Spindle Cell Sarcomas

INTRODUCTION

Spindle cell sarcomas are a large group of tumors that can occur in many different locations and have morphologic similarities. They can usually be distinguished by the clinical setting and morphologic clues, notably the low-power patterns and nuclear features (Table 10.1), as well as the use of immunohistochemistry and molecular diagnostic techniques. Sarcomas that are encountered most frequently within the abdomen (e.g., inflammatory myofibroblastic tumor, gastrointestinal stromal tumor, dedifferentiated liposarcoma, follicular dendritic cell sarcoma) are presented in Chapter 5, tumors with smooth muscle differentiation in Chapter 6, and predominantly myxoid sarcomas (e.g., low-grade myxofibrosarcoma, myxoinflammatory fibroblastic sarcoma, extraskeletal myxoid chondrosarcoma) in Chapter 21. Some of the entities included in this chapter are additionally discussed in other chapters. It should also be remembered that spindle cell carcinoma, especially in relation to epithelial structures and viscera, can mimic sarcomas, and similar considerations apply to melanoma and some types of lymphoma. The differential diagnosis is summarized in Tables 10.2 and 10.3.

MALIGNANT PERIPHERAL NERVE SHEATH TUMOR

Clinical Features

Malignant peripheral nerve sheath tumor (MPNST) can show differentiation toward one of the cell types of the nerve sheath, although such differentiation is usually incomplete. MPNST represents about 6% of adult soft tissue sarcomas and a smaller proportion in childhood. It can arise sporadically, following irradiation, or in patients with neurofibromatosis type 1 (NF1). The incidence of malignant change in NF1 is about 4.6%, and individual patients have at least a 10% lifetime risk of developing a malignant neoplasm.¹ The tumors mostly originate in neurofibromas (especially the plexiform type) or in a nerve trunk in proximal extremities, trunk, head and neck region, mediastinum, or retroperitoneum. The usual presentation is as a painful mass, or as a rapid enlargement of a preexisting neurofibroma with neurologic symptoms and signs. Compared
with sporadic examples, in NF1 MPNST develops at a younger age (with a peak in the fourth decade), is more frequent in males, occurs in axial rather than peripheral sites, is more aggressive, and is more likely to show divergent differentiation.

TABLE 10.1 Nuclear Features of Selected Spindle Cell Sarcomas

Tumor Type	Nuclear Morphology
MPNST	Wavy, buckled, arrowhead shape (tapered at one end)
Synovial sarcoma	Short, oval, darkly staining, apparently overlapping
Leiomyosarcoma	Elongated, nontapered (parallel sided), blunt ended
Myofibrosarcoma	Oval or tapered, small distinct nucleolus
Fibrosarcoma	Tapered at both ends
MPNST, malignant peripheral nerve sheath tumor.

The prognosis relates to tumor size, grade, and presence of tumor at surgical resection margins, but this is generally a high-grade sarcoma. Up to 40% recur, and 65% metastasize with 5-year survival of 44%.²

Pathologic Features

Most MPNSTs are large, deep-seated tumors that arise in a nerve trunk or neurofibroma (e-Figs. 10.1 and 10.2). The tumor forms a mass that expands the nerve and, because of its tendency for intraneural spread, has ill-defined margins. The cut surface is solid and can display focal necrosis, hemorrhage, or myxoid change (e-Fig. 10.3). Microscopically, MPNST can manifest spindled, epithelioid, pleomorphic, or rarely small round cell morphology, and a small proportion of high-grade tumors additionally have heterologous elements representing divergent differentiation. The usual spindled tumor is of intermediate to high grade and displays a fibrosarcoma-like parallel or herringbone pattern of highly cellular fascicles (Fig. 10.1, e-Fig. 10.4). Typically, there are cellular and myxoid zones in an alternating pattern with occasional nuclear palisading (e-Figs. 10.5 and 10.6). Other architectural clues to the diagnosis include infiltration of tumor cells into vessel walls (e-Fig. 10.7), neuroid whorls (e-Fig. 10.8), and the occasional presence of small or large collagenous nodules or rosettes (e-Fig. 10.9). The cells are elongated, with scanty cytoplasm and nuclei which are wavy, serpiginous, buckled, or lanceolate, with one end pointed and the other blunt; in its extreme form, the nucleus can appear triangular (Fig. 10.2, e-Fig. 10.10). Pleomorphic or small round cell areas can occur, and mitoses and necrosis are usual. Some MPNSTs are histologically low-grade (neurofibroma-like) and less cellular, although more cellular than neurofibroma and with focal nuclear atypia and mitotic activity (e-Fig. 10.11). The presence of hyaline nodules or “rosettes” should not

be misinterpreted as indicating low-grade fibromyxoid sarcoma (LGFMS), which is less cellular than MPNST, differs in nuclear morphology, is not pleomorphic, and has fibromatosis-like areas with collagen “cracking.” Unusually among sarcomas, MPNST can infiltrate within and expand nerve bundles (e-Figs. 10.12 and 10.13) and thereby extend proximally, and on occasion into the spinal cord.

TABLE 10.2 Differential Diagnosis of Spindle Cell Sarcomas

	Typical Clinical Features	Microscopic Features	Ancillary Investigations
Malignant peripheral nerve sheath tumor	M > F In neurofibromatosis type 1 or sporadic, axial or in limbs Origin in nerve or neurofibroma	Variably cellular and myxoid, fascicular pattern Nuclei wavy, buckled, or lanceolate with one blunt end Palisading, neuroid whorls, vascular wall involvement, collagenous “rosettes”	S100 protein+ (65%), occasional GFAP+, CK+ (but not usually CK7 or CK19), SOX10+
Cellular schwannoma	F > M Middle age Paravertebral in retroperitoneum or pelvis, can erode bone Also submucosal in nose, stomach, or intestine	Thick capsule, subcapsular lymphoid aggregates Fascicles of cells with eosinophilic cytoplasm, focal pleomorphism, occasional mitoses Lacks Antoni A and B areas Lymphocytes, clusters of foamy cells, thick-walled vessels, hemosiderin	S100 protein diffusely+, CD34+ focally, GFAP+ focally, occasional CK+, CD117−
Clear cell sarcoma	Extremities especially lower limb, young adults Subcutaneous or deep soft tissue, related to tendons or aponeuroses	Nests of rounded or spindled cells, round nuclei with central nucleolus, clear or granular cytoplasm Occasional multinucleated cells, melanin pigment in some	S100 protein+, HMB45+ and melan-A+, other markers negative t(12;22)(q13;q12) EWSR1-ATF1 fusion
Perivascular epithelioid tumor	Intra-abdominal, uterine, extremities (rarely)	Nests of ovoid or spindled cells with clear or granular cytoplasm, delicate fibrous septa Malignant variants often epithelioid	SMA+, HMB45+, melan-A+, desmin±, CD117±, S100 protein+ rarely
Synovial sarcoma	Slowly growing mass, any location but mostly around knee	Sheets of uniform short spindle cells with ovoid nuclei and minimal cytoplasm so that nuclei appear to overlap Many mast cells Poorly differentiated synovial sarcoma is a small round cell tumor	CK+, EMA+, bcl-2+, CD99+, S100 protein+, TLE1+, CD34−, CD117− t(X;18)(p11;q11) SS18-SSX fusions
Spindle epithelial tumor with thymus-like differentiation	Adolescents or young adults, in or adjacent to thyroid Can metastasize	Biphasic pattern with mucous glands in spindle cell component Can resemble synovial sarcoma	CK5/6+, CK7+, CK20−, bcl-2+, CD99+, TLE1+ rarely Genetic features of synovial sarcoma absent
Spindle cell (sarcomatoid) carcinoma	Related to epithelial surface or viscus Previous carcinoma at same site	Pleomorphic spindled tumor cells in sheets, sometimes areas of epithelial morphology or overlying dysplasia Nested reticulin pattern Rare osteochondroid or skeletal muscle differentiation	CK+, EMA+, CD34−, SMA±, desmin−, h-caldesmon−
Sarcomatoid mesothelioma	Sheet-like mass involving peritoneal surface or omentum Can present as metastasis History of asbestos exposure	Fascicles of pleomorphic spindle cells, tapered nuclei, scanty cytoplasm, mitoses, necrosis Desmoplastic or hyalinized stroma Epithelioid component in some	CK+, calretinin+, EMA+ occasionally, D2-40+ occasionally, CD34−, bcl-2−
Solitary fibrous tumor	Circumscribed mass in subcutis, deep soft tissue, abdomen, retroperitoneum, thorax, viscera	Circumscribed, not usually encapsulated Distinct cellular and fibrous areas, focal myxoid stroma, patternless short spindle cells Hemangiopericytomatous pattern focally Malignant variant has hypercellularity, mitoses >4 per 10 hpf, necrosis	STAT6+, CD34+, bcl-2+, CD99+
Adult fibrosarcoma	Older adults, rare Deep soft tissue, pelvis retroperitoneum	Herringbone fascicles of spindle cells with tapered nuclei	Some subsets CD34+, other markers negative
Infantile fibrosarcoma	Mostly first year, <4 y Deep soft tissue, rapid growth	Sheets or fascicles of ovoid cells, hemangiopericytomatous pattern, hemorrhage	SMA+ Occasional CK+, ALK− t(12;15)(p13;q25) ETV6–NTRK3 fusion
Inflammatory myofibroblastic tumor	Mesentery, retroperitoneum, lung, other sites	Fascicular, myxoid, sclerosing patterns, mostly bland myofibroblasts, occasional atypical polygonal cells Marked inflammation, especially plasma cells, often present in clumps	SMA+, ALK+ 55% ALK and other gene rearrangements
Low-grade myofibrosarcoma	Head and neck, extremities, retroperitoneum, bone, infiltrative mass, recurs	Cellular fascicles infiltrate muscle Myofibroblastic morphology, mostly uniform, but focal nuclear atypia is diagnostic Occasional necrosis in higher grade tumors	SMA+, desmin±, h-caldesmon−
Leiomyosarcoma	F > M Limbs, head and neck, retroperitoneum, bowel wall or wall of vessel including inferior vena cava, renal vein	Fascicles at right angles Cells elongated with eosinophilic cytoplasm and nontapered nuclei Paranuclear vacuoles Myxoid change, fibrosis	SMA+, desmin+, h-caldesmon+ Occasional CK+ (dot)
Low-grade fibromyxoid sarcoma	Skin, deep soft tissue, limbs/girdles	Fibromatosis-like areas, swirling fibromyxoid transitions, cellular myxoid areas without pleomorphism Some nuclei lozenge shaped, no nucleoli Giant collagenous rosettes	Occasionally SMA+, or CD34+, mostly lacks markers t(7;16)(q34;p11) FUS-CREB3L2 or FUSCREB3L1 fusion, rarely t(11;22(p13;q12), EWSR1-CREB3L1
Fibromatosis, desmoid type	Deep soft tissue, limbs, head and neck, body cavities	Parallel myofibroblasts evenly dispersed in uniform collagen, slit-like and thickwalled vessels, mast cells Normal mitoses acceptable but not nuclear atypia or necrosis	SMA+, nuclear betacatenin+, CD34−
Perineurioma	Skin, subcutis, most locations Subset in colon Intraneural, sclerosing, reticular, and plexiform variants	Spindle cells with long thin nuclei and very long slender terminal processes, in fascicles or perivascular whorls Fibrous or myxoid stroma Usually no atypia	EMA+, claudin-1+, CD34±, beta-catenin−, S100 protein−
Sclerosing epithelioid fibrosarcoma	Deep soft tissue, limbs/girdles, head and neck Can involve or arise in bone	Multinodular, focal calcification Cellular islands in dense fibrosis Nests of ovoid cells, clear cytoplasm, or single files simulating carcinoma Fibrosarcoma-like spindle cell areas in many cases	Occasional and variable expression of bcl-2, EMA, CK, S100 protein. No specific immunophenotype Some have molecular genetic features of low-grade fibromyxoid sarcoma
Spindle cell rhabdomyosarcoma	Children and adolescents in neck or paratestis More aggressive subset in adults	Fascicles of spindle cells resembling smooth muscle, scattered rhabdomyoblasts In adults, high-grade spindle cell sarcoma in fascicles with variable myoid differentiation	Desmin+, myogenin+ (nuclear), MyoD1+ (nuclear) H-caldesmon−
Follicular dendritic cell sarcoma	Omentum, gastrointestinal tract, liver, spleen, soft tissue	Sheets, whorls, and fascicles of ovoid cells Prominent nuclear membranes, speckled chromatin Intimate admixture of lymphocytes Rarely giant cells, pleomorphism, necrosis	CD21/35+, CD23+, S100 protein±, EMA+, D2-40+, fascin+, clusterin+, desmoplakin+, CD45−
Angiosarcoma	Older adults, head and neck, deep soft tissue	Infiltrative, variably cellular nodules, focal vasoformation, epithelioid areas, hemorrhage	CD31+, CD34+, FLI-1+ (nuclear), ERG+, HHV8−.
Kaposi sarcoma	Skin, soft tissue, lymph nodes, viscera	Curved fascicles, mild pleomorphism Intercellular hemorrhage, hyaline globules	HHV8+ (nuclear), CD31+, CD34+, ERG+, D2-40+, CD117+
Intranodal myofibroblastoma	Inguinal lymph node, rarely submandibular node Very rarely recurs	Rim of lymph node Solid, hemorrhagic cut surface Cellular fascicles of slender spindle cells with nuclear palisading Hyaline-walled vessels, amianthoid fibers, hemorrhage, hemosiderin	SMA+, other markers negative
Intimal sarcoma	Older adults Pulmonary trunk or artery, thoracic or abdominal aorta	Undifferentiated pleomorphic sarcoma Spindle and polygonal cells Myxoid change Can show myoid, endothelial, or osseous differentiation	SMA+ focally, other markers according to differentiation

TABLE 10.3 Immunohistochemistry of Selected Malignant Spindle Cell Tumors

	SS	MPNST	Leiomyosarcoma	Rhabdomyosarcoma	Angiosarcoma	Spindle Cell Carcinoma	Melanoma
CK (pan)	+	+^a	+^a	−^a	±	+	−
EMA	+	+^a	+^a	−	±	+	−
S100 protein	±	±	+^a	−	−	−	+
CD34	−	±	−	−	+	−	−
CD31	−	−	−	−	+	−	−
CD99	+	±	−	−	−	−	−
Bcl-2	+	±	−	−	−	±	−
Desmin	−	−	+	+	−	−	+^a
SMA	−	−	+	−	−	+^a	−
H-caldesmon	−	−	+	−	−	−	−
Myogenin	−	−	−	+	−	−	−
P63	−	−		−	−	+	−
TLE1	+	±	−	−	−	−	−
^aRarely.
SS, synovial sarcoma; MPNST, malignant peripheral nerve sheath tumor.

FIGURE 10.1 Malignant peripheral nerve sheath tumor. Core biopsy showing cellular fascicles alternating with myxoid zones.

FIGURE 10.2 Malignant peripheral nerve sheath tumor. Cells have nuclei that are wavy, buckled, diamond shaped, or pointed at one end. Mitoses are evident.

FIGURE 10.3 Immunophenotype of malignant peripheral nerve sheath tumor.

Ancillary Investigations

About 65% of all spindled MPNSTs express S100 protein, usually focally in scattered single cells (Fig. 10.3, e-Figs. 10.14 and 10.15). Other markers sometimes seen in benign nerve sheath tumors such as GFAP are negative or inconsistently expressed, and NSE and PGP 9.5 are too nonspecific to be of diagnostic use. Epithelial antigens are occasionally demonstrable in MPNST, but CK7 and CK19, seen in most monophasic synovial sarcomas (SSs), are usually negative (Table 10.4). Unlike in SS, CD34 is positive in about 25% of MPNST, and bcl-2 is negative or only focally rather than diffusely positive. SOX10 might be of value as it is positive in the majority of MPNST and in only 7% of SSs.³ Additionally, absence of t(X;18) or SS18-SSX fusion gene products on genetic analysis favors MPNST over SS.

Genetic features of MPNST⁴ include inactivation of the tumor suppressor gene NF1 gene in both sporadic cases and those arising in NF1, p53 gene mutations, deletion of INK4A gene (encoding p16,
an inhibitor of CDK4 and CDK6 that affect pRB phosphorylation) on chromosome 9p21,⁵ and changes to other chromosomes including 17p. Electron microscopy shows a spectrum of Schwann cell differentiation with interdigitating cytoplasmic processes and external lamina in S100 protein-positive cases. Such features can be focally present in S100 protein-negative MPNSTs, which can be useful in diagnosis.

TABLE 10.4 Ancillary Investigations in Synovial Sarcoma and Malignant Peripheral Nerve Sheath Tumor

	CK7	SOX10	EMA	S100 Protein	CD99	CD34	Bcl-2	TLE1	t(X;18)
SS	+	−	+	+	+	−	D	D	+
MPNST	−	+	−	+	+	+	F	F, rare	−
SS, synovial sarcoma; +, positive in some cases; −, negative in nearly all cases; D, diffuse; MPNST, malignant peripheral nerve sheath tumor; F, focal.

Variants

Malignant Peripheral Nerve Sheath Tumor with Divergent Differentiation Heterologous elements can be found in MPNST arising in NF1 and rarely in spontaneous examples. These tumors occur mostly in the head and neck region and trunk and can show mesenchymal (osteochondroid or skeletal muscle) differentiation or rarely an epithelial component. MPNST with divergent skeletal muscle differentiation is termed malignant Triton tumor and is characterized by foci of spindled or rounded rhabdomyoblasts (Fig. 10.4, e-Figs. 10.16 and 10.17). These are often sufficiently differentiated to show cross-striations but can readily be demonstrated with immunostaining for desmin (in cytoplasm) and myogenin (in nuclei) (e-Figs. 10.18 and 10.19). The extremely rare malignant glandular Triton tumor additionally contains mucin-secreting glands that can be bland or resemble adenocarcinoma (e-Fig. 10.20) or SS. Glandular elements can also be seen without accompanying rhabdomyoblastic differentiation and can show goblet cells and focal neuroendocrine differentiation, suggesting intestinal differentiation. Angiosarcoma can also occur rarely as a focal component of MPNST (e-Fig. 10.21).

FIGURE 10.4 Malignant peripheral nerve sheath tumor. Focal rhabdomyoblastic differentiation (Triton tumor) is manifested by rounded rhabdomyoblasts. In some cases, this is a spindle cell component that is best seen by immunostaining for desmin and myogenin.

The heterologous elements lie in a background of high-grade spindle cell sarcoma, which displays focal S100 protein positivity but not desmin or cytokeratins. This allows distinction from pure rhabdomyosarcoma and carcinosarcoma, respectively.

Malignant perineurial cell tumor is a very rare neoplasm composed of elongated bipolar cells in which the nuclei have prominent nucleoli and mitotic activity.⁶ Most are of high-grade malignancy (e-Figs. 10.22 and 10.23). The cells are focally immunoreactive for epithelial membrane antigen and have ultrastructural features of perineurial cell differentiation. In theory, other perineurial cell markers (claudin-1, GLUT-1) might be expressed.

SYNOVIAL SARCOMA

Clinical Features

SS is a translocation-associated sarcoma that is unrelated to synovium in origin or differentiation.⁷ A few cases have arisen in the field of therapeutic radiation for other lesions. It is a tumor typically of young adults with a mean age of 34 years, and nearly half the cases arise in patients younger than 30 years. Examples have been described, however, at any age, with a slight predominance in males. SS arises in connective tissue adjacent to joints, but very rarely within them, and has now been reported in virtually all anatomic locations.⁷ The most common of these is the lower limb, especially around the knee joint, followed by upper limb and head and neck, notably in parapharyngeal tissues. The majority occurs in deep soft tissues, but occasional SSs arise in subcutis or skin. The tumor forms a painful or painless mass, with clinical features related to the location. SS can be slowly growing with a very long history and can attain a large size. Most, however, are <10 cm in maximum dimension. Very small tumors (<1 cm) are sometimes seen.⁸ Imaging reveals focal calcification in up to 20% of cases.

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Tags: Biopsy Interpretation of Soft Tissue Tumors

Jun 18, 2016 | Posted by drzezo in PATHOLOGY & LABORATORY MEDICINE | Comments Off

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