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Background
This tumor is one of the sarcomas that tend to occur in childhood. It is classified as one of the small round blue cell tumors of childhood because under the microscope, it is composed of sheets of these cells. The role of the pathologist has evolved from merely diagnosing to identifying histologic subtypes that may have a bearing on the prognosis.
OUTLINE
PATHOGENESIS CHARACTERIZATION CELL CYCLE ABNORMALITIES Altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma.
Takahashi Y, Oda Y, Kawaguchi K, Tamiya S, Yamamoto H, Suita S, Tsuneyoshi M.
1Department of Anatomic Pathology.
Mod Pathol. 2004 Jun;17(6):660-9. Abstract quote
Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in children. Some reports have discussed the altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma; however, variable frequencies of occurrence have been noted.
In the current study, among 72 cases of rhabdomyosarcoma, the authors evaluated for the expression of p53, MDM2, p16, p21/WAF1, p27, cyclin D1, cyclin E, pRb and E2F-1 protein immunohistochemically and assessed for proliferative activities using MIB-1. We also analyzed the mutation of the p53 gene in 45 cases, the amplification of the MDM2 gene in 18 cases and the mutation of the H-ras gene in 29 cases, using formalin-fixed paraffin-embedded materials. Furthermore, we assessed the correlation between clinicopathologic factors and the results of both immunohistochemical and molecular analyses. Alveolar type affected older patients, and it had a significantly higher mitotic rate compared with the embryonal type (P=0.0226). p53 overexpression was detected in 22 (30.6%) of 72 cases, and 10 (22.2%) of 45 cases had p53 gene abnormalities. As for MDM2, its overexpression was found in nine (12.5%) of 72 cases, and three (16.7%) of 18 cases showed MDM2 amplification. A statistically significant association was observed between immunoreaction for MDM2 and p53 overexpression (P=0.0002), and p53 and MDM2 overexpression was significantly correlated with high MIB-1 labeling indices. E2F-1 labeling indices showed a significantly higher score in alveolar type compared with that seen in embryonal type (P=0.0334), but MIB-1 did not.
In conclusion, our study suggests that p53 overexpression may be related to tumor progression because tumors with p53 overexpression have a high proliferative activity in the current study. Alveolar type had a significantly higher both mitotic rate and E2F-1 labeling indices when compared with the embryonal type. The current study is the first report of the correlation of E2F-1 with alveolar rhabdomyosarcoma.EGFR
- Ganti R,
- Skapek SX,
- Zhang J,
- Fuller CE,
- Wu J,
- Billups CA,
- Breitfeld PP,
- Dalton JD,
- Meyer WH,
- Khoury JD.
1Department of Pathology and Laboratory Medicine, St Jude Children's Research Hospital, Memphis, TN, USA.
Both epidermal growth factor receptor (EGFR) and ErbB-2 play an important role in cancer biology and constitute promising molecular targets of therapy. EGFR and ErbB-2 expression has been observed in rhabdomyosarcoma cell lines but not analyzed systematically in rhabdomyosarcoma tumors.
Tissue microarray sections representing 66 rhabdomyosarcoma tumors (34 embryonal rhabdomyosarcoma, 32 alveolar rhabdomyosarcoma) were surveyed by immunohistochemistry using antibodies specific for EGFR and ErbB-2. Immunostains were assessed for intensity (0: no immunostaining; 1: weak; 2: moderate; 3: strong) and percentage of at least 500 neoplastic cells exhibiting membranous or membranous and cytoplasmic immunostaining. EGFR and ErbB-2 expression was considered positive if the product of intensity and percentage was greater than 10. Patients had a median age of 5.7 years (range 8 months-19.1 years), and of 65/66 patients, 38 were males and 27 were females. Expression of ErbB-2 was identified in 22/66 (33%) cases and tended to be more frequent in the alveolar subtype (13/32, 41%, vs 9/34, 26%, P=0.30). Expression of EGFR was identified in 31/66 (47%) cases and correlated with the embryonal subtype (26/34, 76%, vs 5/32, 16%, P<0.0001) independent of stage, age, and gender. Coexpression of EGFR and ErbB-2 was identified in eight tumors, of which six were embryonal rhabdomyosarcoma. None of the cases exhibited EGFR or ErbB-2 gene amplification, as assessed using fluorescence in situ hybridization. Furthermore, analysis of 11 additional rhabdomyosarcoma tumors (six alveolar; five embryonal) revealed no evidence of mutations in EGFR exons 18, 19, 20, and 21.
In summary, expression of EGFR and/or ErbB-2 is detected in a sizeable subset of rhabdomyosarcoma tumors without evidence of EGFR or ErbB-2 amplification or mutations in the EGFR tyrosine kinase domain. Notably, expression of EGFR correlates with the embryonal subtype, which is also more likely to coexpress EGFR and ErbB-2.PAX/FKHR FUSION
*Departments of Pathology and Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR †Department of Laboratory Medicine, Childrenʼs Hospital, Columbus, OH ‡Department of Pathology, Childrenʼs Hospital of Pittsburgh, Pittsburgh, PA §Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA ∥Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada ¶Childrenʼs Hospital Los Angeles, USC Keck School of Medicine, Los Angeles, CA ♯Department of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
At the molecular level, alveolar rhabdomyosarcomas (ARMS) are characterized by 3 mutually exclusive PAX/FKHR conditions: PAX3/FKHR fusion (present in 60% of cases), PAX7/FKHR fusion (present in 20%), and PAX/FKHR fusion-negativity (present in 20%). The possibility of morphologic variation among these molecular subtypes has not been investigated.
We undertook a blinded retrospective study of 65 cases of ARMS (16 PAX/FKHR fusion-negative, 36 PAX3/FKHR-positive, and 13 PAX7/FKHR-positive by routine reverse transcription-polymerase chain reaction). We evaluated cytohistologic parameters such as microcyst formation, solid foci, differentiation, giant cell formation, anaplasia, nuclear grade, mitosis/karyorrhexis index, rosette formation, geographic necrosis, presence and amount of rhabdomyoblastic differentiation, and the presence of foci resembling embryonal rhabdomyosarcoma. We analyzed the results using a simple chi formula.
Of these features, only totally solid alveolar architecture reached significance (P=0.00014), with 7 of 16 PAX/FKHR-negative cases lacking this feature, compared with 0 of 36 PAX3/FKHR cases and 2/13 PAX7/FKHR cases. These preliminary results indicate that in general, only totally solid alveolar architecture in ARMS may predict the absence of a PAX/FKHR fusion. No features seemed to predict the presence of a particular fusion type.
Our results suggest that histologic assessment of ARMS has limited correlation with PAX/FKHR fusion status.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION GENERAL VARIANTS ADULT
Embryonal rhabdomyosarcoma presenting in an adult: a case report and discussion of immunohistochemical staining.Hardaway CA, Graham BS, Barnette DJ, Feldman BD.
Am J Dermatopathol 2003 Feb;25(1):45-52 Abstract quote Embryonal rhabdomyosarcoma is the most common soft tissue sarcoma of childhood but is rarely seen in adults. We report an embryonal rhabdomyosarcoma of the cheek in a 21-year-old Filipino man presenting as a rapidly enlarging mass. An incisional biopsy was consistent with embryonal rhabdomyosarcoma.
The patient failed to respond to one cycle of chemotherapy after initial diagnosis and workup for metastatic disease. Wide local excision of the tumor was then completed with the use of the Mohs technique to clear the glabrous cutaneous margins during surgery.
A Mohs surgeon and dermatopathologist were involved in interpretation of the Mohs sections. Subsequent immunohistochemical staining revealed a poorly differentiated spindled and epithelioid cell tumor, which stained diffusely positive for vimentin, S-100, and MyoD1. Rare rhabdomyoblasts were present and stained positively for desmin, muscle-specific actin, and phosphotungstic acid hematoxylin. The patient subsequently underwent radiation therapy for a total of 6,000 cGy, followed by two cycles of chemotherapy.
The patient continues to be disease-free at 22 months after his wide local excision.
GYNECOLOGIC
Gynecology Service, Departments of *Surgery daggerPathology, Memorial Sloan-Kettering Cancer Center, New York, NY.
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.HEAD AND NECK
Rhabdomyosarcoma of the head and neck in children.Hicks J, Flaitz C.
Department of Pathology, MC1-2261, Texas Children's Hospital, 6621 Fannin Street, Houston 77030-2399, USA.
Oral Oncol 2002 Jul;38(5):450-9 Abstract quote OBJECTIVE: The purpose of this study was to determine the rhabdomyosarcoma types involving the head and neck (H&N) region in children and their immunophenotype.
DESIGN: Anatomic pathology archives at Texas Children's Hospital were searched for all rhabdomyosarcoma cases over a 20-year period. One-hundred and thirty-seven cases were identified, with 50 being H&N cases. The cases were typed according to the Intergroup Rhabdomyosarcoma Study (IRS) criteria. Immunocytochemistry for myogenic and non-myogenic markers was performed on all H&N cases. Electron micrographs from cases (n=32) where ultrastructural examination had been performed at the time of original diagnosis were reviewed.
RESULTS: Children with H&N rhabdomyosarcomas had a mean age of 5.3 years (median 4 years). There was a male predilection (1.7M:1.0F). Primary tumor sites were: face NOS (18%), orbit/periorbital (16%), nasal cavity/nose (14%), lymph nodes (12%), paranasal sinuses (10%), parameningeal (10%), parotid gland (6%), neck (6%), infratemporal fossa/zygoma (2%), buccal mucosa (2%), palate (2%), and larynx (2%). Metastatic disease at diagnosis (33% of all cases) occurred in the bone marrow (11%), cerebrospinal fluid (6%), peritoneal fluid (6%), lung (4%), parietal pleura (2%), pleural fluid (2%) and pericardial fluid (2%). Rhabdomyosarcoma types (IRS criteria) were: embryonal (60%), alveolar (classic and solid subtypes, 28%), botryoid (4%), undifferentiated (4%), spindle cell (2%) and anaplastic (2%). Immunocytochemical findings were: polyclonal desmin (96%); myogenin (96%); muscle-specific actin (74%), smooth muscle actin (12%). Nonmyogenic markers included: vimentin (100%), CD99 (16%), p53 (16%), pancytokeratin (10%), NSE (8%), LCA (6%), CD20 (6%), EMA (2%), and NB-84 (0%, neuroblastoma). Undifferentiated sarcoma expressed only vimentin. By ultrastructural examination, 44% had readily identified z-bands and myofilaments, 37% had infrequent to rare myofilaments and z-bands, and 19% had myotubular intermediate filaments.
CONCLUSIONS: Distribution of H&N rhabdomyosarcoma IRS types is similar to that for all primary sites, with the exception that embryonal types are modestly increased while alveolar type is mildly decreased. There are many non-myogenic immunocytochemical markers that cross-react with rhabdomyosarcoma. Differentiation between favorable and unfavorable rhabdomyosarcoma types is important for appropriate therapy, and predicting prognosis and survival.
Rhabdomyosarcoma of the oral and maxillofacial region in Jordanians: A retrospective analysis.Al-Khateeb T, Bataineh AB.
Jordan University of Science and Technology
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002 May;93(5):580-5 Abstract quote Objective. The objective was to study the clinicopathologic features of rhabdomyosarcoma (RMS) of the oral and maxillofacial region in Jordanians.
Study Design. Data were collected from records of patients treated between 1989 and 2000 at the Maxillofacial Unit of Jordan University of Science and Technology. The main outcome measures were age, gender, location, stage of disease, histopathologic type, treatment received, follow-up period, and eventual outcome.
Results. Nine patients with RMS aged 4 to 17 years were found, with a male to female ratio of 2:1. Six (67%) bony sites and 7 (78%) soft tissue sites were involved. The extent of disease was locoregional in 8 (89%) cases, nodal in 3 (33%) cases, and distant metastatic in 2 (22%) cases. The Intergroup Rhabdomyosarcoma Study classification of clinical groups was as follows: 2 (22%) cases in stage II, 5 (56%) cases in stage III, and 2 (22%) cases in stage IV. The histopathologic types found were 6 (67%) embryonal, 2 (22%) alveolar, and 1 (11%) undifferentiated. Triple agent chemotherapy was used in the treatment of 8 cases, singly or in combination with surgery or radiotherapy. Two patients are still alive, and 5 patients have died of disease.
Conclusions. The clinicopathologic features of maxillofacial RMS in this group of Jordanians are different from those of people from other countries. Further studies are needed to have a better understanding of the behavior of RMS in the oral and maxillofacial area.
MEDIASTINUM Rhabdomyosarcomas of the anterior mediastinum: report of four cases unassociated with germ cell, teratomatous, or thymic carcinomatous components.
Suster S, Moran CA, Koss MN.
Department of Pathology, Mount Sinai Medical Center, Miami Beach, FL 33140.
Hum Pathol 1994 Apr;25(4):349-56 Abstract quote
Four cases are presented of primary anterior mediastinal tumors in young adults that were characterized by solid, infiltrative lesions showing histologic and immunohistochemical features of rhabdomyoblastic differentiation.
The patients were three men and one woman between 19 and 27 years of age (mean age, 23 years). All patients presented with symptoms referable to their tumors, including cough, chest pain, dyspnea, and left-sided pleural effusion. Grossly and radiographically, the lesions were characterized by their solid, infiltrative appearance.
Histologically, two cases corresponded to the solid variant of alveolar rhabdomyosarcoma, one case was an embryonal rhabdomyosarcoma with a predominant spindle cell component, and the remaining case showed the features of a pleomorphic rhabdomyosarcoma. No glandular, epithelial, or other component could be identified in any of the tumors on extensive sampling.
Immunohistochemical studies showed positive staining of the tumor cells with actin, desmin, and vimentin antibodies, with focal positivity for myoglobin in three cases and focal positive staining with S-100 protein in one case. Stains for low and high molecular weight keratin, carcinoembryonic antigen, alpha-fetoprotein, human chorionic gonadotropin, placental alkaline phosphatase, leukocyte-common antigen, and neuron-specific enolase were negative. All patients experienced rapid recurrence and metastases within the first 6 months after diagnosis. Three patients died within this period due to their tumors; the fourth patient has been lost to follow-up.
Pure primary rhabdomyosarcomas of the anterior mediastinum are highly aggressive neoplasms that should be distinguished from germ cell, teratomatous, or carcinosarcomatous tumors with a focal rhabdomyoblastic component.
SKIN
Primary cutaneous epidermotropic alveolar rhabdomyosarcoma with t(2;13) in an elderly woman: case report and review of the literature.Setterfield J, Sciot R, Debiec-Rychter M, Robson A, Calonje E.
Department of Dermatopathology, St. John's Institute of Dermatology, St. Thomas' Hospital, London, UK.
Am J Surg Pathol 2002 Jul;26(7):938-44 Abstract quote We report a case of a primary cutaneous alveolar rhabdomyosarcoma presenting on the lower limb of a 60-year old woman. The tumor was characterized by aggregates of round blue cells in an alveolar growth pattern in the dermis and subcutis, with the additional unique finding of epidermotropism.
By immunohistochemistry tumor cells were positive for vimentin, muscle-specific actin, desmin, myogenin, and Myo-D1 with focal positivity for CD56, neuron-specific enolase, and S-100 protein. Staining for pan-keratin, HMB-45, melan-A, epithelial membrane antigen, chromogranin, CD99, leukocyte common antigen, and alpha-smooth muscle actin was negative. Interphase fluorescence in situ hybridization analysis from paraffin-embedded tumor demonstrated the presence of the translocation (2;13)(q35;q14) confirming the diagnosis.
Further investigations revealed no tumor in the underlying deep soft tissues, and there was no evidence of metastasis in other organs. A local recurrence associated with a metastasis to a regional lymph node on the right groin was treated with an above-knee amputation and local radiotherapy to the groin area. The patient subsequently developed cutaneous metastases in the amputation stump and died 2 years after initial presentation.
This case indicates that rhabdomyosarcoma may rarely present in the skin in adults and should be included in the differential diagnosis of primary cutaneous small round blue cell tumors not only in children but also in this age group.
Primary cutaneous alveolar rhabdomyosarcoma of the perineum.Gong Y, Chao J, Bauer B, Sun X, Chou PM.
Departments of Pathology (Drs Gong, Sun, and Chou) and Plastic Surgery (Drs Chao and Bauer), Children's Memorial Hospital, Northwestern University Medical Center, Chicago, Ill.
Arch Pathol Lab Med 2002 Aug;126(8):982-4 Abstract quote Primary alveolar rhabdomyosarcoma (RMS) involving perineal skin is extremely rare, particularly in the infant age group.
We report a case of an alveolar RMS in a newborn with abnormal symmetrical perineal overgrowth, causing ambiguous morphologic structure of the genitalia. Clinical and imaging studies were suggestive of Proteus syndrome with lymphatic malformation. Histologic examination of the mass showed cutaneous alveolar RMS with areas of embryonal and pleomorphic RMS features.
Multiple superficially located, cystic-dilated spaces with loose edematous-mucoid hypocellular stroma gave a gross morphologic structure similar to that of lymphatic-type excrescences.
URINARY BLADDER Rhabdomyosarcoma of the Urinary Bladder and Vagina A Clinicopathologic Study With Emphasis on Recurrent Disease: A Report From the Kiel Pediatric Tumor Registry and the German CWS Study
Ivo Leuschner, M.D.; Dieter Harms, M.D.; Adrian Mattke, M.D.; Ewa Koscielniak, M.D.; Jörn Treuner, M.D.
From Kiel Pediatric Tumor Registry (I.L., D.H.), Institute for Pediatric Pathology, University of Kiel, Germany; and the Department of Oncology/Hematology (A.M., E.K., J.T.), Olga Hospital, Stuttgart, Germany.
Am J Surg Pathol 2001;25:856-864 Abstract quote
Rhabdomyosarcomas (RMS) of the urinary bladder and vagina vary in their biologic and clinical behavior and require different types of treatment. Anatomically the two organs are close, and the reason for these differences in behavior is unknown.
We investigated tumor specimens of 51 urinary bladder RMS and 14 vaginal RMS with regard to histologic subtype, growth pattern, differentiation, and proliferation morphologically and immunohistochemically. Recurrences and/or ``second look'' specimens from 15 patients after chemotherapy were compared with the primary tumors.
Within the 65 specimens we found 31 ``classical'' embryonal RMS, 26 embryonal RMS of botryoid subtype (BRMS), 3 embryonal RMS of spindle cell subtype, and 5 alveolar RMS. BRMS is more common in the vagina (11 BRMS of 14 cases) than in the urinary bladder RMS (15 BRMS of 54 cases). Classical embryonal RMS with a polypoid (exophytic) growth pattern is associated with a more favorable prognosis (92% 10-year survival) than the same type with a diffuse intramural (endophytic) growth pattern (68% 10-year survival, p = 0.02). The proliferation rate was associated with the degree of differentiation, but neither showed a correlation with prognosis. A marked maturation after chemotherapy was seen in the majority of recurrences and SL specimens, associated with lowered proliferation activity. Two of 12 patients with recurrences showing chemotherapy-induced maturation died of the disease.
In conclusion, we determined that polypoid embryonal RMS of both the urinary bladder and the vagina have a comparably good prognosis. This includes all botryoid RMS. The poorer prognosis of the group of urinary bladder RMS as a whole was caused by a high incidence of diffusely growing RMS, which have a less favorable prognosis than polypoid RMS. Maturation after chemotherapy occurs frequently in RMS. In contrast to the excellent prognosis reported in other studies, we had two patients with fatal outcome despite chemotherapy-induced maturation in the recurrences.
CHARACTERIZATION General VARIANTS PLEOMORPHIC Pleomorphic Rhabdomyosarcoma in Adults: A Clinicopathologic Study of 38 Cases with Emphasis on Morphologic Variants and Recent Skeletal Muscle-Specific Markers
Mary A. Furlong, M.D., Thomas Mentzel, M.D. and Julie C. Fanburg-Smith, M.D.
Department of Soft Tissue Pathology, Armed Forces Institute of Pathology (MAF, JCF-S), Washington, DC; and Dermatohistopathologisches Gemeinschaftslabor (TM), Friedrichshafen, Germany
Mod Pathol 14:595-603 Abstract quote
Pleomorphic rhabdomyosarcoma (PRMS) is a rare and controversial tumor of skeletal muscle phenotype. Diagnostic criteria for PRMS by combined histology and currently available immunohistochemistry have not been clearly defined.
We report 38 pleomorphic rhabdomyosarcomas in adults, explore morphologic variants, and discuss our experience with both specific and nonspecific skeletal muscle markers in these tumors.
Clinical data, morphology, and immunohistochemistry were reviewed. Electron microscopy was performed. Of 38 cases, there were 28 males and 10 females. Patient ages ranged from 21 to 81 years (median = 54 y; mean = 51 y). Tumors were located in the lower extremity (n = 18), abdomen/retroperitoneum (n = 6), chest/abdominal wall (n = 5), spermatic cord/testes (n = 4), upper extremity (n = 3), and one each in the mouth and orbit. Tumor sizes ranged from 1.5 to 15.0 cm (mean = 7.3 cm; median = 6.8 cm).
The cases were divided into three variants, each with large, atypical, pleomorphic polygonal rhabdomyoblasts (PRMB) with abundant eosinophilic cytoplasm in varying numbers and different morphologic backgrounds of round or spindled rhabdomyoblasts (RMB). 1. Classic PRMS: Predominantly atypical PRMB in sheets (n = 8). 2. Round cell PRMS: Clusters of PRMB throughout the tumor with a background of slightly atypical, medium-sized, round, blue RMB (n = 13). 3. Spindle cell PRMS: Scattered PRMB in a predominance of atypical spindled RMB arranged in a storiform growth pattern (n = 17).
Immunohistochemistry revealed the following: myoglobin (37/38), MyoD1 (19/36), skeletal muscle myogenin (myf4; 19/34), fast skeletal muscle myosin (4/5), desmin (36/38), muscle-specific actin (MSA; 25/35), smooth muscle actin (SMA; 15/33), and muscle specific myogenin (myf3; 25/35). Immunohistochemistry was supportive of skeletal muscle differentiation with at least one positive skeletal muscle-specific marker (myoglobin, MyoD1, fast skeletal muscle myosin, or myf4). In addition, all cases had some positivity for nonspecific muscle markers (desmin, MSA, SMA, myf3). Electron microscopy (EM), performed on eight selected cases from all three morphologic groups, demonstrated definitive skeletal muscle differentiation in all cases.
Follow-up, available on 30 (79%) cases, revealed that 70% of patients died of disease (mean 20 months, range 1 month-108 months), 3% were alive with disease at 12 months (n = 1); and 27% had no evidence of disease (mean, 83 mo; range, 18 to 108 mo).
PRMS, a tumor of predominantly middle-aged adult males in the lower extremity, can be diagnosed by the morphologic presence of scattered PRMB with immunohistochemical evidence of at least one skeletal muscle-specific marker. There are three morphologic variants of PRMS. The appropriate diagnosis of PRMS is significant as it is a high-grade sarcoma, with an aggressive clinical course.
Pleomorphic rhabdomyosarcoma in children: Four cases in the pediatric age group
Mary A. Furlong, MD
Julie C. Fanburg-Smith, MD
Ann Diagn Pathol 5: 199-206, 2001. Abstract quote
Pleomorphic rhabdomyosarcoma is considered rare and controversial, especially in children. Although pleomorphic rhabdomyosarcoma has been observed in children, its sparcity has taken it out of current childhood rhabdomyosarcoma classifications.
We report four pediatric cases of pleomorphic rhabdomyosarcoma, review morphologic, immunohistochemical, and ultrastructural features, and discuss the rare need to include this category in children. The Soft Tissue Registry of the Armed Forces Institute of Pathology was searched for cases coded as “pleomorphic rhabdomyosarcoma” from 1970 to the present. Only cases in patients less than 21 years old were included.
Clinical data, morphology, and immunohistochemical stains were reviewed and follow-up was obtained. Electron microscopy was performed on two cases. Molecular analysis by polymerase chain reaction was performed on one case with available material. Of four patients included, there were three boys and one girl. Patient ages ranged from 9 months to 10 years (median, 4.5 years). Tumors were located on the chest wall (n = 2) and one each on the upper and lower extremities. Tumor size ranged from 4.0 to 10.0 cm (median, 7 cm). Grossly, the tumors were lobulated and circumscribed. Microscopically, architectural patterns varied from solid to fascicular or storiform. All tumors had large, often multinucleated, polygonal, spindled or strap-like rhabdomyoblasts with abundant eosinophilic cytoplasm. Nuclear characteristics ranged from hyperchromatic to vesicular. Most tumor cells had large prominent nucleoli. Background rhabdomyoblasts varied from spindled to polygonal. No tumors displayed areas typical of embryonal or alveolar rhabdomyosarcoma. All tumors exhibited atypical mitotic figures. Immunohistochemistry revealed that the tumors were positive for the following markers: desmin (¾), myoglobin (4/4), myoD1 (3/3), myf4 (3/3), and MSA (4/4). The two cases studied by electron microscopy both showed evidence for skeletal muscle differentiation. One case showed no evidence for a t(2;13) or t(1;13) translocation.
Two patients were alive with no evidence of disease at 12 and 25 years. One patient was dead of disease at 9 years.
Pleomorphic rhabdomyosarcoma is rare but exists in children. The diagnosis should be considered in pleomorphic sarcomas exhibiting skeletal muscle differentiation, which are otherwise devoid of typical areas or chromosomal changes of embryonal or alveolar rhabdomyosarcoma.
SCLEROSING
The Department of Pathology, Cancer Hospital, Fudan University, Shanghai, China.
Sclerosing rhabdomyosarcoma in adults: report of four cases of a hyalinizing, matrix-rich variant of rhabdomyosarcoma that may be confused with osteosarcoma, chondrosarcoma, or angiosarcoma.Folpe AL, McKenney JK, Bridge JA, Weiss SW.
Am J Surg Pathol 2002 Sep;26(9):1175-83 Abstract quote Rhabdomyosarcomas (RMSs) are classified into embryonal (ERMS), alveolar (ARMS), and pleomorphic (PRMS) subtypes. ERMS, including botryoid variants, typically occurs in young children, ARMS typically occurs in older children and young adults, and PRMS occurs in older adults. Although ARMSs show thin fibrous bands separating nests of cells, abundant extracellular matrix production is rare in RMS. In the course of reviewing hyalinizing sarcomas we discovered a distinctive RMS in adults that closely mimicked osteosarcoma or chondrosarcoma because of the extensive matrix production.
Four RMSs with hyalinized matrix were retrieved from our files. These cases were evaluated with respect to patient age and sex, tumor site and size, growth pattern, nuclear grade, cellularity, mitotic figures/20 high power fields, vascular invasion, necrosis, the presence of rhabdomyoblasts, multinucleated cells, and alveolar growth pattern.
Immunohistochemistry for desmin, myogenin, MyoD1, actin, cytokeratin, S-100 protein, collagen II, and CD99 was performed. Reverse transcriptase polymerase chain reaction for the ARMS-associated PAX3/FKHR and PAX7/PKHF was also performed on three cases. The cases involved the forearm, hand, orbit, and nasopharynx of a 40-year-old woman, a 50-year-old man, an 18-year-old man, and a 21-year-old man, respectively. The tumors ranged from 3.7 to 8 cm and consisted of lobules and infiltrating cords of small round malignant cells embedded in a densely hyalinized matrix having both a chondroid and osteoid-like appearance. No definite lacunae or matrix calcification was present. An alveolar pattern was only present focally, and tumor giant cells were not present. One case had a single focus of rhabdomyoblastic differentiation with strap cells. Mitotic activity was >20 mitotic figures/20 high power fields in three of four cases. Immunohistochemically, one case strongly expressed desmin, whereas three cases expressed it focally, with a dot-like pattern. Myogenin was only focally positive, but MyoD1 was present in nearly every cell of each case. Two cases expressed actin and one expressed CD99. No case expressed cytokeratin, S-100 protein, or collagen II. Only one case contained adequate RNA for reverse transcriptase polymerase chain reaction, and this case was negative for the ARMS-associated gene fusions. Follow-up showed one patient to be dead of metastatic disease at 60 months despite intensive therapy, another patient to be disease free at 26 months, and the third patient to be disease free at 5 months. The fourth case is recent.
These cases are a distinctive-appearing rhabdomyosarcoma easily mistaken for variants of chondrosarcoma, osteosarcoma, or even sclerosing epithelioid fibrosarcoma because of their hyalinizing appearance compounded by their typically focal and dot-like desmin expression.
These four cases are essentially identical to the three unusual RMSs recently reported by Mentzel and Katenkamp as "sclerosing, pseudovascular rhabdomyosarcoma in adults." Although the focal alveolar architecture and the primitive cytologic appearance of these hyalinizing RMS suggest a relationship with ARMS, the presence of abundant strap cells in one case, the predominant expression of MyoD1 rather than myogenin, and the absence of ARMS-associated fusions genes point more strongly toward a variant of ERMS. However, the late adult age in two cases is unusual for both EMRS and ARMS, suggesting that sclerosing RMS may prove to be a distinct subtype of RMS. Study of additional cases will be necessary to more fully elucidate its place among RMS and its prognostic significance.
SPINDLE CELL
- Spindle Cell Rhabdomyosarcoma in Adults.
Nascimento AF, Fletcher CD.
From the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Am J Surg Pathol. 2005 Aug;29(8):1106-1113. Abstract quote
The spindle cell variant of rhabdomyosarcoma (RMS) is uncommon and is most often encountered in the paratesticular region of children in whom it has a good prognosis. Only isolated cases in adulthood have been described.
Sixteen cases of spindle cell RMS occurring in adults were retrieved from our files. Eleven patients were male and 5 were female. Patient age ranged from 18 to 79 years (median, 32 years). Tumor size varied from 1.5 to 35 cm (median, 6 cm). The head and neck region, including the oral cavity, parotid gland, nasopharynx, and nasal cavity, was the commonest affected area, accounting for >50% of the cases, followed by retroperitoneum, thigh, leg, subscapular area, hand, vulva, and paratesticular region (1 case each).
Follow-up was available in 12 cases, ranging from 1 to 102 months (median, 16.5 months). Treatment modalities included surgery, chemotherapy, and radiation. Two patients died of uncontrolled local disease 13 and 27 months after diagnosis; 4 were alive without disease at 12, 17, 24, and 102 months, including 1 patient with metastasis to 10 of 50 pelvic lymph nodes at presentation; 3 are alive with localized disease at 16, 17, and 19 months; and 1 was followed for 6 months and showed persistent local disease. One patient is alive at 10 months after diagnosis with evidence of metastatic disease to bone, lungs, and breast. All the tumors showed long fascicles of spindle cells with elongated, vesicular nuclei and pale indistinct cytoplasm. Scattered spindled or polygonal rhabdomyoblasts with abundant brightly eosinophilic cytoplasm were present in all cases. In 3 cases, focal areas showed pseudovascular, sclerosing features. There were no round cell or pleomorphic areas.
Positive immunohistochemical results were as follows: desmin (15 of 15 cases), myf-4 (12 of 12), fast myosin (7 of 9), myoglobin (2 of 3), HHF-35 (9 of 9), and SMA (11 of 14). One tumor was focally positive for keratins and EMA. All tumors were negative for caldesmon, S-100 protein, and GFAP.
Spindle cell RMS is a rare neoplasm in adults and appears to have distinct clinicopathologic features when compared with cases occurring in the pediatric population. Specifically, it appears to be most common in the head and neck region, and although only limited follow-up is available so far, these lesions appear to have a more aggressive clinical course in adults.
SPECIAL STAINS/
IMMUNOPEROXIDASECHARACTERIZATION Special stains Immunoperoxidase
Morotti RA, Nicol KK, Parham DM, Teot LA, Moore J, Hayes J, Meyer W, Qualman SJ.*Department of Pathology, Mount Sinai School of Medicine, New York daggerDepartment of Laboratory Medicine, Children's Hospital, Columbus, OH double daggerDepartment of Pathology, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, AR section signDepartment of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, PA paragraph signDepartment of Hematology and Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
Immunohistochemistry remains the current ancillary method of choice in the pathologic evaluation of small blue round-cell tumors. In at least 20% of cases of rhabdomyosarcoma (RMS), it is considered an essential factor in the final and/or differential diagnosis of the malignancy. Newer immunostains (antimyogenin, MyoD1) generated against intranuclear myogenic transcription factors offer pathologists the best hope for improving the sensitivity and specificity of RMS diagnosis.
A large series of RMS (956) were studied consecutively from the intergroup rhabdomyosarcoma study and children's oncology group files, along with multiple other malignant, benign or reactive lesions. A panel of antibodies to muscle-related antigens (myogenin, MyoD1, desmin, muscle-specific actin) was studied using formalin-fixed, paraffin-embedded tissue, an avidin-biotin/peroxidase complex immunohistochemical technique, antigen retrieval technique as appropriate, and automated immunostaining. Myogenin and MyoD1 were equally sensitive (positive for 97% of RMS cases), with both also showing similar specificity (90% vs. 91% of cases) for the diagnosis of RMS. Myogenin and MyoD1 staining were sometimes intact in areas of coagulative tumor necrosis, but negated by B5 fixation. Isolated, rare benign myogenin-positive nuclei were seen infrequently in reactive lymph nodes. Specifically, both myogenin and MyoD1 had significantly greater extent of expression for alveolar RMS (ARMS) than embryonal RMS (ERMS) (both with P<0.001). Similarly, both myogenin (P=0.001) and MyoD1 (P<0.001) had significantly higher expression for ARMS than RMS, not otherwise specified (NOS). They were never expressed in undifferentiated sarcomas; however, reactive or regenerative myocytes did show expression. Immunostains against intranuclear myogenic transcription factors are, at present, the best available markers for confirming the diagnosis of RMS.
Their differential expression in reactive myogenic lesions, variability in ARMS versus ERMS, and absence in undifferentiated sarcomas suggest new biologic questions to be explored in future studies.ARPP
Immunohistochemical analysis of a muscle ankyrin-repeat protein, Arpp, in paraffin-embedded tumors: Evaluation of Arpp as a tumor marker for rhabdomyosarcoma.
Ishiguro N, Motoi T, Osaki M, Araki N, Minamizaki T, Moriyama M, Ito H, Yoshida H.
Hum Pathol. 2005 Jun;36(6):620-5. Abstract quote
Summary Arpp, a protein including an a nkyrin- r epeat, P EST motif, and p roline-rich region, is a recently identified protein that is exclusively expressed in striated muscles.
This study comprehensively analyzed its expression among soft tissue sarcomas of various histological types and evaluated its potential use for the differential diagnosis of rhabdomyosarcoma (RMS). Formalin-fixed, paraffin-embedded tissues, including 37 RMS cases, 88 non-RMS sarcomas, and 38 carcinomas, were analyzed for Arpp expression. Arpp was detected in 33 (89.2%) of 37 RMS cases by immunohistochemistry.
Western blot analysis revealed expression of Arpp in all RMS cases tested. High expression of Arpp was generally associated with morphological evidence of skeletal muscle differentiation of tumor cells.
In contrast, Arpp displayed 6.3% (8/126) positivity among the non-RMS tumors. Focal or weak expression was seen in malignant fibrous histiocytoma (2/27), synovial sarcoma (1/11), Ewing sarcoma (1/5), and epithelioid sarcoma (3/5), whereas one epithelioid sarcoma displayed strong expression for Arpp.
A comparative analysis of the Arpp profile with that of myogenic markers in RMS revealed that the sensitivity of Arpp (89.2%) was higher than that of myoglobin (59.6%) and comparable with that of myogenin (88.2%), MyoD (80.6%), muscle-specific actin (83.8%), and desmin (89.2%).
These results suggested that Arpp is sensitive to and specific for RMS. Thus, we proposed that Arpp is a novel skeletal muscle-specific marker, which is useful for differential diagnosis of RMS.MYOD1 Are Myogenin and MyoD1 Expression Specific for Rhabdomyosarcoma? A Study of 150 Cases, With Emphasis on Spindle Cell Mimics
Melissa H. Cessna, M.D.; Holly Zhou, M.D.; Sherrie L. Perkins, M.D., Ph.D.; Sheryl R. Tripp; Lester Layfield, M.D.; Clark Daines, M.D.; Cheryl M. Coffin, M.D.
From the Departments of Pathology, University of Utah School of Medicine, and Primary Children's Medical Center, Salt Lake City, Utah, U.S.A.
Am J Surg Pathol 2001;25:1150-1157 Abstract quote
Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma of childhood, displays a variety of histologic patterns. Immunohistochemistry is used extensively to distinguish RMS from its mimics. Myogenin and MyoD1, myogenic transcriptional regulatory proteins expressed early in skeletal muscle differentiation, are considered sensitive and specific markers for RMS and are more specific than desmin and muscle-specific actin and more sensitive than myoglobin. Previous studies have focused on expression of myogenin and MyoD1 in small round cell tumors.
This study assesses myogenin and MyoD1 in rhabdomyosarcoma subtypes and spindle cell tumors considered in the differential diagnosis of RMS.
Formalin-fixed, paraffin-embedded archival tissue from 32 RMS, 107 non-RMS, and 11 benign skeletal muscle samples was stained for myogenin and MyoD1 with standard immunohistochemical techniques. Nuclear positivity was scored on a three-tiered scale. All RMSs expressed myogenin. Alveolar RMS (ARMS) showed strong nuclear staining, especially in tumor cells lining fibrous septae and perivascular regions. In cases with a subtle alveolar architecture on routinely stained sections, myogenin highlighted and enhanced visualization of the alveolar morphologic pattern. Embryonal RMSs (ERMSs) were more variable in myogenin staining pattern and intensity. No cases of nodular fasciitis, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, inflammatory myofibroblastic tumor, myofibrosarcoma, leiomyoma, leiomyosarcoma, or alveolar soft part sarcoma stained for myogenin. Focal nuclear reactivity was seen in desmoid (2 of 10), infantile myofibromatosis (2 of 10), synovial sarcoma (1 of 10), and infantile fibrosarcoma (2 of 10). Non-neoplastic skeletal muscle fiber nuclei stained positively for myogenin in both tumor-associated samples (25 of 40) and benign skeletal muscle samples (5 of 11). Although all RMSs were immunoreactive for MyoD1, cytoplasmic and nonspecific background staining and reactivity of nonmyoid tissues hindered its practical utility in paraffin-embedded samples in this study. Although myogenin is a highly sensitive and specific marker for RMS, it is rarely seen in other spindle cell soft tissue tumors. As previously reported, ARMS stained more strongly than ERMS. In contrast to previous studies, rare non-RMS (7 of 107) displayed focal nuclear reactivity, and entrapped atrophic or regenerative skeletal muscle fibers also stained positively.
Although these are potential pitfalls in the interpretation of myogenin, careful attention to morphology and other features, to the relative paucity of myogenin-positive nuclei in non-RMS, and to the presence of entrapped muscle fibers should prevent incorrect interpretation. Because the extent of myogenin expression in RMS is much greater than in non-RMS, it is a very useful marker when interpreted in the context of other clinicopathologic data.
WT1
The Expression of WT1 in the Differentiation of Rhabdomyosarcoma from Other Pediatric Small Round Blue Cell Tumors.Carpentieri DF, Nichols K, Chou PM, Matthews M, Pawel B, Huff D.
Departments of Pathology (DFC, MM, BP, DH) and Oncology (KN), The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Mod Pathol 2002 Oct;15(10):1080-6 Abstract quote The WT1 gene encodes a transcription factor implicated in normal and neoplastic development.
The purpose of this study was to evaluate the diagnostic utility of a commercial WT1 antibody on a variety of pediatric small round blue cell tumors (SRBCT). A mouse monoclonal antibody (clone: 6F-H2, DAKO) raised against the N-terminal amino acids 1-181 of the human WT1 protein was tested. Microscopic sections from 66 specimens were stained using an antigen retrieval protocol with trypsin. The tumors included peripheral neuroectodermal tumors (PNET/Ewing's), neuroblastomas, desmoplastic small round cell tumors (DSRCT), lymphomas, Wilms' tumors, and rhabdomyosarcomas (RMS). One RMS case was investigated by Western blot analysis and RT-PCR to confirm the antibody specificity. A strong cytoplasmic staining was demonstrated in all RMS (11/11).
The Western blot analysis confirmed the WT1 protein in the tissue, and the RT-PCR confirmed the presence of WT1 mRNA in the peripheral blood and tissue of one RMS patient. The Wilms' tumors had a variable nuclear and/or cytoplasmic positivity in most (17/24) cases. All PNET/Ewing's were negative. The nuclei of two lymphoblastic lymphomas stained strongly. A weak nuclear or cytoplasmic staining was reported in a few DSRCT (3/5), lymphomas (2/10), and neuroblastomas (2/8).
This is a useful antibody in the differentiation of RMS from other SRBCTs. A strong cytoplasmic staining favors an RMS, and a strong nuclear staining is suggestive of a Wilms' tumor. A role for WT1 in the pathogenesis of rhabdomyosarcomas is raised. The limited sampling precludes any conclusions regarding the value of tissue or peripheral blood analysis for WT1 mRNA in patients with rhabdomyosarcoma.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES Small round blue cell tumors
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Rhabdomyoblast-The immature precursor cell of skeletal muscle.
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