**Metastatis of Soft Tissue Sarcomas**

 Fethi Derbel et al.<sup>∗</sup> 

*Department of Surgery, University Hospital Sahloul, Sousse Tunisia* 

## **1. Introduction**

262 Soft Tissue Tumors

Wadayama B, Toguchida J, Yamaguchi T, et al: p53 expression and its relationship to DNA

Although soft-tissue sarcomas account for <1% of all malignancies, they represent a high percentage of cancer-related deaths worldwide [1]. These tumors may arise in virtually any anatomic site, but most originate in an extremity (59%), the trunk (19%), the retroperitoneum (15%), or the head and neck (9%) [2]. Currently, more than 50 histologic types of soft tissue sarcoma have been identified, but the most common are malignant fibrous histiocytoma (28%), leiomyosarcoma (12%), liposarcoma (15%), synovial sarcoma (10%), and malignant peripheral nerve sheath tumors (6%) [3]. Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood.

## **2. The role of the pathology**

As part of the evaluation by a specialist multidisciplinary team, accurate histological characterisation is essential before initiating treatment. The mainstay of diagnosis is histological interpretation±immunohistochemistry, although cytogenetic and molecular genetics investigations and, occasionally, electron microscopy are useful ancillary tools. Cytological analysis of fine-needle aspirates has a limited role in primary diagnosis, but can be used to confirm recurrent disease, or nodal metastases.

The histopathology report is an interpretation based on tumour morphology and immunoprofile in the available sampled tissue, and clinicopathological correlation is mandatory.

Diagnosis is most frequently made on needle core biopsy material, and tumour subtype and grade can be determined in about 80% of core biopsies [4], although pathologists experienced in examining soft tissue tumours have a diagnostic accuracy of 95-99% [4,5]. The amount of tissue can be a limitation, as the biopsy may not represent the entire, frequently heterogeneous tumour, or may miss the tumour. For this reason, correlation

<sup>∗</sup> Sonia Ziadi¹, Medi Ben Hadj Hamida², Jaafar Mazhoud², Mohamed Ben Mabrouk², Abdallah Mtimet², Sabri Youssef², Ajmi Chaouch³, Ali Ben Ali², Ibtissam Hasni⁴, Mrad Dali Kaouthar⁴, Jemni Hela⁴, Moncef Mokni¹ and Ridha Ben Hadj Hamida²

*<sup>1</sup>Department of Pathology, University Hospital Farhat Hached, Sousse, Tunisia 2Department of Surgery, University Hospital Sahloul, Sousse, Tunisia* 

*<sup>3</sup>Department of Anesthesiology and Intensive Care, University Hospital Sahloul, Sousse, Tunisia 4Department of Medical Imaging, University Hospital Sahloul Sousse, Tunisia*

Metastatis of Soft Tissue Sarcomas 265

Fig. 1. Abdominal magnetic resonance imaging showing a 5-cm hepatic mass of segment V [26].

Fig. 2. Operative view showing a large firm mass in segments V and VI of the liver [26].

between the clinicoradiological features and the histopathology report is essential, and rebiopsy considered if there is any discrepancy.

The mitotic count, amount of necrosis and degree of cellular atypia can be underrepresented in biopsies, and a significant proportion of tumours are upgraded after subsequent resection.

The limitations of histology should be appreciated. There is notable morphological overlap between different groups of malignant tumours, with different clinical behaviours and therapeutic responses.

Some tumours are resected after neoadjuvant chemotherapy, or post-adjuvant chemotherapy or radiation. Post-treatment changes include stromal fibrosis and tumoral infarct, the latter difficult to distinguish from necrosis, making grading difficult. Radiation can cause reactive atypia of stromal fibroblasts, obscuring distinction between tumour and stromal tissue.

The clinical behavior of most soft tissue sarcomas is similar and, as defined by the

staging system, is determined by the anatomic location (depth), grade, and size of the tumor. The histologic grade of a soft tissue sarcoma remains the most important prognostic factor.

The features that define the grade are the degree of cellularity, differentiation, pleomorphism, and necrosis as well as the number of mitoses. Certain tumors have an assigned grade based on the histologic diagnosis (eg, Grade 1 for well-differentiated liposarcomas; Grade 3 for rhabdomyosarcoma).

#### **3. Metastasis of sarcomas**

The current American Joint Committee on Cancer (AJCC) staging criteria for soft tissue sarcomas rely on the histologic grade, the tumor size and depth, and the presence of distant or nodal metastases [6]. In the 2002 AJCC staging system, four tumor grades are designated: well differentiated (G1), moderately differentiated (G2), poorly differentiated (G3), and undifferentiated (G4). In this four-tiered system, Grades 1 and 2 are considered low grade and Grades 3 and 4 are considered high grade [6]. Some recommend using other grading systems based on necrosis [7]or mitoses and necrosis [8].

The metastatic potentials for soft tissue sarcomas by grade are as follows: 5% to 10% for lowgrade lesions, 25% to 30% for intermediate grade lesions, and 50% to 60% for high-grade tumors [9].

 Superficial sarcomas are generally less aggressive than their deeper counterparts; for example, atypical fatty tumours in the subcutis do not metastasise or dedifferentiate and rarely recur, unlike similar intramuscular or retroperitoneal tumours [10].

The dominant pattern of metastasis is hematogenous. Lymph node metastasis of soft tissue sarcomas is rare; less than 5% show nodal spread. A few histologic subtypes, including rhabdomyosarcoma, epithelioid sarcoma, synovial sarcoma, angiosarcoma, clear cell sarcoma, and malignant fibrous histiocytoma, show a higher incidence of nodal involvement (10% to 20%) [11]. Alveolar rhabdomyosarcoma can present with widespread nodal as well as bone marrow metastases. Myxoid liposarcoma is known for metastasizing to other soft tissue sites [10].

Distant metastases occur most often to the lung. Of patients with extremity sarcoma, approximately 20% will have isolated pulmonary metastatic disease at some point in the course of their disease [12]. Although pulmonary metastases most commonly arise from

between the clinicoradiological features and the histopathology report is essential, and

The mitotic count, amount of necrosis and degree of cellular atypia can be underrepresented in biopsies, and a significant proportion of tumours are upgraded after subsequent resection. The limitations of histology should be appreciated. There is notable morphological overlap between different groups of malignant tumours, with different clinical behaviours and

Some tumours are resected after neoadjuvant chemotherapy, or post-adjuvant chemotherapy or radiation. Post-treatment changes include stromal fibrosis and tumoral infarct, the latter difficult to distinguish from necrosis, making grading difficult. Radiation can cause reactive atypia of stromal fibroblasts, obscuring distinction between tumour and

staging system, is determined by the anatomic location (depth), grade, and size of the tumor. The histologic grade of a soft tissue sarcoma remains the most important prognostic

The features that define the grade are the degree of cellularity, differentiation, pleomorphism, and necrosis as well as the number of mitoses. Certain tumors have an assigned grade based on the histologic diagnosis (eg, Grade 1 for well-differentiated

The current American Joint Committee on Cancer (AJCC) staging criteria for soft tissue sarcomas rely on the histologic grade, the tumor size and depth, and the presence of distant or nodal metastases [6]. In the 2002 AJCC staging system, four tumor grades are designated: well differentiated (G1), moderately differentiated (G2), poorly differentiated (G3), and undifferentiated (G4). In this four-tiered system, Grades 1 and 2 are considered low grade and Grades 3 and 4 are considered high grade [6]. Some recommend using other grading

The metastatic potentials for soft tissue sarcomas by grade are as follows: 5% to 10% for lowgrade lesions, 25% to 30% for intermediate grade lesions, and 50% to 60% for high-grade

 Superficial sarcomas are generally less aggressive than their deeper counterparts; for example, atypical fatty tumours in the subcutis do not metastasise or dedifferentiate and

The dominant pattern of metastasis is hematogenous. Lymph node metastasis of soft tissue sarcomas is rare; less than 5% show nodal spread. A few histologic subtypes, including rhabdomyosarcoma, epithelioid sarcoma, synovial sarcoma, angiosarcoma, clear cell sarcoma, and malignant fibrous histiocytoma, show a higher incidence of nodal involvement (10% to 20%) [11]. Alveolar rhabdomyosarcoma can present with widespread nodal as well as bone marrow metastases. Myxoid liposarcoma is known for metastasizing

Distant metastases occur most often to the lung. Of patients with extremity sarcoma, approximately 20% will have isolated pulmonary metastatic disease at some point in the course of their disease [12]. Although pulmonary metastases most commonly arise from

rarely recur, unlike similar intramuscular or retroperitoneal tumours [10].

The clinical behavior of most soft tissue sarcomas is similar and, as defined by the

rebiopsy considered if there is any discrepancy.

liposarcomas; Grade 3 for rhabdomyosarcoma).

systems based on necrosis [7]or mitoses and necrosis [8].

**3. Metastasis of sarcomas** 

to other soft tissue sites [10].

therapeutic responses.

stromal tissue.

factor.

tumors [9].

Fig. 1. Abdominal magnetic resonance imaging showing a 5-cm hepatic mass of segment V [26].

Fig. 2. Operative view showing a large firm mass in segments V and VI of the liver [26].

Metastatis of Soft Tissue Sarcomas 267

Fig. 4. Histological examination showing spindle-shaped and pleomorphic malignant cells intermingled with bizarre giant cells and inflammatory cells with a storiform pattern [26]. Other large series including all histologic types of high-grade sarcoma have reported unusual metastatic patterns. Potter et al found 15 distant extrapulmonary metastases in their series of 563 patients (2.7%) [20]. Vezeridis et al [21] also documented extrapulmonary distant metastases, but both of these studies were failing to demonstrate a consistent pattern

In our experience, over a period of 10 years (1998-2007), 13,737 cases of cancer are registered in the central region of Tunisia. 357 (2.6%) cases are soft tissue sarcomas, and 40 (11.2%) of

Histological types who give most metastases are synovial sarcoma, stromal tumor and undifferentiated sarcoma (Table No. I). The lung was the most common site of metastatic

Postulating that soft-tissue sarcomas metastasize via the venous system may account for the predominance of distant recurrence in the lungs. The mechanism of extrapulmonary metastasis is less clear. In 1946, Tedeschi [22] proposed the concept of pluricentric anlage, referring to systemically altered lipid metabolism causing stimulation of undifferentiated mesenchymal cells to explain patients he observed with fatty tumors in multiple soft-tissue locations. While this concept has been used to explain the development of multiple subcutaneous nodules in patients with neurofibromatosis, it seems to be a less robust explanation for the usual clinical course of sarcoma [23]. The mechanism of unusual distant

in terms of anatomic location of the initial unusual metastatic site.

them were diagnosed with metastatic disease.

sarcomas.

metastasis remains obscure.

Fig. 3. Section in the mass in segments V and VI [26].

primary tumors in the extremities, they may arise from almost any histologic variant or primary site [13]. Extrapulmonary metastases usually appear after lung metastasis and represent disseminated disease [14]. Initial metastases to other sites such as the liver, brain, and soft tissue distant from the primary tumor are rare [15, 16]. In our study, we report one case of liver metastases of malignant fibrous histiocytoma[fig 1-4]. Pezzi et al. reported that most metastases of MFH occurred in the lungs (90%), followed by bone (8%). However, liver metastases of this tumour are very rare (1%) [24] [26].

Liposarcoma has a documented tendency for spread to distant extrapulmonary sites other than regional lymph nodes [17, 18, 19]. Cheng et al [17] reported on 60 patients with extremity liposarcoma, of which 22 developed metastases. Of these 22 liposarcoma patients, 13 had exclusively extrapulmonary disease on recurrence.

Distant soft tissue was the most common location of unusual initial spread reported by Cheng et al, including the brain and abdomen [17]. Many investigators have noted an increased prevalence of myxoid liposarcoma to exhibit unusual metastases compared to other subtypes of liposarcoma [19].

primary tumors in the extremities, they may arise from almost any histologic variant or primary site [13]. Extrapulmonary metastases usually appear after lung metastasis and represent disseminated disease [14]. Initial metastases to other sites such as the liver, brain, and soft tissue distant from the primary tumor are rare [15, 16]. In our study, we report one case of liver metastases of malignant fibrous histiocytoma[fig 1-4]. Pezzi et al. reported that most metastases of MFH occurred in the lungs (90%), followed by bone (8%). However, liver

Liposarcoma has a documented tendency for spread to distant extrapulmonary sites other than regional lymph nodes [17, 18, 19]. Cheng et al [17] reported on 60 patients with extremity liposarcoma, of which 22 developed metastases. Of these 22 liposarcoma patients,

Distant soft tissue was the most common location of unusual initial spread reported by Cheng et al, including the brain and abdomen [17]. Many investigators have noted an increased prevalence of myxoid liposarcoma to exhibit unusual metastases compared to

Fig. 3. Section in the mass in segments V and VI [26].

metastases of this tumour are very rare (1%) [24] [26].

13 had exclusively extrapulmonary disease on recurrence.

other subtypes of liposarcoma [19].

Fig. 4. Histological examination showing spindle-shaped and pleomorphic malignant cells intermingled with bizarre giant cells and inflammatory cells with a storiform pattern [26].

Other large series including all histologic types of high-grade sarcoma have reported unusual metastatic patterns. Potter et al found 15 distant extrapulmonary metastases in their series of 563 patients (2.7%) [20]. Vezeridis et al [21] also documented extrapulmonary distant metastases, but both of these studies were failing to demonstrate a consistent pattern in terms of anatomic location of the initial unusual metastatic site.

In our experience, over a period of 10 years (1998-2007), 13,737 cases of cancer are registered in the central region of Tunisia. 357 (2.6%) cases are soft tissue sarcomas, and 40 (11.2%) of them were diagnosed with metastatic disease.

Histological types who give most metastases are synovial sarcoma, stromal tumor and undifferentiated sarcoma (Table No. I). The lung was the most common site of metastatic sarcomas.

Postulating that soft-tissue sarcomas metastasize via the venous system may account for the predominance of distant recurrence in the lungs. The mechanism of extrapulmonary metastasis is less clear. In 1946, Tedeschi [22] proposed the concept of pluricentric anlage, referring to systemically altered lipid metabolism causing stimulation of undifferentiated mesenchymal cells to explain patients he observed with fatty tumors in multiple soft-tissue locations. While this concept has been used to explain the development of multiple subcutaneous nodules in patients with neurofibromatosis, it seems to be a less robust explanation for the usual clinical course of sarcoma [23]. The mechanism of unusual distant metastasis remains obscure.

[25]

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Metastatis of Soft Tissue Sarcomas 269

Liver metastasis of GIST are frequent. It mainly occurs after incomplete resection of the primitive lesion. Surgical resection is the preferred treatment, but there is a high rate of recurrence. Imatinib is the treatment of choice for these cases. With effective treatment, GIST becomes entirely cystic. Upon reactivation, the cysts develop intracystic enhancing nodules

We report a case of liver metastasis of GIST that occurred three years after the incomplete resection of the intestinal tumor treated with Imatinib. The CT scan showed the

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Table 1. Histological type of sarcoma stage IV and metastatic sites (1998-2007: The Central region of Tunisia)

Liver metastasis of GIST are frequent. It mainly occurs after incomplete resection of the primitive lesion. Surgical resection is the preferred treatment, but there is a high rate of recurrence. Imatinib is the treatment of choice for these cases. With effective treatment, GIST becomes entirely cystic. Upon reactivation, the cysts develop intracystic enhancing nodules [25]

We report a case of liver metastasis of GIST that occurred three years after the incomplete resection of the intestinal tumor treated with Imatinib. The CT scan showed the development of intracystic enhancing nodules within Six months of Imatinib.

## **4. References**

268 Soft Tissue Tumors

Fig. 5. Abdominal CT scan showing multiple cystic metastasis of a GIST with intracystic

**Histologic type All of cases Sarcomas Stage IV Metastatic site** 

stromal tumor (GIST) **33 7** (21.21%) liver (6), peritonium

Synovialosarcoma **21 6** (28.57%) Lung (6), bone (2) Leiomyosarcoma **26 5** (19.23%) Lung (6), bone (2),

Ewing sarcoma **7 3** (42.85%) Lung (3), brain (1)

histiocytoma **25 2** (8%) peritonium (1),

round cell tumor **8 2** (25%) Rectum (1), bladder

Rhabdomyosarcoma **23 3** (13%) Lung (1),

Fibrosarcoma **14 1** (7.14%) Liver (1)

Other sarcomas **118 0 Total 357 40** (11.2%) Table 1. Histological type of sarcoma stage IV and metastatic sites Lung (6), liver (5), bone (1), lymph

lymph node (1)

peritonium (2)

lymph node (1)

node (1)

(1)

(1)

Undifferentiated sarcoma **82 11** (13,41%)

enhancing nodules

Malignant fibrous

Desmoplastic Intrabdominal

(1998-2007: The Central region of Tunisia)


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## *Edited by Fethi Derbel*

Soft tissue tumors include a heterogeneous group of diagnostic entities, most of them benign in nature and behavior. Malignant entities, soft tissue sarcomas, are rare tumors that account for1% of all malignancies. These are predominantly tumors of adults, but 15% arise in children and adolescents. The wide biological diversity of soft tissue tumors, combined with their high incidence and potential morbidity and mortality represent challenges to contemporary researches, both at the level of basic and clinical science. Determining whether a soft tissue mass is benign or malignant is vital for appropriate management. This book is the result of collaboration between several authors, experts in their fields; they succeeded in translating the complexity of soft tissue tumors and the diversity in the diagnosis and management of these tumors.

Soft Tissue Tumors

Soft Tissue Tumors

*Edited by Fethi Derbel*

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