Immunohistochemical studies performed on the pancreas FNA specimen were negative for LCA expression but were diffusely positive for myogenin and myoD1 (Fig. 6-8). The diagnosis in this case was first made on the forearm biopsy which showed similar morphologic and immunohistochemical features to that seen in the pancreatic FNA, with abundant small round blue cells containing PAS-positive cytoplasmic vacuoles (Fig. 9-10). The patient in this case was diagnosed with stage IV alveolar rhabdomyosarcoma with pancreatic and bone marrow metastasis. Molecular studies performed on paraffin-embedded tissue confirmed the presence of a PAX3-FOXO1A fusion transcript within the tumor cell population. The patient was treated non-surgically with combination chemotherapy. Unfortunately, the patient developed intracranial recurrence in the form of carcinomatous meningitis and was converted to comfort measures only.
Alveolar rhabdomyosarcoma is a rare tumor which typically presents as a rapidly growing extremity or axial mass. Adolescents and young adults are most often affected, though the tumor can occur across all age groups. The most common sites of alveolar rhabdomyosarcoma metastasis includes the lungs, liver and bones. Pancreatic metastasis of alveolar rhabdomyosarcoma is extremely rare, with only a few cases reported. Alveolar rhabdomyosarcoma is considered to be a high grade tumor that carries a poorer prognosis than most other rhabdomyosarcomas.
Histologically, alveolar rhabdomyosarcoma is composed of a monotonous population of primitive cells. In typical lesions, the neoplastic cells are separated into nests by fibrovascular septations. The periphery of the nests is classically discohesive with a “picket fence” pattern. A solid variant can also occur, which may only exhibit classic “alveolar” pattern focally. Multi-nucleated wreath-like cells may be present. Myogenin and myoD1 are consistently expressed in alveolar rhabdomyosarcoma due to the rhabdomyoblastic origin of the tumor. In contrast to embryonal rhabdomyosarcoma, the nuclear myogenin and myoD1 expression seen in alveolar rhabdomyosarcoma is usually strong and diffuse. Tumors may also express keratins and neuroendocrine markers, which may constitute a diagnostic pitfall if interpreted in isolation.
Alveolar rhabdomyosarcoma is known to harbor recurrent translocations, with the largest subset harboring t(2;13)(q35;q14) and a smaller subset harboring t(1;13)(p36;q14). These translocations result in both PAX3-FOXO1 and PAX7-FOXO1 fusion products, respectively, which act as transcriptional activators. The presence of either translocation is considered specific for alveolar rhabdomyosarcoma, though fusion-negative cases can occur in up to 30% of cases.
The main differential diagnosis of a small round blue cell tumors involving the pancreas in a pediatric or adolescent patient includes alveolar rhabdomyosarcoma, lymphoma, extraosseous Ewing’s sarcoma/primitive neuroectodermal tumor (ES/PNET), desmoplastic small round blue cell tumor (DSRBCT) and neuroblastoma.
ES/PNET are classified under the same family of tumors, and can rarely present as a pancreatic mass. Both tumors are known to share the same t(11,22) translocation resulting in a EWSR1-FLI1 fusion product. The cytologic features of ES/PNET overlap with alveolar rhabdomyosarcoma, with aspirates revealing uniform small round cells with inconspicuous nucleoli. The cytoplasm is relatively clear and with glycogen containing vacuoles, similar to those seen in alveolar rhabdomyosarcoma. Distinguishing ES/PNET from alveolar rhabdomyosarcoma is difficult on cytomorphologic features alone and relies heavily on immunohistochemistry (Table 1). Though both alveolar rhabdomyosarcoma and ES/PNET can express CD56 and CD99, ES/PNET exhibits strong FLI1 positivity which is consistently negative in alveolar rhabdomyosarcoma. Additionally, ES/PNET is consistently negative for myogenin, and myoD1.
Desmoplastic small round cell tumor is a highly aggressive neoplasm, which can also rarely present as a pancreatic mass in young children and adolescents. DSRCT is characterized by a recurrent t(11;22)(p13;q12) chromosomal translocation resulting in a EWSR1-WT1 gene fusion. The cytologic features of DSRCT significantly overlap with alveolar rhabdomyosarcoma. Similar to alveolar rhabdomyosarcoma, smears from DSRCT aspirates are highly cellular and composed of pleomorphic cells with round to oval nuclei, scant cytoplasm and inconspicuous nucleoli. Cells may be arranged in sheets or clusters with surrounding desmoplastic stroma. Rare rosette formation may be found which, if present, can favor DSRCT over alveolar rhabdomyosarcoma. Immunohistochemical staining is vital in distinguishing between the two entities. Cases of DSRCT are immunoreactive for keratins, epithelial membrane antigen (EMA) and neuron specific enolase (NSE). Immunostaining for desmin classically reveals a distinctive dot-like pattern in DSRCT. Additionally, nuclear WT1 positivity is seen in DSRCT while myogenin and myoD1 are consistently negative.
Neuroblastoma is a small round cell tumor composed of sympathetic nervous system precursor neuroblasts. The majority of neuroblastomas arise in the retroperitoneum and involve the adrenal gland, but tumors can arise from neural crest cells at any location. Rare cases of neuroblastoma presenting as a pancreatic mass have been reported. Smears from neuroblastoma aspirates reveal tumor cells with high nuclear-cytoplasmic ratios. Cells may be clustered with Homer-Wright rosette formation or arranged singly. Background purple fibrillary or filamentous neuropil matrix material is classic. Differentiating neuroblastoma from alveolar rhabdomyosarcoma becomes straightforward with immunohistochemistry. Neuroblastoma will express markers of neuronal differentiation including neuron-specific enolase (NSE), and neurofilament protein as well as neuroendocrine markers including chromogranin and synaptophysin. Additionally, myogenin and myoD1 are consistently negative in neuroblastoma.
Another important entity to consider in the differential diagnosis is lymphoma. Patients with primary pancreatic lymphoma present with a pancreatic mass, with or without regional adenopathy. The vast majority of primary pancreatic lymphomas are of non-Hodgkin type, with diffuse large B-cell lymphomas representing the largest proportion of cases. Other lymphomas reported to occur as pancreatic primaries include follicular lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, and rarely Hodgkin lymphoma. Smears of lymphoid neoplasms can show significant overlap with alveolar rhabdomyosarcoma, consisting of discohesive cells with high nuclear-cytoplasm ratios, irregular nuclear membranes, and variable nuclear pleomorphism depending on the subset of lymphoma sampled. Cases of Burkitt lymphoma may exhibit prominent cytoplasmic vacuolization similar to that seen in cases of alveolar rhabdomyosarcoma, further adding to diagnostic difficulty. Lymphoglandular bodies, when present, may serve as a useful clue to separate lymphoma from alveolar rhabdomyosarcoma. Distinguishing alveolar rhabdomyosarcoma from lymphoma becomes straightforward when using immunohistochemistry. Lymphomas will usually exhibit LCA positivity as well as either B-cell or T-cell markers depending on the subset of lymphoma present. In contrast, alveolar rhabdomyosarcoma will not express LCA and will instead exhibit diffuse myogenin and myoD1 positivity.