Leiomyosarcoma of the Uterus

Background

The uterine leiomyosarcoma is a rare sarcoma arising from the smooth muscle cells found within the myometrium. It exhibits histologic features similar to that observed in soft tissue leiomyosarcomas. The behavior and treatment, however, markedly differs. Most cases arise de novo and not from pre-exisiting leiomyomas. A rapid increase in size of a uterine tumor in a post menopausal woman should always prompt an investigation to exclude this possibility. These tumors are usually solitary with a large, poorly circumscribed mass and a soft fleshy consistency with necrosis.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/
Immunohistochemistry/
Electron Microscopy

Differential Diagnosis

Prognosis

Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGY CHARACTERIZATION

INCIDENCE 25% of all uterine sarcomas
1% of all uterine corpus malignant tumors

AGE RANGE-MEDIAN Median 54 years

PATHOGENESIS CHARACTERIZATION

CHROMOSOMAL ALTERATIONS

Analysis of Allelic Loss as an Adjuvant Tool in Evaluation of Malignancy in Uterine Smooth Muscle Tumors.

Esposito NN, Hunt JL, Bakker A, Jones MW.

From the *Division of Anatomic Pathology and daggerMolecular Anatomic Pathology Laboratory, Department of Pathology, and double daggerDepartment of Pathology, Division of Anatomic Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA.

Am J Surg Pathol. 2006 Jan;30(1):97-103. Abstract quote

Uterine smooth muscle tumors of uncertain malignant potential (STUMPs) are difficult both from the diagnostic and patient management standpoint because they cannot be classified as benign or malignant by conventional histologic criteria.

This study's aim was to determine the diagnostic utility of allelic imbalance (AI) analysis in uterine smooth muscle tumors. Using microdissection and genotyping, we tested 5 leiomyomas, 6 STUMPs, and 10 leiomyosarcomas with follow-up for AI across a panel of seven tumor suppressor genes (p16, p21, p53, VHL, XRCC3, RB, and NM-23). None of the 6 patients with STUMP experienced recurrent disease, whereas 8 of the 10 patients diagnosed with leiomyosarcoma died of disease at follow-up. The mean frequency of allelic loss (FAL) for leiomyomas (18%) was not significantly different from that of STUMPs (21%) (P = 1), whereas leiomyosarcomas displayed a significantly higher FAL (52%) than both leiomyomas (P = 0.001) and STUMPs (P = 0.002). Loss of NM-23, a reported tumor metastasis suppressor gene, was found only in leiomyosarcomas (5 of 9, or 56%), and 4 of 5 (80%) of these were the only cases that demonstrated distant metastases (P = 0.04). Additionally, an FAL of >50% correlated with both NM-23 loss (P = 0.008) and distant metastatic disease (P = 0.04).

In conclusion, leiomyomas and STUMPs displayed similar mean FALs and all were clinically benign, whereas uterine leiomyosarcomas had significantly higher frequencies of allelic loss than both leiomyomas and STUMPs. Molecular profiling may thus provide a valuable tool in assessment of malignancy in uterine smooth muscle tumors. Additionally, NM-23 is a promising candidate gene for determination of metastatic potential in these tumors.

HISTOLOGICAL TYPES CHARACTERIZATION

General
Highly cellular tumor composed of smooth muscle cells arranged in intersecting fascicles

Infiltrative borders
Cytologic pleomorphism
Criteria is changing but in general, tumors with >10 mitotic figures/10 hpf are malignant

VARIANTS

CLEAR CELLS

Uterine Epithelioid Leiomyosarcomas With Clear Cells: Reactivity With HMB-45 and the Concept of PEComa

Silva, Elvio G MD*; Deavers, Michael T MD*; Bodurka, Diane C MD�; Malpica, Anais MD*

From the Departments of *Pathology and �Gynecologic Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX.
The American Journal of Surgical Pathology : Volume 28(2) February 2004 pp 244-249 Abstract quote
In this study, we investigated HMB-45 expression in epithelioid uterine leiomyosarcomas with clear cell areas. From 12 epithelioid leiomyosarcomas, we selected 5 that had: 1) clear cell areas and 2) spindle cell areas that were at least focally positive for desmin and caldesmon. The patients' ages ranged from 47 to 82 years (mean 64 years).

Presenting symptoms were uterine bleeding (three), abdominal pain (one), and a pelvic mass (one). There was no history of tuberous sclerosis or lymphangioleiomyomatosis. One patient had stage II disease, one stage III, and three stage IV. All were treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy. Two received radiotherapy, and three were also treated with chemotherapy. The tumors ranged in size from 4 × 3 × 3 cm to 10 × 7 × 6 cm; all had significant cellular atypia, areas of coagulative necrosis, and between 10 and 90 mitoses per 10 high power fields. Vascular invasion was seen in three cases. The epithelioid component varied from 50% to 90% in each case; and the percentage of clear cells was <1% in one case, 5% in one case, and 10% to 80% in three cases. Smooth muscle actin and desmin were positive in all cases. Four cases were positive for HMB-45 only in the clear cell areas. The tumor with <1% of clear cells was negative for HMB-45. All were negative for S-100 and c-kit.

Three patients died of disease at 9, 30, and 32 months; one patient is alive with progressive disease at 6 months, and one patient (stage II disease) is alive with no evidence of disease at 8 months. Unequivocal uterine epithelioid leiomyosarcomas may have clear cells positive for HMB-45.

These tumors might belong to the group of lesion designated as PEComas; however, it is advisable to designate them as uterine leiomyosarcomas. In uterine smooth muscle tumors, some epithelioid cells most likely undergo clear cell changes and become positive for HMB-45. It would be advisable to perform this stain in all epithelioid smooth muscle tumors of the uterus.

STUMP or Smooth muscle tumors of undetermined, intermediate, or borderline category
Tumors with mitotic rates ranging between 5-9 mitotic figures/10 hpf

See Differential Diagnosis Table Below

Epithelioid leiomyosarcomas See Differential Diagnosis Table Below

Myxoid leiomyosarcomas See Differential Diagnosis Table Below

Infiltrating leiomyoma, including leiomyomatosis
Characteristic leiomyoma with infiltrating margins
Common pattern is patches of hypercellular, benign smooth muscle throughout large areas of the myometrium

Disseminated peritoneal leiomyomatosis
Numerous small (<2.0 cm) nodules of bland, benign smooth muscle cells, often arranged in a whorled pattern
Decidual cells common
Pregnancy or functional ovarian tumors commonly associated

Benign metastasizing leiomyoma

Deposits of smooth muscle in lymph nodes, lung, and other organs associated with a morphologically benign uterine smooth muscle tumor

Must have no cytologic atypia, tumor cell necrosis, or abnormal mitotic figures
By definition, there can be no smooth muscle tumor in another organ that could be the source of the metastasis
Mitotic counts are the same as for a leiomyoma

Lipoleiomyoma
Leiomyoma with focal to diffuse fatty differentiation

Neurilemoma-like leiomyoma
Leiomyoma with palisaded nuclei resembling Verocay bodies

Leiomyoma with tubules or glands
Tubules or glands in otherwise characteristic leiomyoma
Very rare
Must exclude endometrial stromal neoplasms or uterine tumors resembling ovarian sex-cord tumors

Parasitic leiomyoma
Uterine serosal leiomyoma that becomes detached from the uterus and derives blood supply from the omentum, peritoneum, or other pelvic structures

Must have benign features
Rare, must be in pelvis and not retroperitoneum

Leiomyoma with vascular intrusion
Usual leiomyoma with vascular intrusion is not visible on gross examination but is a microscopic finding within the confines of a leiomyoma

Intravascular leiomyomatosis
Grossly visible fragments of histologically benign smooth muscle extending into vascular spaces and/or microscopic extension of smooth muscle cells into vascular spaces outside the confines of the leiomyoma
Epithelioid cells, including clear cells, and fat cells may present
Features distinguishing it from intravascular leiomyosarcoma are the same as for distinguishing leiomyoma from leiomyosarcoma

Leiomyosarcoma of the Uterus with a Florid Intravascular Component (“Intravenous Leiomyosarcomatosis”)

Kathleen C. M. Coard, D.M.; Horace M. Fletcher, D.M.

From the Departments of Pathology (K.C.) and Obstetrics and Gynaecology (H.F.), University of the West Indies, Mona, Kingston, Jamaica
Int J Gynecol Pathol 2002;21:182-185 Abstract quote
A leiomyosarcoma of the uterus in a 54-year-old woman exhibited striking involvement of large vessels of the myometrium and broad ligament on both gross and microscopic examination. The pattern of vascular involvement resembled that seen in intravenous leiomyomatosis. Imaging studies showed recurrent tumor within the inferior vena cava 3 months after hysterectomy.

To our knowledge, this is the first reported such case in the literature, for which we propose the designation intravenous leiomyosarcomatosis of the uterus.

SPECIAL STAINS/
IMMUNO-HISTOCHEMISTRY CHARACTERIZATION

CD44

Expression of CD44 standard and isoforms V3 and V6 in uterine smooth muscle tumors: A possible diagnostic tool for the diagnosis of leiomyosarcoma

Christophe Poncelet, MD
Francine Walker, MD, PhD
Patrick Madelenat, MD
Annie-France Bringuier, IA
Jean-Yves Scoazec, MD, PhD
G�rard Feldmann, MD, PhD
Emile Darai, MD, PhD

Hum Pathol 2001;32:1190-1196. Abstract quote

Alterations of CD44 proteins, a family of cell adhesion molecule, have been linked with tumorigenesis, carcinogenesis, and prognosis in various neoplasms.

Our aims were to evaluate and compare CD44 isoforms expression patterns in normal myometrium, uterine leiomyomas, and leiomyosarcomas and to correlate CD44 expression with clinicopathologic parameters. Fresh (n = 15) and formalin-fixed, paraffin-embedded (n = 76) tissues samples of myometrium, leiomyomas, and leiomyosarcomas were used for immunoblotting and immunohistochemistry, respectively. Semiquantitative evaluation was made after immunostaining. Monoclonal antibodies were used. By immunoblotting in myometrium and leiomyomas samples, we observed a band at 85 kd, corresponding to the apparent molecular weight of CD44s, and bands at 140 kd with the monoclonal antibodies against CD44v3 and CD44v6.

In leiomyosarcomas, CD44s and CD44v6 were detected, but not CD44v3. By immunohistochemistry, decreased CD44s expression was found in leiomyomas and leiomyosarcomas (73.9% � 16.6% and 82.1% � 20.7%, respectively) compared with myometrium (97.3% � 6.2%; P < .0001). No CD44v6 staining was detected in myometrium, leiomyomas, and leiomyosarcomas. No CD44v3 expression was detected in leiomyosarcomas, whereas myometrium and leiomyomas expressed CD44v3. For the diagnosis of leiomyosarcoma, the absence of CD44v3 staining had a sensitivity, specificity, and positive and negative predictive values of 100%. In patients with recurrence of leiomyosarcomas, CD44s expression was decreased (P = .03).

We conclude that CD44s immunostaining in leiomyosarcomas may have prognostic significance. The loss of CD44v3 expression could be used as a putative diagnostic tool for uterine leiomyosarcomas.

HDAC8 (HISTONE DEACETYLASE 8)

Use of Histone Deacetylase 8 (HDAC8), a New Marker of Smooth Muscle Differentiation, in the Classification of Mesenchymal Tumors of the Uterus.

de Leval L, Waltregny D, Boniver J, Young RH, Castronovo V, Oliva E.

*Department of Pathology, and the daggerMetastasis Research Laboratory, Center for Experimental Cancer Research, University of Liege, Liege, Belgium double daggerJames Homer Wright Pathology Laboratories, Massachussetts General Hospital, Harvard Medical School, Boston, MA.

Am J Surg Pathol. 2006 Mar;30(3):319-327. Abstract quote

Uterine smooth muscle tumors (SMTs) are usually recognized on the basis of their routine morphologic features; however, their distinction from endometrial stromal tumors (ESTs), the second most common mesenchymal tumor of the uterus, is sometimes problematic.

Histone deacetylases (HDACs) were originally identified as nuclear enzymes regulating histone acetylation. We have recently shown that in normal human tissues, HDAC8 is exclusively expressed in the cytoplasm of cells showing smooth muscle differentiation. In this study, we examined HDAC8 expression in SMTs and ESTs of the uterus to determine whether HDAC8 may be a useful diagnostic tool in the classification of problematic uterine mesenchymal tumors. HDAC8 immunohistochemical staining was performed in 15 leiomyomas (LMs), 9 highly cellular leiomyomas (HCLs), 8 epithelioid SMTs, 13 leiomyosarcomas (LMSs), and 17 ESTs, including 3 with sex-cord differentiation and 5 with smooth muscle differentiation. All tumors were also stained for other smooth muscle markers (desmin, h-caldesmon, smooth muscle actin [SMA], smooth muscle myosin heavy chain) and for CD10.

All LMs had moderate to strong expression of all smooth muscle markers. HDAC8 was detected in 8 of 9 HCLs and in all epithelioid SMTs (8 of 8); however, it was weak in 4 epithelioid SMTs. In contrast, desmin, h-caldesmon and smooth muscle myosin were positive in only 2 of 8, 1 of 8 and 4 of 8 epithelioid SMTs, respectively. All smooth muscle markers had similar frequency of staining in LMSs; however, HDAC8 showed overall moderate intensity compared with other smooth muscle markers, which showed stronger staining. HDAC8, h-caldesmon, and smooth muscle myosin did not stain conventional areas of ESTs or ESTs with sex-cord differentiation, whereas SMA and desmin were positive in those areas in 4 of 12 and 3 of 12 ESTs, respectively. Areas of smooth muscle differentiation in ESTs were positive for HDAC8 in all cases, but they were less constantly positive for the other smooth muscle markers. CD10 was expressed in most ESTs (14 of 17), but it was also positive in 15 of 45 SMTs.

In conclusion: 1) HDAC8 seems to be a specific marker of SM differentiation because conventional ESTs and ESTs with sex-cord differentiation are negative for HDAC8, whereas areas of smooth muscle differentiation in these tumors are consistently positive; 2) HDAC8 gives similar results to those obtained with desmin, h-caldesmon, and smooth muscle myosin in both LMs and LMSs, although the staining for HDAC8 in LMSs tends to be less intense; 3) HDAC8 may be a more sensitive marker than desmin and h-caldesmon in epithelioid SMTs. Thus, HDAC8 detection may be useful in helping the differential diagnosis of uterine mesenchymal tumors.

HMB45

HMB-45 Reactivity in Conventional Uterine Leiomyosarcomas.

Simpson KW,

Albores-Saavedra J.

Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA.

Am J Surg Pathol. 2007 Jan;31(1):95-8. Abstract quote

We studied the human melanoma black-45 (HMB-45) reactivity in 25 uterine leiomyosarcomas including 23 conventional and 2 myxoid variants. Eleven tumors were poorly differentiated, and 14 were well to moderately differentiated. Nine uterine leiomyosarcomas labeled with HMB-45 in 10% or less of the tumor cells. Six were poorly differentiated and 3 were well differentiated.

Our study indicates that 36% of conventional leiomyosarcomas focally express HMB-45. HMB-45 reactivity was more common in the poorly differentiated than in the well-differentiated group of leiomyosarcomas.

In light of our findings and of those recently reported in the literature, we believe that the term PEComa should not be used for uterine leiomyosarcomas with clear cells or for conventional leiomyosarcomas that stain positively with HMB-45.

A uterine leiomyosarcoma that became positive for HMB45 in the metastasis.

Silva EG, Bodurka DC, Scouros MA, Ayala A.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Ann Diagn Pathol. 2005 Feb;9(1):43-5. Abstract quote

Uterine smooth muscle tumors are usually spindle cell lesions, but a minority is composed of epithelioid cells. Foci of clear cells can be found in these latter tumors. Recently, it has been shown that some of these tumors can be positive for HMB45, and some authors have advocated calling these lesions perivascular epithelioid cell (PEC) tumors or PEComas. The case we describe here clearly shows that the so called PEC is just a smooth muscle cell capable of changing its immunophenotype.

The patient involved is a 29-year-old black woman who was found to have an epithelioid leiomyosarcoma of the uterus in November 1995. She was treated with a simple hysterectomy and bilateral salpingo-oophorectomy. A metastatic lesion was found in her liver. She, therefore, also received chemotherapy and was free of disease until October 2002, when a recurrent tumor was detected in her spine. After undergoing resection of the lesion at 2 different times, in 2002 and 2003, the patient was treated with radiotherapy and is currently receiving chemotherapy. On microscopic examination, the tumor in the uterus and liver both proved to be an epithelioid leiomyosarcomas that was diffusely positive for smooth muscle actin. Approximately 15% of the cells had clear cytoplasm, but sections from 2 different blocks were completely negative for HMB45. However, although the tumors resected from the spine in 2002 and 2003 showed features similar to those of the uterine neoplasm, but with a lower percentage of cells positive for smooth muscle actin and more clear cells, several of the clear cells were positive for HMB45.

To the best of our knowledge, this is the first case of a uterine smooth muscle cell tumor that became positive for HMB45 when it metastasized.

p16

The Use of p16 in Enhancing the Histologic Classification of Uterine Smooth Muscle Tumors.

Atkins KA, Arronte N, Darus CJ, Rice LW.

Departments of *Pathology †Obstetrics and Gynecology, University of Virginia, Thornton Gynecologic Oncology Service, Charlottesville, VA.

Am J Surg Pathol. 2008 Jan;32(1):98-102. Abstract quote

BACKGROUND: Uterine smooth muscle tumors can usually be divided histologically into leiomyoma (L) and leiomyosarcoma (LMS). Occasionally, the histologic features are indeterminate and classified as smooth muscle tumor of uncertain malignant potential (STUMP). Recent gene expression studies have found p16 overexpressed in LMS when compared with normal myometrium. This study evaluated the protein expression of p16 by immunohistochemistry in LMS, L, and normal myometrium. Additionally, 8 tumors originally classified as STUMP were evaluated for p16 expression and correlated to their clinical outcome.

METHODS: A tissue microarray was constructed and composed of 15 LMS, 8 STUMPs, 22 L, and 10 samples of normal myometrium. p16 expression was correlated with clinical outcome and histologic features.

RESULTS: Twelve of the 15 LMS strongly and diffusely expressed p16, 3 of the L had focal p16 staining, and none of the normal myometria were p16 positive. Three of the tumors originally classified as STUMP developed metastatic disease and 2 of these tumors had strong, diffuse p16 positivity. Histologically, these 2 cases were characterized by coagulative tumor cell necrosis and only mild cytologic atypia.

CONCLUSIONS: p16 is preferentially expressed in LMS with only rare L showing positivity. Histologically, tumors with coagulative tumor cell necrosis alone were clinically LMS. In those cases in which the type of necrosis is uncertain (coagulative tumor cell vs. hyalinized), the addition of p16 may aid in discerning a subset of STUMP that should be classified as LMS.

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

Problematic uterine smooth muscle neoplasms: a clinicopathologic study of 213 cases
Am J Surg Pathol 1994;18:535-558

Bell, Kempson, and Hendrickson analyzed 213 problematic cases and devised a classification scheme to distinguish between the various categories of smooth muscle neoplasms of the uterine corpus. The following summarizes their findings

The following criteria were evaluated:
Degree of cytologic atypia (none to mild OR moderate to marked)
Presence or absence of coagulative necrosis
Mitotic Index (MI)

Smooth muscle tumors with usual differentiation

Leiomyoma
Leiomyoma with increased mitotic index
MI <20 mf/10 hpf
No coagulative necrosis
No atypia or no more than mild cytologic atypia

Leiomyoma with increased mitotic index but experience limited
MI >/=20 mf/10 hpf
No coagulative necrosis
No atypia or no more than mild cytologic atypia

Atypical leiomyoma with low risk of recurrence
MI<10 mf/10 hpf
No coagulative necrosis
Diffuse moderate to severe cytologic atypia (1/46 failed)

Leiomyoma with atypia but limited experience
MI</=10 mf/10 hpf
No coagulative necrosis
Focal moderate to severe cytologic atypia

Leiomyosarcoma
Any MI
Any degree of cytologic atypia with coagulative necrosis (29/39 failed)

Usually there will be significant cytolgic atypia

Leiomyosarcoma MI>/=10 mf/10 hpf
No coagulative necrosis but with diffuse moderate to severe cytologic atypia (4/10 failed)

Smooth muscle tumors with myxoid stroma

Myxoid leiomyoma
MI<5 mf/10 hpf
No or mild atypia
No coagulative necrosis

Myxoid leiomyosarcoma
Any MI
Moderate to marked atypia with or without coagulative necrosis

Smooth muscle tumors with epithelioid differentiation

Epithelioid leiomyoma
MI<5 mf/10 hpf
No coagulative necrosis
No atypia or no more than mild cytologic atypia

Epithelioid leiomyosarcoma

MI>/=5 mf/10 hpf
No coagulative necrosis
None or any degree of cytologic atypia

OR

Any MI
Any degree of cytologic atypia with coagulative necrosis

ADDITIONAL VARIANTS

MIB-1 (Ki-67), p53, estrogen receptor, and progesterone receptor expression in uterine smooth muscle tumors

Khush Mittal, MD
Rita Iovine Demopoulos, MD

Hum Pathol 2001;32:984-987 Abstract quote

The diagnosis of benign, uncertain malignant potential, and malignant uterine smooth muscle tumors depends on mitotic counts, nuclear atypia, and other morphologic features.

This study was undertaken to evaluate the utility of selected immunohistochemical markers in differentiating these tumors. Fifteen cases of cellular leiomyoma, 7 cases of smooth muscle tumor of uncertain malignant potential (STUMP), and 12 cases of leiomyosarcoma were immunostained for MIB-1 (Ki-67), p53, estrogen receptor and progesterone receptor (PR) using monoclonal antibodies and the avidin-biotin-peroxidase method.

The percentage of cells stained was subjectively assessed to the nearest 5%. One percent was used for rare positive cells. MIB-1 expression of 15% was seen in 11 and expression of p53 in 15% cells was present in 5 of 12 leiomyosarcomas. MIB-1 and/or p53 expression of >15% was seen in all 12 leiomyosarcomas but in none of the 7 STUMP or 15 cellular leiomyomas. PR was absent in 10 of 12 leiomyosarcomas but present in 7 of 7 STUMP and 14 of 15 cellular leiomyomas. MIB-1 of 5% to 10% was seen in 6 of 7 STUMP but in only 1 of 15 cellular leiomyomas.

MIB-1, p53, and PR are useful in differentiating leiomyosarcoma from STUMP and cellular leiomyoma. MIB-1 is useful in distinguishing STUMP from cellular leiomyomas.

PROGNOSIS AND TREATMENT CHARACTERIZATION

Prognostic Factors Extension beyond the uterus poor prognosis

DNA COPY NUMBER

Do DNA copy number changes differentiate uterine from non-uterine leiomyosarcomas and predict metastasis?

Svarvar C, etal

1Department of Plastic Surgery, Helsinki University Central Hospital, Helsinki, Finland [2] 2Department of Pathology, Haartman Institute and HUSLAB, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.

Mod Pathol. 2006 Aug;19(8):1068-82. Abstract quote

DNA copy number changes were investigated in 51 (19 uterine and 32 nonuterine) primary leiomyosarcomas by comparative genomic hybridization.

The aim was to evaluate whether true biological differences exist between uterine and nonuterine leiomyosarcoma and whether changes revealed by comparative genomic hybridization have prognostic value. Genomic imbalances were found in 48 (94%) cases. The most frequent DNA copy number changes were losses in 10q (35%), 13q (57%), and 16q (41%), gains in 1q (41%), and gains and high-level amplifications in 17p (39%). Gains were nearly as frequent as losses in both uterine and nonuterine leiomyosarcoma. Correlation-based tree modeling revealed two clusters that segregated significantly a group of uterine (gains at 1q11-q24) and a group of nonuterine (losses at 13q14-q34, 16q11.1-q24, and 10q21-q26) cases. The nonuterine cluster was associated with subcutaneous origin and a trend toward increased metastasis-free survival.

Further explorative analyses identified aberrations associated with shorter metastasis-free survival time, including losses at 2q32.1-q37 and gains at 8q24.1-q24.3, whereas the cases with losses at 6cen-p25 showed longer metastasis-free survival time.

Survival 5YRS between 40-50% for stage I and II tumors

Recurrence Local within the pelvis

Metastasis Lungs most common, less common bones and liver
Lymph node involvement rare

Vascular Invasion

Is vascular and lymphatic space invasion a main prognostic factor in uterine neoplasms with a sarcomatous component? A retrospective study of prognostic factors of 60 patients stratified by stages.

Rovirosa A, Ascaso C, Ordi J, Abellana R, Arenas M, Lejarcegui JA, Pahisa J, Puig-Tintore LM, Mellado B, Armenteros B, Iglesias X, Biete A.

Department of Radiation Oncology, Hospital Clinic i Universitari, Barcelona, Spain.

Int J Radiat Oncol Biol Phys 2002 Apr 1;52(5):1320-9 Abstract quote
BACKGROUND: Sarcomatous neoplasms of the uterine corpus are still a challenge in terms of obtaining prognostic factors and the most optimum complementary treatment to surgery. The most important prognostic factor is stage; relapses usually appear during the first 2 years, and most patients die within the first 3 years. We have performed a multivariate study of prognostic factors, stratifying patients by stage, to determine their impact on overall survival, disease-free survival, local relapse-free survival, and distant metastasis-free survival. Special emphasis has been given to vascular and lymphatic space invasion (VLSI).

METHODS: Sixty patients diagnosed with uterine neoplasms with a main sarcomatous component were treated at Hospital Clinic i Universitari of Barcelona between January 1975 and June 1999. Pathologic type: 32 carcinosarcomas, 14 leiomyosarcomas, 9 adenosarcomas, and 5 endometrial stromal sarcomas. Treatment: 58/60 surgery, 35/60 postoperative radiotherapy, 2/60 exclusive chemotherapy, and 3/60 complementary chemotherapy. FIGO stages: 43 Stage I, 4 Stage II, 11 Stage III, and 2 Stage IV. Variables analyzed: age, stage, vascular and lymphatic space invasion, myometrial invasion, mitotic index, tumor size, unicentricity/multicentricity, necrosis, and radiotherapy. Statistics: the S and Cox proportional risk models. The partial effect of each risk factor was calculated by hazard ratio (HR) with a confidence interval of 95%.

RESULTS: Early stages: Multivariate analysis showed that tumor size larger than 8 cm and VLSI had an impact on overall survival (HR = 4.01 and HR = 24.45, respectively). VLSI was present in 23% of the cases. Myometrial invasion greater than 50% had an impact on disease-free survival and local relapse-free survival (HR was 9.75 and 3.20, respectively). VLSI had an impact on distant metastasis-free survival (HR = 2.92). Advanced stages: VLSI was present in 89% of the cases. Only leiomyosarcoma type made the overall survival worse (HR = 10.54).

CONCLUSIONS: Vascular and lymphatic space invasion was a relevant prognostic factor in our series, with an impact on overall survival and distant metastasis-free survival in early stages. In advanced stages, VLSI had no impact on survival, but was present in 89% of cases. Myometrial invasion >50% had an impact on local relapse. Advanced stages had a more aggressive behavior, and there was a higher incidence of poor prognostic factors in these stages. Nevertheless, prospective studies are still needed on prognostic factors and on the best treatment option.

TREATMENT TAH-BSO

Multiple agent chemotherapy with doxorubicin may produce a response but may not change overall survival

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Commonly Used Terms

Uterus and Cervix

Uterine Leiomyoma

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Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
INCIDENCE	25% of all uterine sarcomas 1% of all uterine corpus malignant tumors
AGE RANGE-MEDIAN	Median 54 years

HISTOLOGICAL TYPES	CHARACTERIZATION
General	Highly cellular tumor composed of smooth muscle cells arranged in intersecting fascicles Infiltrative borders Cytologic pleomorphism Criteria is changing but in general, tumors with >10 mitotic figures/10 hpf are malignant
VARIANTS
CLEAR CELLS
Uterine Epithelioid Leiomyosarcomas With Clear Cells: Reactivity With HMB-45 and the Concept of PEComa Silva, Elvio G MD; Deavers, Michael T MD; Bodurka, Diane C MD�; Malpica, Anais MD* *From the Departments of Pathology and �Gynecologic Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX.**	The American Journal of Surgical Pathology : Volume 28(2) February 2004 pp 244-249 Abstract quote In this study, we investigated HMB-45 expression in epithelioid uterine leiomyosarcomas with clear cell areas. From 12 epithelioid leiomyosarcomas, we selected 5 that had: 1) clear cell areas and 2) spindle cell areas that were at least focally positive for desmin and caldesmon. The patients' ages ranged from 47 to 82 years (mean 64 years). Presenting symptoms were uterine bleeding (three), abdominal pain (one), and a pelvic mass (one). There was no history of tuberous sclerosis or lymphangioleiomyomatosis. One patient had stage II disease, one stage III, and three stage IV. All were treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy. Two received radiotherapy, and three were also treated with chemotherapy. The tumors ranged in size from 4 × 3 × 3 cm to 10 × 7 × 6 cm; all had significant cellular atypia, areas of coagulative necrosis, and between 10 and 90 mitoses per 10 high power fields. Vascular invasion was seen in three cases. The epithelioid component varied from 50% to 90% in each case; and the percentage of clear cells was <1% in one case, 5% in one case, and 10% to 80% in three cases. Smooth muscle actin and desmin were positive in all cases. Four cases were positive for HMB-45 only in the clear cell areas. The tumor with <1% of clear cells was negative for HMB-45. All were negative for S-100 and c-kit. Three patients died of disease at 9, 30, and 32 months; one patient is alive with progressive disease at 6 months, and one patient (stage II disease) is alive with no evidence of disease at 8 months. Unequivocal uterine epithelioid leiomyosarcomas may have clear cells positive for HMB-45. These tumors might belong to the group of lesion designated as PEComas; however, it is advisable to designate them as uterine leiomyosarcomas. In uterine smooth muscle tumors, some epithelioid cells most likely undergo clear cell changes and become positive for HMB-45. It would be advisable to perform this stain in all epithelioid smooth muscle tumors of the uterus.
STUMP or Smooth muscle tumors of undetermined, intermediate, or borderline category	Tumors with mitotic rates ranging between 5-9 mitotic figures/10 hpf See Differential Diagnosis Table Below
Epithelioid leiomyosarcomas	See Differential Diagnosis Table Below
Myxoid leiomyosarcomas	See Differential Diagnosis Table Below
Infiltrating leiomyoma, including leiomyomatosis	Characteristic leiomyoma with infiltrating margins Common pattern is patches of hypercellular, benign smooth muscle throughout large areas of the myometrium
Disseminated peritoneal leiomyomatosis	Numerous small (<2.0 cm) nodules of bland, benign smooth muscle cells, often arranged in a whorled pattern Decidual cells common Pregnancy or functional ovarian tumors commonly associated
Benign metastasizing leiomyoma	Deposits of smooth muscle in lymph nodes, lung, and other organs associated with a morphologically benign uterine smooth muscle tumor Must have no cytologic atypia, tumor cell necrosis, or abnormal mitotic figures By definition, there can be no smooth muscle tumor in another organ that could be the source of the metastasis Mitotic counts are the same as for a leiomyoma
Lipoleiomyoma	Leiomyoma with focal to diffuse fatty differentiation
Neurilemoma-like leiomyoma	Leiomyoma with palisaded nuclei resembling Verocay bodies
Leiomyoma with tubules or glands	Tubules or glands in otherwise characteristic leiomyoma Very rare Must exclude endometrial stromal neoplasms or uterine tumors resembling ovarian sex-cord tumors
Parasitic leiomyoma	Uterine serosal leiomyoma that becomes detached from the uterus and derives blood supply from the omentum, peritoneum, or other pelvic structures Must have benign features Rare, must be in pelvis and not retroperitoneum
Leiomyoma with vascular intrusion	Usual leiomyoma with vascular intrusion is not visible on gross examination but is a microscopic finding within the confines of a leiomyoma
Intravascular leiomyomatosis	Grossly visible fragments of histologically benign smooth muscle extending into vascular spaces and/or microscopic extension of smooth muscle cells into vascular spaces outside the confines of the leiomyoma Epithelioid cells, including clear cells, and fat cells may present Features distinguishing it from intravascular leiomyosarcoma are the same as for distinguishing leiomyoma from leiomyosarcoma
*Leiomyosarcoma of the Uterus with a Florid Intravascular Component (“Intravenous Leiomyosarcomatosis”)* Kathleen C. M. Coard, D.M.; Horace M. Fletcher, D.M. From the Departments of Pathology (K.C.) and Obstetrics and Gynaecology (H.F.), University of the West Indies, Mona, Kingston, Jamaica	Int J Gynecol Pathol 2002;21:182-185 Abstract quote A leiomyosarcoma of the uterus in a 54-year-old woman exhibited striking involvement of large vessels of the myometrium and broad ligament on both gross and microscopic examination. The pattern of vascular involvement resembled that seen in intravenous leiomyomatosis. Imaging studies showed recurrent tumor within the inferior vena cava 3 months after hysterectomy. To our knowledge, this is the first reported such case in the literature, for which we propose the designation intravenous leiomyosarcomatosis of the uterus.

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
Problematic uterine smooth muscle neoplasms: a clinicopathologic study of 213 cases	Am J Surg Pathol 1994;18:535-558 Bell, Kempson, and Hendrickson analyzed 213 problematic cases and devised a classification scheme to distinguish between the various categories of smooth muscle neoplasms of the uterine corpus. The following summarizes their findings The following criteria were evaluated: Degree of cytologic atypia (none to mild OR moderate to marked) Presence or absence of coagulative necrosis Mitotic Index (MI)
Smooth muscle tumors with usual differentiation
Leiomyoma Leiomyoma with increased mitotic index	MI <20 mf/10 hpf No coagulative necrosis No atypia or no more than mild cytologic atypia
Leiomyoma with increased mitotic index but experience limited	MI >/=20 mf/10 hpf No coagulative necrosis No atypia or no more than mild cytologic atypia
Atypical leiomyoma with low risk of recurrence	MI<10 mf/10 hpf No coagulative necrosis Diffuse moderate to severe cytologic atypia (1/46 failed)
Leiomyoma with atypia but limited experience	MI</=10 mf/10 hpf No coagulative necrosis Focal moderate to severe cytologic atypia
Leiomyosarcoma	Any MI Any degree of cytologic atypia with coagulative necrosis (29/39 failed) Usually there will be significant cytolgic atypia
Leiomyosarcoma	MI>/=10 mf/10 hpf No coagulative necrosis but with diffuse moderate to severe cytologic atypia (4/10 failed)
Smooth muscle tumors with myxoid stroma
Myxoid leiomyoma	MI<5 mf/10 hpf No or mild atypia No coagulative necrosis
Myxoid leiomyosarcoma	Any MI Moderate to marked atypia with or without coagulative necrosis
Smooth muscle tumors with epithelioid differentiation
Epithelioid leiomyoma	MI<5 mf/10 hpf No coagulative necrosis No atypia or no more than mild cytologic atypia
Epithelioid leiomyosarcoma	MI>/=5 mf/10 hpf No coagulative necrosis None or any degree of cytologic atypia OR Any MI Any degree of cytologic atypia with coagulative necrosis
ADDITIONAL VARIANTS
MIB-1 (Ki-67), p53, estrogen receptor, and progesterone receptor expression in uterine smooth muscle tumors Khush Mittal, MD Rita Iovine Demopoulos, MD	Hum Pathol 2001;32:984-987 Abstract quote The diagnosis of benign, uncertain malignant potential, and malignant uterine smooth muscle tumors depends on mitotic counts, nuclear atypia, and other morphologic features. This study was undertaken to evaluate the utility of selected immunohistochemical markers in differentiating these tumors. Fifteen cases of cellular leiomyoma, 7 cases of smooth muscle tumor of uncertain malignant potential (STUMP), and 12 cases of leiomyosarcoma were immunostained for MIB-1 (Ki-67), p53, estrogen receptor and progesterone receptor (PR) using monoclonal antibodies and the avidin-biotin-peroxidase method. The percentage of cells stained was subjectively assessed to the nearest 5%. One percent was used for rare positive cells. MIB-1 expression of 15% was seen in 11 and expression of p53 in 15% cells was present in 5 of 12 leiomyosarcomas. MIB-1 and/or p53 expression of >15% was seen in all 12 leiomyosarcomas but in none of the 7 STUMP or 15 cellular leiomyomas. PR was absent in 10 of 12 leiomyosarcomas but present in 7 of 7 STUMP and 14 of 15 cellular leiomyomas. MIB-1 of 5% to 10% was seen in 6 of 7 STUMP but in only 1 of 15 cellular leiomyomas. MIB-1, p53, and PR are useful in differentiating leiomyosarcoma from STUMP and cellular leiomyoma. MIB-1 is useful in distinguishing STUMP from cellular leiomyomas.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
Prognostic Factors	Extension beyond the uterus poor prognosis
DNA COPY NUMBER
Do DNA copy number changes differentiate uterine from non-uterine leiomyosarcomas and predict metastasis? Svarvar C, etal 1Department of Plastic Surgery, Helsinki University Central Hospital, Helsinki, Finland [2] 2Department of Pathology, Haartman Institute and HUSLAB, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.	Mod Pathol. 2006 Aug;19(8):1068-82. Abstract quote DNA copy number changes were investigated in 51 (19 uterine and 32 nonuterine) primary leiomyosarcomas by comparative genomic hybridization. The aim was to evaluate whether true biological differences exist between uterine and nonuterine leiomyosarcoma and whether changes revealed by comparative genomic hybridization have prognostic value. Genomic imbalances were found in 48 (94%) cases. The most frequent DNA copy number changes were losses in 10q (35%), 13q (57%), and 16q (41%), gains in 1q (41%), and gains and high-level amplifications in 17p (39%). Gains were nearly as frequent as losses in both uterine and nonuterine leiomyosarcoma. Correlation-based tree modeling revealed two clusters that segregated significantly a group of uterine (gains at 1q11-q24) and a group of nonuterine (losses at 13q14-q34, 16q11.1-q24, and 10q21-q26) cases. The nonuterine cluster was associated with subcutaneous origin and a trend toward increased metastasis-free survival. Further explorative analyses identified aberrations associated with shorter metastasis-free survival time, including losses at 2q32.1-q37 and gains at 8q24.1-q24.3, whereas the cases with losses at 6cen-p25 showed longer metastasis-free survival time.
Survival	5YRS between 40-50% for stage I and II tumors
Recurrence	Local within the pelvis
Metastasis	Lungs most common, less common bones and liver Lymph node involvement rare
Vascular Invasion
Is vascular and lymphatic space invasion a main prognostic factor in uterine neoplasms with a sarcomatous component? A retrospective study of prognostic factors of 60 patients stratified by stages. Rovirosa A, Ascaso C, Ordi J, Abellana R, Arenas M, Lejarcegui JA, Pahisa J, Puig-Tintore LM, Mellado B, Armenteros B, Iglesias X, Biete A. Department of Radiation Oncology, Hospital Clinic i Universitari, Barcelona, Spain.	Int J Radiat Oncol Biol Phys 2002 Apr 1;52(5):1320-9 Abstract quote BACKGROUND: Sarcomatous neoplasms of the uterine corpus are still a challenge in terms of obtaining prognostic factors and the most optimum complementary treatment to surgery. The most important prognostic factor is stage; relapses usually appear during the first 2 years, and most patients die within the first 3 years. We have performed a multivariate study of prognostic factors, stratifying patients by stage, to determine their impact on overall survival, disease-free survival, local relapse-free survival, and distant metastasis-free survival. Special emphasis has been given to vascular and lymphatic space invasion (VLSI). METHODS: Sixty patients diagnosed with uterine neoplasms with a main sarcomatous component were treated at Hospital Clinic i Universitari of Barcelona between January 1975 and June 1999. Pathologic type: 32 carcinosarcomas, 14 leiomyosarcomas, 9 adenosarcomas, and 5 endometrial stromal sarcomas. Treatment: 58/60 surgery, 35/60 postoperative radiotherapy, 2/60 exclusive chemotherapy, and 3/60 complementary chemotherapy. FIGO stages: 43 Stage I, 4 Stage II, 11 Stage III, and 2 Stage IV. Variables analyzed: age, stage, vascular and lymphatic space invasion, myometrial invasion, mitotic index, tumor size, unicentricity/multicentricity, necrosis, and radiotherapy. Statistics: the S and Cox proportional risk models. The partial effect of each risk factor was calculated by hazard ratio (HR) with a confidence interval of 95%. RESULTS: Early stages: Multivariate analysis showed that tumor size larger than 8 cm and VLSI had an impact on overall survival (HR = 4.01 and HR = 24.45, respectively). VLSI was present in 23% of the cases. Myometrial invasion greater than 50% had an impact on disease-free survival and local relapse-free survival (HR was 9.75 and 3.20, respectively). VLSI had an impact on distant metastasis-free survival (HR = 2.92). Advanced stages: VLSI was present in 89% of the cases. Only leiomyosarcoma type made the overall survival worse (HR = 10.54). CONCLUSIONS: Vascular and lymphatic space invasion was a relevant prognostic factor in our series, with an impact on overall survival and distant metastasis-free survival in early stages. In advanced stages, VLSI had no impact on survival, but was present in 89% of cases. Myometrial invasion >50% had an impact on local relapse. Advanced stages had a more aggressive behavior, and there was a higher incidence of poor prognostic factors in these stages. Nevertheless, prospective studies are still needed on prognostic factors and on the best treatment option.
TREATMENT	TAH-BSO
	Multiple agent chemotherapy with doxorubicin may produce a response but may not change overall survival