It is also associated with certain inherited diseases, including neurofibromatosis (von Recklinghausen's disease) and Li-Fraumeni syndrome. Chemical exposure to herbicides, chlorophenol wood preservatives, and industrial pollutants, such as vinyl in the manufacturing of plastics, also appear to increase the risk. Recent findings reported by Emory University School of Medicine, Atlanta, Georgia, point to a link between the Epstein Barr Virus (EBV) and the development of soft tissue sarcoma in smooth musclesthroughout the body.19 We could not correlate our findings with risk factors, as there is a paucity of clinical information with submitted specimens.

The striking differences in terms of gene expression pattern among LMS of different differentiation status and clinical aggressiveness imply that several genetic abnormalities are responsible for the genesis and progression of this tumor.20,21 No genetic study for LMS has been published in Pakistan; these studies are recommended to determine the biological pattern of LMS in our population.

Conclusion

In our population, leiomyosarcoma occurs at a relatively younger age, has a late presentation; is more common in females as compared to males and usually excised incompletely. No genetic study for LMS has been published in Pakistan; these studies are recommended to determine the biological pattern of LMS in our population.

References

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