Liver

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2021, Case 33, and is metastatic embryonal rhabdomyosarcoma in the liver. The information provided in this case was accurate and correct at the time of publication in 2021. Any changes in terminology since the time of publication may not be reflected in this case.

Sections of the subcapsular liver nodule show an unencapsulated but distinct population of variably small, somewhat spindled basophilic cells arranged in sheets, nests, and cords in a loosely myxomatous background with some identifiable collagen. Mitotic figures and apoptotic cells are seen. Rare rhabdoid cells are present in some sections. There is poor demarcation from the adjacent liver parenchyma. The clinical, histologic, immunohistochemical, and cytogenetic findings are most consistent with metastatic embryonal rhabdomyosarcoma, most likely from this patient’s urinary bladder primary.

Rhabdomyosarcoma is the most common soft tissue sarcoma in children and adolescents, and embryonal rhabdomyosarcoma is the most common subtype. About one third of embryonal rhabdomyosarcomas occur in children younger than 5 years old, and about half arise in the genitourinary tract with the other half in the head and neck region. There is a slight male predominance (M:F 1.5:1). Patients with tumors of the genitourinary system can present with mass effects and obstruction (such as urinary retention or a scrotal mass), while head and neck tumors may present with mass effects or defects depending on location (eg, proptosis, diplopia, sinusitis, unilateral deafness). Grossly, these lesions form poorly circumscribed masses that impinge on neighboring structures.

Embryonal rhabdomyosarcoma is a malignant tumor of primitive embryonic skeletal muscle cells, composed of variably differentiated spindled to rounded rhabdomyoblasts within myxoid stroma with alternating areas of hyper- and hypocellularity. A cambium layer – a densely cellular area beneath a mucosal surface – is suggestive of the botryoid variant of embryonal rhabdomyosarcoma if identified. Recognizably differentiated rhabdomyoblasts may be sparse. These may be tapered, striated cells with eosinophilic cytoplasm (often called “strap” or “tadpole” cells) or rounded cells with prominent glycogen vacuoles surrounding and indenting the nucleus (called “spider” cells). ​I​mmunohistochemical stains such as myogenin or myoD1, for which nuclear staining is most specific​, are useful to support myogenic differentiation, although they are not diffuse​. Desmin is most often diffusely positive​, but is not specific for rhabdomyosarcoma​. Cytokeratins are usually negative, but aberrant expression has been reported.

Embryonal rhabdomyosarcomas may be considered anaplastic if tumor cells are markedly enlarged and atypical (greater than three times the size of neighboring nuclei). These features may be focal or diffuse, and they are absent in most of the slides from this case.

While there is no characteristic or diagnostic cytogenetic abnormality associated with embryonal rhabdomyosarcoma, the absence of such abnormalities is helpful in resolving the differential diagnosis. For example, alveolar rhabdomyosarcoma is the second most common subtype of rhabdomyosarcoma after embryonal, with significant overlap in affected patient population and body sites. The alveolar type is usually distinct histologically by its alveolar architectural pattern, and 80% of these tumors are found to have either PAX3::FOXO1A or PAX7::FOXO1A fusions, which are generally absent in the embryonal type.

Children with certain genetic syndromes are more likely to develop embryonal rhabdomyosarcoma. ​​These associated syndromes and their characteristically mutated genes include Li–Fraumeni syndrome (TP53), neurofibromatosis type I (NF1), Costello syndrome (HRAS), Noonan syndrome (BRAF, KRAS, NRAS, PTPN11, RAF1, SOS1), Beckwith–Wiedemann syndrome (IGF2, CDKN1C, H19, KCNQ1QT1), and DICER1 syndrome (DICER1). However, only about 5% of patients with embryonal rhabdomyosarcoma have also been diagnosed with one of these genetic syndromes, implying that the majority are sporadic or isolated events.

Treatment of embryonal rhabdomyosarcoma usually involves a combination of primary resection and radiation therapy for localized disease, and/or chemotherapy agents for disseminated disease. The Intergroup Rhabdomyosarcoma Study Group first introduced a combined risk stratification system where patients are staged based on the primary tumor site (eg, bladder/prostate or extremity primaries are given a more advanced stage) and assigned to a clinical group based on surgical and/or pathologic features (eg, presence of residual primary tumor or distant metastases). These two factors are used to determine the patient’s risk category and placement in clinical trials for particular therapies.

Desmoplastic small round cell tumor also occurs in the abdomen (sometimes as multiple nodules) in children and young adults, predominantly males, with nests and sheets of small, basophilic cells. These tumors may also show desmin positivity as part of their classic polyphenotypic immunoprofile (expressing makers of several cell lineages, including epithelial, neural, and muscle). However, desmin positivity is usually expressed in a distinct paranuclear dot pattern, and other markers such as myogenin or myoD1 are typically negative. WT1 staining is positive. Cytokeratins are usually positive, in contrast to embryonal rhabdomyosarcoma. Definitive diagnosis of these tumors is made with identification of a t(11;22) translocation or an EWSR1::WT1 fusion gene.

Hepatoblastoma is the most common primary liver malignancy in children (though pediatric liver malignancies are rare overall) and is typically diagnosed in children less than 3 years of age. Epithelial hepatoblastoma may show a variety of morphologic patterns. Tumors may demonstrate sheets or nests of small cells with high N:C ratios, nuclear pleomorphism, and necrosis. Immunohistochemical stains, including beta-catenin, glypican 3, glutamine synthetase, and SALL4, can be useful to identify different components. The majority of hepatoblastomas harbor genetic abnormalities of the WNT/β-catenin signaling pathway, including CTNNB1 alterations. Hepatoblastoma is often associated with an elevated serum alpha-fetoprotein (AFP).

Synovial sarcoma is a tumor of uncertain differentiation arising in soft tissues that more commonly affects adults but can occur at any age, including in infants, and has been reported following radiation therapy. The monophasic pattern is most common, predominated by uniform, overlapping spindled cells arranged in vague fascicles or sheets and a background of ropy/wiry collagen and rare myxoid change. The other patterns are biphasic (characterized by epithelial elements alongside the spindled population) and poorly differentiated (characterized by more striking atypia and more common in elderly patients). Definitive diagnosis of synovial sarcoma is best made by identification of a t(X;18) translocation resulting in SS18::SSX (SSX1, SSX2 or SSX4) fusion gene product.

Wilms tumor arises in the kidneys from embryonic precursor cells (nephrogenic rests), usually in young children, and may resemble embryonal rhabdomyosarcoma if predominantly blastemal. Although not required for diagnosis, genetic studies have revealed numerous mutations implicated in the pathogenesis of Wilms tumor, including WT1, CTNNB1, IGF2​,​ and WTX, but expression of p53 and β-catenin mutations are most associated with early metastases, such as to the liver. Classically, these tumors demonstrate nuclear immunohistochemical staining for WT1. Myogenin and MyoD1 should not stain the blastemal component of Wilms tumor, though desmin may be variably positive.

1. Which of the following primary sites for embryonal rhabdomyosarcoma indicates​ ​more advanced-stage disease?
   
   
   1. Abdomen
   2. Biliary tract
   3. Orbit
   4. Retroperitoneum
   5. Urinary bladder/prostate
2. Which of the following features is required to classify an embryonal rhabdomyosarcoma as anaplastic?
   
   
   1. Geographic necrosis
   2. Greater than 20 mitoses per high​-​power field
   3. Marked cellular density
   4. Nuclear size variability greater than 3:1
   5. Tumor size greater than 10 centimeters
3. ​​ ​An EWSR1::WT1 fusion transcript is most indicative of what neoplasm?
   
   
   1. Desmoplastic small round cell tumor
   2. Embryonal rhabdomyosarcoma
   3. Hepatoblastoma
   4. Synovial sarcoma
   5. Wilms tumor

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1. Urinary bladder/prostate (e)
2. Nuclear size variability greater than 3:1 (d)
3. Desmoplastic small round cell tumor (a)