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Background: Tuberous Sclerosis Complex (TSC) is a rare multisystem disorder. In 2012 diagnostic criteria for TSC were revised. However, data on the incidence of TSC are limited., Methods: Prospective, national surveillance study in Germany over a 2-year-period (03/2015-02/2017) using current revised criteria for TSC. Patients up to the age of 18 years with a new diagnosis of definite or possible TSC (clinical and/or genetic) were included. The aims of this study were 1) to generate up-to-date data on the incidence of definite or possible TSC, 2) to assess age at first diagnosis, and 3) to compare these data with previous epidemiologic data., Results: In total, 86 patients met inclusion criteria (definite or possible TSC) with a median age at diagnosis of 6 months (range: 5 months before birth - 197 months of age). Among patients identified with features of TSC, 73.3% met criteria for definite diagnosis (median age: 7 months) and 26.7% met criteria for a possible diagnosis (median age: 3 months). 55.8% of patients were male. When excluding prenatally diagnosed patients, median age at diagnosis was 11 months with a range of 0 to 197 months. The 3 most common clinical features at diagnosis of TSC were central nervous system involvement in 73.3% patients (of these 95.2% experienced seizures), cutaneous involvement in 58.1% patients (with the most common lesion being hypomelanotic macules in 92%) and cardiac rhabdomyoma in half of the patients. Cardiac rhabdomyoma were detected by prenatal ultrasonography in 22.1% of patients. The presence of cardiac rhabdomyoma was associated with cardiac arrhythmias in 25.6% (about 13% of all diagnosed patients) in our cohort. The overall prevalence of seizure disorders was 69.8%. The annual incidence rate of TSC is estimated at a minimum of 1:17.785 live births. However correcting for underreporting, the estimated incidence rate of definite or possible TSC is approximately 1:6.760-1:13.520 live births in Germany., Conclusions: This is the first study that assessed prospectively the incidence rate of TSC in children and adolescents using the updated diagnostic criteria of 2012. This prospective surveillance study demonstrates a low age at first diagnosis (median: 6 months), likely due to antenatal detection of cardiac rhabdomyoma. Early diagnosis bears the potential for implementing effective therapies at an earlier stage.

Primary heart tumours in the paediatric population are very rare and they range from 0.01% to 0.04%. Most are benign lesions of which about half are rhabdomyomas. Rhabdomyoma tumour diagnosis is associated with a 75-80% risk of tuberous sclerosis complex (TSC). TSC are characterised with numerous changes of hamartoma-type located in the brain, kidneys, skin and other organs including the heart. More than two-thirds of newborns with TSC present rhabdomyomas in the heart. These changes may be asymptomatic, but in some cases they may cause heart failure, arrhythmias and death. We present a case report of an infant with giant rhabdomyoma tumours in the course of TSC.

Dlk1, a member of the Epidermal Growth Factor family, is expressed in multiple tissues during development, and has been detected in carcinomas and neuroendocrine tumors. Dlk1 is paternally expressed and belongs to a group of imprinted genes associated with rhabdomyosarcomas but not with other primitive childhood tumors to date. Here, we investigate the possible roles of Dlk1 in skeletal muscle tumor formation. We analyzed tumors of different mesenchymal origin for expression of Dlk1 and various myogenic markers and found that Dlk1 was present consistently in myogenic tumors. The coincident observation of Dlk1 with a highly proliferative state in myogenic tumors led us to subsequently investigate the involvement of Dlk1 in the control of the adult myogenic programme. We performed an injury study in Dlk1 transgenic mice, ectopically expressing ovine Dlk1 (membrane bound C2 variant) under control of the myosin light chain promotor, and detected an early, enhanced formation of myotubes in Dlk1 transgenic mice. We then stably transfected the mouse myoblast cell line, C2C12, with full-length Dlk1 (soluble A variant) and detected an inhibition of myotube formation, which could be reversed by adding Dlk1 antibody to the culture supernatant. These results suggest that Dlk1 is involved in controlling the myogenic programme and that the various splice forms may exert different effects. Interestingly, both in the Dlk1 transgenic mice and the DLK1-C2C12 cells, we detected reduced myostatin expression, suggesting that the effect of Dlk1 on the myogenic programme might involve the myostatin signaling pathway. In support of a relationship between Dlk1 and myostatin we detected reciprocal expression of these two transcripts during different cell cycle stages of human myoblasts. Together our results suggest that Dlk1 is a candidate marker for skeletal muscle tumors and might be involved directly in skeletal muscle tumor formation through a modulatory effect on the myogenic programme.

Genital rhabdomyoma is very rare tumor that usually occurs in the vulvar of young women. Epididymis rhabdomyoma in a young man is extremely uncommon and has rarely been reported. Here, we report a case of epididymis rhabdomyoma of a 17-year-old man and review the literatures.

Fine needle aspiration (FNA) is a valuable, noninvasive, commonly used technique in the diagnoses of head and neck tumors. Adult rhabdomyoma is a rare benign tumor of striate muscle tissue usually located in the head and neck region. Cytomorphologically, the tumor cells have eosinophilic finely granular cytoplasm, which sometimes can mimic other tumors. We report a case of adult rhabdomyoma, which was initially misinterpreted as granular cell tumor on FNA biopsy due to lacking of typical cytological features of adult rhabdomyoma. We recommend that adult rhabdomyoma should be included in differential diagnoses when the cytological features are suggestive of granular cell tumor. A panel of immunohistochemical stains including S100, desmin, and myoglobulin may also be helpful in making correct diagnosis., (2009 Wiley-Liss, Inc.)

Cardiac rhabdomyoma (CR) is the most common heart tumor in children and is usually associated with tuberous sclerosis complex (TSC). Tuberous sclerosis complex is a genetic disorder caused by a mutation in either of 2 genes (TSC1 or TSC2) and characterized by the formation of hamartomas in multiple organs. The 2 TSC proteins, hamartin and tuberin, antagonize the mammalian target of rapamycin (mTOR) signaling pathway, thus regulating cell growth and proliferation. Recently, some trials treating TSC with the mTOR inhibitor rapamycin have been published; however, the impact of such treatment on heart tumors is not known. The aim of the present paper was to study the molecular pathobiology of CRs. Six CR samples were studied. The expression of S6K1, pErk, Erk, Akt, pAkt, 4E-BP1, hamartin, tuberin, mTOR, bcl-2, Bax, and Ki-67 was examined using immunohistochemistry and Western blot methods. Increased expression of Bax, mTOR, pS6K, pErk, and 4E-BP1 was found in all CR samples. Hamartin and tuberin expression was decreased in tumors versus normal heart tissues. This is the first study showing mTOR pathway dysregulation and an increased expression of proapoptotic Bax protein in CRs associated with TSC.

Background: We present two cases of adult rhabdomyoma in the parapharyngeal space. They are rare benign tumors with a characteristic histologic appearance., Methods: The tumors were studied by light and immunohistochemical analysis using stains characteristic of striated muscle fibers., Results: Cross-striation was demonstrated by phosphotungstic acid hematoxylin (PTAH), muscle specific actin, desmin, and myoglobin while dystrophin was expressed in the cell membranes. Clonal origin was confirmed by expression of myosin heavy chain-fast only. Expression of myosin-neonatal and myogenin proved slight proliferation with incipient differentiation in an otherwise mature tumor., Conclusion: The head and neck area harbors 90% of adult rhabdomyomas and should be considered in a differential diagnosis in this region. Immunohistochemistry confirms that the tumors are almost totally mature neoplasms of clonal origin., ((c) 2005 Wiley Periodicals, Inc.)

Tuberous sclerosis is a hamartoma syndrome due to mutations in TSC1 or TSC2 in which cardiac rhabdomyomas are seen in approximately 60% of patients. These lesions have an unusual natural history as they are usually most prominent immediately after birth and spontaneously resolve in most cases. To develop a mouse model of this lesion, we used a conditional, floxed allele of Tsc1 and a modified myosin light chain 2v allele in which cre recombinase expression occurs in ventricular myocytes. Mice with ventricular loss of Tsc1 had a median survival of 6 months and developed a dilated cardiomyopathy with the occurrence of scattered foci of enlarged ventricular myocytes. The enlarged cells were periodic acid-Schiff positive indicating the presence of excess glycogen and expressed elevated levels of phospho-S6, similar to findings in patient rhabdomyoma cells. The observations confirm that rhabdomyomas occur through a two hit mechanism of pathogenesis. However, the mice showed no evidence of fetal/neonatal demise, and there was no evidence of proliferation in the lesions. We propose that these differences are due to the timing of loss of Tsc1 in the ventricular myocytes and/or the truncated gestational period in the mouse compared with humans, during which progestational hormones may accentuate the growth of patient rhabdomyomas.

Tuberous sclerosis complex (TSC) is a common autosomal dominant disorder in which affected patients develop a wide variety of benign and malignant tumors. We report here on a 31-week gestational age fetus with pathological features of TSC. Developmental expression of hamartin and tuberin in various tissues was studied using immunohistochemistry. There was loss of expression of hamartin in the tuber and weak expression of the tuberin. Both hamartin and tuberin were expressed in bronchial epithelial cells, cardiac muscles, renal collecting tubules, and neural tissues. The rhabdomyomas stained negatively for tuberin and hamartin. Two genetic loci are responsible for TSC-TSCI and TSC2. The TSC1 gene on chromosome 9 encodes a protein termed hamartin that lacks sequence similarity to any known proteins, whereas the TSC2 gene on chromosome 16 codes for a protein termed tuberin. These results indicate that tuberin and hamartin may play a critical role in development and thus provide a framework for understanding the developmental and hamartomatous manifestations of tuberous sclerosis.

The cytologic features of adult rhabdomyoma, a rare benign tumor of skeletal muscle origin, have been infrequently reported in the literature. We present here a case of a rhabdomyoma involving the floor of the mouth of a 78-year-old man initially diagnosed by fine-needle aspiration cytology. Cytologic features seen on Papanicolaou-stained smear preparation included cohesive clusters of skeletal muscle cells having abundant eosinophilic cytoplasm and often peripherally located nuclei. Although cross-striations and elongated intracytoplasmic inclusions were not identified in the smears, they were noted in the cell block preparation of the aspirated specimen and in the touch preparation and histologic sections of the surgically resected specimen. The cytologic differential diagnosis of this tumor is discussed., (Copyright 2003 Wiley-Liss, Inc.)

Tuberous sclerosis complex (TSC) is a genetically heterogeneous disease caused by mutations of TSC1 or TSC2 genes. It involves multiple organ systems resulting in mild to lethal hamartoma formation due to gene mutation in the germ line and loss of heterozygosity (LOH) in somatic cells. Hamartin (TSC1) and tuberin (TSC2) are expressed broadly. However, little is known about tissue susceptibility to hamartomas when equal or similar amounts of TSC gene expression are present. In this study, we present a 19-week gestational age fetus with pathological features of TSC, which was confirmed by finding LOH of TSC2 in a cardiac rhabdomyoma. Developmental expression of hamartin and tuberin in the TSC fetus, an age-matched non-TSC fetus, and a 26-week gestational age non-TSC fetus were analyzed by immunohistochemistry. We found that in addition to the differential expression of the TSC genes in some normal tissues compared with that in the TSC-affected fetus, the cellular localization and distribution of hamartin and tuberin were dramatically different in different tissues. In general, hamartin and tuberin are mainly expressed in epithelial cells, myocytes, and neural tissues. By comparing the incidence of the hamartomas in early childhood and gene expression in tissues, it appears that tissues with co-expression of hamartin and tuberin are prone to a higher incidence of hamartomas than those expressing only one protein, or two proteins but in different patterns of cellular localization.

Rhabdomyomas are the most common heart tumors seen in infancy. However, whether they represent hamartomas or true neoplasms derived from cardiomyocytes is still controversial. The fetal pattern of atrial natriuretic peptide (ANP) expression (predominant in the atrial and ventricular subendocardium) becomes altered during the early postnatal period to that typical of the adult (all atrial cardiomyocytes and some cells in the ventricular impulse-conducting system). To better comprehend the nature and origin of cardiac rhabdomyomas, we investigated the immunohistochemical expression of ANP in seven surgically excised ventricular specimens and two necropsy cases of multiple, atrial, and ventricular rhabdomyomas in children aged 1 to 34 days. Immunogold labeling for ANP at the ultrastructural level was also performed on three ventricular tumors. Although all atrial tumors were immunoreactive for ANP, these usually showed a variable number of faintly positive cardiomyocytes, contrasting with the diffuse and intense immunoreactivity of the surrounding atrial myocardium. ANP was detected in the ventricular tumors of five (56%) of the nine cases. The positive ventricular tumor cells predominated in the subendocardium and areas with prominent fibrous tissue, usually around blood vessels. Immunoelectron microscopy of the ventricular tumors demonstrated rare, positive cytoplasmic granules surrounded by membranes, usually located near the nuclei. We conclude that cardiac rhabdomyomas exhibit a fetal pattern of ANP immunoreactivity, which suggests delayed maturation of the tumoral cardiomyocytes, reinforcing the notion that cardiac rhabdomyomas are fetal hamartomas.

Eighty-eight patients underwent surgery for various cardiac tumours from January 1978 to June 1998 at our Institute. Seventy-seven tumours were myxomas, 10 were non-myxomatous and one was secondary cardiac tumour. Case records of the patients with non-myxomatous primary cardiac tumours and one secondary tumour were reviewed. Six of these primary tumours were benign and four, malignant. Age of the patients ranged from 26 days to 47 years. Among patients (3 children, 8 adults) with non-myxomatous primary cardiac tumours, dyspnoea on exertion was the commonest symptom and was the cause of presentation in seven out of 11 patients. Of the eight adults, six were in New York Heart Association functional class II/III and two in class IV. Echocardiographic diagnosis was possible in all the patients. Complete excision of the tumour was possible in all benign and two of the four malignant tumours. Incomplete resection was done in the secondary tumour. Of the six benign tumours, three were rhabdomyomas and one each of fibroma, haemangioma and lipoma. The malignant tumours were one each of fibrosarcoma, angiosarcoma, unclassified sarcoma and malignant mesothelioma. The secondary tumour was a malignant thymoma. Follow-up ranged from 1 to 10 years (mean 7.2 years). Of the patients with benign tumours, four out of six are alive; one patient died on the first post-operative day and one lost to follow-up. Two of the four patients with malignant cardiac tumours died, one was lost to follow-up and one is alive two years after surgery. The patient with secondary malignant thymoma to the superior vena cava was lost to follow-up three months after an uneventful recovery from surgery.

A case of a thymic neoplasm with a prominent rhabdomyomatous component is presented. The patient, a 21-year-old asymptomatic man, had an anterior mediastinal mass found on routine chest radiographs. Surgical resection of an encapsulated anterior mediastinal mass was performed. Histologically, two distinct cell populations were apparent, one epithelial and the other myoid. Immunohistochemical studies using antibodies for keratin decorated the epithelial component of this lesion; antibodies for myoglobin and desmin strongly stained the myoid component.

A mesenchymal tumor with the macroscopic and microscopic features of a fetal rhabdomyoma arose in the liver of a 14-year-old boy. Thirteen years previously this boy had been treated for a fetal rhabdomyomatous nephroblastoma with nephrectomy and--for subsequent peritoneal disseminations--with surgical excision, radiotherapy, and chemotherapy. The unusual hepatic location of the rhabdomyomatous tumor in this patient supports the view that this mature tumor developed from a metastasis of the original nephroblastoma. As such, this case may represent an example of irreversible change of a malignant process into a benign tumor probably caused by the action of systemic chemotherapy.

A 50-year-old man presented with a rapidly growing mass in the area of the right lacrimal gland. An initial erroneous histopathologic diagnosis of a pleomorphic adenoma made on a small-incisional biopsy was later corrected to a malignant rhabdoid tumor when a wide local excision of the tumor was performed. The tumor was composed predominantly of dyscohesive, globoid, and eosinophilic cells, which frequently contained cytoplasmic inclusions. These were demonstrated to be composed of whorls of intermediate vimentin filaments. The tumor cells expressed epithelial membrane antigen as well as cytokeratin. Ultrastructurally, they displayed intercellular junctions and interrupted segments of linear basement membrane material. These findings, together with the development of the lesion within the parenchyma of the lacrimal gland, are suggestive of an epithelial origin. The patient was treated with radical surgery and adjunctive radiotherapy and chemotherapy, which are the recommended treatment modalities for this highly malignant tumor.

Interstitial proliferation of striated muscle cells in the lung is rare. A few cases in the literature only document infants with associated lung and other major organ anomalies incompatible with long-term survival. In this report we document a case of diffuse patchy interstitial proliferation of striated muscle cells in the left lung and confirm their nature by immunohistochemistry and electron microscopy. In particular, we show that these skeletal muscle cells express alpha-sarcomeric actin, but not alpha-smooth muscle actin, indicating an antigenetically well-developed striated muscle phenotype despite morphologically embryonal features.

A case of malignant mixed müllerian tumor of the ovary in a 57-year-old woman is reported along with the results of an immunohistochemical study. The tumor, measuring 16 x 10 x 9 cm, was composed predominantly of adenocarcinoma with a smaller amount of anaplastic carcinoma as an epithelial component and chondrosarcoma, liposarcoma, fibrosarcoma and rhabdomyoblasts as mesenchymal elements. Immunohistochemistry using paraffin sections demonstrated cytokeratin (CK) and epithelial membrane antigen (EMA), generally regarded as epithelial markers, not only in the epithelial component but also in chondrosarcoma cells. Vimentin and desmin, generally regarded as mesenchymal markers, were exhibited partly in carcinoma cells as well as in mesenchymal elements. Positive staining for S-100 protein was obtained not only in chondrosarcoma and liposarcoma cells, but also partly in adenocarcinoma cells. This intricate immunohistochemical picture reflected the histologic findings. It is noteworthy that both carcinoma cells and chondrosarcoma cells demonstrated simultaneous expression of CK, EMA, vimentin, desmin and S-100 protein. This somewhat unusual antigen expression by tumor cells may indicate a change in the nature of tumor cells due to microenvironmental factors.

A 32-year-old Caucasian man presented with a tumor in the right side of the neck. Preoperative fine-needle aspiration showed large multinucleated cells with abundant granular cytoplasm that were consonant with the features of a granular cell tumor. At surgery, two separate tumors were found. Histologically, the tumor proved to be an adult rhabdomyoma, the 11th such multifocal case reported. The striated muscle origin of this benign tumor was confirmed by immunohistochemical and ultrastructural studies. The tumor cells were desmin-, myoglobin-, and actin-positive. They showed variable numbers of thick and thin filaments, as well as hypertrophic Z-band material. Histochemical studies showed the presence of basophilic muscle cells, vesicular nuclei, ragged red fibers, and diffuse acid phosphatase positivity. These features, together with the absence of actual muscle cell proliferation and the assumption that the mass of the tumor could be explained by the enormous swelling of the muscle cells, lead us to conclude that an adult rhabodomyoma is merely the result of a process of disorderly degeneration and regeneration rather than a real neoplasm or a hamartomatous lesion.

Two cases of 'adult' rhabdomyoma and 2 of 'fetal' rhabdomyoma have been immunologically studied using several antisera specific of skeletal muscle fibers proteins. This paper also deals with a review of the literature on these rare benign skeletal muscle proliferations. It is concluded that 'adult' rhabdomyoma contains fetal myosin and therefore the term 'adult' does not seem immunologically appropriate any longer. In addition the tumoral cells show the same level of differentiation as seen in neonatal skeletal muscle. Therefore it seems that the definition of neonatal rhabdomyoma is more appropriate for these benign muscular proliferations. The 2 cases of fetal rhabdomyoma appear phenotypically similar to normally developing myoblasts and contain fetal myosin. Therefore it seems that the definition 'fetal' is here appropriate for what appears to be a disorganized proliferation of otherwise normal fetal skeletal muscle fibers. The differential diagnosis between these latter tumors and rhabdomyosarcomas has been discussed.

Electron microscopy of a cardiac rhabdomyoma revealed two varieties of cells: (1) typical "spider cells' characterized by few myofibrils and large aggregates of glycogen particles free in the cytoplasm; and (2) cells with more myofibrils, less glycogen, and glycogen within membrane-limited vacuoles. These differences in myofibril development and glycogen content represent two succeeding stages in the early maturation of normal cardiocytes. The vacuoles containing glycogen were interpreted as autophagic and, consequently, active in the glycogen decrease typical of normal maturing cardiocytes. Rhabdomyoma cells did not show the structures, e.g., T system, characteristic of the late normal heart development. This study supports the theory that arrested cardiocyte maturation is a factor in the pathogenesis of cardiac rhabdomyoma.

A case of adult type rhabdomyoma in the neck region of a 77-year-old man is presented. In electron microscopy, some tumour cells showed irregularly orientated sarcomere formation with distinct Z-bands. All cells contained rod-like inclusions with attached thin cytoplasmic filaments. When stained with antibodies against desmin many tumour cells showed a diffuse peroxidase reaction, but the tumour also contained cells with cross striations. After phosphotungstic acid hematoxylin staining, dense cytoplasmic inclusions were seen; these structures showed strong affinity to antibodies against desmin. Our results apparently confirm the suggestion that the rod-like inclusions in rhabdomyoma cells are modified Z-bands. The desmin staining patterns in the present tumour may represent different stages in disorderly proliferation and degeneration of rhabdomyoma cells.

Immunohistochemical methods were used to demonstrate the distribution of basement membrane laminin and type IV collagen in eight tumors derived from striated muscle (three botryoid, two alveolar, and two adult-type rhabdomyosarcomas; one benign vaginal rhabdomyoma). All of the tumors produced significant amounts of both basement membrane components. Stainings clearly revealed the alveolar nature of the rhabdomyosarcomas, with the alveolar spaces surrounded by distinct basement membranes. Different stages of cellular development were identified in the botryoid sarcomas, with the most immature cells of the cambium layer devoid of external basement membrane around the tumor cells, although the stroma contained finely dispersed basement membrane material and some cells contained intracytoplasmic laminin or type IV collagen, indicative of the synthesis of these proteins. The more mature cells, which had abundant granular cytoplasm, were enveloped by distinct basement membranes and seemed to have coalesced, forming structures resembling myotubes. The adult-type rhabdomyosarcomas were composed of large pleomorphic cells that were surrounded by basement membranes, either individually or in small groups. Some giant cells contained intracytoplasmic laminin. The vaginal rhabdomyoma was composed of round rhabdoblastic cells or elongated strap cells with cross-striations. Cells of both of these types were surrounded by thin but distinct basement membranes. The results suggest that demonstration of basement membranes would be helpful in the diagnosis of tumors derived from striated muscle. The findings concerning different stages of maturation of tumor cells are in accordance with previous in vitro observations of myoblastic cells.