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Sarcomas of the Skin
Key Points
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Sarcomas of the skin comprise numerous rare entities that commonly present as nodules or plaques.
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Cutaneous sarcomas exhibit differentiation toward a variety of mesenchymal lineages.
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Dermatofibrosarcoma protuberans, atypical fibroxanthoma, and cutaneous leiomyosarcoma are the most common types.
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Diagnosis is aided by key immunohistochemical, cytogenetic, and molecular diagnostic studies.
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Complete surgical extirpation is the mainstay of therapy.
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Radiotherapy is used as adjuvant therapy in select patients; chemotherapy plays a limited role.
Introduction
Sarcomas of the skin are a heterogeneous group of non-epithelial primary skin neoplasms. These rare tumors are composed of neoplastic spindle, round, or epithelioid cells that exhibit mesenchymal differentiation. Cutaneous sarcomas are histologically classified according to the mature cell type they resemble, including smooth muscle cells, adipocytes, vascular endothelial cells, skeletal muscle cells, fibroblasts, chondrocytes, osteocytes, and Schwann cells, among other cell types ( Table 15.1 ). Cutaneous sarcomas have a different biologic behavior than their subfascial counterparts, and are generally associated with a better prognosis. While cutaneous sarcomas represent a large group of pathologically diverse tumors, there are common themes in the clinical presentation, diagnosis, and treatment. In addition to a general discussion on the management of cutaneous sarcomas, this chapter includes clinicopathologic descriptions of several of the more common subtypes, including dermatofibrosarcoma protuberans (DFSP), atypical fibroxanthoma (AFX), and superficial leiomyosarcoma (SLMS). Other rare tumor types receive more limited discussion. Some sarcomas arsing within the subcutis are also included in this chapter. While these sarcomas are not technically skin sarcomas, they present as superficial tumors that can involve the overlying skin and often exhibit a biologic behavior that should be distinguished from their subfascial counterparts. Kaposi sarcoma, a tumor of vascular origin associated with human herpesvirus-8 infection, is discussed separately in Chapter 16 . Additional vascular neoplasms, such as angiosarcoma and epithelioid hemangiomaendothelioma, are discussed in Chapter 18 .
Table 15.1
Sarcomas Found in or Close to the Skin
| Histologic Type | |
|---|---|
| Adipocytic | Liposarcoma Well differentiated (atypical lipomatous tumor) Dedifferentiated Myxoid and round cell Pleomorphic |
| Fibroblastic/myofibroblastic | Dermatofibrosarcoma protuberans Desmoid fibromatosis Atypical fibroxanthoma (AFX) Acral myxoinflammatory fibroblastic sarcoma Infantile or congenital fibrosarcoma Low-grade fibromyxoid sarcoma Undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma (UPS/MFH) |
| Smooth or skeletal muscle | Superficial leiomyosarcoma (SLMS) Myoepithelial carcinoma Rhabdomyosarcoma Alveolar Embryonal |
| Vascular origin * | Kaposi sarcoma † Angiosarcoma (vasoformative and epithelioid) Epithelioid hemangioendothelioma Atypical vascular lesions |
| Uncertain differentiation | Pleomorphic hyalinizing angioectatic tumor Clear cell sarcoma (melanoma of soft parts) Epithelioid sarcoma Ewing sarcoma Synovial sarcoma |
| Other | Sarcoma metastatic to skin (e.g. leiomyosarcoma to scalp) |
This list is not comprehensive for all sarcomas, but includes sarcomas described as occurring as primary lesions in the skin or subcutis or extending to involve these.
* Discussed in Chapter 18 .
† Discussed in Chapter 16 .
History
Modern concepts of cutaneous sarcomas emerged gradually from small case series and have further evolved with the development of special techniques such as electron microscopy, immunohistochemistry, cytogenetics, and molecular biology. In 1924, Darier and Ferrand recognized the high local recurrence rate of the tumor now known as DFSP. AFX, first described by Helwig in 1961, shows some histologic features of undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma, but is pathogenically distinct and has a much better clinical outcome. While generally characterized by a benign course, case reports later described the metastatic potential of AFX. SLMS was originally described in 1958 by Stout and Hill. While subcutaneous and visceral leiomyosarcoma are known for their metastatic potential, cutaneous leiomyosarcomas have a much lower rate of metastatic potential and are, therefore, considered a separate entity.
Epidemiology
Sarcomas of the skin are rare. Melanoma, carcinomas, and benign mesenchymal skin tumors are much more commonly found than cutaneous sarcomas. Because of their rarity, national cancer registries do not typically report cutaneous sarcomas as a separate category.
Cutaneous sarcomas are variously categorized as ‘non-melanoma skin cancer’, ‘sarcoma’, or ‘miscellaneous tumors’. When categorized as ‘non-melanoma skin cancer’, the relatively uncommon primary cutaneous sarcomas are overshadowed even by relatively unusual cutaneous carcinomas such as Merkel cell carcinoma. Similarly, the more common subfascial sarcomas represent the majority of cases categorized as ‘sarcomas’. Histologic information for the more common cutaneous sarcomas is available through the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. A SEER review of more than 12,000 patients with cutaneous sarcoma published in 2008 included more than 8500 cases of Kaposi sarcoma. Of the approximately 3500 remaining cutaneous sarcomas, DFSP was the most common type, with an incidence of 4.5 per 1 million persons, followed by cutaneous undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma (UPS/MFH) (1.5 per 1 million persons), SLMS (0.6 per 1 million persons) and cutaneous angiosarcoma (0.4 per 1 million persons). These four diagnostic categories accounted for approximately 95% of reported cases after excluding Kaposi sarcoma. Gender distributions indicated that most cutaneous sarcomas other than DFSP were more common in men, and, overall, blacks had a higher incidence of most sarcomas than did whites or Asians.
Of note, the histologic classification of MFH has evolved over time. AFX was originally described as a superficial variant of MFH. Currently most soft tissue pathologists conceptualize AFX and UPS/MFH as separate entities, as discussed further below. AFX is not reportable for SEER databases.
Pathogenesis and etiology
Cutaneous sarcomas typically arise spontaneously without a clear etiology. Ultraviolet (UV) radiation has been associated with development of AFX, and therapeutic irradiation predisposes to DFSP. Cutaneous trauma, in the form of burns, venous stasis ulcers, insect bites, and even tattoos, has been anecdotally associated with SLMS.
Genetic alterations in cutaneous sarcomas have been characterized. Two broad genetic classes of sarcomas are recognized. The first group has simple cytogenetic features as assessed by a traditional karyotype and is associated with a characteristic chromosomal translocation that is usually balanced or a characteristic gene mutation. The second group has complex cytogenetic features and lack known characteristic mutations; aberrations in the telomerase pathway are common. These distinctions hold true for deep, subfascial sarcomas, but there is less cytogenetic information on cutaneous tumors since they are not commonly analyzed in this fashion. Nonetheless, tumors such as DFSP represent the first class with a characteristic translocation between chromosomes 17 and 22 that results in overexpression from the platelet-derived growth factor-β gene ( PDGFβ ).
Another example is clear cell sarcoma, which can be differentiated from melanoma by identification of a reciprocal translocation between chromosomes 12 and 22 that results in fusion of the Ewing sarcoma region 1 gene ( EWSR1 ) and activating transcription factor 1 ( ATF1 ) genes. Translocations and mutations characteristic of particular tumor types are listed in Table 15.2 .
Table 15.2
Genetic Alterations of Sarcomas that May Present in the Skin
| Histologic Type | Genetic Alteration | Involved Gene(s) |
|---|---|---|
| Alveolar rhabdomyosarcoma | t(2;13)(q35;q14) t(1;13)(p36;q14), double minutes t(2;2)(q35;p23) t(X;2)(q35;q13) |
PAX3-FOXO1A fusion PAX7-FOXO1A fusion PAX3-NCOA1 PAX3-AFX |
| Alveolar soft part sarcoma | t(X;17)(p11;q25) | TFE3-ASPSCR1 fusion |
| Angiomatoid fibrous histiocytoma | t(12;16)(q13;p11) t(12;22)(q13;q12) t(2;22)(q33;q12) |
FUS-ATF1 fusion EWSR1-ATF1 fusion EWSR1-CREB1 fusion |
| Atypical fibroxanthoma | C to T transitions C to G transversions |
P53 |
| Clear cell sarcoma (melanoma of soft parts) | t(12;22)(q13;q12) t(2;22)(q34;q12) |
EWSR1-ATF1 fusion EWSR1-CREB1 fusion |
| Dermatofibrosarcoma protuberans | t(17;22)(q22;q13) Ring form of chromosomes 17 and 22 |
COL1A1-PDGFβ fusion COL1A1-PDGFβ fusion |
| Desmoid fibromatosis | Point mutations in β-catenin gene | CTNNB1 |
| Desmoplastic small round cell tumor | t(11;22)(p13;q12) | EWSR1-WT1 fusion |
| Endometrial stromal sarcoma | t(7:17)(p15;q21) t(6;7)(p21;7p15) t(6;10)(p21;p11) |
JAZF1-JJAZ1 fusion JAZF1-PHF1 fusion EPC1-PHF1 fusion |
| Epithelioid sarcoma | Loss of heterozygosity (22q11) | INI1 loss |
| Ewing sarcoma/PNET | t(11;22)(q24;q12) t(21;22)(q12;q12) t(2;22)(q33;q12) t(7;22)(p22;q12) t(17;22)(q12;q12) inv(22)(q12q12) t(16;21(p11;q22) |
EWSR1-FLI1 fusion EWSR1-ERG fusion EWSR1-FEV fusion EWSR1-ETV1 fusion EWSR1-E1AF fusion EWSR1-ZSG FUS-ERG |
| Extraskeletal myxoid chondrosarcoma | t(9;22)(q22;q12) t(9;17)(q22;q11) t(9;15)(q22;q21) t(3;9)(q11;q22) |
EWSR1-NR4A3 fusion TAF2N-NR4A3 fusion TCF12-NR4A3 fusion TFG-NR4A3 fusion |
| Infantile fibrosarcoma | t(12;15)(p13;q26) | ETV6-NTRK3 fusion |
| Inflammatory myofibroblastic tumor | t(1;2)(q22;p23) t(2;19)(p23;p13) t(2;17)(p23;q23) t(2;2)(p23;q13) |
TPM3-ALK TPM4-ALK CLTC-ALK RANB2-ALK |
| Low-grade fibromyxoid sarcoma | t(7;16)(q33;p11) t(11;16)(p11;p11) |
FUS-CREB3L2 fusion FUS-CREB3L1 fusion |
| Myxoid/round cell liposarcoma | t(12;16)(q13;p11) t(12;22)(q13;q12) |
FUS-DDIT3 fusion EWSR1-DDIT3 fusion |
| Synovial sarcoma | t(X;18)(p11;q11) t(X;18)(p11;q11) |
Predominantly SS18-SSX1 fusion SS18-SSX1, SSX2 or SSX4 fusion |
| Well-differentiated liposarcoma | Amplification of 12q13∼15 locus | MDM2 , CDK4 and others |
Other examples of molecular derangements driving tumorigenesis include amplification of the 1213∼15 locus involving the MDM2 gene and others in well-differentiated liposarcoma, and point mutations in CTNNB1 , the gene encoding β-catenin, in desmoid tumors. These two tumors are usually subfascial and large, but can involve the skin from time to time and are mentioned more for illustration of possible molecular mechanisms.
p53 is mutated with loss of function in sarcomas and many other tumors, usually during tumor progression. Its importance in this process is underscored by the many varieties of tumors encountered in Li–Fraumeni syndrome, where one non-functional copy of this gene is inherited with subsequent somatic loss of heterozygosity associated with the tumors encountered in these patients. Characteristic p53 mutations have also been associated with UV radiation and the development of AFX tumors, as discussed in detail in the AFX section below.
General principles of natural history and diagnosis
Natural history
Cutaneous sarcomas typically have a good prognosis, with some propensity for local recurrence but limited metastatic potential, with several exceptions. Epithelioid sarcoma is particularly aggressive, even when superficial. Patients can rapidly develop regional lymph node involvement and distant bony or pulmonary metastases, often within 1 year of the initial diagnosis. In addition, clear cell sarcoma (melanoma of soft parts) resembles malignant melanoma in the propensity to involve lymph nodes prior to giving rise to distant metastases. Very unlike most other sarcomas, these two metastasize early to lymph nodes while most sarcomas bypass lymphoid tissue and involve lung or other distant organ sites as the initial site of metastasis via a hematogenous route. However, as noted above, more superficially located sarcomas tend to be less associated with metastatic behavior, possibly due to their superficial location, but perhaps also because they tend to be of smaller size. The specific histologic types seen in the skin, such as DFSP, are also generally less likely to metastasize.
Biopsy technique
Biopsy is absolutely necessary to establish a new diagnosis of cutaneous sarcoma. A representative specimen should be obtained. Evaluation of a small biopsy specimen may be non-diagnostic or indeterminate. Punch or elliptic excisional biopsies are commonly employed. A high clinical suspicion should prompt re-biopsy if pathologic findings are discordant with the clinical impression. If an incisional biopsy is planned, the orientation of the incision should be carefully planned so as to be easily encompassed by the subsequent therapeutic excision.
Histopathologic diagnosis
In order to differentiate among the various cutaneous sarcomas, a thorough knowledge of the classic histopathologic features and common variant patterns is essential. Supportive immunohistochemical (IHC) studies are essential in the great majority of cases, because the differential diagnosis often includes biologically diverse tumors of epithelial, melanocytic, and lymphoid differentiation. Almost no IHC marker is entirely sensitive or specific. It is essential to interpret the results of a well-chosen panel of markers in the context of all available clinical and histopathologic data. Molecular testing, when applicable, can be extremely helpful in the settings of uncommon clinical scenarios or unusual histologic features (see Table 15.2 for listing).
Concerning hypercellularity can be seen in reactive conditions such as nodular fasciitis, perhaps the most common benign soft tissue tumor misdiagnosed as sarcoma. Nodular fasciitis is associated with sudden rapid onset, usually good circumscription, histologic similarity to cells in tissue culture, and variably fibrous or myxoid stroma. Nodular lesions of verruga peruana, the cutaneous manifestation of Bartonella bacilliformis infection, are proliferations of hypercellular epithelioid and spindle cells that sometimes resemble Kaposi sarcoma, leiomyosarcoma, fibrosarcoma, or spindle cell melanoma. Consideration of an infectious rather than a neoplastic etiology is based on the clinical presentation of miliary or nodular angiomatous lesions in a patient from endemic regions of Peru, Ecuador, or Colombia. Of note, the mere presence of histologically “sarcomatous” elements in a tumor does not necessarily point to a diagnosis of sarcoma. Such elements can occur focally in primary cutaneous malignancies such as melanoma, squamous cell carcinoma, basal cell carcinoma, Merkel cell carcinoma, and various adnexal carcinomas. In addition, sarcoma in the skin is occasionally metastatic from deeper primary tumors, most commonly from leiomyosarcoma of the uterus or to a lesser degree from other sites with additional histologies. Usually these are late events in disease progression and thus clinical history will help establish the diagnosis.
Electron microscopy
Although IHC studies now provide much information regarding cellular differentiation, this was formerly the domain of electron microscopy. Electron microscopy remains a useful modality in selected cases. For example, electron microscopy can sometimes provide clues as to the differentiation of very poorly differentiated neoplasms that have lost expected IHC markers. However, currently this technique is only very rarely employed in most centers.
Other advanced techniques: cytogenetics, in-situ hybridization, and RT-PCR
A number of subfascial sarcomas are associated with characteristic cytogenetic abnormalities that are readily identified on G-banded karyotypes prepared from short-term cell cultures ( Table 15.2 ). This requires procurement of fresh tissue with prompt transport to a specialized cytogenetics laboratory. Cytogenetic evaluation can be employed with larger cutaneous sarcomas when a portion of the tumor can be spared and devoted to establishing a short-term cell culture. In smaller cutaneous tumors, there may not be sufficient neoplastic tissue for such studies.
When fresh tissue is not available, fluorescence in-situ hybridization (FISH) techniques can be employed on archival paraffin-embedded tissue to search for specific locus re-arrangements, such as those involving the EWSR1 locus at 22q12 in Ewing family tumors, clear cell sarcoma, and other deep sarcomas.
Reverse transcription polymerase chain reaction (RT-PCR) can also be used to demonstrate a specific fusion transcript such as the EWSR1–ATF1 resulting from the balanced translocation t(12;22)(q13;q2) in clear cell sarcoma. This technique can be used for fresh, frozen and archival formalin-fixed material as well, though the success yield drops considerably in archival cases older than 5 years. In comparison, since FISH relies on DNA as the analyte rather than RNA for RT-PCR, the former technique is often more robust in older or less well-preserved tissues.
Clinicopathologic features of specific types of cutaneous sarcomas
Dermatofibrosarcoma protuberans
Clinical features
DFSP is a low-grade sarcoma, apparently showing fibroblastic differentiation, that presents as a nodular, cutaneous mass on the trunk or extremities that is slow-growing and rarely metastasizes unless it shows fibrosarcomatous (“higher grade”) differentiation. The head and neck is a less common site. Over time, the tumor takes on a characteristic protuberant appearance that may have one or more nodules ( Fig. 15.1 ). Tumors may be flesh-colored or show a pink or violet-red coloration. DFSP typically affects adults in middle to later life, but has also been described in infants and children. Men and women are affected equally. Unusual presentations include the depressed indurated plaque of non-protuberant (‘atrophic’) DFSP and pedunculated lesions that closely simulate neurofibromas or fibroepithelial polyps. While regional and distant metastases are uncommon, local recurrence rates for DFSP in various reports range from 0% to 60%. The high propensity for local recurrence may be related to tumor growth into the subcutaneous tissue through finger-like extensions, which may preclude complete resection.
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