Importance of Annulate Bodies in the Diagnosis of Granular Cell Tumors (Schwannomas)

Granular cell tumors (GCTs) were originally characterized ultrastructurally by the presence of many large lysosomes and angulate bodies (ABs). ABs appear to have been forgotten, and the diagnosis of GCT currently depends solely upon the presence of large lysosomes. Most investigators favor a Schwann cell origin for GCT. Recently, reports of granular tumors with large lysosomes but without ABs have suggested other cells of origin. If the ultrastructural criteria for the diagnosis of GCT were maintained as originally described, many of these granular tumors would not qualify as true GCTs. Two granular tumors that were at first considered GCTs are described. Based on the presence of large lysosomes and the presence or absence of ABs, one tumor was considered a true malignant GCT and the other a benign fibroblastic tumor.     

Granular cell tumor of the intrapancreatic common bile duct: one case report and review of the literature

A granular cell tumor (GCT) in a 39-year-old white man is reported. It was localized in the intrapancreatic part of the common bile duct and caused obstruction of the bile downflow. The patient underwent radical surgical procedures because a malignant tumor was clinically suspected. Macroscopically, the tumor appeared as a duct stricture caused by diffuse infiltration of neoplastic cells in the walls. In the cytoplasm smaller and larger PAS-positive granules were present and constantly reactive to S-100 and NSE antibodies. Ultrastructurally, cytoplasmic granules appeared as membrane-bound vacuoles of variable size and shape containing debris, disrupted mitochondria, and myelin figures. No basal lamina around cell cytoplasm was observed. GCTs are relatively uncommon soft tissue tumors usually presenting in the skin and subcutaneous tissues or tongue. The prognosis in any location is quite good, but very rare malignant GCTs (1-2%) are documented. Complete excision reduces the risk of recurrence. Accurate operative diagnosis seems to be critical when the tumors are located in the intrapancreatic common bile duct as in this reported case. Gastro-pancreatico-duodenectomy is too radical a procedure for such a benign lesion and additional assessments and investigations are recommanded before such an extensive radical surgery.     

Germ-cell tumors of the mediastinum.

Mediastinal germ-cell tumors (GCTs) usually occur within the anterior mediastinum, accounting for about 15% of all mediastinal cysts and tumors. They are associated with the thymus, presumably arising from extragonadal germ cells or thymic cells with germ-cell potential. Mediastinal seminoma develops primarily in young males with rare cases reported in females; likewise, embryonal carcinoma, endodermal sinus tumor or yolk-sac tumor, choriocarcinoma, and malignant mixed or combined GCTs also overwhelmingly affect males. Mature cystic teratoma affects males and females equally. The prognosis for mediastinal mature cystic teratoma and seminoma is very good. Nonseminomatous malignant GCTs of the mediastinum often present with advanced disease and do not respond as well to chemotherapy as their gonadal counterparts. Nonetheless, it is important to separate mediastinal GCTs from other undifferentiated malignant tumors, especially thymic carcinoma, which has a poor prognosis. Clearly, some patients with mediastinal GCTs respond very well to modern therapies.     

Malignant advanced granulosa cell tumor of the adult testis: case report and review of the literature

Testicular granulosa cell tumors (GCTs) are very rare neoplasms. Although adult GCTs are thought to have a relatively indolent course, several reports have demonstrated the malignant potential of these lesions. In case of distant metastases, the overall survival is very short. To date, there is no well-established treatment for these tumors owing to poor results and very rapid progression. A 55-year-old male patient was diagnosed with a testicular GCT with distant lung metastases. He underwent surgical treatment with orchiectomy and adjuvant polychemotherapy (cisplantine, etoposide, and bleomycine) as well as metastasectomy of the right lung. We report the first case of a successfully treated testicular GCT with bipulmonary metastases at initial diagnosis. Thirty-nine months after treatment, the patient is alive with no evidence of disease. We subsequently reviewed all reported cases of an adult GCT in the published literature (25 published cases). This review will summarize all reported cases and discuss treatment options. The current case suggests that a combination of varying treatment modalities could be a promising and reasonable way to manage malignant advanced GCT of the adult testis.     

Identification of microRNAs From the miR-371~373 and miR-302 clusters as potential serum biomarkers of malignant germ cell tumors

Current serum biomarkers for diagnosis and monitoring of malignant germ cell tumors (GCTs) show limited sensitivity and specificity. We previously observed that microRNAs of the miR-371～373 and miR-302 clusters are overexpressed in all malignant GCTs, regardless of patient age, histologic subtype, or anatomic site, but are not reported to be coordinately up-regulated in other tumor types or disease states. Herein we show that levels of all 8 main members of the miR-371～373 and miR-302 clusters were elevated in the serum of a 4-year-old boy at the time of diagnosis of yolk sac tumor. Levels returned to normal during an uneventful clinical follow-up, with kinetics similar to those of the conventional marker α-fetoprotein. We describe in detail the multiplex polymerase chain reaction protocol used to quantify serum microRNA levels, which is highly robust and reproducible. Our study indicates that miR-371～373 and miR-302 cluster microRNAs are promising candidate biomarkers for improving disease monitoring (and potentially diagnosis) in malignant GCTs.     

Granular cell tumours of the gastrointestinal tract: expression of nestin and clinicopathological evaluation of 11 patients

AIMS: Granular cell tumours (GCTs) in the gastrointestinal (GI) tract are rare, with few series reported in the literature. Nestin is a recently identified intermediate filament protein that is expressed in neuroectodermal stem cells and skeletal muscle progenitor cells and has been shown to be expressed in gastrointestinal stromal tumours (GISTs) and GI schwannomas. Herein, we describe the clinicopathological and immunohistochemical features of 11 GI GCTs, introducing nestin as an additional marker that identifies these tumours. METHODS AND RESULTS: The archives of the departments of pathology at London Health Sciences Centre (London, Ontario) and St Michael's Hospital (Toronto, Ontario) were searched for GCTs occurring in the GI tract, yielding 11 cases. Histological features were assessed and immunohistochemistry was performed with S100 protein, nestin, glial fibrillary acidic protein (GFAP), CD34, desmin, CD117, and inhibin-alpha. Charts were reviewed for clinical information. Ages at diagnosis ranged from 31 to 73 years; there were six males and four females. All GCTs were solitary, six in the oesophagus, three in the caecum, one in the rectum and one perianal. Most lesions were discovered incidentally. The size of the GCTs ranged from 4 mm to 30 mm. All were submucosal, typically firm, with a white-yellow appearance. Histologically, the GCTs showed moderate cellularity, predominantly solid growth with areas of nesting. While lesional cells were mainly plump and polygonal, areas of spindling were present in several tumours, more frequently in the colorectum. Margins were circumscribed. Nuclei were round to oval, with even chromatin and small nucleoli. Mitoses were rare to absent and necrosis was absent in all cases. Staining with periodic acid-Schiff, with diastase predigestion, showed globular and diffuse positivity within the cytoplasm. Moderate to strong expression of S100 protein and nestin was observed in 11 of 11 and seven of seven tumours, respectively. GFAP, CD34, desmin, CD117 and inhibin-alpha were negative. While patients were variably managed with resection or observation, all remain clinically well, without disease progression. CONCLUSIONS: Although rare, GI GCTs have characteristic clinicopathological features. Nestin may be a useful immunohistochemical marker for identifying these tumours; the presence of this persistent stem cell cytoskeletal filament within GI GCTs suggests that these lesions may arise from a multipotential stem cell in the GI tract.     

Fine-needle aspiration cytology of tongue swellings: A study of 75 cases

Tongue swellings and growths are traditionally evaluated by surgical biopsy. Most of them, however, are easily accessible by fine-needle aspiration (FNA). We reviewed 75 lesions presenting as tongue swellings, which were examined by fine-needle aspiration cytology (FNAC) in our institutions over a period of 11 yr. The lesions included 17 malignant tumors: 12 cases of squamous carcinoma (SQC), 2 metastases, and 3 non-Hodgkin's lymphomas (NHL). In addition, 15 benign tumors and 43 nonneoplastic benign conditions were found. Thirteen of the 17 malignant lesions were diagnosed cytologically as malignant, 3 as suspicious for malignancy, and 1 as atypical, with biopsy recommended. There were no false-positive diagnoses. There were no clinical complications resulting from FNA. We conclude that FNAC of the tongue permits rapid and reliable diagnosis, and we recommend this method as the first diagnostic step in the evaluation of tongue swellings. Diagn. Cytopathol. 1998;18:387–392. © 1998 Wiley-Liss, Inc.     

Fine-needle aspiration cytology of tongue swellings: A study of 75 cases

Tongue swellings and growths are traditionally evaluated by surgical biopsy. Most of them, however, are easily accessible by fine-needle aspiration (FNA). We reviewed 75 lesions presenting as tongue swellings, which were examined by fine-needle aspiration cytology (FNAC) in our institutions over a period of 11 yr. The lesions included 17 malignant tumors: 12 cases of squamous carcinoma (SQC), 2 metastases, and 3 non-Hodgkin's lymphomas (NHL). In addition, 15 benign tumors and 43 nonneoplastic benign conditions were found. Thirteen of the 17 malignant lesions were diagnosed cytologically as malignant, 3 as suspicious for malignancy, and 1 as atypical, with biopsy recommended. There were no false-positive diagnoses. There were no clinical complications resulting from FNA. We conclude that FNAC of the tongue permits rapid and reliable diagnosis, and we recommend this method as the first diagnostic step in the evaluation of tongue swellings. Diagn. Cytopathol. 1998;18:387–392. © 1998 Wiley-Liss, Inc.     

Imbalances of chromosome arm 1p in pediatric and adult germ cell tumors are caused by true allelic loss: a combined comparative genomic hybridization and microsatellite analysis

Previous studies on childhood germ cell tumors (GCTs) report highly variable frequencies of losses at chromosome arm 1p. Since deletions at 1p portend a poor prognosis in other embryonal tumors, this study aims to clarify the question of the frequency of true allelic loss at 1p and whether it constitutes a prognostic parameter. We analyzed 13 GCTs from different gonadal and extragonadal sites of children (4 teratomas, 9 malignant GCTs) and 18 GCTs of adolescents and adults (3 teratomas; 15 malignant GCTs) using automated microsatellite analysis with 23 polymorphic markers and chromosomal "high resolution" comparative genomic hybridization (HR-CGH). With this combined approach, we detected loss of heterozygosity (LOH) at 1p in 8/9 childhood malignant GCTs with concordant data from HR-CGH and microsatellite analyses. In contrast, LOH at 1p was not detected in childhood teratomas (0/4) and constituted a rare event in GCTs of adolescence and adulthood (3/18). The commonly deleted region was located at distal 1p36-pter, with a proximal boundary between the markers D1S450 and D1S2870. These data unequivocally demonstrate that deletion at 1p is common in childhood GCTs and results in allelic loss. This observation argues for the presence of a classical tumor suppressor at distal 1p. Considering the high frequency of LOH at 1p and the overall favorable prognosis of childhood GCTs, a prognostic impact of LOH at 1p in childhood GCTs appears unlikely. However, since two postpubertal tumors with LOH at 1p progressed, a prognostic relevance in this age group seems possible, warranting a prospective evaluation.     

Cytomorphological diagnosis of malignant eccrine tumors: report of two cases

Though FNAC has been successfully used in diagnosing various neoplastic and nonneoplastic cutaneous lesions, there is a paucity of case reports describing the cytomorphological features of adnexal tumors. We hereby describe the cytological features of two histologically confirmed cases of malignant eccrine tumors. Case number 1 presented with an ulcerated infraclavicular swelling whereas case number 2 presented with a cystic swelling over left foot. FNA and histological examination of the resected specimens was performed using standard techniques. A cytological diagnosis of low grade papillary adenocarcinoma arising from skin adnexal structures was given in case number 1. Aspirate from case number 2 was reported as positive for malignant cells, and histological examination was advised. Histological examination revealed the presence of malignant eccrine acrospiroma in case number 1 and papillary digital adenocarcinoma in case number 2. Careful cytological examination displayed the characteristic of two cell population seen in eccrine tumors in both the cases. Diagnosis of malignant eccrine tumors cannot be made with certainity on cytology alone, hence the need to document the cytological features of these entities is emphasized.     

Neurofibromatosis type 1 and malignancy in childhood

Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary neurocutaneous syndrome characterized by multi‐system involvement and an increased incidence of both benign and malignant tumors. In this study, we evaluated the clinical presentation and prognosis of NF1 and malignancy. Between 1975 and 2013, 26 (5%) of the 473 patients with NF1 at our center developed non‐neurofibroma neoplasms. The patient files of 26 subjects with tumors, other than optic glioma, were analyzed retrospectively to evaluate clinical features and treatment results. The age at diagnosis of NF1 ranged from 3 months to 16 years (median 5.5 years). The age range at tumor diagnosis was 1.5–33 years (median 8 years) in these 26 patients. The tumor histological subtypes included the following: 12 soft‐tissue tumors (6 malignant peripheral nerve sheath tumors (MPNST), 5 rhabdomyosarcomas (RMS) and 1 malignant fibrous histiocytoma), 11 brain tumors (6 low‐grade gliomas, 3 high‐grade gliomas, and 2 medulloblastoma), 2 neuroblastomas and 1 non‐Hodgkin's lymphoma. Twelve of 26 patients were alive at the time of the study. Although benign brain tumors with NF1 are more common, high‐grade brain tumors also occur. Thus, careful and regular follow‐up is crucial for early detection of malignancy in NF1 patients.     

Discovery of an antigen containing 3-hydroxyanthranilic acid in the blood serum of patients with tumors in various situations

Investigation of an unusual antigen containing the carcinogenic tryptophan metabolite 3-hydroxyanthranilic acid as hapten (3-HAA-antigen) showed that it is present in the blood serum of most patients with malignant tumors in different situations and in different stages of the disease. The 3-HAA-antigen was found only rarely in patients with noncancerous diseases and was not found in the blood of healthy donors or of patients with benign tumors. The importance of the results for the diagnosis of cancer irrespective of its situation is discussed.Presented by Academician of the Academy of Medical Sciences of the USSR A. I. Serebrov.Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 82, No. 7, pp. 850–852, July, 1976.     

Extragonadal malignant germ cell tumors: a clinicopathological and immunohistochemical analysis of 48 cases at a single Chinese institution

Primary extragonadal malignant germ cell tumors (EMGCTs) are rare and characterized by the location in the midline of the body, including mediastinum, CNS, retroperitoneum and coccyx. EMGCTs present with different clinical and biologic characteristics in different tumor locations. Accurately diagnosing MEGCTs would be very difficult by performing on HE staining alone, and requires immunohistochemical verification. This study was to investigate the biological feature of EMGCTs and diagnostic value of immunohistochemical markers OCT3/4, CD117, PLAP, AFP, β-HCG and CD30 in EMGCTs. A retrospective study was performed on 48 patients with EMGCTs. EMGCTs were found to occur predominantly in males, especially for mediastinal MGCTs. The tumor locations included mediastinum, CNS and retroperitoneum. The mediastinum and CNS were the most common sites of EMGCTs. Seminoma/germinomas (64.6%) was the most common histological subtypes of EMGCTs. Chest pain, dyspnea, cough and fever were the most common clinical presentations in mediastinal MGCTs. Headache, visual disturbances, endocrine abnormalities, and signs of increased intracranial pressure were common clinical symptoms in CNS MGCTs. Abdominal mass with or without pain, backache and weight loss were common clinical presentations in retroperitoneal MGCTs. PLAP, CD117 and OCT3/4 were highly expressed in seminomas/gernimomas. CD30, EMA and CK AE1/3 staining were positive in embryonal carcinoma. AFP and β-HCG positive staining are characteristic in yolk sac tumors and choriocarcinoma, respectively. Patients with seminomas/germinomas had a better prognosis than those with NS/G-GCTs. Our finding suggests that the accurate diagnosis of EMGCTs is critical not only for predicting the tumor progression but also for patient management. Immunohistochemical markers have become an important tool in the diagnosis and differential diagnosis of EMGCTs.     

Malignant Granular Cell Tumor: Immunocytochemical and Ultrastructural Observations

Malignant granular cell tumor is an exceedingly rare tumor and only a few cases are documented in the literature. We report a malignant granular cell tumor of the subcutaneous tissue of the thigh in a 59-year-old man, and discuss the ultrastructural and immunocytochemical findings and their diagnostic value.     

Malignant Granular Cell Tumor: Immunocytochemical and Ultrastructural Observations

Malignant granular cell tumor is an exceedingly rare tumor and only a few cases are documented in the literature. We report a malignant granular cell tumor of the subcutaneous tissue of the thigh in a 59-year-old man, and discuss the ultrastructural and immunocytochemical findings and their diagnostic value.     

Ploidy of primary germ cell tumors of the testis. Pathogenetic and clinical relevance

The ploidy of testicular germ cell tumors (GCT), a heterogeneous group of neoplasms, was studied by DNA flow cytometry. The DNA index for infantile yolk sac tumor (N = 10), seminomas (N = 20), and nonseminomas (N = 36), was: 1.91, 1.66, and 1.43, respectively. These values differed significantly one from another (p less than 0.01). The seminoma and nonseminoma components of combined tumors (N = 16) had a significantly different median DNA index of 1.61 and 1.40, respectively. Three of the 10 infantile yolk sac tumors, but only one of the 72 testicular GCT of adults were diploid. The consistent aneuploidy of testicular GCTs of adults might be helpful in the differential diagnosis of primary nongerm cell tumors of the testis, and in differentiating between metastases of testicular GCTs and primary extragonadal malignant GCTs. These data fit into a model of pathogenesis of testicular GCTs of adults in which all tumors, with the possible exception of spermatocytic seminoma, pass through a seminoma stage. Tumor evolution seems to result from net loss of chromosomes from a (near)tetraploid carcinoma in situ cell. The pathogenesis of infantile yolk sac tumor might be different from that of testicular GCTs of adults.     

Diffuse membranous immunoreactivity for podoplanin (D2-40) distinguishes primary and metastatic seminomas from other germ cell tumors and metastatic neoplasms

Podoplanin has been shown to be expressed in primary germ cell tumors (GCTs), with conflicting results regarding its specificity. However, podoplanin expression in metastatic GCTs and other metastatic tumors has not been extensively examined. The goal of this study was to evaluate the distribution and specificity of podoplanin using monoclonal antibody D2-40 in primary testicular and metastatic GCTs in comparison with other metastatic neoplasms. In total, 122 tumors were studied: 43 primary GCTs, 33 metastatic GCTs, 11 metastatic melanomas, 25 metastatic carcinomas, and 10 lymphomas. All foci of seminoma showed strong, diffuse membranous staining in more than 90% of cells in primary and metastatic GCTs. In contrast, other GCT components showed only focal cytoplasmic and/or partial membranous staining in a subset of cases. Among non-GCTs, only 1 metastatic melanoma, 1 lymphoma, and 3 metastatic carcinomas showed focal, weak cytoplasmic staining. Diffuse membranous immunoreactivity for podoplanin as detected by monoclonal antibody D2-40 is highly sensitive and specific for primary and metastatic seminoma. Immunodetection of podoplanin may be useful to support seminoma in the differential diagnosis of poorly differentiated epithelioid malignant neoplasms.     

Serous tumors of low malignant potential of the ovary

Serous ovarian tumors of low malignant potential (SLMP) – also called borderline tumors of the ovary – represent a heterogeneous group of ovarian epithelial neoplasms. In general, this tumor type has a favorable prognosis. Nevertheless, 10–20% of SLMP exhibit a progressively worsening clinical course, with widespread peritoneal implants and death of the patient within 5 years. The criteria for recognizing the SLMP with an unfavorable prognosis and for distinguishing SLMP from highly differentiated ovarian carcinomas are summarized in this report. The importance of supporting methods, e.g., DNA cytophotometry, is demonstrated, revealing that in most cases aneuploidy can be regarded as an indicator for aggressiveness of the tumor and for poor clinical outcome. The importance of the new concept of micropapillary serous carcinomas (MPSC), the relationship of this variant of SLMP to invasive serous carcinomas, and the prognostic importance of invasive vs noninvasive peritoneal implants are discussed. (The concepts of molecular pathology of SLMP will be discussed in part 2 of this serial paper.) Received: 23 August 1999 / Accepted: 200 January 2000