February 2017

A 19 year-old woman with back pain

Janice Ahn MD, Melina Flanagan, MD MSPH

 

Patient History:

A 19-year-old woman presented with back pain which she described as muscle spasms with radiation to the lower extremities. She had undergone surgical resection of an upper arm mass in the previous year at an outside facility with subsequent chemotherapy and radiation. Imaging demonstrated numerous lesions suspicious for metastatic foci in the thoracic and lumbar vertebrae with extra-osseous spread, causing moderate spinal canal stenosis. Imaging of the brain also revealed multiple intra-axial lesions.

A lumbar puncture was performed to guide treatment: if the metastatic foci were localized to the vertebrae, focal spinal radiation would be indicated, but leptomeningeal involvement or seeding of the CSF would warrant craniospinal radiation therapy. Subsequently, a laminectomy also was performed.

Microscopic Findings:

Cerebrospinal fluid findings are demonstrated in Figures 1-4. A cell block was noncontributory due to insufficient cells.


Figures 1 A-C. Atypical enlarged cells with occasional karyorrhexis and possible mitoses. (Papanicolaou stain)


Figure 2. Atypical round to polygonal cells with binucleate forms (arrowhead) and karyorrhexis (Papanicolaou stain).


Figure 3. Enlarged atypical cell with eccentric nucleus. (Diff-Quik stain)

Tissue finding from the laminectomy are shown in Figures 4-6.


Figure 4. Small round blue cells with abundant cytoplasm infiltrating bone and normal bone marrow constituents. (H&E)


Figure 5.
Strong cytoplasmic staining for desmin.


Figure 6.
Distinct nuclear staining for myogenin.

In addition to the above cases, the original case from the outside facility was reviewed and showed an infiltrative small round blue cell neoplasm with loosely cohesive cells, divided into nests by fibrous septae. Necrosis was present. The neoplastic cells were strongly positive for myogenin, desmin, vimentin and negative for cytokeratin, EMA, LCA, and S100. Cytogenetic studies supported the final diagnosis.

Diagnosis

Which of the following cytogenetic translocations is most likely present in this patient’s neoplasm?

Answer

Please select an answer above.

Discussion

Discussion

This patient presented with leptomeningeal spread of the alveolar subtype of rhabdomyosarcoma (RMS), which had originally presented as a rapidly enlarging soft tissue mass of the upper arm.

Rhabdomyosarcoma is the most common soft tissue malignancy of childhood and has four histologic subtypes: embryonal, spindle cell/sclerosing, alveolar, and pleomorphic.1-4 Embryonal RMS is the most common subtype and typically occurs in the pediatric population, commonly prior to age 10, in the head and neck region as well as the genitourinary tract.3 Microscopically, embryonal RMS is composed of primitive mesenchymal cells in various stages of myogenesis with varying number of rhabdomyoblasts.3 The presence of a cambium layer or marked atypia further sub-classifies this type into the botryoid and anaplastic variants, respectively.3 Spindle cell/ sclerosing RMS was previously considered a variant of embryonal RMS, and was listed as a separate category in the 2013 version of WHO due to its frequent occurrence in the paratesticular sites of pediatric patients and a particularly favorable outcome.2,5

Alveolar RMS, occurs in a slightly older population from ages 15-20.4,6,7 It arises in the deep soft tissue of the extremities, but also is seen in the paraspinal and perineal regions. Unlike the embryonal type, alveolar RMS demonstrates rapid growth and is often disseminated at presentation6; the overall 5-year survival is less than 50%.8 Microscopically, the tumor is composed of dyshesive small round blue cells with fibrovascular septae and scattered multinucleated giant cells with rhabdomyoblastic differentiation. A solid variant of the alveolar type demonstrates the same cytomorphology but is organized in a denser, compact pattern.

Pleomorphic RMS occurs in the adult population, most commonly in the 6th decade.1,6 It arises in the deep soft tissues of the lower extremity and, like the alveolar subtype, is rapidly growing and has a poor prognosis1,6. Microscopically, this subtype is composed of pleomorphic polygonal cells demonstrating myogenic differentiation by immunohistochemistry.6

The utility of cytologic evaluation of soft tissue tumors has been much debated.9 However, as in other tissue types, cytology is a minimally invasive, technically uncomplicated, and cost effective screening tool.9,10 As in the present case, it is most useful in the diagnosis of recurrent tumors or metastasis, as opposed to primary diagnosis.9 The cytomorphology of RMS varies subtly with each subtype but is generally composed of small lymphocyte-like cells with finely granular hyperchromatic nuclei and infrequent nucleoli.7,10-12 Cellular pleomorphism is more typical of embryonal RMS and larger polygonal cells may be more characteristic of the alveolar subtype.9 Binucleate cells and multinucleated giant cells are seen in varying numbers, particularly in the alveolar subtype, and the giant cells often demonstrate a strap-like or tapering tail of cytoplasm, corresponding to rhabdomyoblastic differentiation. 7,10-12 Cells may be arranged singly or in cohesive groups.10,12 Though distinction of the alveolar subtype from other subtypes would be useful for its prognostic implications, the differences are subtle, and differentiation, let alone diagnosis of RMS, frequently relies on ancillary studies.9,10

In cases with sufficient specimen for the creation of a cell block, evidence of skeletal muscle differentiation in RMS can be demonstrated by immunoreactivity for desmin, muscle-specific actin, myogenin, and myo-D1.9 Moreover, cytologic specimens may be submitted for cytogenetic analysis, namely Fluorescence In-Situ Hybridization (FISH) testing for a fusion gene involving forkhead box protein O1 (FOXO1). The majority of patients with alveolar RMS express a PAX3-FOXO1 gene fusion and a smaller subset, PAX7-FOXO1, resulting from t(2;13) or t(1;13) translocation, respectively.4 Tumors with the former, PAX3-FOXO1, behave aggressively and these patients have a survival rate of less than 10% in the setting of metastasis.4,13  On the other hand, tumors with the PAX7-FOXO1 are associated with a more favorable outcome.4,13 These cytogenetic studies provide an additional level of diagnostic certainty in both cytologic and tissue biopsy specimens. 

In the present case, the diagnosis of alveolar RMS was made on the initial soft tissue mass based upon the microscopic tissue findings and FISH positivity for PAX3-FOXO1 fusion protein. The patient’s age and primary tumor location in the extremities are consistent with the alveolar subtype of RMS. While leptomeningeal spread is a well-known complication of RMS, and CSF screening is often part of the work-up, there are not many published reports of the CSF appearance of RMS.

References :

  1. Montgomery EA BF. Pleomorphic rhabdomyosarcoma. In: Fletcher CDM BJ, Hogendoorn PCW, Mertens F, ed. WHO Classification of Tumours of Soft Tissue and Bone. Lyon: IARC; 2013:132-133.
  2. Nacimiento AF BF. Spindle cell/sclerosing rhabdomyosarcoma. In: Fletcher CDM BJ, Hogendoorn PCW, Mertens F, ed. WHO Classification of Tumours of Soft Tissue and Bone. Lyon: IARC; 2013:134-135.
  3. Parham DM BF. Embryonal rhabdomyosarcoma. In: Fletcher CDM BJ, Hogendoorn PCW, Mertens F, ed. WHO Classification of Tumours of Soft Tissue and Bone. Lyon: IARC; 2013:127-129.
  4. Parham DM BF. Alveolar rhabdomyosarcoma. In: Fletcher CDM BJ, Hogendoorn PCW, Mertens F, ed. WHO Classification of Tumours of Soft Tissue and Bone. Lyon: IARC; 2013:130-132.
  5. Jo VY, Fletcher CD. WHO classification of soft tissue tumours: an update based on the 2013 (4th) edition. Pathology. 2014;46(2):95-104.
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  8. Ognjanovic S, Linabery AM, Charbonneau B, Ross JA. Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975-2005. Cancer. 2009;115(18):4218-4226.
  9. Qian X. Soft tissue. In: Cubas SE DB, ed. Cytology: Diagnostic Principles and Clinical Correlates. Philadelphia: Saunders Elsevier; 2009:451-494.
  10. Klijanienko J, Caillaud JM, Orbach D, et al. Cyto-histological correlations in primary, recurrent and metastatic rhabdomyosarcoma: the institut Curie's experience. Diagn Cytopathol. 2007;35(8):482-487.
  11. Nelson AC, Singh C, Pambuccian SE. Cytological diagnosis of metastatic alveolar rhabdomyosarcoma in the ascitic fluid: Report of a case highlighting the diagnostic difficulties. Cytojournal. 2012;9.
  12. Atahan S, Aksu O, Ekinci C. Cytologic diagnosis and subtyping of rhabdomyosarcoma. Cytopathology. 1998;9(6):389-397.
  13. Sorensen PH, Lynch JC, Qualman SJ, et al. PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group. J Clin Oncol. 2002;20(11):2672-2679.