Plain radiography may show enlargement of neuroforamen when a dumb-bell shaped neurofibroma is involving a spinal nerve root.

High-resolution sonography of a neurofibroma shows a round homogeneous hypoechoic mass (Fig. 15.2) located centrally along the course of a peripheral nerve with distal acoustic enhancement, simulating a cystic lesion (pseudocystic appearance) [52, 53]. A sonographic target lesion with hypoechoic periphery and hyperchoic center may be seen, corresponding to myxomatous peripheral and fibrocollagenous central regions, respectively [53]. In diffuse neurofibromas, hyperechoic masses permeated by multiple interconnecting hypoechoic tubular or nodular structures have been reported in the subcutaneous fat zone. Differential diagnoses include cutaneous lymphoma, angiomatous lesions, cellulitis, and hemorrhage [54]. Sonography, even with duplex and color Doppler techniques, is not able to distinguish among neurofibromas, schwannomas, and malignant peripheral nerve sheath tumors [53, 55].

On CT, localized neurofibromas appear as a well-defined hypodense (compared with muscles) mass from the presence of Schwann cells (fat content of myelin), myxoid tissue (high water content), entrapment of fat, and cystic areas of hemorrhage or necrosis [56]. After intravenous contrast injection, over half of neurofibromas show little or no contrast enhancement (Fig. 15.3). Visible bony erosions associated with dumbbell tumors are seen with CT [57].

On MRI, a neurofibroma is spindle or ovoid in shape and is in contiguity with a specific nerve [58]. It shows low to intermediate signal intensity (or isointense to adjacent muscles) on T1W images and high signal intensity on T2W images. The high signal intensity on T2W images may be homogeneous or showing a characteristic “target sign” with a hyperintense periphery and a hypointense central region [59–61]. The high peripheral signal is related to myxoid and water contents and the central low signal is related to dense collagen and fibrillary tissues. It is important to use a wide window setting to allow demonstration of this sign [62]. After intravenous contrast, enhancement is inhomogeneous in two-thirds of cases and uniform in the rest. A neurofibroma is typically fusiform in shape with tapering ends contiguous with the parent nerve. When large, the tumor has a fascicular appearance (fascicular sign). A “split-fat” sign has been described when a neurofibroma originating from the nerve in an intramuscular location is surrounded by a rim of fat. Muscle atrophy may be seen in the muscle supplied by the nerve with neurofibroma. The diffuse form of neurofibroma presents as an ill-defined network of interconnecting neurofibromas extending through the involved subcutaneous tissue, showing low signal intensity on T1W images, high signal intensity on T2W images, and significant intravenous contrast enhancement on MR imaging. Prominent internal vascularity is common [51]. Plexiform neurofibromas, when deep, appear as hypodense multilobular masses within a major nerve distribution on CT scans and large conglomerate of masses of neurofibromas on MR imaging (Fig. 15.4). When superficial, plexiform neurofibromas in patients with NF-1 tend to be unilateral, have nontarget signal characteristics, exhibit a diffuse and infiltrative morphology, extend to the skin surface in a branching reticular fashion with small fascicles or nodules (Fig. 15.5), and can be mistaken for venous malformation by MR imaging [63–65].

Plain radiography usually does not reveal the mass itself, but may show scalloping of bone adjacent to the tumor.

Ultrasonography may show, especially in large nerves, a mass eccentrically positioned with respect to the affected nerve. However, there may be limitations, even with meticulous scanning technique, in demonstrating this eccentric positioning in up to 40 % [55].

On CT scan, schwannoma appears as a well-defined isodense or hypodense mass compared to muscles and shows enhancement after IV enhancement except in necrotic areas. Scalloping of the adjacent bone and expansion of the spinal canal are characteristic features on CT (Fig. 15.6a, b).

MR imaging findings are similar to those described in neurofibromas, including a mass with a fusiform, spindle, or oval shape, in contiguity with a specific nerve, and showing a target sign, and “split-fat” sign. A mass eccentrically positioned in relation to the nerve and showing heterogeneity with cystic degenerative changes suggests a schwannoma [67]. A low signal peripheral rim (epineurium) is seen in 70 % of schwannomas versus in 30 % of neurofibromas [68–70]. The target sign in schwannoma is attributed to a central area of more cellular Antoni type A neurilemmoma and to a peripheral rim of hypocellular Antoni type B neurilemmoma [71].

Although often normal, plain radiography may show a soft tissue mass (Fig. 15.7a), secondary changes in adjacent bones (erosion or overgrowth), and is essential for evaluation of metastases to chest (lungs and pleura). Calcification (chondroid, osteoid, or amorphous) is uncommonly seen.

Sonography shows inhomogeneous hypoechoic masses that may have areas of hemorrhage, necrosis and calcifications [50]. A sonographic target sign is not present [53]. Duplex Doppler sonography shows a hypervascular pattern with corkscrew neovasculature, high velocities, and variable spectral waveforms [77].

Multi-detector CT (MDCT) may show abdominal primary tumor and metastases to the abdomen. On CT, MPNSTs are hypodense and ill-defined in outline with marginal enhancement after IV contrast medium.

Angiography may show increased vascularity with characteristic corkscrew vessels at both ends of the tumor due to hypertrophy of the nutrient blood supplies to the nerve [71].

MPNSTs share MR imaging findings described above with benign peripheral neurogenic tumors. The involvement of the entering and exiting nerves results in the spindle shape of most MPNSTs . Although MRI can determine the site, extent, and change in size of plexiform neurofibromas, it does not reliably determine malignant changes [76, 78–80]. While any neurofibroma that rapidly increases in size in patients with NF-1 should be viewed with suspicion for malignant transformation, the growth rate of plexiform neurofibromas that give rise to MPNSTs is not a reliable predictor of malignancy. There may be periods of rapid growth, especially in adolescence, followed by periods of relative inactivity [81, 82]. Features that are concerning for malignancy include: tumor size over 5 cm in diameter, ill-defined margin, heterogeneity, intratumoral cystic changes, fat plane invasion or infiltration, absence of target or fascicular sign [59, 61, 62, 83], peritumoral edema, presence of peripheral enhancement, and history of having MPNST or previous radiation therapy (Figs. 15.7b–d, 15.8a–d). Only evidence of metastases (such as lung, pleura, bone, retroperitoneal node, and bone) is definitive for diagnosis of MPNSTs (Fig. 15.7e). While the split fat sign was present in 76.5 % of benign and larger PNSTs, only 33.3 % of MPNSTs showed this sign [58]. Whole body (head to feet) MRI with several table movement steps has been used in assessing the benign tumor burden in patients in NF-1 [84].

Bone scintigraphy may show findings indicating increased vascularity or mineralization and identify sites of bony metastases.

FDG-PET has recently proven to be useful in detecting metastatic and recurrent disease [85] and in the differentiation between benign and malignant peripheral nerve tumors using qualitative and semiquantitative SUV_max (maximum standardized uptake value) assessment [86, 87] (Fig. 15.8e–g). In patients with NF-1, FDG-PET is 95 % sensitive in the detection of MPNSTs. Because of the overlap in SUV_max for benign (ranging from 0 to 5.3, mean 1.5 ± 0.37) and malignant (ranging from 3.8 to 13.0, mean 8.5 ± 0.63) lesions, the addition of PET using 11C-methionine (measuring amino acid transport rate, protein synthesis, and cell proliferation in malignant tissues) has been found to improve specificity from 72 to 91 %[86]. In another series [87], no MPNSTs were detected with an SUV_max <2.5 and a small number of benign tumors had an SUV_max >3.5. Both benign and malignant peripheral nerve tumors had SUV_max between 2.5 and 3.5. The authors recommend that symptomatic neurofibromas with SUV_max ≥3.5 should be excised, and lesions with SUV_max between 2.5 and 3.5 should be reviewed clinically. In another study, Son and colleagues found varying degrees of FDG uptake in a patient with multiple benign neurofibromas on PET-CT and concluded that a low SUV_max may indicate benignity, but a high SUV_max does not always indicate malignancy [88]. Using ROC analysis, Warbey et al. found a significant difference in SUV_max between early (90 min) and delayed (4 h) imaging and between tumor grades, and recommended using a cutoff SUV_max value of 3.5 on delayed imaging to achieve maximal sensitivity in diagnosing MPNST [89]. The overlap of SUV_max between different tumor grades, however, did not allow accurate prediction of grade on an individual basis. The authors suggest that tumors with an SUV_max in the 3.0–3.5 range should be clinically reviewed at multidisciplinary and multi-specialist management meetings. In another ROC analysis [90], using SUV_max thresholds of 4.5, 6.1, and 8.5 were associated with sensitivities of 100, 94, and 65 % and specificities of 83, 91, and 100 %, respectively, for detecting malignancy. The authors also found that benign schwannomas are less reliably distinguished from the MPNSTs based on the SUV_max. In a pediatric series of NF-1 and plexiform neurofibromas, Tsai found that the SUV_max of typical and atypical plexiform neurofibromas (2.49 [SD = 1.50]) was significantly different from MPNSTs (7.63 [SD = 2.96]). Using an SUV_max cutoff value of 4.0, sensitivity and specificity were 100 and 94 %, respectively for distinguishing plexiform neurofibromas and MPNSTs [91]. Nodular target lesions seen on MRI in patient with NF-1 and plexiform neurofibromas were found to have increased FDG uptake similar to that of MPNSTs, although they might be benign on biopsy [92]. Careful longitudinal clinical and imaging monitoring were recommended using MRI and FDG-PET to identify lesions of greatest concern to be biopsied. FDG-PET imaging can help in guiding targeted needle core biopsy of PNSTs [90], directing biopsy to the more metabolically active areas of the tumor. A newer tracer with 18 F-thymidine, which detects DNA turnover, may be useful in distinguishing low grade MPNSTs from active benign plexiform neurofibromas [76].

The macroscopic appearance of MPNSTs is highly variable, ranging from large and ominous to subtle. Most will present similar to other soft tissue sarcomas as bulky fusiform or expansive tumors with variable infiltration into surrounding structures. They tend to be large tumors, averaging 6–10 cm in dimension, the majority >5 cm [2, 6]. Identifiable origination from a nerve may or may not be present. MPNSTs have a firm tan to grey interior with areas of hemorrhage and necrosis, similar to other aggressive sarcomas. A pseudocapsule typically represents tumor-infiltrated soft tissue, often with reactive features. At the other end of the spectrum, foci of MPNST arising within an underlying plexiform neurofibroma (malignant degeneration) may not be grossly visible at all, identifiable only at the microscopic level.

Classic / conventional MPNST may display a wide variety of architectural arrangements, frequently posing a significant diagnostic challenge given its resemblance to a number of other soft tissue tumors. The most frequent appearance is one of a hypercellular sarcoma with interwoven fascicles of spindle cells (Fig. 15.9) [93]. Other patterns include a fibrosarcoma-like herringbone pattern, hemangiopericytoma-like with staghorn vasculature, and alternating loose and dense cellular regions (similar to Antoni A and Antoni B regions in schwannomas) (Fig. 15.10) [2]. Perivascular condensation of tumor cells is another helpful feature [2]. Growth within nerve fascicles is also common, though invasion into surrounding tissues is typical. Individual tumor cells are spindle shaped with variable amounts of surrounding pink cytoplasm; nuclei tend to be wavy or indented with tapered ends [2]. Large zones of geographic necrosis are seen in over one half (Fig. 15.11), and mitotic figures are generally easy to find (Fig. 15.12), often numbering several per single high power field.

Fine needle aspiration cytology is being increasing employed in the diagnostic workup of soft tissue lesions, and our knowledge of the salient cytologic features of MPNST has become increasing refined over the past decade. Cytology aspirate smears of MPNST are typically hypercellular with a combination of cohesive cell clusters of variable size and cellularity together with numerous single tumor cells and naked nuclei [94, 95]. A fascicular pattern may be encountered in some cell clusters, though is not universally present; storiform or whorled patterns may also be encountered [30]. A fibrillary background may be present [95]. Individual tumor cells are spindle shaped with variable contour; they may be elongated with tapered ends, kinked, angulated, or comma-shaped [30, 94, 95]. Wavy nuclei, representing a quite helpful diagnostic feature when detected, are inconsistently present in MPNST cytology samples [94, 95]. Nuclear pleomorphism is a frequent finding, as are mitotic figures (including atypical forms) [30, 95]. A “dirty” necrotic background material may be seen [30].

The majority (85 %) of MPNSTs are high grade sarcomas. As such, they show evidence of hypercellularity, invasion of surrounding tissues (often with vascular invasion), together with nuclear pleomorphism, elevated mitoses (generally >5 mitoses per 10 high power field), ± necrosis [1]. It is the presence of necrosis that distinguishes high grade from intermediate grade tumors. Low grade MPNSTs make up the minority, appearing histologically similar to cellular neurofibroma, though having comparably increased cellularity and significant nuclear atypia (hyperchromasia and larger nuclear size) (Fig. 15.13a, b).

Similar to low grade peripheral nerve sheath tumors, MPNSTs may show S100 positivity by immunohistochemistry; unfortunately S100 is detected in only 50 % of cases, and more often only scattered individual cells are S100 positive [18, 96–99]. Low grade MPNSTs tend to have more diffuse S100 positivity compared to their higher grade counterparts [98]. SOX10, a pan-schwannian marker, will be positive in up to 50 % of MPNST, but unfortunately nearly half of MPNSTs will be negative for both SOX10 and S100 [97, 100]. Interestingly, it has been demonstrated that MPNSTs have a heterogeneous cell composition, containing EMA and Glut1-positive perineurial cells, as well as CD34 positive endoneurial fibroblasts [99]. In some cases, cellular structures resembling tactoid bodies can be found (Fig. 15.14). Collagen IV is often present between individual tumor cells or cell groups, positivity tends to be focal and discontinuous [18]. Nestin, GFAP, Leu7, and NSE are demonstrable in some cases [96, 101]. A variety of cell cycle regulatory proteins may also be detected by immunohistochemistry, with low and high grade tumors showing different profiles. Whereas p16 and p27 tend to be positive in low grade MPNSTs, p16 and p27 expression tends to be lost in high grade MPNST, which instead often shows nuclear p53 expression [98, 102, 103].

Approximately 15 % of MPNSTs exhibit some form of divergent differentiation, harboring various mesenchymal or epithelial / epithelioid components [104]. Features of the most well-recognized of these variants are summarized below. It should be noted however, that a wide variety of heterologous elements may much more rarely be encountered; these include areas of fibroblastic [105] smooth muscle differentiation [93], or primitive neuroectodermal tumor (PNET)-like differentiation [106]. Examples of MPNST with pluridirectional differentiation have been described, bearing a mixture of two or more of the following malignant tissue types: epithelioid, rhabdomyoblastic, osteogenic, chondroblastic, lipogenic, and pigmented neuroectoderm [2, 18, 107–111].