Hepatobiliary neuroendocrine carcinoma in cats: a clinicopathologic, immunohistochemical, and ultrastructural study of 17 cases.

Hepatobiliary neuroendocrine carcinoma was diagnosed in 17 cats in a period of 10 years. Seven tumors were of intrahepatic origin, one of which was a composite containing components of epithelial and neuroendocrine carcinoma. Nine tumors were of extrahepatic origin, and one tumor was located in the gall-bladder. The cats were adult and geriatric, and the male : female ratio varied according to tumor group. Hepatomegaly, anorexia, weight loss, and vomiting were the most common clinical signs observed in the cats with hepatic neuroendocrine carcinoma. The cats with extrahepatic neuroendocrine carcinoma showed these signs plus icterus (5/9) and high concentrations of hepatic enzymes. Histologically, the hepatic neuroendocrine carcinomas had two patterns, one with acinar structures separated by vascular stroma lined by cuboidal or columnar cells and the other solid with groups of anaplastic cells separated by vascular stroma. The composite tumor consisted of both bile duct carcinoma and neuroendocrine carcinoma. The extrahepatic neuroendocrine carcinomas and the gallbladder neuroendocrine carcinoma were characterized by solid sheets or groups of round to oval cells with vascular or fibrovascular stroma. Immunohistochemical examination of 10 of the neuroendocrine carcinomas revealed that all 10 stained with neuron-specific enolase; one bile duct carcinoma and the gallbladder carcinoma stained with chromogranin; four of five bile duct carcinomas and the gall bladder carcinoma stained with synaptophysin; and one bile duct carcinoma stained with gastrin. One cat with hepatic carcinoma had duodenal ulcer; in this cat, ultrastructural studies showed neurosecretory granules leading to the diagnosis of Zollinger-Ellison syndrome. In four cats in which necropsy was permitted, carcinomatosis (4/4), lymph nodes (4/4), lungs (2/4), and intestines (1/4) were the metastatic sites. Fourteen of the 17 cats were euthanatized during or immediately after surgery.

Canine hepatic neuroendocrine carcinoma: an immunohistochemical and electron microscopic study.

Ten dogs with neuroendocrine carcinoma of the liver were selected for inclusion in the study. Clinical signs were anorexia (7), vomiting (5), polydipsia/polyuria (3), icterus (2), lethargy (2), weight loss (2), paresis (1), ataxia (1), weakness (1), collapse (1), and urinary tract infection (1). Hematologic and biochemical abnormalities included anemia (2/8), leukocytosis (4/8), high liver enzyme activity (serum alkaline phosphatase, 7/9; alanine transaminase, 7/9; aspartate transaminase, 8/9), and high total bilirubin (6/9). Grossly, the tumors were diffuse, involving all liver lobes in six dogs, and two dogs had various-sized nodules in addition to diffuse involvement. Histologically, there were eight tumors with solid or trabecular pattern (group A), one tumor with cords or rows of neoplastic cells (group B), and one tumor with multiple rosette-like structures (group C). Immunohistochemical studies revealed that all 10 neoplasms were positive for at least one of the endocrine markers used: neuron-specific enolase (NSE; 8/10), synaptophysin (5/10), and chromogranin-A (3/10). A panel of NSE, chromagranin-A, and synaptophysin detected 100% of the tumors in our series. Electron microscopy confirmed the diagnosis by the presence of intracytoplasmic neurosecretory granules in the two examined cases. Our results show that neuroendocrine markers commonly used in humans can be used for the diagnosis of hepatic neuroendocrine carcinoma in dogs, preferably a panel of synaptophysin, chromagranin-A, and NSE because chromogranin-A alone is not as useful in dogs as in humans.

Feline cystic thymoma: a clinicopathologic, immunohistologic, and electron microscopic study of 14 cases.

Cystic thymoma was diagnosed in 14 cats in a period of 6 years. The most common clinical sign was laboured breathing. The tumours were characterized by various-sized cystic spaces with central vessels. The epithelial cells varied from oval to spindle to polygonal cells enclosing cystic spaces or in pure epithelial cell components. The nuclei of the neoplastic cells had scattered chromatin and small nucleoli. The cytoplasm was pale eosinophilic. The concentration of mature lymphocytes varied from area to area with rare germinal centres. Immunohistochemically, the epithelial cells stained only with AE(1)/AE(3). The central vessels were positive for vimentin, smooth muscle actin, and factor VIII antigen. Electron microscopy revealed that the cyst walls were lined by epithelial cells that were joined by desmosomes, and the walls were well separated from the cystic spaces by a well-defined basement membrane. The neoplastic epithelial cells contained scattered tonofilaments. Three of the cats had metastasis to the lymph nodes and lungs. Two novel cases of ectopic cystic thymoma have also been described. Results of this study reveal that cystic thymoma is uncommon in cats, and that the histomorphologic, immunohistochemical, and electron microscopic features are similar to those of cystic thymoma in humans.

Neuroendocrine carcinoma of the nasopharynx in a dog.

Neuroendocrine carcinoma of the nasopharynx was diagnosed in a 9-year-old male Golden Retriever. The mass was identified by computed tomography of the nasal cavity and nasopharyngoscopy, and it was surgically excised. Histologic, cytochemical, and electromicroscopic examination of specimens confirmed the type of tumor. The dog was clincally improved for 150 days but was then reexamined because of respiratory difficulty and poor appetite. Thoracic radiographs revealed multiple nodules in all lung lobes, and ultrasonography revealed a mass in the spleen. The dog died the next day.

Clinicopathologic and electron microscopic study of cutaneous neuroendocrine (Merkel cell) carcinoma in a cat with comparisons to human and canine tumors.

Malignant neuroendocrine carcinoma of the skin (Merkel cell tumor) was diagnosed in an 18-year-old spayed female Maine Coon Cat. The diagnosis was made on the basis of morphologic and electron microscopic findings. The cat was euthanatized 321 days after surgical excision of the tumor. The tumor's malignancy contrasted with the benign nature of Merkel cell tumors reported in dogs and was consistent with the malignancy of Merkel cell tumors reported in humans.

Fibrosarcoma mimicking plasmacytoma or carcinoma: an ultrastructural study of 4 cases.

Because the fibroblast has a remarkable capability of phenotypic modulations, reflected in both morphologic and immunohistochemical (IHC) changes, ultrastructural studies are mandatory to identify the variants of fibroblasts. Myofibroblasts or histiofibroblasts are such examples, demonstrating chimeric ultrastructural features of fibroblastic cells in common with smooth muscle cells or with histiocytes, respectively. The presence of epithelioid fibroblastic cells sharing morphologic features with epithelial or plasma cells has not been yet characterized. The authors identified 4 cases of fibrosarcomas (FS) characterized by an unusual phenotype and associated with peculiar ultrastructural findings. The electron microscopic (EM) findings were correlated with the histologic appearance and immunoprofile. All tumors were located in the extremities, 3 in soft tissues and 1 in the bone. By light microscopy 2 cases were composed predominantly by round uniform cells with a striking plasmacytoid appearance. One case mimicked carcinoma, composed predominantly by epithelioid cells and scattered giant tumor cells. The fourth case showed a mixture of plasmacytoid-like and epithelioid cells. By IHC, tumor cells were positive for vimentin and in 2 cases also for epithelial membrane antigen. Kappa/lambda light chain and cytokeratins markers were negative. By EM all 4 tumors showed in addition to classic features of fibroblasts, unusual epithelial-type features, such as secretory granules of "neurosecretory-type" (3 cases), rudimentary cell junctions (3 cases), microvilli (2 cases), and lumen-like structures (1 case). One plasmacytoid-type tumor showed finely granular extracellular deposits. The study describe 4 examples of fibrosarcomas with unusual features at the ultrastructural level, which are associated microscopically with a peculiar phenotype, mimicking plasmacytoma or carcinoma. These findings broaden the spectrum of fibroblastic cell variants in neoplasia.

Ultrastructure of submucosal glands in human anterior middle nasal turbinates.

The abundant glands situated in the lamina propria of the human anterior middle nasal turbinate were complex tubules that consist of serous, seromucous, and mucous cells, either singly or in combination. Serous granules were homogeneously dense, but could have a small lighter core. Seromucous granules had a dense rim and a large compartment of appreciably lighter density. Gradation between serous and seromucous granules made precise identification of these secretory cell types difficult. Mucous cells were of conventional morphology. The secretory tubules, which possessed a complement of myoepithelial cells, gradually transformed into ducts or the changeover was relatively sudden. The ductular portions of the tubules consisted either of tall prismatic cells or of shorter columnar cells, both of which lacked secretory granules, but had many mitochondria in their supranuclear cytoplasm. In many cases the ducts, for most of their length, consisted of secretory cells. These glands clearly participate in the elaboration of the glycoconjugate coat that serves to protect the nasal mucosa and keeps it from drying out.

Primary fibrosarcoma and malignant fibrous histiocytoma of bone--a comparative ultrastructural study: evidence of a spectrum of fibroblastic differentiation.

As primary bone fibrosarcoma (FS) and malignant fibrous histiocytoma (MFH) have similar clinical, radiographic, or survival manifestations, ultrastructural and immunohistochemical studies were undertaken to determine the differentiation pathways of constituent malignant cells. Twelve cases of primary intraosseous FS and MFH were selected for this ultrastructural comparative study and were analyzed for fibroblastic or modified fibroblastic differentiation. There were 4 FS cases and 8 MFH cases, of which 5 were storiform-pleomorphic, 2 were giant cell, and 1 was myxoid type. All FS consisted of spindle fibroblasts with a prominent rough endoplasmic reticulum and Golgi apparatus, variable amounts of vimentin intermediate filaments, and extracellular collagen fibrils. The MFH were composed of a mixture of spindle and pleomorphic fibroblasts (8/8), histiofibroblasts (4/8), and myofibroblasts (3/8). Variable numbers of undifferentiated cells were found in both tumors. In conclusion, fibroblastic differentiation and collagen production was noted in all cases. The often pleomorphic histiofibroblasts present in some MFH cases most likely represent "modified fibroblasts," similar to myofibroblasts. These findings support the hypothesis that the fibroblast and its variants are the predominant cell types found in these tumors, suggesting that the diagnostic entity MFH should be classified as a pleomorphic fibrosarcoma.

Large plaque-type blue nevus with subcutaneous cellular nodules.

Unusual or atypical melanocytic nevi can be confused with malignant melanoma. The authors present two cases of an unusual variant of blue nevus that were misdiagnosed initially as malignancy. Both lesions were asymptomatic and characterized clinically by childhood onset, with slow enlargement during adolescence and subsequent nodule formation. One lesion, which measured 24 cm in greatest dimension, was located on the anterior chest wall of a 53-year-old woman. The other lesion, which measured approximately 15 cm in greatest dimension, was located on the lateral abdominal wall of a 20-year-old man. Both lesions were characterized by a multifocal dermal and subcutaneous proliferation of fusiform and dendritic pigmented melanocytes. The histologic appearance of individual foci ranged from dermal melanocytosis to common blue nevus and cellular blue nevus. The cellular foci were located in the subcutis and involved, in one patient, the stroma of the breast. The cells were immunoreactive for S-100 protein, gp100 (HMB-45), and Melan-A (A103). Ultrastructural analysis revealed melanocytes typical of blue nevus. The woman underwent complete excision of the lesion, and the man underwent only partial excision of the lesion. On clinical follow-up of 32 and 19 months, respectively, both patients are alive and well with no evidence of recurrence or progression. Because the lesions presented clinically as large plaques and were diagnosed histologically as blue nevi with subcutaneous foci of cellular blue nevus, we term this rare variant of blue nevus large plaque-type blue nevus with subcutaneous cellular nodules. Recognition of this lesion enhances our knowledge of the morphologic spectrum of melanocytic tumors and helps to avoid confusion with malignant melanoma.

Cytokeratin-positive malignant tumors with reticulum cell morphology: a subtype of fibroblastic reticulum cell neoplasm?

Cytokeratin-positive interstitial reticulum cells (CIRCs) have been described as a subset of fibroblastic reticulum cells (FBRCs) normally found in lymph nodes, the spleen, and tonsils. Although tumors derived form other reticulum (dendritic) cells, specifically follicular dendritic cells, interdigitating dendritic cells, and cytokeratin-negative FBRCs, have been well documented and are now accepted, this is not the case for tumors of CIRCs. A possible reason for this failure is the difficulty in distinguishing them from other tumors, particularly carcinoma. We report three cases of cytokeratin-positive malignant tumors with a reticulum cell morphology: two located in the mediastinum and one in the soft tissue in the proximal forearm. All cases coexpressed vimentin, and one case coexpressed smooth muscle actin and desmin, resulting in a phenotype similar to that of some normal CIRCs. Although metastatic carcinoma from an occult or regressed primary tumor cannot be excluded completely, we raise the possibility of a CIRC origin for these cases.

Low-grade fibrosarcoma with palisaded granulomalike bodies (giant rosettes): report of a case that metastasized.

"Hyalinizing spindle cell tumor with giant rosettes" is a tumor recently described by Lane et al. and thought by them possibly to represent a form of low-grade fibromyxoid sarcoma. Proof of a metastatic potential was lacking. We report an example of this tumor on the arm of a 28-year-old woman. The ultrastructural study of the tumor confirmed the fibroblastic nature of the lesion, which subsequently metastasized to the lung. Histologically, the giant rosettes simulated palisaded granulomas. Our findings warrant classifying the tumor as a sarcoma, and we suggest the designation low-grade fibrosarcoma with palisaded granulomalike bodies (giant rosettes).

Thrombotic microangiopathy as a complication of long-term therapy with gemcitabine.

Three patients with pancreatic carcinoma treated with gemcitabine for 1 year developed clinical and laboratory findings compatible with an indolent form of the hemolytic-uremic syndrome. Renal biopsy specimens in two of these patients showed the characteristic features of thrombotic microangiopathy, and a skin biopsy specimen from the third patient, who presented with livedo reticularis, showed intravascular fibrin deposition. Thrombotic microangiopathy may represent a toxic effect of long-term gemcitabine therapy.

Role of electron microscopy in the evaluation of soft tissue neoplasms, with emphasis on spindle cell and pleomorphic tumors.

The current significant role of transmission electron microscopy in the evaluation of soft tissue tumors when correlated with conventional histological and immunohistochemical studies is discussed for the following entities: myxofibrosarcoma, storiform-pleomorphic fibrosarcoma (malignant fibrous histiocytoma), and myofibrosarcoma; dermatofibrosarcoma protuberans; hemangiopericytoma; monophasic synovial sarcoma; extrarenal rhabdoid tumor; soft tissue perineurioma; and gastrointestinal stromal tumors, notably the so-called autonomic nerve variant.

Changes in nasal epithelium in patients with severe chronic sinusitis: a clinicopathologic and electron microscopic study.

OBJECTIVE: Defective ciliary ultrastructure and impaired mucociliary clearance play an important role in the development of respiratory disease and sinusitis. Changes in the ciliary ultrastructure of the sinonasal epithelium have been documented in patients with primary ciliary dyskinesia. However, secondary ciliary dyskinesias and epithelial cytopathologic changes have been underappreciated as a consequence of respiratory dysfunction and chronic sinusitis. STUDY DESIGN: Thirty-two patients with severe chronic sinusitis were evaluated for ciliary and epithelial abnormalities. MATERIALS AND METHODS: Fourteen patients (44%) were children who underwent full allergy, sweat, and immunologic workups. Eighteen patients (56%) were adults who had severe refractory sinusitis and had failed previous sinus surgery. All patients underwent nasal epithelium biopsies of the middle turbinate and evaluation by light and transmission electron microscopy. RESULTS: Ciliated cells were found in 23 patients (72%) with 9 patients (28%) having no cilia. Foci of normal ciliated epithelium were found in only 19% of the patients, often in epithelial invaginations. Variable numbers (usually a minor population) of cilia in 20 cases (87%) exhibited ultrastructural defects including compound cilia and microtubule and dynein arm defects. All of the patients showed variable loss of differentiated epithelial cells ranging from denuded epithelium to basal cell hyperplasia often associated with squamous metaplasia, secondary to chronic sinonasal disease. The lamina propria was often edematous with dilated capillaries, plasma cells, lymphocytes, and hyperplastic seromucous glands. CONCLUSIONS: This study demonstrates that ciliary dyskinesias are primarily the result rather than the cause of chronic sinusitis. Patients with chronic sinusitis of uncertain origin exhibit a prominent loss of differentiated epithelial cells, as well as ciliary defects, most of which are likely to be secondary to the chronic disease process. These changes slow down mucociliary clearance and lead to a vicious cycle leading to chronicity.

Skeletal and extraskeletal myxoid chondrosarcoma: a comparative clinicopathologic, ultrastructural, and molecular study.

BACKGROUND: Skeletal myxoid chondrosarcoma (SMC) is considered to be either a typical chondrosarcoma with prominent myxoid alterations or an altogether unique malignant cartilage tumor. Extraskeletal myxoid chondrosarcoma (EMC) is a relatively rare but well-recognized neoplasm. It was initially thought to be a low grade sarcoma of cartilage derivation and was recently found, in most cases, to contain a reciprocal t(9;22), resulting in a fusion of the EWS and CHN genes. Are SMC and EMC the same entity arising in two different locations, or are they two separate entities? To the authors' knowledge, this study represents the first systematic attempt to answer this question. METHODS: Forty consecutive cases of EMC (20 cases) and SMC (20 cases) were compared by light and electron microscopy, immunohistochemistry, and molecular analysis. The mean clinical follow-up for both groups was 55 months. Histologic criteria for SMC consisted of 95% myxoid matrix, with only minimal hyaline cartilage formation. RESULTS: The gender distribution was identical in both groups (13 males and 7 females). The mean age was 55 years for EMC patients and 45 years for SMC patients. The EMC tumors were predominantly located in the deep soft tissues of the lower extremity (60%) and buttock (20%), and the mean tumor size was 13 cm. SMC was most commonly located in the bones around the hip joint (pelvis 35%; proximal femur 20%) and shoulder (20%); the mean size was 9 cm. Histologic grade in the EMC group correlated with survival (82% of the high grade tumors metastasized). Electron microscopy performed in 8 EMC cases revealed intracisternal microtubules in 3 cases and prominent mitochondria in 5, whereas in 5 SMC cases it revealed only inconspicuous organelles. Molecular analysis for the EWS-CHN fusion RNA resulting from the t(9;22) was performed in 15 cases (9 EMC and 6 SMC) and was detected in 7 of 9 EMC cases and 0 of 6 SMC cases. In one case, the molecular structure of the EWS-CHN fusion RNA was novel. The probability of metastasis was significantly higher (P=0.004) for the EMC group than for the SMC group. CONCLUSIONS: Although similar light microscopic features are noted in EMC and SMC, fundamental differences are noted at the ultrastructural and molecular levels, suggesting that EMC and SMC represent two distinct entities in the chondrosarcoma family of tumors.

Neuroendocrine differentiation is a common feature of thymic carcinoma.

Immunohistochemical evidence of neuroendocrine differentiation in the form of reactivity for synaptophysin, neuron-specific enolase, and/or chromogranin was found in 11 of 19 (58%) thymic carcinomas having the typical morphologic features of that tumor type. Four of these 19 cases were studied ultrastructurally, and neuroendocrine-type cytoplasmic dense-core granules were found in two. In contrast, 84 thymomas were negative for these markers, except for a focal immunoreactivity for neuron-specific enolase in areas of medullary differentiation in half of the lymphocyte-rich tumors. The results of this study show that in the thymus, similar to most other organs, neuroendocrine differentiation is not limited to tumors with an identifiable neuroendocrine appearance in hematoxylin-eosin-stained slides, such as carcinoid tumor and small cell carcinoma, but rather that it represents a common event shared by the major types of malignant epithelial tumors of that organ.

Presacral carcinoid tumors: report of three cases and review of the literature.

The clinical, microscopic, immunohistochemical, and ultrastructural features of three carcinoid tumors of the presacral region are reviewed. All tumors occurred in young women and did not involve the rectum. The predominant microscopic pattern was trabecular. The differential diagnosis included paraganglioma and myxopapillary ependymoma. Immunohistochemically, neuroendocrine markers and low molecular weight cytokeratins were expressed in all cases. Neurosecretory granules were identified in the single case studied by electron microscopy. One case was associated with a tailgut cyst (retrorectal cystic hamartoma). Two patients were treated with complete local excision and are free of disease 3 and 4 years after surgery. One case metastasized to both breasts and recurred locally after an incomplete excision. This report expands the already long list of sites where carcinoid tumors can arise. The frequent association of these tumors with tailgut cysts and their histologic similarities to rectal carcinoid tumors suggest that the most likely derivation of presacral carcinoid tumors is from hindgut rests.

Primary leiomyosarcoma of bone: a clinicopathologic, immunohistochemical, and ultrastructural study of 33 patients and a literature review.

Leiomyosarcoma of bone is a rare tumor in an unusual location. Previous analysis of this entity mostly involved small numbers of cases with limited follow-up. Thirty-three patients with leiomyosarcoma of bone between 1977 and 1996 were studied, and the histologic appearance and grade were correlated with subsequent treatment and clinical behavior. To be included in this study the tumor had to be intraosseous, with other primary sites of origin clinically excluded. Also, most of the sarcomatous tissue (> or =70%) had to be of intramedullary location with only limited extraosseous extension. The patient's age at diagnosis ranged from 13 to 77 years (average 44.4). The gender distribution was equal. The long bones were preferentially affected (64%), with the lower extremity, around the knee joint, predominantly involved. Five patients (15%) developed postradiation leiomyosarcomas. The histologic analysis showed that the osseous leiomyosarcomas are most commonly of the classic type, followed by the epithelioid, myxoid, and pleomorphic variants. Immunoreactivity for smooth muscle markers (smooth muscle actin, common muscle actin, desmin) was positive in all tumors, and ultrastructural confirmation was obtained in 21% of cases. All sarcomas were histologically graded, which accurately reflected the subsequent prognosis. Seventy-five percent of the lesions were high-grade and the rest low-grade. The histologic grade of the tumors correlated with both the recurrence as well as the metastatic rates and together with the clinicopathologic stage of disease represented the cornerstone on which prudent therapy should be based.

Thymic neuroblastoma in adults: report of three cases with special emphasis on its association with the syndrome of inappropriate secretion of antidiuretic hormone.

We report three cases of neuroblastoma arising within the thymus of elderly patients. All tumors consisted of primitive neuroblasts showing focal gangliocytic differentiation within nests of neuropil. All stained for neuroendocrine markers but were negative for cytokeratins and for the MIC2 gene product. One tumor was associated with the syndrome of inappropriate secretion of antidiuretic hormone, an endocrinopathy we found in three of five case reports of thymic neuroblastoma in adults. Immunohistochemical stains confirmed production of antidiuretic hormone by this tumor. One patient died of progressive disease, one patient is disease free at 18 months, and the other patient died of unrelated causes, a spectrum that reflects the variable clinical behavior others have reported. The possible histogenesis of these purely neural tumors includes malignant transformation of a mediastinal teratoma, aberrantly located sympathetic ganglia, neuroectodermal cells native to the normal thymus, and precursors of thymic epithelial cells that have differentiated along neural lines.