Cutaneous rhabdomyosarcoma with FUS::TFCP2 fusion: A case report emphasizing early detection.

Rhabdomyosarcoma with TFCP2 rearrangement is a recently identified malignant neoplasm characterized by immunohistochemical evidence of rhabdomyoblastic differentiation, keratin expression, upregulation of ALK, and an aggressive clinical course. This neoplasm has a tendency to affect craniofacial bones, with only a few reported cases of extra-osseous tumors. Here, we present a case of cutaneous rhabdomyosarcoma with FUS::TFCP2 fusion in a 35-year-old female. Notably, the tumor exhibited a pathologic spectrum, initially resembling sclerosing dermatitis at presentation but progressing into a high-grade malignant tumor within 8 months. The distinctive immunoprofile of this neoplasm highlights the importance of early molecular studies for diagnosis, even in the presence of low-grade cytomorphology. Early detection may offer an opportunity for timely resection before the tumor becomes unresectable.

Recurrent VGLL3 fusions define a distinctive subset of spindle cell rhabdomyosarcoma with an indolent clinical course and striking predilection for the head and neck.

The mammalian Vestigial-like (VGLL) transcriptional cofactor family of proteins VGLL1-4 has recently emerged as an important player in the tumorigenesis of diverse neoplasms. The role of VGLL3 in soft tissue tumors is exemplified by its amplification in myxoinflammatory fibroblastic sarcoma and its rearrangement (fused to CHD7, CHD9, or MAMLD1) in hybrid schwannoma-perineurioma. This study characterizes a distinctive low-grade myogenic neoplasm with a striking predilection for the head and neck, characterized by VGLL3 fusions. The study includes five males and one female patient, aged 30-71 years (median, 56). Three tumors originated in the tongue, with one case each in the nasopharynx, oral cavity, and oropharynx. The VGLL3 fusion partners included TCF12 (n = 3), EP300 (n = 2), and PPARGC1A (n = 1). The tumor size range was 0.8-1.6 cm (all, but one, was <1 cm). Histologically, all tumors displayed bland spindle to ovoid cells arranged into vague fascicular and diffuse patterns. Mitotic activity ranged from 1 to 7 per 10 HPFs. Five tumors were muscle-centered and infiltrative, and one was centered beneath nasopharyngeal mucosa. Immunohistochemistry revealed consistent expression of desmin (diffuse in four and patchy in two cases) associated with patchy smooth muscle actin expression (4/6), and focal reactivity for myogenin (5/6) and myoD1 (1/3). All patients were managed surgically; one patient each received adjuvant radio- or chemotherapy. Three patients with follow-up were without disease at 8, 19, and 60 months and one was alive with unknown disease status at 24 months. All VGLL3 fusions were in-frame and involved exon 2, fused with either TCF12 exon 16, EP300 exon 31, or PPARGC1A exon 5, respectively. This series characterizes a distinctive subset of spindle cell rhabdomyosarcoma (RMS) with a predilection for the head and neck in adults, defined by VGLL3 fusions, likely indolent behavior and limited rhabdomyoblastic differentiation. Further delineation of this entity and differentiation from more aggressive molecular subtypes of spindle cell RMS is mandatory to define the most appropriate therapeutic strategy and avoid overtreatment.

ZFP64::NCOA3 gene fusion defines a novel subset of spindle cell rhabdomyosarcoma.

Spindle cell rhabdomyosarcoma represents a rare neoplasm characterized by monomorphic spindle cells with a fascicular architecture and variable skeletal muscle differentiation. Following incidental identification of a ZFP64::NCOA3 gene fusion in an unclassified spindle cell sarcoma resembling adult-type fibrosarcoma, we performed a retrospective archival review and identified four additional cases with a similar histology and identical gene fusion. All tumors arose in adult males (28-71 years). The neoplasms were found in the deep soft tissues, two were gluteal, and one each arose in the thigh, abdominal wall, and chest wall. Morphologically, the tumors were characterized by spindle cells with a distinctive herringbone pattern and variable collagenous to myxoid stroma. The nuclei were relatively monomorphic with variable mitotic activity. Three tumors had immunoreactivity for MyoD1, and four contained variable expression of desmin and smooth muscle actin. All cases tested for myogenin, CD34, S100, pankeratin, and epithelial membrane antigen were negative. Targeted RNA sequencing revealed a ZFP64::NCOA3 fusion product in all five tumors. Three patients developed distant metastases, and two ultimately succumbed to their disease within 2 years of initial diagnosis. This study suggests ZFP64::NCOA3 fusions define a novel subtype of rhabdomyosarcoma with a spindle cell morphology and aggressive clinical behavior. The potential for morphologic and immunohistochemical overlap with several other sarcoma types underscores the value of molecular testing as a diagnostic adjunct to ensure accurate classification and management of these neoplasms.

Epithelioid Rhabdomyosarcoma at the High Parietal Area of the Head: A Case Report.

Epithelioid rhabdomyosarcoma is a rare condition, which may be clinically misinterpreted as melanoma due to its morphological appearance. Careful morphological and immunohistochemical analysis play an important role in its diagnosis. This case report describes the clinicopathological features of an epithelioid RMS diagnosed at the high parietal area of the head. A 71-year-old male patient presented a red-brown pigmented ulcerative nodule in the high parietal region of the head. Previous biopsy and computer tomography imaging revealed a malignant melanoma in stage I (pT2, sN0, Mx). After tumor operation, histological and immunohistochemical analysis of the tumor were conducted. Histological analysis showed an erosive lesion with a monomorphic cell population containing small cells with prominent nucleoli. A positivity was confirmed for CD10, Vimentin, and Desmin. MyoD1 was detected, as well as a fluctuating signal for p53. Molecular analysis revealed a negativity for Sox-10, and a weak positivity for CK8/18 by absence of p40. Based on the morphological and immunohistochemical findings, the tumor was diagnosed as epithelioid RMS.

A subset of epithelioid and spindle cell rhabdomyosarcomas is associated with TFCP2 fusions and common ALK upregulation.

Rhabdomyosarcomas with TFCP2 fusions represent an emerging subtype of tumors, initially discovered by RNA-sequencing. We report herein the clinicopathological, transcriptional, and genomic features of a series of 14 cases. Cases were retrospectively and prospectively recruited and studied by immunohistochemistry (MYF4, MYOD1, S100, AE1/E3, ALK), fluorescence in situ hybridization with TFCP2 break-apart probe (n = 10/14), array-comparative genomic hybridization (Agilent), whole RNA-sequencing (Truseq Exome, Illumina), or anchored multiplex PCR-based targeted next-generation sequencing (Archer® FusionPlex® Sarcoma kit). Patient's age ranged between 11 and 86 years, including 5 pediatric cases. Tumors were located in the bone (n = 12/14) and soft tissue (n = 2/14). Most bone tumors invaded surrounding soft tissue. Craniofacial bones were over-represented (n = 8/12). Median survival was 8 months and five patients are currently alive with a median follow-up of 20 months. Most tumors displayed a mixed spindle cell and epithelioid pattern with frequent vesicular nuclei. All tumors expressed keratins and showed a rhabdomyogenic phenotype (defined as expression of MYF4 and/or MYOD1). ALK was overexpressed in all but three cases without underlying ALK fusion on break-apart FISH (n = 5) nor next-generation sequencing (n = 14). ALK upregulation was frequently associated with an internal deletion at genomic level. TFCP2 was fused in 5' either to EWSR1 (n = 6) or FUS (n = 8). EWSR1 was involved in both soft tissue cases. FISH with TFCP2 break-apart probe was positive in all tested cases (n = 8), including one case with unbalanced signal. On array-CGH, all tested tumors displayed complex genetic profiles with genomic indexes ranging from 13 to 107.55 and recurrent CDKN2A deletions. FET-TFCP2 rhabdomyosarcomas clustered together and distinctly from other rhabdomyosarcomas subgroups. Altogether, our data confirm and expand the spectrum of the new family of FET-TFCP2 rhabdomyosarcomas, which are associated with a predilection for the craniofacial bones, an aggressive course, and recurrent pathological features. Their association with ALK overexpression might represent a therapeutic vulnerability.

Undifferentiated Sarcoma as Intermediate Step in the Progression of Malignant Melanoma to Rhabdomyosarcoma: Histologic, Immunohistochemical, and Molecular Studies of a New Case of Malignant Melanoma With Rhabdomyosarcomatous Differentiation.

Malignant melanoma (MM) may display highly variable phenotypic diversity, sometimes associated with loss of immunohistochemical melanocytic markers and acquisition of nonmelanocytic lineage of differentiation. Primary cutaneous MM with rhabdomyosarcomatous differentiation is extremely rare with only 5 reported cases in the literature. To date, a chronological progression of a MM to rhabdomyosarcoma has not been conclusively documented. A 96-year-old man underwent a re-excision of an "atypical fibroxanthoma" of the forearm, which revealed a small lentigo maligna melanoma associated with a dominant dermal high-grade spindle cell nodule admixed with a population of malignant polygonal epithelioid cells. On immunohistochemical studies, the spindle cells were completely negative for all melanocytic markers, whereas a small population of polygonal neoplastic cells at the periphery was positive for Desmin and Myo-D1, supporting early rhabdomyosarcomatous transformation. Several subsequent re-excisions demonstrated merely nodules of malignant pleomorphic epithelioid cells with rhabdomyosarcomatous differentiation and devoid of melanocytic markers. In addition, both rhabdomyosarcomatous component and original MM displayed identical mutations. Therefore, the histologic, immunohistochemical, and molecular findings documented for the first time a chronological progression from an invasive MM to a pleomorphic rhabdomyosarcoma through an intermediate stage of undifferentiated sarcoma/atypical fibroxanthoma. Interestingly, subsequent recurrences of pure rhabdomyosarcomatous component displayed skip lesions/microsatellitosis, marked tumor-infiltrative lymphocytes, and rare junctional nests of rhabdomyosarcomatous cells in the epidermis, histologic features that were not described in primary cutaneous rhabdomyosarcoma and therefore could serve as morphologic clues to the diagnosis of rhabdomyosarcomatous transformation in an MM.

Assessment of programmed death-ligand 1 expression and tumor-associated immune cells in pediatric cancer tissues.

BACKGROUND: Programmed death 1 (PD-1) signaling in the tumor microenvironment dampens immune responses to cancer, and blocking this axis induces antitumor effects in several malignancies. Clinical studies of PD-1 blockade are only now being initiated in pediatric patients, and little is known regarding programmed death-ligand 1 (PD-L1) expression in common childhood cancers. The authors characterized PD-L1 expression and tumor-associated immune cells (TAICs) (lymphocytes and macrophages) in common pediatric cancers. METHODS: Whole slide sections and tissue microarrays were evaluated by immunohistochemistry for PD-L1 expression and for the presence of TAICs. TAICs were also screened for PD-L1 expression. RESULTS: Thirty-nine of 451 evaluable tumors (9%) expressed PD-L1 in at least 1% of tumor cells. The highest frequency histotypes comprised Burkitt lymphoma (80%; 8 of 10 tumors), glioblastoma multiforme (36%; 5 of 14 tumors), and neuroblastoma (14%; 17 of 118 tumors). PD-L1 staining was associated with inferior survival among patients with neuroblastoma (P = .004). Seventy-four percent of tumors contained lymphocytes and/or macrophages. Macrophages were significantly more likely to be identified in PD-L1-positive versus PD-L1-negative tumors (P < .001). CONCLUSIONS: A subset of diagnostic pediatric cancers exhibit PD-L1 expression, whereas a much larger fraction demonstrates infiltration with tumor-associated lymphocytes. PD-L1 expression may be a biomarker for poor outcome in neuroblastoma. Further preclinical and clinical investigation will define the predictive nature of PD-L1 expression in childhood cancers both at diagnosis and after exposure to chemoradiotherapy. Cancer 2017;123:3807-3815. © 2017 American Cancer Society.

Clinicopathologic analysis of spindle cell/sclerosing rhabdomyosarcoma.

BACKGROUND: Clinical characteristics and optimal treatment strategies for spindle cell/sclerosing rhabdomyosarcoma (ssRMS) have not been well established because of its rarity. PROCEDURE: Retrospective re-evaluation of sarcoma specimens (1997-2014) identified 16 ssRMSs (median age 20 years, range 7-39 years). Clinicopathological features, clinical course, and outcome were analyzed. RESULTS: Primary disease sites were the head and neck (10 cases) and other regions (6 cases). Nine cases were at Intergroup Rhabdomyosarcoma Study preoperative stage 3. The primary tumors were >5 cm in 13 cases. Two patients had lymph node metastases, but none had distant metastases at presentation. At follow-up (median period 39 months, range 4.6-201), seven patients were alive without disease. Among nine patients treated with the vincristine, actinomycin, and cyclophosphamide (VAC) regimen, five responded well, with four surviving free of disease. Among ten patients with recurrent or progressive disease, three experienced local recurrence, four had distant metastases, and three had both. None exhibited bone marrow invasion. Eight of the ten patients died in median time from relapse to death of 18 months (range 11-56). CONCLUSIONS: Although most ssRMSs present as a bulky tumor, nodal or distant metastases are rare at presentation. ssRMSs initially show good response to VAC, but >50% of tumors recur or progress; these data suggest a worse prognosis of ssRMS compared to the pediatric embryonal variant. As relapse typically occurs as local or distant solitary lesion without bone marrow invasion, localized treatment combined with chemotherapy would contribute to improve the prognosis of recurrent ssRMS.

Cutaneous Pleomorphic Rhabdomyosarcoma Occurring on Sun-Damaged Skin: A Case Report.

Rhabdomyosarcoma (RMS) is a malignant soft tissue tumor with skeletal muscle differentiation that can rarely present as a primary cutaneous tumor. There are 3 main subtypes of RMS: embryonal, alveolar, and pleomorphic. Primary cutaneous pleomorphic RMS is extremely rare, there being only 9 reported cases in the literature, 2 of which are radiation induced. We present a case of primary pleomorphic RMS occurring on the sun-damaged skin of the face of an 89-year-old woman. The tumor was diagnosed by histology, immunohistochemistry, and electron microscopy. The patient was treated by surgery and adjuvant radiotherapy. The tumor recurred rapidly after surgical excision. She died 2 months after the diagnosis from complications of treatment, local symptoms of tumor, and concurrent illnesses. Primary cutaneous pleomorphic RMS is a rare tumor of adults and pursues an aggressive clinical course.

Rhabdomyosarcoma in children in the light of isotope ratio mass spectrometry.

Rhabdomyosarcoma is the third most common solid tumor in children and the most common soft tissue sarcoma in this age group. However, 5-year survival is only observed in approximately 70% of cases, and the prognosis for patients with progressive disease is still poor. The authors hypothesize that the still unidentified differences in embryonal and alveolar tumor biology reflect the complex chemical reactions occurring during cell growth and metabolism and may be pursued in isotopic fractionation processes. Presented herein is the first evaluation of the nitrogen and carbon isotope ratio using isotope ratio mass spectrometry in the two major rhabdomyosarcoma histologic types. 15N enrichment was found in tumor tissues of embryonal histological type. The obtained result may indicate that individual patient considerations such as isotope ratio, in addition to widely accepted prognostic factors, may facilitate patient classification in terms of risk groups.

Recently characterized soft tissue tumors that bring biologic insight.

Previously unrecognized but clinicopathologically (and often molecularly) distinct types of soft tissue tumor continue to be characterized, allowing wider recognition, more consistent application of diagnostic criteria, more reliable prediction of tumor behavior and enhancement of existing classification schemes. Examples of such 'entities' that have become much better understood over the past decade or so include deep 'benign' fibrous histiocytoma, hemosiderotic fibrolipomatous tumor, PEComa, spindle cell liposarcoma, myoepithelial tumors of soft tissue and spindle cell/sclerosing rhabdomyosarcoma. These tumor types, as well as the insights which they have engendered, are briefly reviewed here.

HES6 enhances the motility of alveolar rhabdomyosarcoma cells.

HES6, a member of the hairy-enhancer-of-split family of transcription factors, plays multiple roles in myogenesis. It is a direct target of the myogenic transcription factor MyoD and has been shown to regulate the formation of the myotome in development, myoblast cell cycle exit and the organization of the actin cytoskeleton during terminal differentiation. Here we investigate the expression and function of HES6 in rhabdomyosarcoma, a soft tissue tumor which expresses myogenic genes but fails to differentiate into muscle. We show that HES6 is expressed at high levels in the subset of alveolar rhabdomyosarcomas expressing PAX/FOXO1 fusion genes (ARMSp). Knockdown of HES6 mRNA in the ARMSp cell line RH30 reduces proliferation and cell motility. This phenotype is rescued by expression of mouse Hes6 which is insensitive to HES6 siRNA. Furthermore, expression microarray analysis indicates that the HES6 knockdown is associated with a decrease in the levels of Transgelin, (TAGLN), a regulator of the actin cytoskeleton. Knockdown of TAGLN decreases cell motility, whilst TAGLN overexpression rescues the motility defect resulting from HES6 knockdown. These findings indicate HES6 contributes to the pathogenesis of ARMSp by enhancing both proliferation and cell motility.

CD133 marks a myogenically primitive subpopulation in rhabdomyosarcoma cell lines that are relatively chemoresistant but sensitive to mutant HSV.

BACKGROUND: Rhabdomyosarcoma (RMS) is characterized by features of skeletal muscle and is comprised of two major histological subtypes, embryonal (E-RMS), and alveolar (A-RMS). Subsets of each RMS subtype demonstrate resistance to multimodal therapy leading to treatment failure. Cancer stem cells or cancer-initiating cells (CIC) represent a theorized population of cells that give rise to tumors and are responsible for treatment resistance. PROCEDURE: We investigated the ability of CD133, a putative CIC marker, to distinguish a chemoresistant, myogenically primitive population in alveolar (RH30), and embryonal (RD) RMS cell lines. We tested CD133+/- cells for sensitivity to engineered herpes simplex virus (oHSV). RESULTS: Relative to CD133- cells, CD133+ A-RMS, and E-RMS cells demonstrate an enhanced colony-forming ability, are less differentiated myogenically, and are more resistant to cytotoxic chemotherapy but equally sensitive to oHSV oncolysis. Compared to CD133- RD cells, CD133+ cells express relatively high levels of genes typically expressed in skeletal muscle progenitor satellite cells including PAX7, c-MET, and the GLI effectors of the hedgehog signaling pathway. In contrast, CD133+ RH30 cells were not associated with enhanced expression of satellite cell markers or Hh targets. CONCLUSIONS: Our findings demonstrate that CD133+ cells from A-RMS and E-RMS cell lines are characterized by a myogenically primitive phenotype. These cells have the capacity to form colonies in vitro and are more resistant to chemotherapy than CD133- cells. CD133 expression may denote a subset of RMS cells with an important role in tumorigenesis and treatment failure. These resistant cells may be effectively targeted by oHSV therapy.

Cytoplasmic p63 immunohistochemistry is a useful marker for muscle differentiation: an immunohistochemical and immunoelectron microscopic study.

TP63, a member of the TP53 gene family, is a nuclear marker of myoepithelial cells. Antibody against p63 is frequently used to aid in the diagnosis of prostate carcinoma, as well as in the identification of myoepithelial cells in other tissues including the breast. p63 is also a marker for squamous cell carcinoma. Recently, it was found that all p53 family members are involved in regulating the process of muscle differentiation through the retinoblastoma (RB) protein. Ablation of these p53 family functions blocks the differentiation program and promotes malignant transformation by enabling cooperating oncogenes to transform myoblasts. We therefore studied p63 expression in a number of neoplasms with myogenic differentiation. Immunohistochemical staining for p63 was performed on paraffin sections from 38 rhabdomyosarcomas, five leiomyomas, five leiomyosarcomas, five rhabdomyomas, five rhabdomyomatous Wilms tumors, three normal cardiac muscles, one medullomyoblastoma, one pleuropulmonary blastoma with rhabdomyomatous differentiation, and one teratoma with prominent rhabdomyoblasts. Each case was also stained with desmin. Unlike the nuclear staining scored in myoepithelial cells, only cytoplasmic staining for p63 was considered positive. Of 38 cases of rhabdomyosarcoma, 36 showed cytoplasmic p63 staining; 24 of these showed highlighting of cross-striations superior to that of desmin. In addition, 5/5 rhabdomyomas, 5/5 rhabdomyomatous Wilms tumors, 1/1 pleuropulmonary blastoma with rhabdomyomatous differentiation, 1/1 teratoma with atypical rhabdoblasts, and 1/1 medullomyoblastoma exhibited cytoplasmic p63 staining. Normal cardiac muscle samples (3/3) also demonstrated positive cytoplasmic staining and distinct cross-striations. Smooth muscle tumors exhibited only very focal and faint cytoplasmic staining in 5/5 leiomyomas and 4/5 leiomyosarcomas. Immunoelectron microscopic study of skeletal muscle showed p63 localization to the Z bands of sarcomeres. We conclude that p63 immunostain is a sensitive marker for skeletal muscle differentiation and highlights the cross-striations of strap cells with exceptional definition.

A rare case of paratesticular embryonal rhabdomyosarcoma diagnosed by fine needle aspiration: a case report.

BACKGROUND: Rhabdomyosarcoma is the most common soft tissue sarcoma of children < 15 years of age. CASE: We report a case of a paratesticular rhabdomyosarcoma diagnosed by fine needle aspiration (FNA) in an 18-year-old man with enlargement of the right testis. The FNA material revealed mainly isolated small to median-sized malignant cells with various shapes. Among these, large rhabdomyoblasts were observed. Some neoplastic cells showed longitudinal striations. Immunocytochemistry was strongly positive against vimentin and desmin, and results for cytokeratins, smooth muscle antibody, epithelial-membrane antigen, S-100 and neuron-specific enolase were negative. Histologic examination of the surgical specimen was in agreement with the FNA findings. CONCLUSION: FNA is a safe and accurate procedure, without implications, that could be used in the outpatient setting, allowing a preliminary, preoperative diagnosis, even for soft tissue tumors.

Beyond "Triton": Malignant Peripheral Nerve Sheath Tumors With Complete Heterologous Rhabdomyoblastic Differentiation Mimicking Spindle Cell Rhabdomyosarcoma.

Spindle cell rhabdomyosarcoma (RMS) is an aggressive sarcoma type with a predilection for the head and neck and frequent transactivating MYOD1 mutations. Malignant peripheral nerve sheath tumors (MPNST) show heterologous (most often rhabdomyoblastic) differentiation in 10% of cases; such tumors have been referred to as malignant "Triton" tumors. MPNST frequently harbors inactivating mutations in SUZ12 or EED, resulting in PRC2 dysfunction and loss of histone H3 lysine 27 trimethylation (H3K27me3), most often seen in sporadic and radiation-associated, high-grade tumors; immunohistochemistry (IHC) for H3K27me3 is a useful diagnostic marker. We recently encountered a tumor showing H3K27me3 loss but with otherwise typical features of spindle cell RMS. The purpose of this study was to evaluate H3K27me3 in spindle cell RMS and further investigate putative spindle cell RMS with loss of H3K27me3. IHC for H3K27me3 was performed on 50 tumors diagnosed as spindle cell RMS. Targeted sequencing of all exonic and selected intronic regions of ~450 genes was performed on the tumors with H3K27me3 loss using hybrid capture with a custom probe set and massively parallel (next-generation) sequencing (NGS). Of the 50 patients, 32 were male and 18 were female with a median age of 33 years (range, 6 wk to 77 y). Tumors most often involved head and neck (N=23), extremities/limb girdles (N=11), and trunk wall (N=5). Three cases (6%) showed loss of H3K27me3; based on all available evidence, we believe at least 2 of these cases in fact represent MPNST with complete heterologous rhabdomyoblastic differentiation: a deep-seated groin mass in a 76-year-old female and a paratesticular mass in a 22-year-old male (neither of whom had a history or signs of type 1 neurofibromatosis). The tumors showed similar histologic appearances: fascicular architecture, marked nuclear atypia, eosinophilic cytoplasm, and a high mitotic rate; rhabdomyoblasts were not apparent. One tumor showed focal areas with scant myxoid stroma and alternating hypocellularity and hypercellularity. By IHC, the tumors showed diffuse staining for desmin, myogenin, and MyoD1, whereas S100 protein and SOX10 were negative. NGS on 2 tumors revealed (1) 2-copy deletion of NF1, CDKN2A, and SUZ12 and a TP53 mutation with arm-level loss of 17p; and (2) 2-copy deletion of CDKN2A and an NF1 mutation with loss of 17q11, findings characteristic of MPNST. NGS on the third tumor showed no distinctive alterations. MPNST may occasionally show complete heterologous rhabdomyoblastic differentiation without histologic evidence of residual conventional MPNST, closely mimicking spindle cell RMS. IHC for H3K27me3 reliably distinguishes MPNST from spindle cell RMS.

Clinicopathologic features of rhabdomyosarcoma of gynecologic origin in adults.

Rhabdomyosarcoma (RMS) is the most common soft tissue tumor found in children. Up to 20% of RMS tumors in children originate in the genital tract making this the second most common site. RMS of gynecologic origin in adults is much less common. The purpose of this study was to describe the clinical and pathologic features of RMS of the adult female genital tract. We reviewed the histologic slides of women 16 years of age and older and included them in our study if they contained the classic histologic features of RMS as described by the 2002 World Health Organization classification of tumors. Rhabdomyoblastic components present in other established malignancies were not studied. We identified 15 patients, with a median age of 48 years (range, 16 to 69). Eleven (73%) of the tumors were of embryonal histology (cervix, 8; uterus, 2; and ovary, 1). Of the remaining 4 tumors, 2 were of alveolar (vulva) and 2 of pleomorphic (uterus, 1; fallopian tube, 1) histologic subtype. The majority (79%) of these patients presented with locoregional disease and had surgery as their primary intervention (73%). The median progression-free survival (PFS) and disease-specific survival was 9 months [95% confidence interval (CI), 1-24] and 21 months (95% CI, 14-28), respectively. The 5-year disease-specific survival was only 29%. There was a significant difference in PFS between cases of embryonal compared to cases with nonembryonal histology (19 vs. 3 mo, respectively) (P=0.04). Adult RMS of gynecologic origin presents with locoregional disease and most are morphologically similar to pediatric RMS; however, adult RMS behaves more aggressively, with worse overall survival. It is unclear whether these divergent outcomes are the result of differences in clinical management or because these tumors are biologically distinct.

Dedifferentiated liposarcomas with divergent myosarcomatous differentiation developed in the internal trunk: a study of 27 cases and comparison to conventional dedifferentiated liposarcomas and leiomyosarcomas.

Dedifferentiated liposarcoma (DLPS) is one of the most frequent sarcomas of the retroperitoneum and represents most undifferentiated sarcomas of the internal trunk. In about 5% cases, the dedifferentiated component is an heterologous sarcoma such as leiomyosarcoma or rhabdomyosarcoma. We reviewed a series of 65 sarcomas with a myogenic differentiation developed in the internal trunk for which initial diagnoses were leiomyosarcoma (37), rhabdomyosarcoma (6), malignant mesenchymoma (6), and DLPS (16). Immunostainings for MDM2, CDK4, alpha smooth actin, desmin, caldesmon, myogenin, c-kit, and progesterone receptor were performed. In 48 cases, the amplification status of MDM2 and CDK4 could be evaluated with quantitative polymerase chain reaction on paraffin-embedded tissues extracted DNAs. After review of the cases, final diagnoses were leiomyosarcoma (35), rhabdomyosarcomatous (20) or leiomyosarcomatous (7) DLPS, probable DLPS (2), and malignant mesenchymoma (1). DLPS were bigger tumors (median: 18.2 cm) than leiomyosarcomas (median: 12 cm). They had a lower 5-year recurrence-free survival than leiomyosarcomas (45% vs. 71%) but a higher 5-year metastasis-free survival (73% vs. 39%). There was no significant difference in overall survival (57% vs. 34%). Outcome of patients with a DLPS with a myosarcomatous component did not differ from conventional DLPS. In conclusion, most sarcomas with a rhabdomyosarcomatous differentiation occurring in the internal trunk of adults are DLPS. Moreover, DLPS with a myogenic component have a low metastatic potential, similar to conventional DLPS and significantly lower to the metastatic potential of leiomyosarcomas.

Primary osseous rhabdomyosarcoma with focal matrix formation mimicking osteosarcoma.

We present an unusual case of primary osseous pleomorphic rhabdomyosarcoma with focal matrix formation mimicking osteosarcoma. The patient was a 21-year-old man who had suffered from pain and slight enlargement of his left calf for 2 months. A plain radiograph demonstrated a large, predominantly osteolytic mass in the region of the proximal fibula with features typical of malignant primary bone tumor. On open surgical biopsy, the tumor consisted of atypical cells, some of them presenting spindle morphology. Between them, there were bands of densely hyalinized matrix with osteoid appearance, but without definite lacunae or calcifications, and an osteosarcoma was diagnosed. Consequently, the tumor was removed. The postoperative tissue presented more pleomorphic cells with some definite rhabdomyoblasts. Desmin, actin, Myf4, and MyoD1 were positive in tumor cells, and a diagnosis of rhabdomyosarcoma was eventually made. Only few cases of primary pure bone rhabdomyosarcoma have been reported. Other bone tumors with rhabdomyosarcomatous differentiation have been described: dedifferentiated chondrosarcoma, fibrosarcoma, and osteosarcoma. Our case does not meet the criteria for sclerosing rhabdomyosarcoma, as matrix formation is focal and cells are spindle-shaped and pleomorphic. However, it is a further example of a diagnostic error in connection with primary osseous tumor.

Diagnostic utility of cyclin D1 in the diagnosis of small round blue cell tumors in children and adolescents.

Small round blue cell tumors (SRBCTs) of children and adolescents are often diagnostically challenging lesions. With the increasing diagnostic approach based on small biopsies, there is the need of specific immunomarkers that can help in the differential diagnosis among the different tumor histotypes to assure the patient a correct diagnosis for proper treatment. Based on our recent studies showing cyclin D1 overexpression in both Ewing sarcoma/primitive peripheral neuroectodermal tumor (EWS/pPNET) and peripheral neuroblastic tumors (neuroblastoma and ganglioneuroblastoma), we immunohistochemically assessed cyclin D1 immunoreactivity in 128 cases of SRBCTs in children and adolescents to establish its potential utility in the differential diagnosis. All cases of EWS/pPNET and the undifferentiated/poorly differentiated neuroblastomatous component of all peripheral neuroblastic tumors exhibited strong and diffuse nuclear staining (>50% of neoplastic cells) for cyclin D1. In contrast, this marker was absent from rhabdomyosarcoma (regardless of subtype) and lymphoblastic lymphoma (either B- or T-cell precursors), whereas it was only focally detected (<5% of neoplastic cells) in some cases of Wilms tumor (blastemal component) and desmoplastic small round cell tumor. Our findings suggest that cyclin D1 can be exploitable as a diagnostic adjunct to conventional markers in confirming the diagnosis of EWS/pPNET or neuroblastoma/ganglioneuroblastoma. Its use in routine practice may also be helpful for those cases of SRBCT with undifferentiated morphology that are difficult to diagnose after application of the conventional markers.