Small cell carcinoma of the urinary bladder. A clinicopathologic, morphometric, immunohistochemical, and ultrastructural study of 18 cases

A multiinstitutional review of 3778 patients with a primary malignancy of the urinary bladder revealed 18 cases (0.48%) of small cell carcinoma which were histologically and morphometrically identical to pulmonary small cell undifferentiated carcinoma. Age, sex, and symptoms at first presentation were comparable to that known in transitional cell carcinoma. Sixteen patients (89%) developed metastatic disease, with most frequent involvement of regional lymph nodes, liver, skeleton, and abdominal cavity. The unfavorable clinical outcome was worse as compared with that reported in advanced stage poorly differentiated transitional cell carcinoma, and was similar to the rapidly fatal outcome of pulmonary small cell undifferentiated carcinoma. Fourteen patients (78%) died by tumor at a mean follow-up period of 9.4 months, and only one patient was free of recurrent disease more than 5 years after cystectomy. This apparent aggressive tumor behavior was independent of the presence of neuroendocrine differentiation characteristics at immunohistochemical (13 cases, 72%) or electron microscopic study (eight cases, 44%). The prolonged survival periods (15-38 months) of the five patients who received combination chemotherapy suggested that, just as in small cell lung carcinoma, chemotherapy may be profitable. A unified concept of histogenesis of bladder cancer with a common origin from a multipotent mucosal stem cell is proposed.     

Small cell lung carcinoma: clinicopathological, immunohistochemical, and ultrastructural study.

Sixty-seven cases of small cell lung carcinoma (SCLA) in Tri-Service General Hospital (TSGH) during the past 16 years were studied. For patients with extensive stage of disease, the mean survival time and 2-year survival rate were 7.2 months and 3.1% versus 13.4 months and 16.7% for patients with limited stage. A better prognosis was obtained by treatment with a combination of intensive chemotherapy and radiotherapy. Immunohistochemical studies were performed by the peroxidase-antiperoxidase method. The positive rates in descending order were bombesin (80%), synaptophysin (74.3%), neurofilament (68.6%), neuron-specific enolase (60%), low molecular weight cytokeratin (54.3%), high molecular weight cytokeratin (25.7%), chromogranin-A (22.9%), adrenocorticotrophic hormone (0). Seven cases were examined and found to be ultrastructure; only 3 cases were found to contain neurosecretory granules. We emphasize that electron microscopy is not necessary as a routine diagnostic procedure, while light microscopy should be employed whenever possible; the immunohistochemical study should be considered within this context.     

Leiomyosarcoma of bone. A clinicopathologic, immunohistochemical, and ultrastructural study of five cases.

The authors identified five leiomyosarcomas (LMS) in a review of 13 nonmatrix-producing spindle cell sarcomas of bone. Only two were initially recognized as LMS; the others had been diagnosed as malignant fibrous histiocytoma (two) and fibrosarcoma (one). The patients, four of whom were women, ranged in age from 32 to 70 years. Sites included proximal humerus (two), distal femur (two), and rib (one). All tumors presented with clinical and radiographic features consistent with a diagnosis of primary bone neoplasms, although one probably represented a solitary metastasis from a primary uterine LMS. Radiographs showed lytic bone destruction with a moth-eaten appearance, and three cases had soft tissue extension. Histologically, all tumors showed broad, interlacing fascicles of spindle cells with pleomorphic nuclei, frequent mitoses, and necrosis. Two cases had a focal storiform pattern and bizarre multinucleated cells, and two other cases had focally prominent osteoclast-like giant cells. Extensive immunoreactivity for muscle actin was seen in all cases and for desmin in three. In each case, electron microscopy showed definite smooth muscle differentiation including cytoplasmic filaments with densities. At this writing, two patients are free of disease (including the patient with a presumed metastasis), one is alive with locally recurrent disease, and two are dead of disease. Experience suggests that LMS of bone is a distinct clinicopathologic entity that may be more common than previously recognized. Application of immunohistochemistry and electron microscopy to nonmatrix-producing bone sarcomas should facilitate diagnosis of additional cases.     

Balloon cell malignant melanoma of the skin. A clinicopathologic study of 34 cases with histochemical, immunohistochemical, and ultrastructural observations.

Balloon cell malignant melanoma (BCMM) is a rare histologic variant of malignant melanoma (MM). Thirty-four patients with BCMM from the files of the Armed Forces Institute of Pathology (AFIP) were studied by means of clinicopathologic correlation and histochemical, immunohistochemical, and ultrastructural methods to better define this entity. The cytoplasmic features of the balloon cells observed in BCMM resemble those noticed in balloon cell nevus (BCN), but the presence of nuclear pleomorphism, atypia, and mitoses and the absence of intervening stroma help distinguish BCMM. The cells also show many histochemical, immunochemical, and ultrastructural features of conventional melanoma cells. Although it is generally believed that balloon melanoma cells represent a degenerative change, the immunohistochemical and electron microscopic findings suggest that the balloon tumor cells are most likely metabolically active melanocytic cells. Microscopically, BCMM also must be differentiated from other clear cell tumors such as clear cell sarcoma (MM of soft parts), hibernoma, xanthoma, sebaceous neoplasms, metastatic renal cell carcinoma, (malignant) clear cell acrospiroma, (malignant) granular cell tumor, granular (clear) cell basal cell carcinoma, clear cell syringoma, and atypical fibroxanthoma. The prognosis of BCMM usually correlates with the tumor thickness similar to that in other histologic types of cutaneous MM. Nineteen (57.5%) of 33 patients with adequate follow-up information died of disseminated tumors from 2 months to 12 years after the initial treatment. Six (18.2%) patients developed local recurrences: four of these patients died of metastasis and two were alive with metastatic tumor at last contact. Five (15.2%) patients were alive with metastatic tumors, and seven (21.2%) were alive without evidence of disease at last contact. Recognition of BCMM is important because of its malignant biologic behavior.     

Primary carcinoma of the small intestine. A clinicopathologic and immunohistochemical study

A clinicopathologic and immunohistochemical study of fifty-two primary carcinomas of the small intestine (20 duodenal, 18 jejunal, and 14 ileal) was performed. Most of these neoplasms were located in the proximal duodenum, proximal jejunum, and distal ileum. Most of these tumors produced both sialomucin and sulfomucin, although the adjacent mucosa showed hyperplastic changes with increased sialomucin secretion. Argyrophil cells were recognized in seven duodenal (35%), 13 jejunal (72%), and nine ileal (69%) carcinomas. Eighteen of the 29 tumors showing positive argyrophil reactions also had argentaffin cells. The common features of mucins and endocrine cells in these tumors suggest the multipotency of small intestinal carcinoma. The prognosis correlated with the histologic type, carcinoembryonic antigen (CEA) grading, invading pattern of tumor margins, and vascular permeation and regional lymph node metastasis.     

Small cell carcinoma of the urinary bladder. A clinicopathologic study of five cases

AIMS AND BACKGROUND: Small cell carcinoma of the bladder (SCCB) is a rare entity characterized clinically by an aggressive behavior with a high incidence of systemic metastases. We report the clinicopathologic findings of five cases. METHODS: We reviewed five consecutive patients with SCCB treated at our institute. In each case the following clinical data were recorded: age, sex, presenting symptoms, endoscopically determined location of the tumor, clinical staging, node involvement (if any), site of metastases (if any), treatment, follow-up and outcome. RESULTS: There were four male and one female patients, age range 42 to 68 years, mean 57.6 years. The clinical presentation was not different from conventional transitional cell carcinoma, with hematuria being the most frequent complaint (four cases). Microscopic examination revealed oat cells in three cases and an intermediate variant in one. At the time of diagnosis the tumors were staged as T3bN2M0, T2N2M0, T4N0M0, T3aN0M0, and T2N0M0. Primary therapy consisted of radical cystectomy alone (one case), transurethral resection (TUR) alone (one case), TUR with chemotherapy (two cases), or TUR with chemotherapy and radiotherapy (one case). Four patients died of progressive disease, with survival from the time of diagnosis ranging from 7 to 16 months (mean, 12.2 months). One patient died of myocardial infarction (unrelated to the primary disease) one month after diagnosis. CONCLUSION: Our study indicates that primary small cell carcinoma of the urinary bladder is as aggressive as its pulmonary counterpart and the overall prognosis of this tumor is very poor.     

Small cell carcinoma of the prostate. Part I. A clinicopathologic study of 20 cases

Clinical information and histological slides of 20 cases of small cell carcinoma of the prostate seen at The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston over a 23-year period were reviewed. Patient's ages ranged from 30 to 89 years (median, 67 years). In nine cases, pure adenocarcinoma of the prostate preceded recognition of the small cell component by 7 months to 8 years (median, 18 months); five of these were initially at Stage A. There was a small cell component at presentation in 11 cases (10, Stage D). Small cell carcinoma was merging with the adenocarcinoma in 11 cases and represented 30% to 90% of total tumor volume. Eleven of 20 patients died of their disease. Those presenting initially with a pure adenocarcinoma survived between 7 months and 9 years (median, 24 months). After the recognition of the small cell carcinoma component, regardless of a prior history of adenocarcinoma, death followed within 1.5 years (median, 5 months). This study suggests a biologic difference in behavior in prostatic carcinoma containing a small cell carcinoma component. The small cell component may manifest early or late in the disease.     

Small cell carcinoma of the major salivary glands. An immunohistochemical study.

Small cell carcinomas of the major salivary glands are rare tumors, accounting for less than 1% of malignant neoplasms at these sites. To date, approximately 41 such tumors have been described. They recently have been classified into two groups, based on the ultrastructural presence or absence of intracytoplasmic neuroendocrine (NE) granules, "small cell neuroendocrine carcinoma" and "small cell ductal carcinoma". This study concerns 11 primary small cell carcinomas that had been previously studied ultrastructurally; it was undertaken to determine whether these lesions possessed a neuroendocrine phenotype, using a battery of immunohistochemical stains. Antibodies to epithelial membrane antigen (EMA), cytokeratin (CK), Leu 7, vimentin (VIM), synaptophysin (SYN), chromogranin (CHR), and neuron-specific enolase (NSE) were employed, with the avidin-biotin-peroxidase complex technique and paraffin sections. All tumors in this study expressed at least one neuroendocrine marker. In eight tumors EMA was found; CK was present in all 11 cases, seven of which demonstrated focal paranuclear staining. Leu 7 was seen in eight tumors, VIM was expressed in two cases, SYN was found in three tumors, and CHR was detected in three neoplasms. Anti-neuron-specific enolase labeled eight tumors. From the preceding data one may conclude that all small cell salivary gland carcinomas have neuroendocrine characteristics, even though dense core granules cannot be demonstrated in some of them ultrastructurally.     

Medullomyoblastoma. A histologic, immunohistochemical, and ultrastructural study

The light and electron microscopic features of a medullomyoblastoma arising in the cerebellar vermis of a 3-year-old boy are described. Differentiation along both glial and neuronal lines was present in the medulloblastoma component of the tumor. Astrocytic differentiation was confirmed by the observation of compact bundles of 8 to 10 nm glial filaments in cellular processes on ultrastructural examination, and by positive immunostaining for glial fibrillary acidic protein (GFAP). Neuroblastic differentiation was suggested by the demonstration of axon-like processes on silver impregnation, and ultrastructurally by the observation of microtubules, dense-core and clear vesicles, and rare synapse-like structures within cytoplasmic processes. The presence of both primitive and well-differentiated striated muscle fibers in the tumor was confirmed by the demonstration of thick and thin myofilaments and Z bands on electron microscopy, and by positive immunostaining for myoglobin. These findings clearly establish the presence of both neuroectodermal and rhabdomyoblastic components in this neoplasm, and thus set it apart from the pure rhabdomyosarcomas, which may also occur in the cerebellar vermis in children. This case also illustrates the usefulness of electron microscopy and immunohistochemistry in the diagnosis and histogenetic evaluation of primitive or poorly differentiated small cell tumors of the central nervous system.     

Small cell osteosarcoma. A clinicopathologic study of 27 cases

We report a study of 27 patients with small cell osteosarcoma (SCO), 17 from the M. D. Anderson Cancer Center (MDAH) and ten from the Pediatric Oncology Group (POG). There were 12 male patients and 15 female patients; 19 were white, five were black, and three were Hispanic. They ranged from 6 to 28 years of age with a median of 14 years. Histologically there were three patterns: Ewing's-like, lymphoma-like, and spindle cell. All cases showed osteoid formation and a few had chondroid areas. There was cytoplasmic glycogen in ten cases. Initial treatment for MDAH patients included intraarterial infusion of cisplatin in ten, amputation in four, partial mandibulectomies in two, and biopsy with local radiotherapy and systemic chemotherapy in one. All POG patients had resection or amputation followed by adjuvant chemotherapy. Twelve patients are alive, of whom nine have had significant follow-ups for 25 to 90 months. Fourteen patients are dead of lung, spine, and brain metastases from 1 to 23 months after initial diagnosis. One patient is alive with lung relapse at 4 months. In summary, SCO is a high-grade variant of osteosarcoma, with an incidence of up to 4% of all osteosarcomas, that affects patients of the same age group and has the same anatomic location as conventional osteosarcoma. Currently, SCO appears to have a prognosis that is the same as or slightly worse than that of conventional osteosarcoma. Furthermore, although intraarterial infusion is effective for the primary tumors in the bone, distant metastases are difficult to control.     

Clear cell squamous cell carcinoma. A histologic, immunohistologic, and ultrastructural study

Squamous cell carcinomas (SCCs) usually show a standard histopathologic picture only varying with regard to their degree of differentiation. The authors describe a case of clear cell SCC that was studied by light and electron microscopy. The clear cells showed an empty cytoplasm that was periodic acid-Schiff and alcian blue negative. By electron microscopy these cytoplasms consisted of empty spaces and were not surrounded by membranes, which would be consistent with lipid vacuoles. The differential diagnosis of this uncommon variant of SCC requires consideration of other clear cell tumors.     

An immunohistochemical and ultrastructural study of the sinusoids of hepatocellular carcinoma.

The sinusoids of 30 human hepatocellular carcinomas of various types were examined by electron microscopy and histochemically for binding to the Ulex europaeus lectin (UEA1). A population of sinusoidal macrophages was identified with an antibody to lysozyme (muramidase). The UEA1 binding was negative in normal sinusoids but positive in the tumor vessels. Macrophages resembling Kupffer cells were found within the tumor vessels but in smaller numbers than in either normal or cirrhotic liver tissue. Fibrolamellar and sclerosing carcinomas contained the smallest numbers. Ultrastructurally, endothelial cells of tumor vessels were thicker than normal, with fewer fenestrations. They contained bundles of microfilaments and showed basement membrane formation. Subendothelial myoid cells were found. These findings indicate that the sinusoidal vessels of hepatocellular carcinomas show features of true capillaries and precapillary blood vessels. The degree of this difference from normal hepatic sinusoids may reflect the relative immaturity of the cancer cells.     

Intramuscular myxoma. A clinicopathologic, immunohistochemical, and electron microscopic study

This clinicopathologic study concerns 17 cases of intramuscular myxoma, including an immunohistochemical survey of 10 cases and an electron microscopic examination of 4. There was a female preponderance in a ratio of 14:3. The most common sites of tumors were the large muscles of the thigh (seven cases), followed by those of the buttock (three) and the lower leg (three). The size of the tumor ranged from 1.5 to 20 cm (median, 6 cm) in the greatest diameter. Neither recurrence nor metastasis was seen in any of 15 patients for whom information was available. In addition to the conventional microscopic features, such as hypocellularity, absence of a plexiform capillary network, and no detection of typical glycogen-rich lipoblasts, the following findings were regarded as helpful to differentiate an intramuscular myxoma from myxoid liposarcoma: hypovascularity of the tumor, demonstrated by angiography; a homogeneous computed tomography appearance with low density, absence of S-100 protein immunoreactive cells such as lipoblasts; and electron microscopically, the constituent cells were predominantly fibroblast-like cells with a prominent secretory activity, together with a small number of primitive mesenchymal cells and histiocyte-like cells, but with no lipoblasts. After simple excision, the 15 patients who could be followed are well with no recurrence during various periods of follow-up.     

Small cell carcinoma of the urinary bladder. A clinicopathologic analysis of 22 cases.

Small cell carcinoma of the urinary bladder is an uncommon tumor. The authors report the clinicopathologic findings in a series of 22 cases. Fifteen men and 7 women were studied; their ages ranged from 51 to 87 years (mean, 62.4 years). The most frequent presentation was hematuria (94.4%). At diagnosis, three patients had Stage B disease, six had Stage C, and ten had Stage D (unknown stage in three). Histologically, 6 were oat cell type tumors, 11 were of intermediate cell type, and 5 were of combined cell type. Immunohistochemical studies demonstrated positivity for neuron-specific enolase in ten of ten cases, cytokeratin in seven of ten cases, chromogranin in eight of nine cases, serotonin in seven of nine cases, and S-100 protein in four of ten cases. Neuroendocrine differentiation was seen in five of seven cases examined by electron microscopy. Treatment and follow-up data were available for 19 patients: 10 (52.6%) were dead of disease, 5 (26.3%) were alive and well, 3 (15.8%) were alive with disease, and 1 (5.3%) died of an unrelated cause. The 2-year survival rate was 50% for patients with Stage B, 25% for patients with Stage C, and 33% for patients with Stage D disease. Although overall survival was poor, some cases responded well to therapy. Based on the authors' experience, radical cystectomy with adjuvant chemotherapy appears to be the treatment of choice.     

Small cell undifferentiated carcinoma of salivary gland origin: an ultrastructural study.

A case of small cell carcinoma of salivary gland was studied by light and electron microscopy. Light microscopy showed sheets of small uniform cells with scanty cytoplasm and pyknotic nuclei. Electron microscopy showed two distinct cell types; an electron-lucent epithelial-appearing cell, and a denser cell with processes containing bundles of filaments and other features suggesting myoepithelial differentiation. Neurosecretory granules were absent. These findings support a salivary duct origin, and are evidence against a neurendocrine derivation for this tumor.     

Prolactin cell carcinoma of the pituitary. Clinicopathologic, immunohistochemical, and ultrastructural study of a case with cranial and extracranial metastases

A patient with a primary adenohypophyseal neoplasm who had a long course marked by multiple surgical resections, radiation therapy, and high-dose dopamine agonist therapy developed local invasion as well as cranial and extracranial osseous metastatic lesions. The serum prolactin levels were greatly elevated, and immunohistochemical studies demonstrated prolactin in the cytoplasm of primary and metastatic tumor cells. Ultrastructural features of lactotrophic differentiation, including misplaced granule exocytosis, were observed. This is the third reported case of prolactin cell carcinoma that metastasized despite high-dose dopamine agonist therapy. Analysis of the patient's serum prolactin showed no abnormality in the chromatographic profile of biologic activity.     

Renal sarcomas of childhood. A clinicopathologic and ultrastructural study

Of 230 consecutive primary renal tumors of childhood collected over a 26-year period, 19 (8.2%) were sarcomas. The histologic criteria devised by the National Wilms' Tumor Study for diagnosis of "sarcomatous variants" of Wilms' tumor could be applied to all but three cases, namely, a rhabdomyosarcoma, a spindle-celled tumor, possibly leiomyosarcoma, and an unclassified primitive tumor. The most prevalent subtype was the bone-metastasizing, "clear cell" sarcoma. Correlative histologic and ultrastructural study supports the concept of subsets of tumors within the category now called "sarcomatous Wilms' tumor." Although this designation has the practical value of alerting the oncologist to the need for aggressive therapy, an origin in nephrogenic mesoderm cannot be cogently proposed for all of these tumors. This study also shows that the histologic features of the different subtypes of renal sarcomas may overlap. Hence, electron microscopy is indispensable for appropriate subclassification of these tumors.     

A clinicopathologic and immunohistochemical study of gastrointestinal stromal tumors.

The clinicopathologic and immunohistochemical features in 120 cases of gastrointestinal stromal tumor (GIST) were reviewed. Excluding 24 cases of gastric schwannoma, 96 cases of GIST consisting of 62 benign tumors and 34 sarcoma (low grade, 17; high grade, 17), with 9 cases arising in the esophagus, 57 in the stomach, 28 in the small intestine, and 2 in the colon, were studied. All esophagus and colon tumors were benign and resembled a conventional leiomyoma histologically. However, the gastric and small intestine benign tumors mostly showed histologic features of cellular or epithelioid leiomyoma. Immunohistochemically, desmin caused a positive reaction in all esophagus and colon tumors, but only 26% of gastric and small intestine tumors. However, muscle-specific actin (HHF35) caused a positive reaction in most GIST (92%). The 10-year survival rates of the patients with gastric sarcoma and those with intestinal sarcoma were 74% and 17%, respectively. These results showed that histologic and immunohistochemical features were distinctly different, depending on the location in the gastrointestinal tract; that most GIST, excluding schwannoma, had smooth muscle differentiation; and that sarcomas had a more favorable prognosis when they occurred in the stomach rather than the intestine.     

Small cell bronchogenic carcinoma: a distinct clinicopathologic entity.

Since small cell carcinoma is a treatable disease, with surgery being beneficial in a few cases and with chemotherapy, radiotherapy, and immunotherapy contributing to prolonged survival in patients with inoperable disease, it is essential that the clinical and pathologic features of small cell carcinoma be quickly recognized in a newly presenting patient so that appropriate therapy may be offered.