Metabolic characterization of human soft tissue sarcomas in vivo and in vitro using proton-decoupled phosphorus magnetic resonance spectroscopy.

We applied 1H-decoupling and nuclear Overhauser enhancement to obtain well-resolved 31P magnetic resonance spectra accurately localized to 20 soft tissue sarcomas in vivo, using three-dimensional chemical shift imaging. Fifteen spectra had large phosphomonoester signals (21% of total phosphorus) that contained high amounts of phosphoethanolamine (compared to those of phosphocholine) but no signals from glycerophosphoethanolamine, and glycerophosphocholine was detected in only four cases. Prominent nucleoside triphosphates (52% of phosphorus) and low inorganic phosphate (10% of phosphorus) indicated that a large fraction of these 15 sarcomas contained viable cells, and this impression was confirmed histologically in 13 of the sarcomas. High-resolution in vitro 31P spectra of extracts of surgical specimens of four of the sarcomas studied in vivo and six additional sarcomas confirmed the in vivo assignments of metabolites and revealed considerable inter- and intratumoral variations of metabolite concentrations associated with histological variations in the relative amounts of cells and of matrix materials or spontaneous necrosis. Seven sarcomas, all high grade with pleomorphic or round cells rather than spindle cells, contained an unidentified phosphodiester signal in vivo; its absence in the extract spectra indicates that it may be from an abnormally mobile membrane component. We have documented a means to obtain new information about in vivo metabolism in human sarcomas and to provide a basis on which to examine the uses of 31P magnetic resonance spectroscopy in the clinical management of sarcomas.

Intravascular fasciitis: a report of 17 cases.

Seventeen cases of intravascular fasciitis were reported from the files of the AFIP (14 cases) and the Pathology Department, Thomas Jefferson University Hospital (three cases). It is characterized by the histologic features of nodular fasciitis but with intraluminal, intramural, and extramural involvement of small to medium-sized veins and arteries and multinodular or serpentine growth along the course of affected blood vessels. A painless, slowly growing mass was most common. Fourteen patients (82%) were under age 30 (range 1/2-57 years); the sex ratio was about equal. Seven cases were located in the upper extremity (three hand, two wrist or forearm, two shoulder), three on the ankle or lower leg, five on the head and neck, and two in the chest wall and breast. Most cases were small with a mean diameter of 1.5 cm, but two were elongated masses measuring 4-5 cm in length. At surgery, four cases showed intimate association with large veins or arteries. This type of fasciitis is rare and has been found in only one of 14 consecutive cases of modular fasciitis operated at this university hospital between 1969 and 1978. Six of 15 consultation cases were originally confused with sarcoma. Intravascular fasciitis is benign. Seven patients were free of disease from 2.5 to 20 years (mean 9.5 years); two patients had local recurrences.

Synovial sarcoma: a clinical, pathological, and ultrastructural study of 26 cases supporting the recognition of a monophasic variant.

Twenty-six cases of synovial sarcoma (14 biphasic, 12 monophasic) were subjected to a clinicopathological study that included electron-microscopic examination of six tumors. Monophasic tumors were composed predominantly of uniform, densely packed, small spindle cells with scant cytoplasm identical to those of the "stromal" elements of typical biphasic tumors. The arrangement of these cells into narrow interlacing fascicles, forming tight whorls and showing little collagenization, was distinctive for this tumor. Major clinical differences between the two types of synovial sarcoma were the tendency for monophasic tumors to arise in distal extremity locations (seven of 10), and the poorer prognosis of monophasic tumors, 30% surviving 5 years compared to 58% for biphasic tumors. At the ultrastructural level, monophasic tumors and the spindle-cell components of biphasic tumors were identical. Both were composed of spindle or polygonal cells attached by numerous desmosomes. Prominent Golgi, abundant RER, perinuclear microfilaments, and glycogen aggregates were characteristic. Intercellular spaces containing elongated cytoplasmic filopodia were observed consistently, as were fragments of basement membrane-like material. The EM findings concur with those described previously in normal and pathologic synovium, and support a synovioblastic origin for the monophasic variant of synovial sarcoma.

Adenomyoepithelioma of the breast. A spectrum of biologic behavior.

Adenomyoepitheliomas of the breast have been considered to have limited metastatic potential; axillary node metastasis has been reported, but there has been no report of distant metastasis. We report six cases, including two malignant adenomyoepitheliomas, one of which metastasized to the lung and brain. Patient age ranged from 26 to 63 years (mean 46). Primary tumors were solitary and measured 0.9-3.5 cm (mean 1.7). Five of six tumors presented as palpable masses. Two patients treated by local resection have no evidence of disease at 5 and 18 months' follow-up. Two patients treated by local resection had recurrences, one at 48 the other at 60 months. The fifth patient had a spindle-cell type adenomyoepithelioma diagnosed as malignant because of high mitotic rate and cytologic atypicality of the myoepithelial component. This patient was treated by mastectomy and has no evidence of disease at 18 months. The sixth patient, initially treated by local excision, had six local recurrences over 52 months treated by reexcisions, mastectomies, and radiation. A lung metastasis was resected at 54 months and brain metastases were identified at 60 months with death occurring at 64 months. Both malignant adenomyoepitheliomas had high mitotic rates [11-14/10 high-power fields (HPF)] diffusely throughout the tumors and foci of cytologically malignant cells. The malignant adenomyoepithelioma that metastasized had an infiltrative growth pattern that increased with successive local recurrences. The four other tumors had only isolated areas of mitotic activity (maximum 1-9/10 HPF) and minimal cytologic atypia. Immunohistochemistry performed on five of six cases confirmed dual epithelial/myoepithelial cell populations in all tumors examined, including the metastasis. Electron microscopic examination of the malignant adenomyoepithelioma that metastasized also confirmed dual epithelial/myoepithelial cell populations in a local recurrence and the lung metastasis. We conclude that there is a spectrum of behavior for breast adenomyoepitheliomas with potential for local recurrence and, rarely, distant metastasis.

Pulmonary angiitis and granulomatosis. The relationship between histological features, organ involvement, and response to treatment.

The histologic findings, natural history, and response to treatment were investigated in 62 patients with pulmonary angiitis andgranulomatosis seen over a 23 year period. Three histologic types were recognized: lymphocyte depleted angiitis and granulomatosis, 24 cases (39 per cent); benign lymphocytic angiitis and granulomatosis, 14 cases (22 per cent); and malignant lymphoproiferative angiitis and granulomatosis, 24 cases (39 per cent). Lymphocyte depleted angiitis and granulomatosis corresponds to Wegener's granulomatosis of either the "limited" or "classic" variant. The lesions frequently show extensive liquefactive necrosis. Eosinophils may be abundant, but lymphocytes and plasma cells are relatively scarce. Histiocytic proliferation with the occasional presence of sarcoid-like granulomas was observed only in cases with no evidence of glomerular involvement. Cyclophosphamide is highly effective regardless of whether extrapulmonary manifestations are present. Benign lymphocytic angiitis and granulomatosis is characterized by dense benign infiltrates of lymphocytes, plasma cells, and histiocytes. Necrosis may be absent or minimal; the angiitis is usually mild to moderate. Only one of 14 patients (7 per cent) had extrapulmonary involvement (skin). Chlorambucil is highly effective, sometimes resulting in dramatic cures. Malignant lymphoproliferative angiitis and granulomatosis corresponds to lymphomatoid granulomatosis. Its lesions show extensive coagulative necrosis, a highly atypical lymphoreticular infiltrate with frequent mitoses, and angioinvasion. Extrapulmonary involvement is frequent (83 per cent), particularly in the skin (46 per cent) and central nervous system (33 per cent). The mortality is high: 65 per cent of the patients were dead within the first year of disease. Although cytotoxic drugs were of no value, corticosteroids were associated with prolonged remissions in three young patients.

Interobserver variation in the identification of breast carcinoma in intramammary lymphatics.

Nine surgical pathologists participated in a microscopic review of 35 cases of pT1-2 N0 M0 breast carcinoma. The pathologists outlined strict criteria for the identification of intramammary lymphatics and blood vessels and for the identification of cancerous emboli in these vascular channels. Each mastectomy case was studied by three different pathologists. All three concurred on the presence or absence of intralymphatic cancer in 12 of the 35 cases. Observers agreed on the absence of blood vessel invasion in 30 of the 35 cases. There was no consistent bias on the part of a single reviewer, either alone or with another pathologist, in identifying the emboli. We conclude that the identification of intralymphatic cancerous emboli in mastectomy specimens is not a reliably reproducible prognostic finding on which recommendation of systemic chemotherapy in stage I breast carcinoma patients can be based.

Immunohistologic study of blood group substances in polyps of the distal colon. Expression of a fetal antigen.

Forty-four polyps and 14 adenocarcinomas of the left colon from 28 patients were studied for the presence of blood group substances of the A, B system, using the method of specific erythrocytic adherence. Forty-one percent of all polyps and 57% of all cancers were found to have reactivity for blood group substances. Fifty-four percent of villous adenomas (seven of 13), 39% of tubular adenomas (five of 13), 14% of mixed tubulovillous adenomas (one of seven), and no hyperplastic polyps (zero of four) showed reactivity for blood group substances. Lesional blood group substance reactivity, when present, was the same as that for the patient's own blood group type, with the exception of two patients of B blood group type, whose lesions had A-blood group substance reactivity. Cytologic atypia showed no correlation with the presence of blood group substances. Polyps with blood group substance reactivity were seen more frequently in patients with cancer. Twelve patients had both a cancer and a polyp studied, with both polyp and cancer showing similar blood group substance reactivity for nine of these patients. A, B, H-blood group substances in the left colon are normally absent in the adult and present only in the fetus. The reappearance of these fetal antigens in both polyps and cancers adds immunologic evidence to the theory that colonic adenocarcinoma evolves through a polyp-cancer sequence.

Mass screening for breast disease. Results, problems, and expectations.

The first 18 months' experience of the Breast Diagnostic Center of Jefferson Medical College have been reviewed. Almost 14,000 patients were screened for breast disease, using a combination of clinical examination. Xeroradiography, and thermography. In this group of 14,000 women, 106 cases of cancer were discovered, in incidence of almost 8 per 1000 women screened. Of these 106 cases of cancer, 45.3% were clinically occult or not recognized by clinical examination, and within this group at the time of mastectomy only a small percent had any evidence of axillary lymph node metastases. The combination of several technics of examination is proving to be more reliable for the early detection of breast cancer than any of the technics alone, and programs such as these may make a significant difference in the death rate from breast cancer.

Nonpalpable in situ ductal carcinoma of the breast. Predictors of multicentricity and microinvasion and implications for treatment.

Fifty breasts with nonpalpable ductal carcinoma in situ (DCIS) were examined for the presence of microinvasion, multicentricity, and number of involved ducts to see if the biopsy specimen could have predicted the findings in the remainder of the breast. When DCIS was an incidental finding, fewer ducts were involved and no evidence of either microinvasion or multicentricity was found. Solid and cribriform DCIS were rarely multicentric or microinvasive; micropapillary DCIS was often multicentric, rarely microinvasive; comedocarcinoma was more likely to be both microinvasive and multicentric. Ductal carcinoma in situ as an incidental finding may be treated by excision alone; papillary and micropapillary DCIS are best treated by therapy aimed at the entire breast, although axillary dissection may not be required. Therapy for comedocarcinomas should include the entire breast and the axillary nodes.

Localization and significance of clinically occult breast lesions: experience with 469 needle-guided biopsies.

Experience with 469 clinically occult breast lesions is presented. The overall incidence of malignancy observed was 32%, just about one in three. The technique of needle-guided biopsy is described, insuring precise localization and excision of minute radiographic findings, yet without leaving a conspicuous scar to remind the patient of her experience. Although it is too early to speculate about a possible increase in survival of these "earliest" breast cancers, the observed decreased incidence of axillary node metastasis implies a lowered death rate from breast cancer in these patients. It is not unreasonable to extrapolate the extent of patient salvage from axillary node status. Many of these cancers were uncovered in the course of screening asymptomatic patients, and this further implies the efficacy of such screening programs in the early detection of breast cancer. The surprisingly high incidence of multicentricity in these tiny cancers must not be ignored when recommending adequate and appropriate therapy for these impalpable malignancies.

Carcinoma of the nasopharynx. A 25-year study.

Between 1958-1983, 79 patients with a diagnosis of epithelial tumor of the nasopharynx received definitive irradiation at Thomas Jefferson University Hospital. Seventy-two percent of the patients had a Stage IV lesion. The dose to the nasopharynx was over 6,000 cGy in all but four patients. The 5- and 10-year actuarial survivals were 33% and 19% respectively. The 5-year disease-free survival was 33%. Histology had no bearing on survival. Survival was influenced by the stage of primary tumor and nodes. Advanced nodal disease correlated with distant metastasis, being present in 13/15 cases with hematogenous spread.

Novel immunohistochemical localization of 28,000 molecular-weight (Mr) calcium binding protein (calbindin-D28k) in enterochromaffin cells of the human appendix and neuroendocrine tumors (carcinoids and small-cell carcinomas) of the midgut and foregut.

Calbindin-D28k is a highly conserved 28,000 (dalton) molecular-weight (Mr) calcium binding protein with broad tissue distribution, yet cell-type-specific expression predominantly in subpopulations of central and peripheral nervous system neurons, distal tubular cells of the kidney, and enteric neuroendocrine cells. A polyclonal antiserum against rat renal calbindin-D28k and a monoclonal antibody to calbindin-D28k purified from chicken intestine (clone CL-300) were used for immunohistochemical evaluation of formalin-fixed, paraffin-embedded tissues from multiple areas of the human small and large intestines and 93 primary neoplasms of the gastrointestinal tract (foregut, midgut, and hindgut derivatives) and the lung (foregut derivative). Calbindin-D28k immunostaining was obtained in a minority of enterochromaffin (neuroendocrine) cells, predominantly of the appendix and small intestine, as well as in autonomic neurons of the neural plexuses. Focal cytoplasmic Golgi-type staining was obtained with monoclonal antibody CL-300 in the appendiceal surface epithelium and dendritic macrophages confined to the appendiceal lymphoid follicles. Epithelial progenitor cells in enteric crypts and absorptive, goblet, and Paneth cells were calbindin-D28k negative, while no immunoreactivity was demonstrated in the mucosae of the colon and rectum. Calbindin-D28k staining was consistently detected in subpopulations of neuroendocrine phenotypes in midgut (appendiceal/ileal) and foregut (bronchial) carcinoids and small-cell carcinomas, but was absent in adenocarcinomas, squamous cell carcinomas, leiomyomas/leiomyosarcomas, schwannomas, and lymphomas. Our observations suggest that calbindin-D28k is a novel adjuvant neuroendocrine marker that is potentially useful in diagnostic tumor immunohistochemistry.

Low-grade mucoepidermoid carcinoma of the breast.

Two cases of primary breast carcinoma morphologically identical to low-grade mucoepidermoid carcinoma of salivary gland origin occurred. To our knowledge, this article represents the first description of this tumor type in the breast. Both lesions were well circumscribed, wholly or partially cystic, and composed of intimately associated, well-differentiated, squamous and mucinous glandular epithelium. It is suggested that these may represent an indolent tumor type in the breast analogous to their behavior in the salivary gland.

Differential distribution of the neuron-associated class III beta-tubulin in neuroendocrine lung tumors.

OBJECTIVE: To study the immunoreactivity profile of the neuron-associated class III beta-tubulin isotype (beta III) in epithelial lung tumors. DESIGN: One hundred four formalin-fixed, paraffin-embedded primary and metastatic lung cancer specimens were immunostained with an anti-beta III mouse monoclonal antibody (TuJ1) and an anti-beta III affinity-purified rabbit antiserum. Paraffin sections from fetal, infantile, and adult nonneoplastic lung tissues were also examined. RESULTS: In the fetal airway epithelium, beta III staining is detected transiently in rare Kulchitsky-like cells from lung tissues corresponding to the pseudoglandular and canalicular but not the saccular or alveolar stages of development. beta III is absent in healthy, hyperplastic, metaplastic, and dysplastic airway epithelium of the adult lung. In contrast, beta III is highly expressed in small cell lung cancer, large cell neuroendocrine carcinoma, and in some non-small cell lung cancers, particularly adenocarcinomas. There is no correlation between expression of beta III and generic neuroendocrine markers, such as chromogranin A and/or synaptophysin, in pulmonary adenocarcinomas. Also, focal beta III staining is present in primary and metastatic adenocarcinomas (to the lung) originating in the colon, prostate, and ovary. beta III is expressed to a much lesser extent in atypical carcinoids and is rarely detectable in typical carcinoids and squamous cell carcinomas of the lung. The distribution of beta III in small cell lung cancer and adenocarcinoma metastases to regional lymph nodes and brain approaches 100% of tumor cells, which is substantially greater than in the primary tumors. CONCLUSIONS: In the context of neuroendocrine lung tumors, beta III immunoreactivity is a molecular signature of high-grade malignant neoplasms (small cell lung cancer and large cell neuroendocrine carcinoma) although its importance in atypical carcinoids must be evaluated further. In addition, beta III may be a useful diagnostic marker in distinguishing between small cell lung cancers and certain non-small cell lung cancers (poorly differentiated squamous cell carcinomas), especially in small biopsy specimens. To our knowledge, beta III is the only tumor biomarker that exhibits a substantially more widespread distribution in poorly differentiated than in better differentiated pulmonary neuroendocrine tumors. However, the significance of beta III phenotypes in non-small cell lung cancer, particularly adenocarcinoma, with respect to neuroendocrine differentiation and prognostic value, requires further evaluation.