Statistically, the most common spindle cell tumors of apparent dermal or mucosal origin are not of mesenchymal lineage but rather spindle cell epithelial (typically squamous cell) or melanocytic tumors. The cytomorphology will usually indicate malignancy with high-grade cytology, necrosis, and increased mitotic activity, which should initiate lineage-directed workup.

Useful features include identification of a concurrent in situ lesion evidencing parallel immunohistochemical characteristics (e.g., aberrant p16, p53 for carcinoma; BRAF, PRAME for melanoma), and variable expression of high-molecular weight cytokeratins (CK5/6, AE1/AE3) or melanocyte-specific markers. Awareness of the pseudoepitheliomatous induction overlying a granular cell tumor (the latter a nested to diffuse proliferation of bland polygonal cells with abundant granular eosinophilic cytoplasm, round homogenous nuclei, and positivity for PAS/SOX10/S100) can avoid misdiagnosis as a squamous cell carcinoma (Figure 1A, B; Tables 3 and 4).1, 2, 3

Distinction between the nosologically related atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) is still controversial. Diagnosis of AFX should never be rendered on biopsy material but rather as on the differential with PDS, deferring definitive classification to the resection specimen. AFX and PDS are rapidly growing, ulcerating lesions which present on the sun-damaged actinic skin (often scalp) of elderly males. Both are comprised by fascicles to hypercellular sheets of severely atypical fibroblastic, histiocytoid, and epithelioid cells with brisk – even atypical – mitotic figures, and scattered osteoclast-like giant cells (Figure 1C). AFX (in contrast to PDS) should not harbor coagulative necrosis, lymphovascular or perineural invasion, and infiltration of the subcutaneous tissue (the latter not adequately evaluated on biopsy). IHC fails to demonstrate evidence of specific cellular differentiation with negativity for cytokeratins, desmin, S100, SOX10, p63, ERG, and CD34. As such, AFX/PDS are diagnoses of exclusion after other dermal malignancies (spindle carcinoma/melanoma, leiomyosarcoma, cutaneous angiosarcoma) are plausibly excluded (Table 3)4, 5, 6, 7, 8, 9, 10, 11, 12, 13

Lesions of fibroblastic/myofibroblastic differentiation show frequently hypercellular proliferations of bland to reactive-appearing spindle cells. Fibroblasts have tapered nuclei with wispy pale stellate cytoplasmic processes and variable positivity for CD34. Myofibroblasts have fusiform nuclei with moderate pale amphophilic cytoplasm, are frequently arranged in elongated fascicles, and are immunoreactive to SMA, MSA, calponin, and rarely desmin and keratins (Table 1). The lesional periphery is typically not appreciable in biopsy specimens, but infiltration is intrinsic to most of these neoplasms and should not be interpreted as unequivocal evidence of malignancy.

Nodular fasciitis (NF) in the head and neck presents as a well-defined superficial mass in young adults with a history of rapid growth and/or recent trauma. Cranial fasciitis (CF) is a morphologic analog but presents in the scalp of pediatric patients <2 years of age and can erode into the adjacent cortical cranial vault. These erstwhile termed ‘pseudosarcomatous fasciitesare cellular proliferations of feathery-appearing spindle and stellate cells in a myxoid to collagenous stroma. The cells are arranged in vague fascicles to whorls with scattered osteoclastic giant cells and lymphoplasmacytic inflammation (Figure 1D). Skeletal muscle infiltration is a disproportionately common feature of NF in the head and neck. Moderate cytonuclear atypia is acceptable, as is brisk (but always non-atypical) mitotic activity. Due to hypercellularity, reactive atypia, and increased proliferation, these can be challenging to distinguish from a sarcoma. Recognition of morphologic patterns and FISH confirmation of USP6 rearrangement is useful in this context, although 14% of NF and 33% of CF are documented to be negative (Table 1).14, 15, 16

While fibromatous lesions of this site show significant morphologic overlap, both Gardner fibroma and desmoid fibromatosis can prompt genetic workup for underlying germline APC mutations indicative of familial adenomatous polyposis syndrome, rendering their recognition clinically relevant. All are considered benign but may present as locally aggressive lesions. Nuchal-type and Gardner-type fibromas occur in soft tissues of the posterior cervical spine and are paucicellular masses predominated by dense ‘cracked’ collagen fibers and a scant distribution of bland fibroblasts (Figure 1E). Entrapment of pre-existing structures (skeletal muscle, fibroadipose tissue, skin adnexa) is characteristic. Both are virtually indistinguishable morphologically, with the exception that nuchal-type fibroma can uniquely show a traumatic neuroma-like proliferation of nerve bundles. Desmoid fibromatosis presents in a wide age range as a painless mass in the cervical musculature. In contrast to Gardner- and nuchal-type fibromas, desmoid fibromatosis is more densely cellular with destructive sweeping myofibroblastic fascicles accompanied by arcuate, compressed capillaries in parallel orientation (Figure 2A). Nuclear beta-catenin positivity is a useful but neither sensitive nor specific diagnostic adjunct for both Gardner fibroma and desmoid fibromatosis (Table 1).17, 18, 19

Inflammatory myofibroblastic tumor (IMT) presents over a wide age range in the upper respiratory tract with symptomatology of compressive mass effect. Biopsy diagnosis of IMT is problematic due to inherent geographic heterogeneity – admixture of three histologic patterns, any one of which may variably predominate in each specimen and mimic other defined neoplastic entities. The first is paucicellular with scant fibro/myofibroblasts in dense collagenous stroma, evocative of desmoid fibromatosis or scar. The second shows loose myxoid stroma with stretched ‘fasciitis-like’ fibroblasts, proliferative vasculature, and conspicuous inflammation, which may masquerade as granulation tissue. The third is hypercellular with myoid to fibrohistiocytic cells arranged in fascicles resembling a smooth muscle tumor or dermatofibroma (Figure 1F). The inflammatory population includes lymphocytes, plasma cells, and granulocytes. Peripheral infiltration is permissible. ALK is positive by IHC in up to 60% of cases; ALK FISH is important to confirm as: 1) recurrent or metastatic IMT can be targeted with tyrosine kinase inhibitors, and 2) reactivity for ALK by IHC is also encountered in another far more malignant lesion distinctive to the craniofacial bones – namely rhabomyosarcoma with TFCP2 rearrangement (discussed below; Tables 1 and 3).20, 21, 22, 23, 24, 25

Low-grade myofibroblastic sarcoma (LGMS, formerly termed ‘myofibrosarcoma’) arises in the tongue and oral mucosa, often of adult males, as an irregularly contoured mass on imaging. In contrast to the spatial inhomogeneity of IMT, LGMS ubiquitously shows a sweeping fascicular arrangement of nondescript myofibroblasts with at least focally significant atypia and increased mitotic activity as a suggestion of malignancy. Overt infiltration of skeletal muscle fibers (through both the tumor center and periphery in a ‘checkerboard’ appearance) is characteristic (Figure 2B). As LGMS lacks a recurring genomic identity, the diagnosis is one of exclusion after judiciously eliminating morphologic mimics. These include spindle cell/sclerosing rhabdomyosarcoma, which should be positive for MyoD1 and myogenin instead of SMA and calponin. Desmoid fibromatosis is another infiltrative and fascicular, locally aggressive myofibroblastic neoplasm, but should not have a demonstrable level of nuclear atypia or even mitotic activity; beta-catenin IHC is not reliable but may be useful if aberrant (Table 1).26, 27, 28, 29, 30, 31, 32, 33

Spindle cell and pleomorphic lipoma (SCPL) represent the two lesional extremes of a morphologic continuum, arising characteristically in the subcutaneous posterior cervical tissues of middle-aged males. They can also present in the scalp and face (latter of which lacks a fascial plane and can show skeletal muscle infiltration). SCPL are well-circumscribed, subcutaneous masses comprised by a significantly variable proportion of ropy collagen, bland fasciculated spindle cells, and mature adipocytes. The neoplastic spindle cells are morphologically nonspecific but have blunted nuclei with scant eosinophilic cytoplasm and can sometimes predominate in variant ‘low-fat’ and ‘fat-free’ tumors (Figure 2C). Myxoid stroma is another characteristic feature, as are floret-like giant cells (so-called ‘pleomorphic’ cells, which is an archaic misnomer).34, 35, 36, 37 (Table 1)

Most peripheral nerve sheath tumors are benign; the clinical concern is either symptomatic or cosmetic. Both neurofibroma and acoustic schwannoma arise multifocally in the context of established syndromes (neurofibromatosis type I and II, respectively), and with the appropriate clinical correlation should present a straightforward differential. Schwannoma and perineurioma consist predominantly of neoplastic Schwann and perineurial cells, respectively. In contrast, neurofibroma is a composite of neoplastic Schwann cells (S100+, SOX10+) which entrap other cellular lineages, resulting in a mixed immunoprofile – perineural cells (EMA+, GLUT1+), axons (NF+), and fibroblasts (CD34+) (Table 2). Any nerve sheath tumor may display degenerative (‘ancient’) change with bizarrely enlarged, multinucleated, and smudged nuclei; in the absence of other atypical features, this should not suggest malignant transformation.46,52

Neurofibroma is encountered in the cutaneous tissues and oral cavity of middle-aged females, approximately 50% of whom have underlying neurofibromatosis I. Histologically, it is most frequently of the diffuse subtype – an unencapsulated lesion showing bland, mitotically quiescent cells with serpiginous to ovoid nuclei and inconspicuous cytoplasm. Intervening irregular collagen bundles and variable amounts of myxoid ground substance construe an overall hypocellular and haphazard appearance (Figure 2D; Table 2).38, 39, 40, 41

Perineurioma presents as a sporadic radiolucent mass (rarely expansile) in in the oral cavity or gnathic bones of middle-aged patients.4, 5, 6 Morphologic features are like those of other extraneural sites, including an unencapsulated but circumscribed swirling perivascular proliferation of bland tapering perineurial cells (resembling fibroblasts) within an admixed fibrillary collagenous to myxoid stroma (Figure 2E).42, 43, 44, 45, 46, 47 Meningothelial meningioma (a neurogenic EMA-positive central nervous system malignancy occurring in the skull base and other extracranial head and neck sites) also demonstrates a whorled syncytial arrangement of ovoid cells, the distinction from which can be problematic (Table 2).53, 54, 55

Non-vestibular craniofacial schwannoma is a sporadic (ie, not associated with neurofibromatosis type II, as are their acoustic counterparts) mass encountered in the soft tissues but also characteristically in the parapharyngeal space and in juxta/intraosseous locations. Schwannoma shows geographically hypercellular areas of elongated, wavy cells with foci of nuclear palisading and fibrillar intercellular stroma. These are juxtaposed with hypocellular areas composed of delicate interconnecting cellular processes and hyalinized vasculature, which can resemble neurofibroma (Figure 2F; Table 2). Of note – in distinct contrast to conventional schwannomas – those of the nasal cavity, paranasal sinuses, and larynx are frequently unencapsulated.48, 49, 50

These neoplasms are unequivocally malignant with primitive-appearing cells showing significant nuclear atypia, necrosis, and atypical mitotic activity. This high-grade appearance renders many morphologically similar, and features of differentiation can be absent or focal. Rhabdomyogenic differentiation (to some degree) can be postulated based on the presence of scant to abundant, eccentrically located hypereosinophilic cytoplasm, cross-striations, and positivity for desmin, confirmed subsequently by MyoD1 and/or myogenin. Neoplasms of endothelial differentiation, likewise, will typically show at least focal vasoformation, erythrocyte extravasation, and positivity for CD31 and ERG (Table 3).

Embryonal rhabdomyosarcoma (ERMS) in the head and neck occurs in children presenting with symptoms of orbital compression. ERMS is a loosely myxoid neoplasm of alternating cellularity, comprised by rhabdomyoblasts in various states of differentiation (primitive spindle cells, tadpole cells, strap cells, and rhabdoid cells) which can condense immediately beneath mucosal surfaces to form a ‘cambium layer’ (Figure 3A; Table 3). In contrast, alveolar rhabdomyosarcoma (ARMS) is categorized as a malignancy of small round cells arranged in completely solid sheets or nested pseudo-alveolar structures imparted by central loss of cellular cohesion (Figure 3B; Table 3). Spindle cell rhabdomyosarcoma (scRMS) and sclerosing rhabdomyosarcoma (sRMS) are a morphologic continuum but regarded biologically as a single entity with a predilection for soft tissue sites in the head and neck, including parameningeal spaces. scRMS shows frankly invasive cellular fascicles to whorls of quite monomorphic myoid to myofibroblastic to even fibrohistiocytic spindle cells (Figure 3C; Table 3). While both scRMS and sRMS can have a variably prominent sclerotic matrix, sRMS shows a distinctive pseudoangiomatoid pattern of intersecting hyaline cords lined by round to epithelioid cells.56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67

Rhabdomyosarcoma (RMS) with TFCP2 fusion is characteristically intraosseous – preferentially involving gnathic and other craniofacial bones – but addressed herein due to its unique phenotypic mimicry of other neoplasms in this site. A dismal malignancy of young adults, this particular RMS is biphasic with an admixture of monotonous spindle to epithelioid (and occasionally rhabdoid) cells arranged in fascicles to discohesive sheets (Figure 3D; Table 3). Immunophenotypically, they consistently express ALK1 in a cytoplasmic distribution (masquerading as IMT with co-expression of myogenic markers) and epithelial antigens (mimicking spindle cell carcinoma).61, 62, 63, 64

Angiosarcoma of the head and neck is a rare but highly lethal malignancy, favoring the suprafascial tissues of the scalp in elderly males (a clinical presentation similar to AFX and PDS). At least focal anastomotic angioformation is evident in this neoplasm otherwise composed of solid sheets of pleomorphic spindle cells with hemorrhage and extravasated erythrocytes (Figure 4A). Most angiosarcomas in this location are high-grade, but they can deceptively harbor areas showing only mild cytonuclear atypia with minimally increased mitotic activity. Epithelioid variants in particular – but also spindled – can be focally positive for cytokeratins and EMA, which should not be misinterpreted as evidence of carcinoma. While c-MYC amplification is considered a hallmark of post-radiation and lymphedema associated angiosarcoma, this aberration is non-specific and also documented in the specific context of de novo head and neck angiosarcomas (Table 3).68, 69, 70, 71

In most head and neck-localized series, synovial sarcoma (SS) presents in the cervical soft tissues of young adults with compressive symptoms. Tumors are most frequently monophasic, showing monomorphic and up to moderately atypical spindle cells arranged in narrow zigzagging fascicles with interspersed hemangiopericytomatous vasculature (Figure 3E). In addition to these features, biphasic SS also contains epithelial elements in the form of distinct glands or canaliculi. Both monophasic and biphasic SS can harbor a third poorly-differentiated pattern, comprised by patternless sheets of mitotically active monomorphic small round blue cells evocative of Ewing sarcoma or small cell carcinoma. Both Ewing sarcoma and poorly differentiated SS can express strong membranous CD99. Reliable distinction of SS is now straightforward via use of fusion-specific IHC or by molecular confirmation of the definitional and canonical SRY fusion. Another important differential diagnosis (especially for biphasic SS) includes a spindle cell carcinoma or melanoma. Features supporting the latter include conspicuous cytonuclear atypia, identification of a precursor lesion, and absence of characteristic cellular architecture and vascular morphology of SS (Table 3).72, 73, 74, 75, 76, 77, 78, 79

Conventional Ewing sarcoma of the head and neck may present intraosseously and show classic morphologic and immunophenotypic features. However, for the purposes of this section – adamantinoma-like Ewing sarcoma (ALES) is a recently characterized variant frequenting multiple extraosseous tissues in the head and neck, including the parotid and thyroid glands and sinonasal tract of young adults. ALES demonstrates a proliferation of monotonous small round cells similar to conventional Ewing sarcoma, but additionally a more lobular architecture imparted by fibrotic septations. Evocative of a basaloid squamous cell carcinoma (SCC), these nests may show distinct peripheral cellular palisading, central squamous pearls (evidence of ‘adamantinoma-like’ epithelial differentiation), and intraepithelial growth mimicking a precursor in situ lesion (Figure 3F). Indeed, the immunoprofile (diffusely positive p16, p40, and cytokeratins) would also corroborate the consideration of an SCC. However – the former usually shows nuclear homogeneity characteristic of translocation-associated sarcomas (rather than marked cytologic atypia), should evidence unequivocal membranous reactivity for CD99, and finally would harbor EWSR1 rearrangement rather than complex genomic insults (Table 3).80, 81, 82, 83, 84, 85

Epithelioid hemangioma (EH) conventionally harbors FOS and FOSB rearrangements, but a recently defined subset particular to superficial tissues of the head and neck instead demonstrates GATA6::FOXO1 fusions. These show morphologic overlap with classic EH – admixture of predominantly solid but also vasoformative epithelioid endothelial cells accompanied by extravasated erythrocytes and a brisk lymphoplasmacytic infiltrate. The cells show round nuclei centered within abundant eosinophilic cytoplasm, moderate cytonuclear atypia and non-atypical mitotic activity. In contrast to classic EH, however, those with GATA6::FOXO1 rearrangement do not evidence either salient eosinophilia, ‘hobnail/tombstone’ luminal cytology, or intracytoplasmic vacuoles (‘blister cells’) (Table 4). The main differential is with lobular capillary hemangioma (also termed ‘pyogenic granuloma’), which presents as an ulcerated, exophytic lesion in the oral mucosa of young women, sometimes during pregnancy. In contrast to EH, these how a distinct multilobulated capillary-venular architecture: compressed thin-walled channels with inner plump (but not epithelioid, per se) endothelial and outer pericytic layers, proliferating around larger, ectatic ‘feeder’ venules.86,87

This spectrum of mesenchymal neoplasms, encompassing so-called ‘pericytoma with t(7:12)’ and distinctive epithelioid neoplasm with frequent S100 reactivity, are now united as a group of neoplasms of uncertain lineage with underlying GLI1 aberrations (fusion or amplification). These disproportionately affect the head and neck, particularly the glossal tissues of young adults, and harbor significant potential for both local recurrence and distant metastasis. Morphologically, they are multilobulated lesions, comprised by a solid proliferation of ovoid to epithelioid cells with a delicate arborizing capillary network (Figure 4B). Stroma may be myxoid to hyalinized, and protrusion into vascular spaces is common. The cells are distinctly monotonous, with round nuclei situated centrally within a moderate amount of clear to palely eosinophilic cytoplasm. Interestingly, the subset of GLI1-amplified tumors also shows co-amplification of the 12q13–15 DDIT3/MDM2/CDK4/STAT6 loci and analogous positivity by IHC – not to be interpreted as evidence of a myxoid/round cell liposarcoma, atypical lipomatous tumor, or solitary fibrous tumor, respectively (Tables 4 and 5).88, 89, 90, 91, 92, 93, 94