Acinic cell carcinoma of the lung ("Fechner tumor"). A clinicopathologic, immunohistochemical, and ultrastructural study of five cases.

The clinical, pathological, immunohistochemical, and ultrastructural features in five cases of primary acinic cell carcinoma of the lung are presented. The patients' ages ranged from 44 to 75 years (mean, 56); four were women and one a man. The lesions were discovered incidentally on routine chest x-ray and ranged from 1.2 to 4 cm in greatest diameter. Three tumors were located in the right middle lobe, one in the right upper lobe, and one in the left upper lobe. In three cases, the lesions presented as asymptomatic subpleural nodules in proximity to secondary bronchi, one case presented as an endobronchial tumor that led to obstructive symptoms, and one case as a well-circumscribed deep parenchymal nodule. Histologically, the tumors were composed of clear cells with abundant granular cytoplasm growing as solid sheets with focal acinar, microcystic, and papillocystic areas. Immunohistochemical stains showed strong positivity of the tumor cells for low-molecular-weight cytokeratins and epithelial membrane antigen (EMA). Focal weak cytoplasmic positivity was observed in three cases with alpha-1-antichymotrypsin and in one case with amylase. Stains for vimentin, S-100 protein, chromogranin, and lysozyme were negative in all cases examined. Electron microscopy performed in four cases showed abundant zymogen-type cytoplasmic granules of variable electron density characteristic of acinar-type secretory cells. All patients were treated by lobectomy alone. Follow-up of 3 to 10 years in four cases revealed that all patients were alive and well, with no evidence of recurrence or metastases. Because of their relatively indolent behavior and favorable prognosis, primary acinic cell carcinoma of the lung must be distinguished from other primary and metastatic clear cell tumors of the lung.     

Epithelioid hemangioendothelioma of bone. A clinicopathologic, ultrastructural, and immunohistochemical study

In a review of 29 cases of solitary and multicentric hemangioendothelial sarcomas of bone, 14 were found to have histologic features of epithelioid hemangioendotheliomas. These were characterized by the presence of epithelioid or "histiocytoid" endothelial cells that were either round or spindle-shaped. Intracytoplasmic vacuolization was noted, and some showed nesting of cells, mimicking metastatic adenocarcinoma. The presence of a myxoid matrix suggested the diagnosis of chondrosarcoma in some cases. Some of the tumors strongly resembled the lesions formerly designated as intravascular bronchioloalveolar tumor, angioglomoid tumor of bone, or malignant myxoid angioblastoma of bone. Factor VIII-related antigen was detected in five of the six cases examined, and ultrastructural study in five cases confirmed the endothelial nature of the tumor cells; Weibel-Palade bodies were present in three cases. There were 11 men and three women, and the tumors were seen predominantly in patients who were under 30 years of age (10 cases). Four cases involved solitary tumors, and nine were multicentric in bone. The multicentric tumors had a predilection for the bones of one lower extremity (five cases). The total series had a protracted clinical course, and the multicentric tumors appeared to follow a less aggressive course.     

Neuroendocrine carcinoma of the colon and rectum. A clinicopathologic, ultrastructural, and immunohistochemical study of 24 cases

To further characterize the clinicopathologic spectrum of colorectal neuroendocrine neoplasia, 24 carcinomas with neuroendocrine differentiation were subtyped as either small cell neuroendocrine, oat cell variant (six cases), small cell neuroendocrine, intermediate variant (16 cases), or moderately differentiated neuroendocrine carcinoma (two cases). Five oat cell variants, 14 intermediate variants, and two moderately differentiated tumors were studied with antibodies to cytokeratin, vimentin, epithelial membrane antigen (EMA), neuron-specific enolase (NSE), chromogranin (CRG), synaptophysin (SYN), neurofilament, S-100 protein, carcinoembryonic antigen (CEA), and Leu-7. All tumors were immunoreactive for cytokeratin and the majority were also positive for EMA and NSE. Positivity for specific neuroendocrine markers was uncommon, with SYN reactivity noted in one oat cell variant and four intermediate variants, and CRG positivity observed in four intermediate variants and one moderately differentiated tumor. Ultrastructural analysis of four oat cell, eight intermediate, and one moderately differentiated tumor revealed neurosecretory-type, dense-core granules in all lesions, except two oat cell variants studied from paraffin-retrieved material. Hepatic and regional lymph node metastases were noted in five of six oat cell, eight of 16 intermediate, and two of two moderately differentiated tumors. Of 17 patients with follow-up (four oat cell, 11 intermediate, and two moderately differentiated tumors), only two individuals were alive after 1 year. There were no detectable differences in survival or response to treatment between morphologic subtypes. The prognosis of colorectal neuroendocrine carcinoma appears worse than for adenocarcinoma of comparable stage. Their distinction is thus warranted, especially in regard to the intermediate variant and moderately differentiated tumors, which may be potentially misinterpreted as forms of adenocarcinoma.     

Small-cell neuroendocrine carcinoma of the ampullary region. A clinicopathologic, immunohistochemical, and ultrastructural study of three cases.

We report the clinicopathologic, immunohistochemical, and ultrastructural features of three small-cell neuroendocrine carcinomas of the ampullary region of the duodenum. All patients were men; their ages were 51, 62, and 66 years. The therapy consisted of pancreatoduodenectomy. All patients died of the disease; median survival was 10 months from the diagnosis. The histological appearance was identical to pulmonary and extrapulmonary small-cell carcinoma. The neuroendocrine differentiation was demonstrated ultrastructurally by the presence of dense-core granules, and by the positive immunoreaction for neuron-specific enolase and Leu-7 in each case. One case expressed a focal positivity for chromogranin A (PHE-5) and argyrophilic granules. The same case showed the presence of neurofilaments on frozen material. Neurofilament proteins could not be demonstrated in any case in paraffin sections. Neoplastic cells exhibited cytoplasmic immunostaining for cytokeratins (CAM 5.2) in all cases. In one case, a large number of neoplastic cells (60-70%) exhibited nuclear Ki-67 positivity. We postulate that the disease's histogenesis was from epithelial stem cell expressing both epithelial and neuroendocrine characteristics. The clinical behavior of small-cell neuroendocrine carcinomas of the ampullary region appears to be extremely aggressive, with early metastases and fatal outcome.     

Clear cell tumor of the lung. Immunohistochemical and ultrastructural evidence of melanogenesis.

Clear cell tumors of the lung (CCTL) are rare neoplasms of uncertain differentiation. A previous study of eight CCTL demonstrated a lack of epithelial features, but their exact nature remained unknown. In the current study of nine CCTL, immunohistochemistry using preliminary enzymatic digestion showed strong reactivity with the antimelanocytic markers HMB-45 (seven cases) and HMB-50 (six cases) and focal positivity for S-100 (nine cases), neuron-specific enolase (three cases), synaptophysin (one case), and Leu-7 (one case). Staining for cytokeratin, epithelial membrane antigen, chromogranin, and glial fibrillary acid protein was uniformly negative. Frozen-section immunoreactivity for vimentin and the antimelanocytic monoclonal preparation NKI/BETEB was noted in the one CCTL for which snap-frozen tissue was available. Ultrastructural examination of three glutaraldehyde-fixed CCTL showed rare neoplastic cells containing the full spectrum of melanosomes in two, one of which also contained neurosecretory-type granules. Aberrant melanosomal forms were identified in the third case. Melanosomes were not identified in the remaining five CCTL studied from formalin- or paraffin-retrieved material. The findings indicate that CCTL exhibits melanocytic differentiation. This feature may be of considerable value in distinguishing CCTL from other clear cell neoplasms.     

Clear cell tumor of the lung: surgical and immunohistochemical findings

We encountered a clear cell tumor of the lung (CCTL) that was located peripherally, adjacent to the visceral pleura. The tumor could be directly observed during surgery. We believe that this case report describing the surgical and related pathological findings is highly informative. A chest radiograph during routine examination of an asymptomatic 65-year-old woman being treated for hypertension and hyperlipidemia revealed a nodular shadow in the left lung field. Wedge resection was performed by video-assisted thoracic surgery. The in vivo color of the tumor was red, suddenly changing to white after the tumor was clamped. Pathology examination showed a uniform pattern consisting of large clear cells without cytologic atypia or increased mitotic activity. Immunohistochemistry revealed tumor cells positive for vimentin and melanocytic markers (HMB-45 and melan-A) and negative for epithelial membrane antigen and cytokeratin. With the absence of clinical findings in both kidneys, the tumor was diagnosed as a benign CCTL.     

Microcystic adenomas (serous cystadenomas) of pancreas. A clinicopathologic investigation of eight cases with immunohistochemical and ultrastructural studies

Microcystic adenomas are rare tumors, which have only recently been distinguished from other cystic pancreatic lesions. This study details eight cases diagnosed at the Cleveland Clinic. Seven occurred in females. The mean age at diagnosis was 66 years. Abdominal or epigastric pain was the most common symptom. A history of extrapancreatic tumors was frequent, and one patient had a concomitant renal carcinoma with adrenal and renal cysts. The adenomas were multicystic, ranging in size from 2 to 14 cm. Cuboidal epithelial cells with vacuolated or clear cytoplasm containing abundant glycogen lined the cysts. The intervening stromal septa were collagenous and hypocellular. The epithelial cells exhibited strongly positive immunostaining for cytokeratins AE1 and AE3, but did not stain with CEA and Uro-2,3, and 4. Ultrastructurally, the epithelial cells rested on well-formed basal lamina and a delicate subepithelial capillary network. They had blunted apical microvilli and contained glycogen, few lipid droplets, and occasional apical secretory granules. Five adenomas were resected, and three had only a diagnostic biopsy. There were no metastases, but one patient died of postoperative complications following local excision. Elderly or high-risk patients may benefit more from biopsy alone than from attempts at total surgical resection of these benign tumors.     

T-cell signet-ring cell lymphoma. A histologic, ultrastructural, and immunohistochemical study of two cases

The histologic, ultrastructural, and immunologic characteristics of two signet-ring cell lymphomas of T-cell derivation are presented. Histologically, both lymphomas were diffuse large cell lymphomas with many neoplastic cells containing cytoplasmic vacuoles imparting a signet-ring configuration. Ultrastructural examination revealed the vacuoles to consist of electron-lucent spaces containing variable numbers of microspherules. Immunohistochemical studies showed that both lymphomas expressed T-cell phenotypes with no reactivity with antibodies to B-cell antigens. In contrast to previous reports which have shown signet-ring cell lymphomas to be invariably B-cell in derivation and usually follicular center cell type, this study demonstrates that these lymphomas may also be of T-cell origin.     

Anaplastic thyroid carcinoma with osteoclast-like giant cells. A clinicopathologic, immunohistochemical, and ultrastructural study

Two anaplastic thyroid carcinomas with osteoclast-like giant cells (OCL-GC) are reported. Light microscopically, one case resembled an aneurysmal bone cyst with cellular connective-tissue septae separating cavernous, blood-filled sinuses. The second case had sheets of anaplastic cells and a separate focus of papillary carcinoma without areas of transition. Multinucleate OCL-GC, pleomorphic mononuclear cells, and histiocytoid mononuclear cells with nuclei similar to those within the OCL-GC were seen in each case. With formalin-fixed, paraffin-embedded tissue, the majority of OCL-GC and histiocytoid mononuclear cells in both cases showed immunoreactivity using monoclonal antibodies to vimentin and KP-1, with the latter preparation directed against cells of monocytic/histiocytic lineage. Staining for keratin, epithelial membrane antigen, neuron-specific enolase, chromogranin, calcitonin, and thyroglobulin was negative in all cell types. Ultrastructural examination of one case showed two distinct types of mononuclear cells--one with morphologic characteristics similar to those of the OCL-GC, and another with pleomorphic nuclei and short cytoplasmic extensions joined by poorly formed desmosomes. The findings indicate that the anaplastic thyroid carcinomas studied represent poorly differentiated epithelial tumors infiltrated by reactive OCL-GC of monocytic/histiocytic lineage apparently derived from histiocytoid mononuclear cells via cellular fusion.     

Primary synovial sarcomas of the mediastinum: a clinicopathologic, immunohistochemical, and ultrastructural study of 15 cases

A series of 15 cases of primary mediastinal neoplasms displaying histopathologic, immunohistochemical, and ultrastructural features of synovial sarcoma is presented. The patients' ages ranged from 3 to 83 years, with a male-to-female ratio of 2:1. Nine cases presented as anterior mediastinal masses with chest pain, shortness of breath, and pleural effusion, and 6 cases were in paravertebral location in the posterior mediastinum and presented with neck or back pain and pleural effusion. The tumors measured from 5 to 20 cm in greatest diameter and showed a tan white, soft to rubbery cut surface with areas of hemorrhage and necrosis and foci of gelatinous material. Four cases showed areas of cystic degeneration. In 7 cases, the tumors were well circumscribed; in 6 cases, the tumors grossly invaded the pleura, pericardium, heart, great vessels, chest wall, rib, and vertebra. Histologically, 5 cases displayed a biphasic growth pattern, with well-formed glandular elements admixed with a monotonous spindle cell population. Ten cases were exclusively composed of a monotonous atypical spindle cell proliferation. Immunohistochemical studies showed focal positivity of the tumor cells for cytokeratin and/or epithelial membrane antigen, and strong positivity for vimentin and bcl-2 in the spindle cells in all cases studied (10 of 10). Eight cases also showed focal positivity for CD99. Electron microscopic examination in 5 cases showed oval to spindle tumor cells with closely apposed cell membranes, abundant cytoplasmic intermediate filaments and rough endoplasmic reticulum, and immature desmosome-type cell junctions. Ten patients were treated by complete surgical excision and two by partial excision followed by radiation therapy. In 4 patients, the tumors were inoperable and treated with radiation therapy only. Clinical follow-up was available in 5 patients and showed local recurrence with metastases to lung, lymph nodes, and epidural space from 1 to 3 years in 4 cases and liver metastases and death due to tumor after 6 month in 1 case. Synovial sarcoma should be considered in the differential diagnosis of biphasic and monophasic spindle cell neoplasms of the mediastinum.     

Acute interstitial pneumonia. A clinicopathologic, ultrastructural, and cell kinetic study

Eight cases of acute interstitial pneumonia were studied to define the clinical and pathologic features and to determine the relationship to chronic interstitial pneumonia. Clinically, this disease differs from the chronic interstitial pneumonias by a sudden onset and a rapid course. Five patients died of respiratory failure after 23 days to 2 months, and two died of other complications after 3 1/2-6 months. An etiologic agent could not be identified in any case. The histologic hallmark was interstitial fibrosis and edema associated with type II pneumocyte hyperplasia. The fibrosis differed from that seen in the chronic interstitial pneumonias by extensive fibroblast proliferation and relatively little collagen deposition. Autoradiographic studies of tritiated thymidine (3H-TdR) uptake showed high labeling indices in interstitial cells and type II pneumocytes. Evidence of acute lung injury, including both endothelial and epithelial cell damage, was a prominent ultrastructural feature. These findings emphasize that acute interstitial pneumonia is a clinically and pathologically distinct form of interstitial pneumonia that should be separated from the group of chronic interstitial pneumonias.     

Cardiac paragangliomas. A clinicopathologic and immunohistochemical study of four cases

Cardiac paragangliomas are extremely rare neoplasms. Four surgically resected tumors were examined by immunohistochemistry and electron microscopy. The patients ranged in age from 18 to 36 years. All patients had hypertension and elevated urine catecholamine levels. Three tumors were located on the posterior left atrium, and one tumor was located in the interventricular groove at the aortic root. The tumors ranged in size from 5 to 7 cm, and they displayed a prominent Zellballen pattern without significant necrosis or mitosis. The tumors were mostly unencapsulated and infiltrated adjacent cardiac tissue in two cases. Immunoperoxidase staining showed that all tumors were positive for chromogranin and neuron-specific enolase. Three tumors were positive for methionine enkephalin. Positive staining for S-100 protein was seen in the sustentacular cells of all tumors but was negative in chromaffin cells. All tumors were negative for insulin, glucagon, gastrin, vasoactive intestinal polypeptide, somatostatin, adrenocorticotropic hormone, calcitonin, serotonin, pancreatic polypeptide, and rat atrial peptide. Ultrastructural studies of all four tumors showed moderate numbers of predominantly norepinephrine-type granules and a few epinephrine-type granules. These results show that cardiac paragangliomas are commonly found in close proximity to the left atrium and have immunohistochemical and ultrastructural features similar to other paragangliomas.     

Atypical inflammatory histiocytic tumor of the cerebellum. A histological, immunohistochemical, and ultrastructural study

We report a primary histiocytic tumor involving the cerebellum. Microscopically, the tumor was composed of nests of pleomorphic cells surrounded by thin vascular septa invaded by lymphocytes. Immunocytochemistry and electron microscopy confirmed the histiocytic origin of the tumor. Although we considered several diagnoses, we ultimately concluded that "atypical inflammatory histiocytic tumor of the cerebellum" best characterized the lesion. This case represents another example of the diversity of histiocytic tumors and shows that they can occur in the central nervous system.     

Basaloid squamous cell carcinoma of the head and neck. A clinicopathologic and immunohistochemical study of 40 cases.

In this study of 40 cases of basaloid squamous cell carcinoma, 83% arose in the pyriform sinus, base of tongue, tonsil, and larynx. The 35 men and five women ranged in age from 27 to 88 years (median 62). In patients for whom social habits were recorded, 24 of 26 patients were smokers and 22 of 25 drank ethanol. Most presented with stage III or IV disease. Twenty-seven patients had regional metastases at the time of presentation and 15 developed distant metastases. Seventeen patients died with disease (median survival 18 months). The tumors were composed of moderately pleomorphic basaloid cells forming nests, cords, and frequent cribriform patterns. Squamous dysplasia of surface mucosa, focal squamous differentiation within invasive basaloid squamous cell carcinoma, or foci of conventional squamous cell carcinoma were present, alone or in combination. All studied neoplasms were immunohistochemically positive for keratins with the 34 beta E12 antibody. Approximately 80% were immunoreactive using AE1/AE3 or CAM 5.2. Epithelial membrane antigen, carcinoembryonic antigen, and S100 protein were found in 83%, 53%, and 39%, respectively, of the cases. Diffuse, weak immunoreactivity for neuron-specific enolase was seen in 75% of tumors. Synaptophysin, chromogranin, muscle-specific actin, and glial fibrillary acidic protein were absent. Basaloid squamous cell carcinoma has been confused with adenoid cystic carcinoma and small cell undifferentiated carcinoma, but is usually distinguishable in routine hematoxylin and eosin-stained sections, or, in rare problematic cases, with the aid of immunohistochemical studies. Distinction is warranted because the biologic behavior of basaloid squamous cell carcinoma differs from that of both of these lesions.     

Amyloid tumor. A clinicopathologic study of four cases.

Four examples of amyloid tumors were studied to determine whether there was an association with myelomatosis. Three patients had follow-up examinations of 12 years, 9 years, and 2 1/2 years, respectively. A local recurrence developed in one patient and a second lesion developed in this patient and in one other who also had a transient monoclonal 7S globulin peak. In spite of these findings, none of our patients developed myelomatosis. A study of the scanty literature on amyloid tumors reveals that only patients with lesions of the lung and urinary bladder have had long-term follow-up. They have invariably remained free of disease. Several reports of bone lesions have inferred that amyloid tumors occurring here signify solitary myeloma despite a lack of follow-up confirmation. Our longest surviving patient developed two bone lesions over a 12-year period without developing myelomatosis. Our findings lead us to conclude that there is little evidence to regard the presence of an amyloid tumor at any site as a manifestation of solitary myeloma or myelomatosis.     

Leiomyosarcoma of the urinary bladder. A clinicopathologic and immunohistochemical study of 15 cases

We present the clinicopathologic and immunohistochemical features of 15 vesical leiomyosarcomas. The nine male and six female patients ranged in age from 16 to 72 years (median: 49 years). Gross hematuria was the most common complaint. The tumors most often arose in the dome of the bladder (50%) and ranged in size from 1 to 10 cm (median: 5 cm). Five patients underwent total cystectomy, nine had a partial cystectomy or local excision, and one was only biopsied. Based on the highest of five sets of mitotic counts per case, eight tumors had one or fewer mitotic figures per 10 high-power fields (MF/10HPF); none of these patients developed metastases during a follow-up interval of 1 month to 20 years (mean: 62 months). Five tumors showed three to six MF/10HPF; one patient in this group died after 6 years with unresectable metastases, whereas the others are disease free with follow-up of 8 months to 8 years (mean: 62 months). Two tumors contained 10-15 MF/10HPF; one produced widespread metastases and was fatal after 3 months, whereas the other has not recurred or metastasized after 9 months. All tumors had infiltrating margins and invaded the bladder musculature--important features in their distinction from vesical leiomyoma. Nine leiomyosarcomas had zones of myxoid intercellular material; six of these were predominantly or exclusively myxoid. The myxoid foci often closely resembled inflammatory pseudotumor, particularly in superficial portions of the neoplasms. In two cases, an intense superficial plasma cell infiltrate mimicked a plasma cell granuloma. All 12 leiomyosarcomas studied immunohistochemically were negative for epithelial markers (cytokeratins and epithelial membrane antigen); staining for muscle-specific actin and vimentin was uniformly positive, and eight neoplasms also expressed desmin.     

Glycogen-rich clear cell carcinomas of the breast. A clinicopathologic and ultrastructural study

Ten cases of glycogen-rich clear cell carcinoma of the breast are described. Only two previous case reports have been published. These neoplasms are composed of clear cells with abundant glycogen. Ultrastructurally, two cases showed large quantities of non-membrane-bound glycogen and numerous empty glycogen lakes. neoplastic cells formed tight junctions, immature desmosomes, and occasionally had short microvilli. In nine cases the glycogen-rich carcinoma grew in a solid pattern only, while one case had both solid and papillary patterns. One case was associated with a signet-ring cell carcinoma. Seven of nine patients who underwent axillary dissections had nodal metastases. Five patients died with residual disease, and one is currently alive with local skin recurrence. These data suggest that glycogen-rich clear cell carcinoma is associated with frequent lymph node metastases and mortality.     

Pleomorphic carcinomas of the lung show a selective distribution of gene products involved in cell differentiation,cell cycle control,tumor growth,and tumor cell motility: a clinicopathologic and immunohistochemical study of 31 cases

We investigated 31 cases of pleomorphic carcinomas of the lung, with a double component of neoplastic epithelial cells and of spindle and/or giant cells. To correlate the morphologic diversity of these two cell components with their immunophenotype, we evaluated the expression of several gene products involved in cell differentiation (cytokeratins, epithelial membrane antigen, carcinoembryonic antigen, vimentin, S-100 protein, smooth muscle actin, desmin), cell cycle control and apoptosis (p53, p21Waf1, p27Kip1, FHIT), tumor growth (proliferative fraction, assessed by Ki-67 antigen, and microvascular density, assessed by CD34 immunostaining), and tumor cell motility (fascin). We found the epithelial component to be significantly more immunoreactive for cytokeratins, epithelial membrane antigen, carcinoembryonic antigen, cell cycle inhibitors p21Waf1, p27Kip1 and tumor suppressor gene FHIT, whereas the sarcomatoid component, independent of tumor stage and size, was more immunoreactive for vimentin, fascin, and microvascular density. Accordingly, we suggest a model of tumorigenesis whereby the mesenchymal phenotype of pleomorphic cells is likely induced by the selective activation and segregation of several molecules involved in cell differentiation, cell cycle control, and tumor cell growth and motility. Whether pleomorphic carcinomas of the lung are tumors with a dismal prognosis still remains an unsettled issue. In our series, however, stage I pleomorphic carcinomas have the same clinical behavior as ordinary non-small cell lung cancer, and only a high proliferative index (Ki-67 labeling index >35%) is associated with a worse prognosis in these tumors.