Rhabdomyosarcoma (RMS) is the most common aggressive pediatric soft tissue sarcoma, comprising 4%−8% of all malignancies1
and 10%−12% of all malignant solid tumors in children.2
RMS of the breast is an extremely rare neoplasm mainly confined to adolescent girls.3
Most tumors with RMS features in the breast are variants of metaplastic carcinoma, malignant phyllodes tumor,4
or metastatic growth from extra-mammary primary sites.3,5
If it is a secondary tumor, the extra-mammary primary is usually located in the extremities, neck, orbit, retroperitoneal space and trunk,6-9
with a possibility of breast metastasis of approximately 6%.3,7,9
For both primary and metastatic breast RMS, alveolar is the most common histological subtype and there is a strong correlation between alveolar type and breast metastasis.3,6,7,9,10
To the best of our knowledge, most of the published articles about breast RMS were case reports. Here we collected five cases of breast RMS, either primary or secondary, and reviewed the related literature to summarize its clinicopathologic features and biological behavior.
Five cases of primary or secondary breast RMS were collected. Three were inpatients of Fudan University Shanghai Cancer Center (FUSCC), and one was an outpatient of FUSCC who had a bilateral core needle biopsy. The last patient had a lumpectomy in Xinhua Hospital, Shanghai. All cases were initially diagnosed between January 2007 and March 2009. Histological sections of all cases were reviewed and confirmed by two breast pathologists and a soft tissue pathologist.
Paraffin blocks of the most representative sections of the three inpatients and one outpatient were selected for immunohistochemistry. Sections of 5 μm thickness were cut from the paraffin blocks, floated onto silanized glass slides, before deparaffinization in xylene and rehydration through graded ethanol. Immunohistochemistry using the Envision method was carried out with each antibody. Diaminobenzidine was used as the chromogen and sections were counterstained using haematoxylin. All antibodies used are shown in Table 1, along with the antibody clone and dilution, antigenic retrieval method, and incubation time. Appropriate positive and negative controls were included.
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Table 1. Details of antibodies used in immunohistochemistry
Clinical records of the five patients were reviewed (Table 2). All patients were female ranging from 16 to 46 years old (mean, 30 years). Clinically, they all presented with a rapidly growing, painless mass. Three cases were metastases with the primary tumor sites of the right labium majus, the left nasal meatus, and the nasopharynx. The other two cases were considered to be primary tumors free of any other benign or malignant neoplastic processes outside the breast. The primary tumor in case 1 was 10 cm with left inguinal lymph nodes metastasis. After six cycles of chemotherapy, the tumor had shrunk to 2−3 cm, and an extensive resection of the vulva was performed. Three months after surgery a right breast lump measuring 13 cm×10 cm was discovered. The patient in case 2 unintentionally found a left-sided 5 cm×4 cm breast mass, which rapidly increased to 10 cm×9 cm in the following two months. Given that the tumor was growing so fast, two courses of chemotherapy were ordered before mastectomy. Case 3 had been diagnosed as alveolar RMS in her right breast 20 months previous and she had a modified radical resection in another hospital with metastatic disease found in all 17 axillary lymph nodes. She presented at our hospital with a left breast lump. Cases 4 and 5 were metastatic disease. Both of them involved bilateral breast and developed into multi-focus disease.
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Table 2. A summary of clinical data
Grossly, the surgical specimens revealed round or ovoid, soft or firm, non-encapsulated but well-demarcated tumors. On sectioning, their cut surfaces consisted of homogeneous grayish yellow or white tissue. The tumor size ranged from 2.5 cm to 13 cm (mean, 7.6 cm). Three were embryonal RMS, and two were alveolar (including a solid variant). Microscopically, the embryonal cases displayed primitive differentiated small round, oval or polygonal mesenchymal cells with sparse eosinophilic cytoplasm and densely stained nuclei (Figure 1A). A few scattered signet-ring-like tumor cells with asymmetrical nuclei and eosinophilic cytoplasm could also be found in case 4 (Figure 1B). Alveolar RMS had a typical alveolar appearance (Figure 1C). Even the metastasized axillary lymph nodes displayed the obvious alveolar structure (Figure 1D). Tumor cells were arranged in nests or sheets separated by fibrous septa. These nests or sheets contained central clusters of cells with loss of cohesion around the periphery. The tumor cells were also small round, oval or polygonal with sparse cytoplasm. Their nuclei stained densely. Case 5 was a case of a solid variant alveolar RMS lacking fibrous stroma but with sheets of cells. Their nuclei were round or oval and less dense (Figures 1E and 1F). The cytoplasm was relatively rich and lightly stained. All the specimens were thoroughly examined, and no metaplastic carcinoma or malignant phyllodes tumor areas were detected in any case.
Among the four cases with immunohistochemical results, all tumor cells were positive for vimentin, desmin (Figure 2A), myogenic differentiation 1 (MyoD1) (Figure 2B), myogenin (Figure 2C), and negative for leucocyte common antigen (LCA), E-cadherin, neuron specific enolase (NSE), CD99, chorioallantoic membrane 5.2 (CAM5.2), and epithelial membrane antigen (EMA). Case 4 also showed a few cells with positive perinuclear staining for AE1/AE3 (Figure 2D).
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Figure 1. Histological features. 1A: An embryonal RMS displayed primitive differentiated small round, oval or polygonal mesenchymal cells with sparse eosinophilic cytoplasm and density nuclei (HE, original magnification×400). 1B: A few scattered signet-ring-like tumor cells with asymmetrical nuclei and eosinophilic cytoplasm could be seen in some regions in case 4 (HE, original magnification×400). 1C: A typical alveolar RMS contained central clusters of cells with loss of cohesion around the periphery, cell clusters are separated by fibrous septa (HE, original magnification×200). 1D: Involved axillary lymph node of case 3 displayed an alveolar structure (HE, original magnification×100). 1E, 1F: The solid variant alveolar RMS lacked the fibrous stroma and formed sheets of cells. Their nuclei were round or oval and less dense (HE, original magnification×100, 400).
Figure 2. Immunophenotype (IHC, original magnification×400). RMS was positive for desmin (2A), MyoD1 (2B), myogenin (2C). Case 4 showed a few cells with positive perinuclear staining for AE1/AE3 (2D).
Two primary inpatients (cases 2 and 3) were followed up. Case 2 had no recurrence or metastasis with an overall survival of 34 months up to June 2010. Case 3 died of lung and bone metastasis in August 2009 with an overall survival of 28 months. Unfortunately, we lost contact with the other three cases.
As we mentioned in the beginning, primary breast RMS is a rarity. It often presents as a sarcomatoid component of metaplastic carcinoma and malignant phyllodes tumors. In the current study we excluded the above-mentioned situations and will just discuss pure breast RMS.
Breast RMS usually occurs in adolescent females of 12–20 years old.11 In Hays et al, they reported the age at diagnosis for 26 patients (including primary and secondary) raged from 11.5 years to 20.2 years old, with a mean of 15.2 years.3 The authors summarized all the literature about breast RMS that had been published from 1980 to 1994. Most reports indicated that the age at diagnosis was between 11.5 and 20.2 years old with a peak between 14 and 16 years of age. We have reviewed articles from 1995 until the present and found that the age at onset of most cases was from 11 to 31 years old. The mean age of our series was 30 years old, older than the mean age reported in other studies. Our cohort even included two middle-aged women who were 41 and 46 years old. Since the year 1995 Kyriazis et al,12 Dausse et al,13 Attili et al,14 and Italiano et al15 had reported breast RMS patients aged 51, 45, 40, and 46 year-old, respectively.
Most cases manifest as rapidly progressive enlarging and painless breast masses. The tumor volume of case 2 doubled in two months and metastatic tumor of case 1 measured 13 cm. The mass can be very large in size. In Hays et al,3 they reported seven primary RMSs, three with a maximum diameter ≥10 cm. Mohammadi et al16 have reported a 20-year-old woman with sino-nasal RMS metastasis to the right breast that measured 10 cm×10 cm. Our cases indicated that metastatic breast RMS had more chances of being bilateral and multifocal. Both primary and secondary breast RMS can present unilaterally or bilaterally and do not favor a specified quadrant. The primary tumor sites are usually the extremities (such as hand, forearm, thigh and foot), nasopharynx, paranasal sinuses and trunk. In Hays et al’s series, primaries in eight of their total 19 metastatic cases were confined to the extremities, seven cases were located in the nasopharynx/paranasal sinuses, and four cases were in the trunk.3 Case 1 in our series was very peculiar with the primary location in the right labium majus that metastasized to the right breast. No literature has reported a case such as this up to now.
The gross features are always round or oval, well-demarcated but non-encapsulated masses. The texture can be soft or hard. Their cut surfaces consist of homogeneous grayish yellow or white tissue with focal zones of necrosis. Nearly all neoplastic cells are poor-differentiated small round or polygonal cells with sparse eosinophilic cytoplasm. Their nuclei are round or oval and densely stained. Mitotic figures were easily found. No cytoplasmic cross striations are identified, only a few researchers have found cross striations in routine H&E slides.12,17
and “strap” cells with peripherally placed nuclei are helpful for the diagnosis. However, it is not sufficient evidence to diagnose RMS unless there is clear evidence of rhabdomyoid origin.12
Dispersed signet-ring-like tumor cells with asymmetrical nuclei and red-stained cytoplasm can be seen in case 4. We speculated that these cells are in the process of differentiation. Case 5 was a case of alveolar RMS, the solid variant. It was difficult to diagnose by only the microscopic findings and required consideration of the patient’s history and the immunohistochemistry results. It is worth pointing out that in Hays’ series, nine (37.5%) of their 24 alveolar RMS were identified as the “solid” variant.3
Metastatic breast RMS usually has the same cytological and histological features as the primary sites. Although primary or metastatic RMS of the breast are mostly of the alveolar subtype,3
our series had more embryonal cases than alveolar cases. Particularly, among the three secondary cases, two were embryonal RMSs. It suggests that embryonal RMS also has metastatic potential.
In order to make a correct diagnosis, immunochemistry is essential. MyoD1 and myogenin are two useful markers.18,19 In our series, these two markers displayed diffuse strong nuclear positivity in all cases. It indicated their myogenic origination. More than 90% of RMSs, including those that are poorly differentiated, are positive for desmin. Many comparative studies have proven that desmin is superior to other muscle markers for the identification of RMS.19 Nevertheless, desmin is not a specific marker for striated muscle. Muscle smooth actin (MSA), cytokeratin, LCA and CD99 are negative.20 Occasionally, RMS can be aberrantly positive for cytokeratin, S-100, neurofilaments, and B-cell proteins (such as CD20 and immunoglobulins).21 In our report, case 4 showed focal perinuclear staining for AE1/AE3. Genetic analysis is a useful technique for histological typing.22 According to Barr and his colleagues, embryonal RMS often exhibit a deletion of the short arm of chromosome 11, while 72%−75% of alveolar RMS exhibit the distinctive translocation t(2;13)(q35;q14) between the PAX (on the long arm of chromosome 2) and FKHR gene (on the long arm of chromosome 13). Ten percent of cases with this type exhibited the translocation t(1;13)(p36;q14) between the PAX7 genes (on the short arm of chromosome 1) and FKHR.23,24
Differential diagnosis includes other malignancies with small round cells and the subtypes of myogenic tumors.18 Breast embryonal RMS with sheets of cohesion-lost and primitive rhabdomyoblastic cells may be mistaken as a primary malignant lymphoma, plasmocytoma and myelosarcoma. But this can be easily resolved by immunohistochemical studies. Sometimes, RMS of the breast demonstrating a targetoid growth pattern needs to be distinguished from invasive lobular carcinoma. The latter does not have an alveolar configuration, and is negative for myogenic markers and not immunoreactive for E-cadherin. Desmoplastic small round cell tumor (DSRCT) also has a predilection in occurring in children and adolescents, and the most common sites are the abdominal cavity and intrapelvic area. The small round tumor cells form variably sized and irregular nests. Central necrosis can be identified in some large nests. The neoplastic cells are representatively uniform with round or oval hyperchromatic nuclei and scant cytoplasm. Mitotic figures are frequent. DSRCT is also positive for desmin. All these make it difficult to differentiate RMS from DSRCT. Whereas, a distinctive dot-like intracytoplasmic positive can be seen with desmin in DSRCT, and MyoD1 and myogenin are always negative. The cytogenetic feature of DSRCT differs from RMS with a translocation t(11; 22)(p12;q12). Peripheral primitive neuroectodermal tumor (pPNET) is another small round cell malignancy in young people and is mostly located in limbs and adjacent to the spine. The differential points are the presence of Homer-Wright rosettes, positive for CD99, negative for myogenic markers, and the distinctive translocation t(11;22)(q24;q12) of the pPNET.
The prognosis for primary or metastatic RMS in the breast is poor.3,16 The overall survival rate at 10 years is about 40%.15 Little et al25 believed that the initial tumor size is a decisive factor, and lesions over 5 cm had a significant risk of metastasis and a poor prognosis. However, case 2 in our series was in good condition at last follow-up although the tumor was over 5 cm. Nogi et al have reported a 13-year-old girl with primary breast alveolar RMS who underwent modified radical mastectomy with nine lymph nodes involved. Two weeks after the operation, she showed multiple bone and lung metastases and died in 8 months.22 Compared with case 2, our case 3 was older with axillary lymph node metastases and had a poorer prognosis. It is possible that axillary lymph node status and age play a role in the prognosis of primary breast RMS patients.
In conclusion, breast RMS is an extremely uncommon malignancy with unique clinical, pathological and cytogenetic characteristics. It often strikes children and adolescents. However, there is still a chance that it can attack middle-aged women. Although there is a prevalence of alveolar histology in breast metastatic RMS, our series indicates that the embryonal tumor also has metastatic potential. Immunohistochemical studies can give an advantage to make the right diagnosis. Axillary lymph node status and age may play a role in the prognosis of primary breast RMS patients. In view of exceedingly low incidence and insufficient number of reported cases, more research is necessary to better understand this disease.