Soft Tissue Tumors

All categories of soft tissue tumors have been reported to involve the upper aerodigestive tract. These include neoplasms that show fibroblastic, myofibroblastic, vascular, myogenous, and neural differentiation. Some neoplasms appear more unique to the area, e.g., angiofibroma, while most can occur throughout the soft tissues of the entire body. This chapter will discuss the more common soft tissue tumors that involve this area (neural tumors have been discussed in Chapter 8; bone and cartilagenous tumors will be discussed in Chapter 12).

It should be noted that the vast majority of neoplasms of the upper aerodigestive tract are epithelial and that some of these can show a spindle cell phenotype, e.g., spindle cell or sarcomatoid carcinoma and myoepitheliomas. Also, melanomas frequently show a spindled cell phenotype when they involve this area. These tumors have markedly different prognoses and require different treatments than those for soft tissue tumors. Because of this, one should be comfortable using immunohistochemistry or other methods with the diagnosis of these lesions, and to help exclude epithelial or melanocytic neoplasms (Table 11.1).¹

FIBROBLASTIC/MYOFIBROBLASTIC TUMORS

Fibroblastic or myofibroblastic tumors make up the majority of soft tissue tumors of the aerodigestive tract and range from nonneoplastic or benign proliferations (fibromas) to high-grade malignancies (undifferentiated high-grade pleomorphic sarcomas). Distinguishing between these tumors is important because they have vastly different prognoses (Table 11.2). Such distinctions cannot always be made with small biopsy specimens, however, although high-grade malignancies can usually be distinguished from lower grade neoplasia and reactive conditions.

“Fibroma”

A variety of benign fibrous lesions that may or may not be neoplastic can be found within the upper aerodigestive tract and have been termed “fibromas.” These include nasal and oral fibromas (traumatic/irritation fibromas, peripheral ossifying fibromas, cementifying fibromas, etc.). One should be cautious regarding the use of the term fibroma within the upper aerodigestive tract outside of these lesions.

TABLE 11.1 Immunohistochemical Profiles of Spindled Cell Neoplasms of the Upper Aerodigestive Tract

EMA

S100

HMB

SMA

DES

Myo

β-Cat^a

Bcl-2

CD31

CD34

HHV

CD21

ALK

PAX3

−^b

−

+/−

−

Melanoma

−

+^c

−

+/−

−

Nodular fasciitis

−

Fibromatosis

−

−/+

−

Myofibroma

−

−/+

−

SFT

−

+/−

−

IMT

−/+

−

+/−

−

−/+

LGMFS

−

+/−^d

−

−/+

−

Fibrosarcoma

−

−/+

−

−/+

−

+/−

−

UHGPS

−

+/−

−

−/+

−

LM/LMS

−

Rhabdomyoma

−

+/−

−

ERMS

−

+/−

−/+

−

−/+

Angiofibroma^e

−

Glomangiopericytoma

−

Angiosarcoma

−

−/+

+^f

−

Spindle cell lipoma

−

Synovial sarcoma^g

−/+

−

+/−

−

BSS

−

+/−

−/+

Neurofibroma

−

Schwannoma

−

+/−

−

+/−

−

Neurothekoma

−

MPNST

−

+/−

−

−/+

−

+/−

−

Meningioma

−/+

−

FDCT

−

+/−

−

β-cat, β-catenin; ALK, anaplastic lymphoma kinase; BSS, biphenotypic sinonasal sarcoma; CK, cytokeratin; Des, desmin; EMA, epithelial membrane antigen; ERMS, embryonal rhabdomyosarcoma; FDCT, follicular dendritic cell tumor; HHV, human herpes virus 8; HMB, HMB45; IMT, inflammatory myofibroblastic tumor; LGMFS, low-grade myofibroblastic sarcoma; MPNST, malignant peripheral nerve sheath tumor; Myo, myogenin; SC, sarcomatoid carcinoma; SFT, solitary fibrous tumor; SMA, smooth muscle actin; UHGPS, undifferentiated high-grade pleomorphic sarcoma.

^aNuclear localization.^bSarcomatoid carcinomas can show variable reactivity with antibodies to traditionally mesenchymal antigens (e.g., S100, SMA).^cOther more specific markers for melanoma (e.g., Melan A) can also be used.^dSome LGMFSs are immunoreactive with antibodies to desmin and not with antibodies to SMA.^eThe pattern listed is for the spindled cell component of the tumor.^fKaposi sarcoma.^gThe pattern listed is for the spindled component of the tumor.

TABLE 11.2 Fibroblastic/Myofibroblastic Lesions of the Upper Aerodigestive Trace

Tumor	Site	Helpful Clinical	Helpful Histology	Helpful IHC, etc.
“Fibroma”	Nasal (nasal fibroma) Oral (traumatic, etc.)	Small (<1 cm), often incidental	Low cellular and collagenized	None
Nodular fasciitis	Mouth	Recent, rapidly growing lesion	Loose with chronic inflammation and extravasated red cells	USP6 translocation
Fibromatosis	Throughout the UADT	More common in women	Dense collagen Little atypia or mitotic activity	Nuclear staining with antibodies to β-catenin more likely than with other F/MFLUADT
Myofibroma	Most common in the mouth	Often in children May be multiple	Characteristic hypocellular and hypercellular areas	None
Solitary fibrous tumor	Throughout the UADT	Rarely associated with hypoglycemia	Variable cellularity with hemangiopericytoma-like vasculature	Strong and diffuse immunoreactivity with antibodies to CD34 and STAT6
Inflammatory myofibroblastic tumor	Throughout the UADT	Can be associated with fever, anemia, and thrombocytosis	Different growth patterns with looser, NF-like areas with mixed inflammation, more compact, storiform areas with plasma cells, and more sclerotic areas	Immunoreactivity with antibodies to ALK more likely than with other F/MFLUADT
Low-grade myofibroblastic sarcoma	Most common in the mouth, esp., the tongue	Seen in adults More often in men	Usually hypercellular with low-grade spindled cells arranges in short fascicles	Immunoreactivity with desmin more likely than with other F/MFLUADT
Fibrosarcoma	Throughout the UADT, more common in the sinonasal area	Most often occur in older adults	Very cellular with “herringbone” growth pattern Only mild cellular atypia	None; diagnosis of exclusion
Undifferentiated high-grade pleomorphic sarcoma	Throughout UADT	Most often occurs in older adults	Marked atypia and abundant mitotic activity Often has storiform architecture May have multinucleated giant cells or marked inflammation	Giant cells may be reactive with antibodies to CD68
F/MFLUADT, fibroblastic/myofibroblastic lesions of the upper aerodigestive tract; UADT, upper aerodigestive tract.

Nasal fibromas or fibrous polyps are small, smooth polypoid lesions that develop in or near the nasal vestibule.² They are usually less than 1 cm in size and frequently present incidentally. Histologically, mature fibroblasts are arranged haphazardly within dense collagen (Fig. 11.1, eFigs. 11.1 and 11.2). More than mild cytologic atypia is not seen and mitotic figures are usually not present. The lesions are benign and do not recur after resection.

A number of different lesions occur in the mouth, which have been termed fibroma.³,⁴ These lesions all appear to be reactive, yet have a few differences between them. Traumatic or irritation fibromas are the most common. These are polypoid lesions that are composed of subepithelial, haphazardly arranged, bland fibroblasts within a collagenous stroma. The overlying squamous epithelium can be normal or can show changes consistent with continued trauma such as parakeratosis or acanthosis. The lesions can be ulcerated and chronically inflamed (epulis fissuratum), may have large, stellate fibroblasts (giant cell fibroma), and may contain odontogenic epithelium (retrocuspid papule).⁴ Some mesenchymal cells of the gingiva may have a pluripotent nature and be able to differentiate into either osteoblasts or cementoblasts; thus some apparently reactive fibromas within the mouth can form osteoid or cementum (peripheral ossifying fibroma or peripheral cementifying fibroma, respectively) (Figs. 11.2 and 11.3, eFig. 11.3).⁴ (Ossifying fibroma of the bone will be discussed in Chapter 12.)

FIGURE 11.1 Nasal fibroma with low cellular, somewhat edematous stroma.

FIGURE 11.2 Oral peripheral cementifying fibroma with overlying pseudoepitheliomatous hyperplasia.

Nodular Fasciitis

Nodular fasciitis and its related lesions usually affect the subcutaneous soft tissue.⁵,⁶,⁷,⁸ These lesions have rarely been reported in the mouth and very rarely in the nasal cavity, and one should be wary of diagnosing them elsewhere in the upper aerodigestive tract.⁹,¹⁰ They characteristically affect young adults. Clinically, they present as rapidly enlarging, solitary, and often tender masses and are usually less than 2 cm in size. The lesions do not recur if they are completely resected. They are now considered neoplastic and characteristically have MYH9-USP6 translocations.¹¹

FIGURE 11.3 Cement formation in an oral peripheral cementifying fibroma.

Nodular fasciitis is well-circumscribed; however some minor degree of infiltration into surrounding skeletal muscle can be present.⁵ The tumors are composed of proliferating fibroblasts and myofibroblasts arranged in a haphazard or somewhat storiform appearance in a background loose, somewhat myxoid stroma (Fig. 11.4, eFig. 11.4).⁵,⁶,⁷,¹⁰ Zonation, a characteristic feature consisting of alternating degrees of cellularity within single intermediate-power fields, is usually present. The fibroblasts may be plump but usually show only minimal cytologic or nuclear atypia (Fig. 11.5). Older lesions may have a more collagenized stroma (eFig. 11.5). The number of mitotic figures varies greatly from case to case, but can be high. Background mixed inflammatory cells and extravasated red cells are usually seen (eFig. 11.6). As with other myofibroblastic lesions, the spindled cells are typically immunoreactive with antibodies to SMA (Fig. 11.6).

As nodular fasciitis is neither aggressive nor malignant, it is important to distinguish it from other fibroblastic or myofibroblastic lesions of the area such as fibromatosis and inflammatory myofibroblastic tumor (Table 11.2). Fibromatosis usually does not present as a rapidly growing mass and is not well-circumscribed. Furthermore, while some areas of fibromatosis may be more proliferative, the tumors are generally much more collagenized. Immunostaining with antibodies to β-catenin may also be helpful (see below). Distinguishing nodular fasciitis from inflammatory myofibroblastic tumors in small biopsy specimens may be impossible. Inflammatory myofibroblastic tumors can appear more inflamed and have more sclerotic areas; however, they often have areas very reminiscent of nodular fasciitis. Clinical history and immunostaining with antibodies to ALK1 (see below) may be helpful. Identifying a USP6 translocation, usually with break-apart FISH, can clinch a diagnosis.¹¹

FIGURE 11.4 Nodular fasciitis of the floor of the mouth with a storiform architecture.

FIGURE 11.5 Loose stroma and bland spindled cells in a case of nodular fasciitis.

FIGURE 11.6 Strong SMA immunoreactivity seen with nodular fasciitis.

Fibromatosis

Aggressive or desmoid-type fibromatosis can involve the head and neck and may occasionally be sampled in biopsies from the upper aerodigestive tract.²,¹²,¹³ In one study, involvement of the neck was noted in roughly 20% of the extra-abdominal desmoid tumors studied.¹² The tumors can occur at any age and are somewhat evenly distributed throughout the first five decades of life. Extra-abdominal desmoids occur slightly more often in women, although they are not usually associated with pregnancy. The tumors frequently recur, especially when wide excision is not an option (some have noted that sinonasal tract fibromatoses recur less commonly than other extra-abdominal fibromatosis).¹³ Although the tumors do not, by definition, metastasize, they can cause death due to the local destruction and entanglement of vital structures. This is especially true in the head and neck. Fibromatoses are neoplastic, and cytogenetic abnormalities can frequently be identified, especially involving the long arm of chromosome 5.¹⁴ This is interesting as abdominal fibromatoses have long been recognized to occur with familial adenomatous polyposis syndrome (Gardner syndrome), a hereditary disorder characterized by mutations of the adenomatous polyposis coli (APC) gene, which is located on the long arm of chromosome 5.¹⁵,¹⁶

Grossly, the tumors are white-tan and rubbery and appear whorled and infiltrative.²,¹²,¹³ Histologically, they are composed of interlacing bundles and fascicles of spindled to plump myofibroblasts (Figs. 11.7 and 11.8, eFigs. 11.7 and 11.8). Collagen deposition is usually seen and can vary in amount within a tumor, thus rendering some areas hypocellular in appearance while other areas appear moderately cellular. The margins of fibromatoses are infiltrative and fascicles of spindled myofibroblasts can be seen dissecting through adjacent soft tissues. Frequently, entrapped skeletal muscle can be seen with degenerating changes, and it is important not to confuse these changes with epithelial or multinucleated giant cells (Fig. 11.9, eFig. 11.9). Occasional mitotic figures may be present; however, more than mild cellular or nuclear atypia should exclude the diagnosis.

FIGURE 11.7 A low cellular area in a case of extra-abdominal fibromatosis.

FIGURE 11.8 Bland spindled cells and abundant collagen seen in a case of extra-abdominal fibromatosis.

The neoplastic cells of fibromatoses have an immunophenotype similar to other myofibroblastic tumors and are immunoreactive with antibodies to vimentin and SMA. Focal desmin immunoreactivity can be observed. It has recently been noted that most of these tumors, regardless of whether they actually have β-catenin or APC mutations, will show nuclear localization of β-catenin by immunohistochemistry, and that this can be helpful for distinguishing these tumors from other fibroblastic or myofibroblastic tumors.¹⁷

Myofibroma/Myofibromatosis

Myofibromas are uncommon tumors that have a marked predilection for the head and neck and are somewhat more common in boys and men.¹⁸,¹⁹,²⁰,²¹,²² The tumors can be solitary or multifocal (myofibromatosis). Most solitary myofibromas and cases of myofibromatosis occur in children, although both can be diagnosed at any age. These tumors are most often identified in the mouth when they involve the upper aerodigestive tract. They are generally benign and have even been noted to regress. Multifocal tumors that involve vital structures can sometimes lead to the death of the patient.

FIGURE 11.9 Entrapped, degenerating skeletal muscle cells in a case of extra-abdominal fibromatosis.

Myofibromas can vary in size and are circumscribed but not encapsulated with a whorled or lobulated cut surface.¹⁸ Microscopically, the tumors are composed of haphazardly arranged, interweaving bundles and short fascicles of plump spindled cells (Fig. 11.10).¹⁸,¹⁹,²⁰,²¹ The cytoplasm is pale and eosinophilic and can rarely have small vacuoles. The spindled cells have oval, rounded, or tapered nuclei with vesicular chromatin and small, indistinct nucleoli (Fig. 11.11). The tumors often have hypocellular and hypercellular areas with many small slitlike vessels. In the more cellular areas, the vessels may display a hemangiopericytoid appearance often with the intravascular polypoid projection of tumor (eFig. 11.10). Occasional mitotic figures may be noted (up to 5 per 10 high-powered fields). Despite their gross appearance of circumscription, infiltration of surrounding tissue is usually present with entrapped soft tissue elements (e.g., peripheral nerved or skeletal muscle) (eFig. 11.11). Multinucleated giant cells can be present, as can degenerative myxoid changes and necrosis (eFigs. 11.12 and 11.13). Some cases have abundant stromal collagen.

FIGURE 11.10 Haphazardly arranged myofibroblasts seen in a myofibroma.

FIGURE 11.11 Bland spindled and somewhat stellate cells are seen in this myofibroma.

Immunohistochemically, the tumor cells express SMA and MSA (eFig. 11.14).¹⁸,¹⁹,²⁰,²¹ Antibodies to desmin are usually nonreactive. Focal reactivity with antibodies to S100 protein has been described but most tumors are nonreactive. These tumors need to be distinguished from other myofibroblastic lesions that can be seen with biopsy (Table 11.2). They lack the inflammatory background of inflammatory myofibroblastic tumors and of nodular fasciitis, and the less cellular areas of myofibromas do not have the loose appearance of either of those tumors. The alternating hypocellular and hypercellular areas seen with these tumors are not present in low-grade myofibroblastic sarcomas or fibromatoses, at least not to the same degree.

Extrapleural Solitary Fibrous Tumor

Many sinonasal tract tumors originally described as “hemangiopericytomas” appear to be more closely related to glomus tumors (see below).²³ In fact, once such tumors are reclassified, true solitary fibrous tumors of the upper aerodigestive tract are found to be much less common than they were once believed to be. Nonetheless, small series have been published of these tumors within the sinonasal area and the mouth, while a few scattered case reports have described these tumors in the larynx.²⁴,²⁵,²⁶,²⁷,²⁸,²⁹ The tumors arise submucosally in adults of either sex and may either appear as lumps or as polypoid masses. Solitary fibrous tumors are mostly benign, but some (10%-15%) will behave aggressively and may recur or even metastasize.³⁰ Most tumors have a NAB2-STAT6 translocation.³¹

These tumors are characteristically well-circumscribed rubbery lesions, although circumscription would obviously be difficult to assess with the piecemeal specimens removed for the sinonasal tract.²⁴,²⁵,²⁶,²⁷,³⁰ They usually have admixed hypercellular and hypocellular areas and may have focal myxoid change. The neoplastic cells are bland, spindled to ovoid, haphazardly arranged, and have oval to polygonal nuclei with fine chromatin and inconspicuous nucleoli. These cells are intertwined between collagen fibers of varying thicknesses (Fig. 11.12, eFig. 11.15). Mitotic activity can be present but is usually low (less than 2 mitotic figures per 10 high powered fields), and necrosis should not be seen. In fact, when increased mitotic activity (>3 mitotic figures per 10 high-powered fields), necrosis, marked cytologic atypia, or infiltrative margins are seen, the tumors are more likely to behave malignantly.³⁰,³²,³³ Many thin-walled, small to medium-sized vessels are present that often have a prominent “staghorn” appearance and can focally have a thickened, collagenous cuff (eFig. 11.16). Mast cells are usually present. While some entrapped normal tissue may be present, the lesions rarely infiltrate bony tissues (eFig. 11.17).

FIGURE 11.12 A solitary fibrous tumor of the nasal cavity with numerous spindled cells and entrapped collagen.

FIGURE 11.13 Strong immunoreactivity with antibodies to CD34 is seen with solitary fibrous tumors.

Immunohistochemically, solitary fibrous tumors react strongly with antibodies to STAT6, vimentin, CD34, and bcl-2 (Fig. 11.13).²⁴,³⁴ Some staining, albeit weak, is often seen with antibodies to CD99. Antibodies to specific vascular and muscle markers are usually nonreactive (weak, focal reactivity with antibodies to SMA may rarely be seen). The differential diagnosis for solitary fibrous tumors is broad, and the diagnosis is often considered a diagnosis to be made after the exclusion of numerous other entities. In the sinonasal area, glomangiopericytomas must be excluded. This is easily accomplished by immunostaining the tumors with antibodies to STAT6, CD34, β-catenin, and SMA. At all sites, other tumors, such as synovial sarcomas, fibrosarcomas, myofibroblastic tumors, and various neural tumors, must be excluded (Table 11.1). Unlike synovial sarcomas, solitary fibrous tumors do not express TLE1.³⁵

Inflammatory Myofibroblastic Tumor

Extrapulmonary inflammatory myofibroblastic tumors occur throughout the body. A little more than 10% of these involve the upper aerodigestive tract.³⁶,³⁷,³⁸,³⁹,⁴⁰ The tumors can be found in patients of all ages, but children are more frequently affected. Within the upper aerodigestive tract, they present with the nonspecific symptoms of a mass lesion; however, clinical features can include fever and anemia. Infrequently patients may be found to have thrombocytosis or hypergammaglobulinemia. Some inflammatory myofibroblastic tumors have rearrangements of ALK on the short arm of chromosome 2.⁴¹ The tumors occasionally recur (approximately 20%); however, death from disease is rare.

Grossly, the tumors can range from fleshy to firm and may have hemorrhage, necrosis, or calcification.³⁶,³⁷ The histologic features seen with these tumors can be quite variable and have been generally described as having three different patterns, all of which may be seen in any particular tumor. One pattern resembles granulation tissue or nodular fasciitis and is composed of loosely arrayed, stellate to plump spindled cells with abundant eosinophilic cytoplasm (Figs. 11.14 and 11.15, eFig. 11.18). The cells are embedded within a myxoid or edematous stroma with numerous small blood vessels, a mixed inflammatory infiltrate, and extravasated red cells. Mitotic figures are common but atypical forms are not present. Another pattern is more compact, with the myofibroblasts having a fascicular or storiform growth pattern. Plasma cells are abundant with this pattern and typical mitotic figures can frequently be found (eFigs. 11.19 and 11.20). The third pattern is characteristically less cellular with dense collagen (Fig. 11.16). Fewer mitotic figures are identified in these areas and the inflammatory infiltrate tends to be less prominent. Calcifications can sometimes be seen in these areas.

Immunohistochemically, the myofibroblasts show immunoreactivity with antibodies to vimentin, SMA, and MSA (eFig. 11.21).³⁶ Limited reactivity with antibodies to desmin can be seen; however, tumor cells have not been found to be immunoreactive with antibodies to myoglobin.⁴² Immunoreactivity with antibodies to cytokeratin is seen in up to 36% of the cases. Consistent with the activation of ALK, approximately 30% can be found to overexpress ALK1 by immunohistochemistry.⁴³

FIGURE 11.14 An inflammatory myofibroblastic tumor of the larynx with a cellular appearance somewhat akin to nodular fasciitis.

FIGURE 11.15 A nodular fasciitislike area within an inflammatory myofibroblastic tumor.

These tumors can be distinguished from other myofibroblastic tumors by their characteristic inflammatory infiltrate and variable growth patterns. Occasionally ALK1 immunostaining may be helpful, especially when the tumor expresses the protein; however, some have shown ALK1 staining not to be unique to inflammatory myofibroblastic tumors.⁴³ The large spindled cells with eosinophilic cytoplasm may occasionally appear reminiscent of the rhabdomyoblasts or strap cells seen with embryonal rhabdomyosarcomas. Cross striations and less differentiated areas should not be seen with inflammatory myofibroblastic tumors nor should immunoreactivity with antibodies to myogenin. The characteristic inflammatory cell infiltrate seen with inflammatory myofibroblastic tumors is not usually seen with embryonal rhabdomyosarcomas.

FIGURE 11.16 A more collagenized area within an inflammatory myofibroblastic tumor.

Low-Grade Myofibroblastic Sarcoma

Myofibroblastic differentiation is common in soft tissue neoplasms. The diagnosis of low-grade myofibroblastic sarcoma is used to connote what is believed to be a specific clinicopathologic entity.⁴⁴,⁴⁵ In the two largest reports discussing these lesions, they have been noted to occur more frequently in men and have been limited to adults (although some case reports discuss younger patients). Approximately a quarter of these tumors have been found to develop in the mouth.⁴⁶ The tumors recur in approximately 40% of cases; however, less than 10% have been found to metastasize.

Low-grade myofibroblastic sarcomas are firm and fibrous and most have ill-defined margins; however, they can appear distinctly circumscribed.⁴⁴,⁴⁵ Histologically, the tumors usually appear to infiltrate surrounding soft tissues. Neoplastic cells are arranged in fascicles of varying lengths; however, herringbone, hemangiopericytoid, and storiform growth patterns have been noted. Cellularity can vary, but areas of hypercellularity are always found (Figs. 11.17 and 11.18, eFigs. 11.22 and 11.23). Tumor cells are spindled and have pale, eosinophilic cytoplasm with tapered nuclei (eFig. 11.24). The nuclei have fine or vesicular chromatin and inconspicuous nucleoli. Most cases have little atypia, although occasional examples display moderate atypia with enlarged, pleomorphic, hyperchromatic nuclei and prominent nucleoli. Occasional stellate cells with elongated cell processes may be seen. Mitotic activity is present and up to 10 mitotic figures per 10 high-powered fields have been found. Tumor necrosis may is noted focally in rare cases.

FIGURE 11.17 Most cases of low-grade myofibroblastic sarcoma have areas of high cellularity.

FIGURE 11.18 A low-grade myofibroblastic sarcoma with infiltration into surrounding skeletal muscle.

Immunohistochemically, these tumors react with antibodies to vimentin and SMA and frequently with antibodies to desmin (eFig. 11.25).⁴⁴,⁴⁵ They do not react with antibodies to cytokeratins or S100 protein. Most do not react with antibodies to CD34, although occasional cases may have limited weak staining. This immunohistochemical staining pattern of these tumors should help to distinguish them from other spindle cell lesions, such as neural tumors, solitary fibrous tumor, sarcomatoid carcinoma, and malignant melanoma. It is obviously not very helpful for distinguishing the tumors from smooth muscle tumors or other myofibroblastic proliferations. Low-grade myofibroblastic sarcomas have more atypia than leiomyomas and they have infiltrating borders. Also, the fascicular cell arrangement of leiomyomas is much more pronounced, and the individual cells of those tumors are more eosinophilic with blunted rather than tapered nuclei. Leiomyosarcomas also have more eosinophilic cells and often have a more prominent fascicular appearance. They typically have more cytologic atypia than low-grade myofibroblastic sarcomas.

Distinguishing low-grade myofibroblastic sarcomas from the various other myofibroblastic lesions of the upper aerodigestive tract may be particularly challenging (Table 11.2). Low-grade myofibroblastic sarcomas should be more cellular and show more cytologic atypia than fibromatoses, and fibromatoses are much less frequently immunoreactive with antibodies to desmin. Myofibromas have more plump cells and typically show less cytologic atypia than low-grade myofibroblastic sarcomas. Although, the cellularity of low-grade myofibroblastic sarcomas can vary, the typical biphasic cellularity seen with myofibromas is not seen with these tumors. Like fibromatoses, myofibromas infrequently show immunoreactivity with antibodies to desmin. Finally, inflammatory myofibroblastic tumors typically have a more pronounced inflammatory cell infiltrate and have areas with looser stroma than in low-grade myofibroblastic sarcomas. They also frequently have ALK rearrangements and express ALK1 by immunohistochemistry.⁴⁷

Fibrosarcoma

Fibrosarcomas have been reported to involve the upper aerodigestive tract, especially the sinonasal area.²,⁴⁸,⁴⁹,⁵⁰ Most patients are adults, although rare cases of infantile fibrosarcomas have been reported. Adult fibrosarcomas typically arise in middle-aged or older individuals. Patients present with nonspecific complaints such as pain, obstruction, or bleeding. Destruction of adjacent bone is often seen by imaging. The tumors often metastasize, especially to the lungs, and 5-year survival rate is approximately 50% for adult fibrosarcomas that are grade 2 or higher.⁵⁰

Most adult fibrosarcomas are highly cellular and usually show only limited collagen production (although it is typically present, at least focally) (Fig. 11.19, eFig. 11.26).²,⁵¹ Less cellular areas may, however, be seen within a tumor. The elongated spindled cells are arranged in bundles that often intersect to form the classic “herringbone” pattern (Fig. 11.20, eFig. 11.27). Most tumors have rather uniform cells with spindled to oval nuclei and little pleomorphism. Mitotic figures are usually abundant. Immunohistochemically, fibrosarcomas will react with antibodies to vimentin and may have limited reactivity with antibodies to SMA.⁵²

Adult fibrosarcomas need to be distinguished from a number of lesions including the other fibroblastic and myofibroblastic tumors discussed in this chapter (Tables 11.1 and 11.2). In general, fibrosarcomas are typically more cellular and mitotically active than benign or the lower grade malignancies. Low-grade fibrosarcomas have been reported at this site that are difficult to distinguish from fibromatoses and may have a better prognosis than higher grade (grade 2 or above) fibrosarcomas (eFig. 11.28). Some have suggested using a mitotic count to distinguish these lesions, designating tumors with 6 to 10 mitotic figures per 10 high-powered fields as “borderline” and those with more than 10 as fibrosarcomas. β-Catenin immunostaining may also be helpful. Other spindle celled tumors, especially monophasic synovial sarcomas and malignant peripheral nerve sheath tumors, need to be distinguished from these malignancies. This can usually be accomplished with immunohistochemistry (Table 11.1). Adult fibrosarcomas typically have limited cellular atypia, and more pronounced atypia should lead to a diagnosis of pleomorphic sarcoma. Finally, as with all spindle cell sarcomas of the upper aerodigestive tract, these tumors need to be distinguished from sarcomatoid carcinomas, especially after radiation therapy for squamous cell carcinoma. Intraepithelial neoplasia (squamous dysplasia) or focal squamous differentiation can often be identified with sarcomatoid carcinomas, and many sarcomatoid carcinomas show immunoreactivity with antibodies to cytokeratins.

FIGURE 11.19 High cellularity is the norm for fibrosarcomas.

FIGURE 11.20 A “herringbone” growth pattern is seen with this fibrosarcoma of the maxillary sinus.

Adult fibrosarcoma is a diagnosis now made only after other, better-defined entities have been excluded.⁵³ With this in mind, previous reports of fibrosarcoma of the upper aerodigestive tract should be interpreted with some caution, especially as there appears to be significant overlap between what some might call fibrosarcoma and others might call malignant peripheral nerve sheath tumors.⁴⁹ Recently, some have described a low-grade sarcoma of the sinonasal tract that can have limited myogenic and S100 immunoreactivity, that has both histologic and immunohistochemical features that overlap with these tumors (see below).⁵⁴

Undifferentiated Sarcoma

Undifferentiated sarcomas usually involve the extremities, but have been noted within the upper aerodigestive tract.⁴⁸,⁵⁵,⁵⁶,⁵⁷,⁵⁸ The tumors occur in older adults, often in the sixth and seventh decades of life. Once other lesions such as sarcomatoid carcinomas or dedifferentiated liposarcomas are distinguished from these tumors, it appears that they have an overall poor prognosis with a 5-year survival rate of 50% to 60%.⁴⁸ Interestingly, some of these lesions involving the head and neck have been reported after radiotherapy, which has also been suggested as a risk factor for the transformation of conventional squamous cell carcinomas to a sarcomatoid carcinoma.⁵⁹

Histologically, these tumors have a variable appearance and may appear spindled, epithelioid, round cell or pleomorphic. Pleomorphic tumors are characterized by marked cytologic and nuclear pleomorphism (Fig. 11.21, eFig. 11.29).⁵⁵,⁵⁶,⁵⁷,⁵⁸ Many tumor cells will be spindled, but large round and polygonal tumors cells are often noted with atypical multinucleated tumor cells. Some cells will have abundant eosinophilic cytoplasm and some may appear finely vacuolated. Cellularity is usually high, although some tumors have a myxoid or fibrous background and appear less cellular. Mitotic figures are abundant and necrosis and hemorrhage are common. Osteoclastlike giant cells are often present and can be numerous (Fig. 11.22, eFigs. 11.30 and 11.31). Background inflammation may be present and can occasionally be prominent.

The diagnosis of undifferentiated sarcoma is one of exclusion. In the upper aerodigestive tract, a sarcomatoid or spindle cell carcinoma must first be ruled out. Immunostaining with antibodies to cytokeratin can be helpful, although a lack of staining does not exclude carcinoma. A careful search for a squamous component to the tumor or overlying squamous dysplasia should be made and the identification of either should lead one to diagnose the lesion as a sarcomatoid carcinoma. Dedifferentiated liposarcomas and chondrosarcomas as well as osteosarcomas should be distinguished from these lesions because of their different prognoses, and a careful search for well-differentiated liposarcoma or chondrosarcoma or osteoid production should be made. Immunohistochemistry can be used when needed to distinguish leiomyosarcomas and angiosarcomas from these tumors.

FIGURE 11.21 A storiform growth pattern and moderate cellular atypia is seen with this undifferentiated high-grade pleomorphic sarcoma of the tongue.

FIGURE 11.22 Numerous osteoclastlike giant cells can be seen with some undifferentiated high-grade pleomorphic sarcomas.

Other Myofibroblastic Tumors

Other myofibroblastic tumors have rarely been reported to involve the upper aerodigestive tract, and these include dermatofibromas or benign fibrous histiocytomas, dermatofibrosarcomas, giant cell angiofibroma, infantile fibrosarcomas, low-grade fibromyxoid sarcoma, and sclerosing epithelioid fibrosarcoma, among others. One should keep in mind that most soft tissue tumors can develop in the head in neck and can, either primarily or through secondary extension, come to involve the upper aerodigestive tract.

MYOGENIC TUMORS

Neoplasms showing either smooth muscle or striated muscle differentiation have been identified in the upper aerodigestive tract. Other than rhabdomyosarcomas, most of these tumors occur in adults.

Leiomyomas

Leiomyomas have been described throughout the upper aerodigestive tract but have been most frequently identified in the mouth.⁶⁰,⁶¹,⁶²,⁶³,⁶⁴ As with at other anatomic sites, they appear to be slightly more common in women. These tumors are usually described as small, often less than a centimeter in greatest dimension, and are noted to be circumscribed and rubbery (Fig. 11.23). A variety of histologic appearances have been documented and have been classified as solid or conventional, vascular (angioleiomyoma), and epithelioid. Conventional leiomyomas appear similar to leiomyomas from other sites in the body and are circumscribed, moderately cellular neoplasms with broad fascicles of oval to spindled cells that have a moderate amount of eosinophilic cytoplasm and oval, “cigar-shaped” nuclei (Fig. 11.24, eFig. 11.32). Mitotic figures should be rare and necrosis should not be present. Angioleiomyomas are similar except that they have numerous vascular spaces surrounded by thick, muscular walls (eFig. 11.33).⁶⁰ Epithelioid leiomyomas are very uncommon and are composed of large, epithelioid cells with abundant eosinophilic cytoplasm; spindled cells may be difficult to find.⁶³ Leiomyomas should react with antibodies to smooth muscle antigens such as SMA, MSA, and desmin (eFigs. 11.34 and 11.35).⁶³,⁶⁴ For the most part, these tumors show a typical morphology, and with their immunophenotype, they should be readily distinguished from other spindle cell tumors. As their name indicates, these tumors behave in a benign fashion and have not been noted to recur or metastasize. If necessary, desmin immunoreactivity can usually be used to exclude tumors with pericytic differentiation (e.g., myopericytoma) that can appear similar to angioleiomyomas.⁶⁵

FIGURE 11.23 Leiomyomas are typically well-circumscribed.

Leiomyosarcomas

Leiomyosarcoma are very uncommon in the upper aerodigestive tract.⁶¹,⁶²,⁶⁴,⁶⁶,⁶⁷,⁶⁸ They have been noted in the mouth, sinonasal area, pharynx, and larynx. The tumors have mostly arisen in adults, and the small studies that exist have not shown a definitive sex predilection. The tumors vary greatly in size, and a single tumor that was only 3 mm in greatest dimension has been reported.⁶⁶ Histologically, the tumors are infiltrative rather than circumscribed. They are composed of fascicles of spindled cells with eosinophilic cytoplasm; however, cytologic features of malignancy are also seen, with cellular and nuclear atypia, increased mitotic activity, and tumor necrosis (Fig. 11.25, eFig. 11.36). Smooth muscle differentiation should be identified by immunohistochemistry. Leiomyosarcomas metastasize in more than 50% of the patients affected, and nearly one-third of these patients may die of their disease.

FIGURE 11.24 The typical cigar-shaped nuclei of a leiomyoma.

Rhabdomyoma

Rhabdomyomas are benign tumors showing striated muscle differentiation. The adult and fetal forms have a marked predilection for involving the mucosa of the upper aerodigestive tract.⁶²,⁶⁹,⁷⁰,⁷¹,⁷² A single case has been reported in a patient with Birt-Hogg-Dube syndrome.⁷³

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