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Available online at www.sciencedirect.com

www.elsevier.com/locate/semdp

Needle biopsy of mesenchymal lesions of the head and neck: Evolving concepts and new strategies for diagnosis Leslie G. Dodd, MDn, Johann Hertel, MD Department of Pathology and Lab Medicine, University of North Carolina, Chapel Hill, North Carolina

article info

abstra ct

Keywords:

Sarcomas are a rare and heterogeneous group of neoplasms that can be a significant

Sarcoma

diagnostic challenge in routine practice. Recent advances in the understanding of

Head and neck

molecular mechanisms underlying oncogenesis have led to an array of novel diagnostic

Fine-needle aspiration

tools. Here we review several sarcomas of the head and neck region, focusing on

Core needle biopsy

neoplasms with new molecular findings and highlighting novel diagnostic tools. & 2015 Elsevier Inc. All rights reserved.

Introduction Sarcomas of the head and neck (H/N) region are extremely rare, accounting for 1% of all human malignancies. Despite their scarcity, they represent a heterogeneous group of lesions with over 50 different subtypes cataloged by the World Health Organization (WHO).1 Because of the diversity and infrequency of these malignancies, they present a diagnostic challenge for pathologists. This review focuses on sarcomas that are somewhat common to the H/N region and highlights some new ancillary tests that can be useful in the diagnosis of these lesions. In recent years, there has been a rapid growth in the knowledge and understanding of the molecular mechanisms underlying sarcomagenesis. At the same time, treatment for sarcoma has become more sophisticated and tailored to specific tumor subtypes. As a result, there is increased pressure on the pathologist to provide a precise assessment of tumor type and extent of involvement prior to definitive management. For the pathologist, this frequently means issuing a specific diagnosis on a small amount of tissue,

usually obtained by a less invasive type of procedure such as fine-needle aspiration (FNA) and/or needle core biopsy. Increased insight has come from detection of previously cryptic or unrecognized recurrent genetic alterations as well as an improved understanding of subtype-specific cellular signaling events critical to tumorigenesis.2–4 These new findings have been rapidly translated into molecular assays, which can be used for diagnostic purposes and may eventually prove to be therapeutic targets. Newer immunohistochemical (IHC) stains and molecular diagnostic techniques such as fluorescence in situ hybridization (FISH) allow for the detection of molecular aberrations, which in many cases allows the pathologist to provide a specific diagnosis on “small” biopsy specimens. While numerous techniques exist for identifying molecular alterations (polymerase chain reaction, genome sequencing, etc.), “in situ” technologies offer numerous advantages over other methods in that they can be performed on formalin-fixed paraffin-embedded (FFPE) tissue (including cell blocks) as well as cytologic smears. In this review, we focus on some of the more common types of sarcomas that occur in the H/N, with an update on

n Correspondence to: Department of Pathology, Women’s and Children’s Hospitals, 3rd Floor, Room 30149, 101 Manning Drive, Chapel Hill, NC 27514. E-mail address: [email protected] (L.G. Dodd).

http://dx.doi.org/10.1053/j.semdp.2014.12.009 0740-2570/& 2015 Elsevier Inc. All rights reserved.

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new or evolving entities. Only a select group of neoplasms, focusing primarily on those with recent molecular discoveries and novel markers, is discussed.

Rhabdomyosarcoma Rhabdomyosarcoma (RMS) represents one of the most common H/N sarcomas, particularly in the pediatric population. RMS is classified into distinctive subtypes based on a combination of clinical, histologic, and cytogenetic features.5 Embryonal RMS (ERMS) represents the most common subtype and the most frequent sarcoma in the pediatric population. The peak incidence of ERMS is under the age of 15 years, with about half of all cases arising in children younger than 5 years. About 50% of ERMS occur within the H/N region, particularly the orbital soft tissues, nasopharynx, and oral cavity. Alveolar RMS (ARMS) is the second most common subtype of RMS, accounting for about 20% of all cases. This subtype is usually seen in a slightly older population (mean age 7–9 years) and tends to have a more aggressive course than ERMS.6 The histologic appearance of ERMS can be somewhat variable. In its most classic form, it has small rounded “blue” cell morphology with very primitive rhabdomyoblasts. The cells may be compact or loosely arranged in an edematous stroma. Individual rhabdomyoblasts tend to have high nuclear-to-cytoplasmic ratios, but there is usually some evidence of rhabdomyoblastic differentiation within the tumor (Fig. 1A). ERMS nuclei tend to be relatively monotonous

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in size, but there may be extensive nuclear membrane irregularity. The presence of numerous enlarged, hyperchromatic cells should raise the possibility of an “anaplastic” form of ERMS. The presence of a diffuse anaplastic component should be reported, as it represents a potential indicator of more aggressive behavior.7 In its typical form, small nests of tumor cells separated by thin fibrovascular septa characterize ARMS. Cell nests tend to have an intact peripheral layer, but cells in the center are often dyscohesive (Fig. 1B). The cells are small, primitive rhabdomyoblasts. Pleomorphism is usually more apparent in alveolar rhabdomyosarcoma, and larger cells with more eosinophilic cytoplasm, occasionally even with visible cross striations, are found. The distinction between ERMS and ARMS is often difficult as there is substantial morphologic overlap between both.8 Both subtypes are characterized by a small rounded cell having minimal if any visible cytoplasm on fine-needle aspiration (FNA) preparations.9 FNA or small core needle biopsies seldom exhibit enough architectural detail to draw a clear distinction between these 2 major subtypes (Fig. 1C and D). Fortunately, there are distinct cytogenetic differences between the 2 subtypes that can be exploited diagnostically. ERMS tends to have a complex karyotype with multiple gains in chromosomes 2, 8, 11, 12, 13, and 20.5 ARMS, in contrast, is frequently characterized by a recurrent translocation involving fusion of the FOXO1 gene (formerly known as FKHR for forkhead in rhabdomyosarcoma) with either a PAX3 (most common) or PAX7 gene in about 80% of cases. FISH for FOXO1 is a reliable and convenient method of determining the

Fig. 1 – (A) Embryonal variant of rhabdomyosarcoma (ERMS) comprises sheets of primitive cells, some with eosinophilic cytoplasm (H&E stain). (B) Alveolar variant of rhabdomyosarcoma (ARMS) has a distinct nested pattern and central dyscohesive tumor cells (H&E stain). Aspirate of both (C) ERMS and (D) ARMS showing a malignant small round cell population (Romanowsky stain).

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presence of the translocation on FFPE material10,11 and cytologic specimens.12,13 There is some evidence that PAX– FOXO1 gene fusion partner status may confer a prognostic advantage, but to date, this information has yet to be incorporated into the “risk stratification” model for rhabdomyosarcoma treatment.8,14,15 Fully 20% of ARMS cases will not display either of these translocations. This is known as the “translocation-negative” or “fusion-negative” variant of ARMS.5 Although not completely understood at present, it is thought that the fusionnegative group may harbor cryptic rearrangements. Because chemotherapy for ERMS and ARMS differs significantly, it is important to establish a definitive diagnosis of ARMS prior to initiation of therapeutic intervention. As such, the presence of the “fusion-negative” variant of ARMS presents a true diagnostic challenge, and the prognostic significance of this tumor type has yet to be fully resolved.16,17

Sclerosing rhabdomyosarcoma Within the last 10 years, a sclerosing type of rhabdomyosarcoma has emerged as a distinctive histologic variant of rhabdomyosarcoma with a predilection for the H/N of adults.18–21 Sclerosing rhabdomyosarcoma (SR) is characterized histologically by the production of a dense hyalinized or sclerosing matrix material, which can lead to diagnostic confusion with a number of other sarcomas, particularly osteosarcoma, sclerosing epithelioid fibrosarcoma, and chondrosarcoma. To date, relatively little is known about this subtype of RMS. While it is largely a tumor of adults, rare cases have been found in the pediatric population.22 In the few patients with adequate follow-up, a significant percentage have shown disease recurrence or metastases after surgical removal.21,23 SR tends to show complex cytogenetic features24,25 and, as such, does not appear to be related to the FOXO1 subtype of alveolar RMS. To date, there is still some controversy as to the exact classification of this tumor. In the current WHO classification system, it is grouped with socalled “spindle cell” variant of RMS that tends to occur in younger patients.23 But even in the short interval between the 2013 WHO classification and the present, additional

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information is emerging indicating these are probably genetically distinct neoplasms. Rearrangement of the NCOA2 (nuclear receptor coactivator 2) gene has been identified in a set of pediatric spindle cell RMS, but not in adult cases.26 SR is characterized histologically by a small rounded or occasionally spindled cell proliferation embedded in a densely sclerotic matrix background. The degree of hyalinization can be so extensive that the cellular component assumes a pseudoalveolar or even pseudovascular appearance (Fig. 2A). Occasionally, cells demonstrate a more spindled or epithelioid appearance with distinctive cytoplasmic clearing of cells entrapped in the collagenous matrix. Mitoses are usually frequent in sclerosing RMS, and areas of necrosis may be encountered. The cytologic features of SR have not been well characterized, and descriptions of the FNA findings of this tumor have been confined to case reports.27,28 Aspirates of SR tend to be modestly cellular comprising fairly monotonous cells with ovoid to spindled configuration. Cytoplasm tends to be absent or indistinct, and stromal material may or may not be present (Fig. 2B). As this appearance is nonspecific, ancillary immunohistochemical staining, particularly stains for desmin and MyoD1, is helpful in classifying this lesion as a RMS. Of note, myogenin expression is often weak in this variant.19,21,23

Alveolar soft part sarcoma Alveolar soft part sarcoma (ASPS) is a rare malignant lesion of uncertain histogenesis, which preferentially occurs in the deep soft tissues, particularly the thigh. An estimated 12–25%, however, occur in the H/N, most commonly within periorbital soft tissues and the tongue region.29–31 ASPS tends to have a peak incidence in adolescents and young adults, although it has been reported in almost every age group. Interestingly, the H/N is a more common location for pediatric patients with ASPS. It is a fully malignant neoplasm that tends to metastasize to the brain, lungs, and bone. Patients with smaller, confined tumors often have a more indolent course with a long disease-free interval. The most striking histologic feature of ASPS is the nesting or “alveolar” configuration of tumor cells. Individual nests

Fig. 2 – Sclerosing rhabdomyosarcoma (SR) from the paranasal sinus of a middle-aged male. (A) Histologic appearance is characterized by primitive tumor cells embedded in an extensively hyalinized background (H&E stain). (B) Papanicolaoustained aspirate displays spindled cells with ill-defined cytoplasmic boundaries. In this example, matrix material was not identified.

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comprise epithelioid cells having abundant cytoplasm encircled by fine fibrovascular tissue (Fig. 3A). Cell nests may be solid or show a “pseudoalveolar” pattern due to loss of cell cohesion. Individual cells have abundant granular or occasionally clear cytoplasm and large vesicular nuclei. In addition, a rare so-called “solid” pattern of ASPS seems to have a predilection for the tongue (Fig. 3B). Cytologic features of ASPS include numerous epithelioid cells with voluminous amounts of cytoplasm when intact, but bare nuclei are also common (Fig. 3C). The cytoplasm can be either clear or eosinophilic with fine-to-coarse granularity, and nuclei often contain a single macronucleolus.32,33 Aspirates of ASPS overlap in appearance with a number of other tumors including renal cell carcinoma, granular cell tumor, and in some instances RMS. ASPS has a unique genetic signature: an unbalanced translocation involving the ASPCR1 gene on chromosome 17 and the transcription factor 3 (TFE3) locus on the X chromosome.34 This translocation can be detected now by a number of molecular methods including PCR and FISH. In addition, TFE3 is a commercially available immunohistochemical marker that detects the fusion protein and localizes to the nucleus of ASPS cells (Fig. 3D). Thus far, TFE3 appears to be sensitive for detecting ASPS as well as other TFE3 fusionpositive tumors (translocation-related renal cell carcinoma).35,36 It should be noted, however, that TFE3 will also stain granular cell tumor,37 a lesion easily be confused with ASPS, particularly on small biopsy specimens that often lack architectural detail. TFE3 has also been reported to be positive in a subset of paragangliomas and adrenocortical carcinoma.36,38

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Solitary fibrous tumor Solitary fibrous tumor (SFT), a lesion initially described in the pleura, has subsequently been reported in a variety of sites including superficial and deep soft tissues as well as other organs.39,40 About 10% occur in the H/N region, including the orbit and meninges.41 SFT encompasses the neoplasm formerly known as hemangiopericytoma, so named because of its presumed pericytic origin.42–44 Although use of the term “hemangiopericytoma” is discouraged, it is still often employed to describe tumors with a classical “staghorn” type of branching vasculature seen in histologic, but not cytologic preparations. The behavior of SFT is often unpredictable, and a subset of these tumors will recur either locally or distantly, often after a long disease-free interval. Recently, there has been an effort to “risk stratify” the behavior of SFT on clinical and histologic variables including patient age, tumor size and location, and mitotic rate.45 SFT is classically described as a tumor with a “patternless” pattern (Fig. 4A). While this is an accurate description, it applies to only a subset of SFT. Aside from “classic” SFT, there are several histologic variants, including fat-forming and giant cell subtypes (giant cell angiofibroma). The classic variant is characterized by alternating hypo- and hypercellular regions comprising small ovoid to spindle cells with indistinct cytoplasm. The vasculature of SFT can have a highly variable appearance, ranging from a relatively inconspicuous vascular proliferation, to small slit-like vessels, to the dramatic staghorn-type vasculature associated with socalled “hemangiopericytoma” (Fig. 4B).

Fig. 3 – Alveolar soft part sarcoma (ASPS). (A) Classic histopathology shows a distinctive nested arrangement (H&E stain). (B) A more “solid” variant of ASPS infiltrating skeletal muscle (H&E stain). (C) Fine-needle aspiration of ASPS showing numerous loosely cohesive tumor cells with voluminous clear cytoplasm (Romanowsky stain). (D) Nuclear staining for TFE3 in ASPS.

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Fig. 4 – Solitary fibrous tumor (SFT). (A) So-called “patternless” pattern (H&E stain). (B) Typical for SFT are numerous branching vascular configurations of “staghorn” type (H&E stain). (C) Aspirates tend to show elongate spindled cells associated with fragments of metachromatic stromal material (Romanowsky stain). (D) Positive immunohistochemical staining for STAT6 (Courtesy of Dr. C.D. Fletcher).

SFT is difficult to confidently diagnosis on small core needle biopsy or FNA specimens. The cytologic features are relatively nonspecific.46–48 Samples are comprised of cohesive fragments of spindled cells, often in association with metachromatic matrix material (Fig. 4C). Cytoplasm tends to be scant and inconspicuous. Nuclei are most often small with smooth regular borders. The complex vascular pattern identified in histologic sections of SFT does not appear to have any parallel in cytologic samples of the same. SFT is consistently immunoreactive for CD34 and variably reactive for bcl2, CD99, beta-catenin, and epithelial membrane antigen (EMA). This immunoprofile is not entirely specific and overlaps that of other spindle cell neoplasms. Until recently, SFT was considered a karyotypically diverse neoplasm without a distinctive molecular signature. In 2013, a recurrent gene fusion, NAB2–STAT6, was identified in SFT.49,50 Whole-exome sequencing revealed a previously cryptic intrachromosomal inversion that juxtaposed NAB2 and STAT6 genes to produce a fusion gene and subsequent protein that is believed to act as a transcriptional activator. This finding was rapidly confirmed by others and quickly translated into an immunohistochemical assay to detect STAT6 protein expression.51–53 Positive nuclear staining for STAT6 is fairly specific and sensitive for SFT, making it a potentially invaluable adjunct for the diagnosis of spindle cell tumors on small biopsy specimens (Fig. 4D).

Synovial sarcoma Synovial sarcoma (SS) is one of the most common neoplasms of soft tissue, thought to represent about 5–10% of all

malignant soft tissue tumors. SS has a wide patient age distribution, but a peak incidence occurs in adolescents and young adults, 15–35 years of age. It may occur at almost any site in the human body, but the majority arise in the deep soft tissues of the extremities. H/N SS tends to occur in the paravertebral region of the neck, the parotid gland, and temporal regions.54,55 Prognosis is directly related to tumor size, and complete surgical resection offers the best promise for a favorable outcome in all sites, including H/N.55,56 SSs are traditionally considered biphasic tumors. Truly biphasic SSs characteristically have an undifferentiated spindle cell component as well as an epithelial element. The epithelial component may be easily recognizable and may assume a well-organized gland-like or papillary configuration, present either focally or dispersed throughout the neoplasm. More commonly, the glandular or epithelial foci are an inconspicuous feature and require ancillary immunohistochemical (IHC) staining for identification. Monophasic variant of SS is the more common variant and closely resembles a number of other highgrade spindle cell sarcomas (Fig. 5A). Monophasic SS comprises a dense population of monotonous small spindled, ovoid or carrotshaped cells forming a “dark blue” tumor. The cellular component is most often laid down as alternating sweeping fascicles of spindled cells, sometimes arranged in a distinctive “herringbone” pattern. Monophasic SS may also display the “staghorn antler” vascular pattern that is commonly associated with SFT. In addition, the variant is termed “poorly differentiated” SS because its round cell morphology tends to mimic that of other malignant small round cell tumors, particularly Ewing sarcoma (EWS). This subtype comprises an estimated 5% of all SS.57

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Fig. 5 – (A) Histology of a monophasic synovial sarcoma (SS) showing a “herringbone” architecture (H&E stain). (B). Ethanolfixed preparation of SS showing a monotonous spindle cell population (Papanicolaou stain). (C) Air-dried preparation of SS showing small monomorphic cells, which could easily be misidentified as another small blue cell tumor (Romanowsky stain).

Aspirates of SS are usually very cellular. Most appear as a diffuse population of small spindled to ovoid cells, representing the undifferentiated spindle cell component (Fig. 5B and C). It is rare to find unequivocal evidence of glandular differentiation on cytologic samples of SS.58,59 More often, cells are dispersed or in small cohesive aggregates. Individual cells tend to be ovoid or round with scant, ill-defined cytoplasm and indistinct cellular borders. Nuclear borders are usually sharp and will sometimes show subtle membrane irregularity. SS is characterized by the t(X;18)(p11;q11) translocation, which is exclusive to this neoplasm. Molecular methods of detecting this translocation, including PCR and FISH, are both sensitive and specific for SS and represent the “gold standard” for diagnosis (Fig. 6A). In instances where these techniques are either unavailable or impractical, IHC staining represents an alternative method for diagnosis confirmation. However, the IHC profile of SS is nonspecific, and other neoplasms in the differential diagnosis, namely SFT, malignant peripheral nerve sheath tumor (MPNST) and EWS, often cannot be excluded based on a panel of conventional IHC markers. Transducin-like enhancer protein 1 (TLE1) is a new marker identified by gene expression profiling and was initially thought to be sensitive and specific for SS.60 TLE1 tends to show strong nuclear expression in the majority of SS studies to date61–63 (Fig. 6B). However, TLE1 positivity has also been demonstrated in benign peripheral nerve sheath tumors, and subsets of MPNST and SFT illustrating its lack of complete specificity.62,63

Angiosarcoma Angiosarcoma (AS) is a high-grade vascular malignancy, and one of the most common subtypes of H/N sarcoma. AS commonly occurs on sun-exposed skin of elderly adults. Scalp and facial skin are frequent sites of involvement.64 The histologic appearance of AS is highly variable. Most H/N-based AS tend to be high-grade malignancies originating in the dermis and tending to invade into the deeper soft tissues (Fig. 7A). Vascular channels and solid areas are comprised of either spindled or epithelioid cells and can be intermixed throughout the tumor. In the more solid areas, tumor cells display spindled or epithelioid morphology or a combination of both. Spindle cell foci can assume a herringbone pattern and be confused with a variety of other high-grade spindle cell sarcomas. A subset will show a predominantly epithelioid morphology. The epithelioid variant of AS is easily mistaken for other types of malignancy, most commonly adenocarcinoma (Fig. 7B). Despite being very hemorrhagic neoplasms, angiosarcomas often yield surprisingly cellular aspirates. The cytologic features of AS are rather nonspecific but are consistent with a high-grade sarcoma.65 Cell morphology may be either spindled or epithelioid but is most often obviously malignant (Fig. 7C). Cells tend to be single and dispersed with occasionally loosely adherent small groups. The vasoformative histologic pattern characteristic of AS in tissue does not have a cytopathologic correlate. As such, there are no diagnostic morphologic features to separate AS from other high-grade

Fig. 6 – Synovial sarcoma (SS). (A) FISH breakapart probe for SS demonstrating a split between the red and green signals in most cells indicating a translocation. (B) TLE1 nuclear staining in a poorly differentiated variant of SS.

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Fig. 7 – Angiosarcoma. (A) The lesion is hemorrhagic and composed of fascicles of pleomorphic spindle cells (H&E stain). (B) Epithelioid variant—a lesion easily confused with other entities, particularly carcinoma (H&E stain). (C) Aspirates tend to be bloody but often contain loose aggregates or individual large tumor cells (Romanowsky stain).

sarcomas. IHC staining can be very helpful in confirming a diagnosis of AS. CD31 is a relatively sensitive and specific marker for endothelial differentiation, being strongly positive in the majority of AS cases. CD34, another common marker of vascular tumors, is much less specific than CD31. AS also stains with D2-40, Fli-1, as well as a variety of epithelial markers. This leads to potential confusion with large cell carcinomas. This is particularly so with the epithelioid variant. The protein product of the transcription factor ERG has recently been shown to be a sensitive marker of vascular malignancies,66,67 though it will stain an assortment of other neoplasms including prostate cancer, Ewing sarcoma, and epithelioid sarcoma.68,69 Nonetheless, positive ERG/CD31 staining is probably the best IHC combination in current use for documenting a vascular neoplasm. In addition, it has recently been discovered that secondary (post-radiation) AS frequently harbors high-level amplification of MYC, another feature that can be exploited for diagnostic purposes.70,71

Summary H/N sarcomas represent a major diagnostic challenge because of their relative rarity and diversity. Most patients with a suspected sarcoma are subjected to an initial biopsy, often using FNA or core needle, in attempt to provide information about tumor type and grade. Accurate interpretation of this material is imperative for optimal patient treatment and management.72 The last decade has seen a rapid increase in knowledge regarding the molecular pathogenesis of many sarcomas. Many of these findings have been translated already into diagnostic tests, including FISH assays and IHC markers, which can facilitate accurate and specific diagnoses on small specimen samples. While ancillary molecular techniques are invaluable for diagnosis, they have inherent limitations and require judicious use in conjunction with traditional morphology.

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Needle biopsy of mesenchymal lesions of the head and neck: Evolving concepts and new strategies for diagnosis.

Sarcomas are a rare and heterogeneous group of neoplasms that can be a significant diagnostic challenge in routine practice. Recent advances in the un...
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