BCL2 oncogene translocation is mediated by a chi-like consensus.

Examination of 64 translocations involving the major breakpoint region (mbr) of the BCL2 oncogene and the immunoglobulin heavy chain locus identified three short (14, 16, and 18 bp) segments within the mbr at which translocations occurred with very high frequency. Each of these clusters was associated with a 15-bp region of sequence homology, the principal one containing an octamer related to chi, the procaryotic activator of recombination. The presence of short deletions and N nucleotide additions at the breakpoints, as well as involvement of JH and DH coding regions, suggested that these sequences served as signals capable of interacting with the VDJ recombinase complex, even though no homology with the traditional heptamer/spacer/nonamer (IgRSS) existed. Furthermore, the BCL2 signal sequences were employed in a bidirectional fashion and could mediate recombination of one mbr region with another. Segments homologous to the BCL2 signal sequences flanked individual members of the XP family of diversity gene segments, which were themselves highly overrepresented in the reciprocal products (18q-) of BCL2 translocation. We propose that the chi-like signal sequences of BCL2 represent a distinct class of recognition sites for the recombinase complex, responsible for initiating interactions between regions of DNA separated by great distances, and that BCL2 translocation begins by a recombination event between mbr and DXP chi signals. Since recombinant joints containing chi, not IgRSS, occur in brain cells expressing RAG-1 (Matsuoka, M., F. Nagawa, K. Okazaki, L. Kingsbury, K. Yoshida, U. Muller, D. T. Larue, J. A. Winer, and H. Sakano. 1991. Science [Wash. DC]. 254:81; reference 1), we further suggest that the product of this gene could mediate both BCL2 translocation and the first step of normal DJ assembly through the creation of chi joints, rather than signal or coding joints.

Neural properties of cultured human endocrine tumor cells of proposed neural crest origin.

Cells from human endocrine tumors of proposed neural crest origin--five pheochromocytomas, two medullary carcinomas of the thyroid, and two bronchial carcinoids--were grown in monolayer culture. Cells from all nine tumors, including epithelial forms of medullary carcinoma of the thyroid and bronchial carcinoid cells, and epithelial and neuron-like pheochromocytoma cells demonstrated all-or-nothing, short-duration action potentials.

Surface marker identification of small cleaved follicular center cell lymphomas with a highly favorable prognosis.

Between 1976 and 1980, 143 cases of non-Hodgkin's lymphoma have been prospectively analyzed for correlations between surface marker phenotype, histomorphology, and prognosis. This study analyzed 44 adults with tumors classified by Lukes-Collins criteria as small cleaved follicular center cell lymphomas. Two surface marker phenotypic subsets were membrane immunoglobulin, immunoglobulin D (IgD), or a receptor for the third component of the complement system (C'3) (Group I = IgD+ and/or C'3+, group II = IgD-C'3-). Eleven of the 44 patients have died with a projected median survival of 58 months. Four patients in Group I have died with a median survival of 58 months while seven patients in Group II have died with a median survival of 30 months. The difference in the survival curves for the two subgroups is statistically significant (p = 0.01). An analysis of variables such as stage, age, sex, and sites of involvement revealed no differences between the two groups. When classified histologically, the two groups were morphologically indistinguishable and had similar distributions of nodular (follicular) and diffuse variants. Of interest, five patients in Group I were judged to require no initial therapy whereas none in Group II remained untreated initially. The expression of the second heavy chain delta and/or a receptor for C'3 appears to define a subgroup of small cleaved follicular center cell lymphomas with an indolent course and an excellent prognosis.

Prognostic significance of peritumoral lymphatic and blood vessel invasion in node-negative carcinoma of the breast.

The prognostic significance of intramammary lymphatic and blood vessel invasion was evaluated in a retrospective series of 221 patients with node-negative carcinoma of the breast treated with modified radical mastectomy. To facilitate identification of lymphatic and blood vessel invasion, the tumors were studied with an immunohistochemical technique using antibodies to endothelial markers. Peritumoral lymphatic and blood vessel invasion (PLBI) (encompassing both lymphatic and blood vessel invasion) was an adverse prognostic indicator independent of menopausal status, tumor size, and other histologic variables. Recurrence of disease and death resulting from carcinoma were significantly higher for patients with PLBI-present (+) tumors compared with patients with PLBI-absent (-) tumors (P less than .0001). The risk of recurrence for patients with PLBI+ tumors was 4.7 times that for their PLBI- counterparts. The presence of intratumoral lymphatic and blood vessel invasion (ILBI) is less important because few examples were found without concomitant PLBI. When PLBI was separated into lymphatic invasion and blood vessel invasion individually, the prognostic significance was retained in both groups. The immunohistochemical approach reduced both false-negative and false-positive observations and identified about 40% of PLBI that would have been missed by routine histologic examination alone. The presence of PLBI appears to be a potentially useful discriminant in predicting the outcome of patients with node-negative carcinoma of the breast.

Inducible microsomal prostaglandin E synthase is overexpressed in colorectal adenomas and cancer.

Recently, an inducible microsomal human prostaglandin E synthase (mPGES) was identified. This enzyme converts the cyclooxygenase (COX) product prostaglandin (PG) H(2) to PGE(2), an eicosanoid that has been linked to carcinogenesis. Increased amounts of PGE(2) have been observed in many tumor types including colorectal adenomas and cancers. To further elucidate the mechanism responsible for increased levels of PGE(2) in colorectal tumors, we determined the amounts of mPGES and COX-2 in 18 paired samples (tumor and adjacent normal) of colorectal cancer. With immunoblot analysis, mPGES was overexpressed in 83% of colorectal cancers. COX-2 was also commonly up-regulated in these tumors; marked differences in the extent of up-regulation of mPGES and COX-2 were observed in individual tumors. Immunohistochemistry revealed increased mPGES immunoreactivity in neoplastic cells in both colorectal adenomas and cancers compared with adjacent normal colonic epithelium. Cell culture was used to investigate the regulation of mPGES and COX-2. Chenodeoxycholate markedly induced COX-2 but not mPGES in colorectal cancer cells. Tumor necrosis factor-alpha induced both mPGES and COX-2, but the time course and magnitude of induction differed. As reported previously for COX-2, overexpressing Ras caused a several-fold increase in mPGES promoter activity. Taken together, our results suggest that overexpression of mPGES in addition to COX-2 contributes to increased amounts of PGE(2) in colorectal adenomas and cancer. The mechanisms controlling the expression of these two enzymes are not identical.

Streptozocin-treated Verner-Morrison Syndrome: plasma vasoactive intestinal peptide and tumor responses.

A patient with watery diarrhea, hypokalemia, hypochlorhydria, and a non-beta islet cell carcinoma of the pancreas (Verner-Morrison syndrome) was found to have an elevated vasoactive intestinal peptide (VIP) concentration in the plasma as well as in the tumor. Treatment with streptozocin resulted in a dramatic subjective and objective tumor response in this patient. Plasma VIP concentration fell into the normal range after four courses of treatment, diarrhea ceased after the third course of therapy, and measurable tumor mass markedly decreased during that same period of time. The patient remains in clinical remission with no evidence of tumor regrowth 18 months after the beginning of treatment. In this patient, plasma VIP measurements were an excellent marker of tumor activity and correlated well with objective disease measurements and clinical response.

Distribution of calcitonin-containing cells in the normal neonatal human thyroid gland: a correlation of morphology with peptide content.

C-cells have been mapped in the thyroid glands of 6 human neonates by means of immunoperoxidase localization of calcitonin and tissue calcitonin content as measured by radioimmunoassay. The C-cells were concentrated in a zone in the upper two-thirds of the lateral lobes bilaterally, where they were identified individually and in small groups in both an intrafollicular and parafollicular distribution. In contrast to findings in the adult, C-cells were predominantly intrafollicular in the neonate. The relative numbers of C-cells counted per unit area of thyroid tissue correlated strongly with the calcitonin content of immediately adjacent tissue sections. In areas rich in C-cells, as many as 75 immunoperoxidase-stained cells per low-power field were counted, and the concentration of calcitonin was as high as 540 to 2100 mU/g fresh weight, values that were as great as 10 times those observed in the normal adult thyroid gland. The prominence of the C-cell population and increased tissue calcitonin content in the human neonatal thyroid gland may reflect an as yet undefined physiologic role for calcitonin in the newborn.

The role of immunohistochemistry in the diagnosis of poorly differentiated malignant neoplasms.

The development and refinement of immunohistochemical methodologies over the past decade has had a major impact in many different areas of diagnostic pathology. The generation of increasing numbers of well-characterized polyclonal antisera and monoclonal antibodies directed to a variety of antigenic determinants has made the phenotyping of neoplasms a reality. The results of such immunohistochemical analyses have provided an important starting point for the further workup and management of patients with undifferentiated or poorly differentiated malignant neoplasms of unknown origin. It should also be apparent, however, that the results of immunohistochemical analyses in such clinical settings are subject to a large number of variables and that these procedures must be controlled rigorously. The results of extensive performance testing, particularly with new reagents, must be available in order to establish their specificities and sensitivities under different conditions of tissue fixation and processing. Such studies not only will establish more precise and reproducible diagnostic criteria but also will be important for the definition of new clinical and pathological entities and for the characterization of novel prognostic parameters.

Amyloidosis in systemic lupus erythematosus.

Amyloidosis occurs in a significant proportion of patients with rheumatologic diseases. The fibrillar amyloid proteins in such patients are composed predominantly of amyloid A protein, which is characteristic of the amyloid deposits associated with chronic inflammatory diseases. Only four patients with amyloidosis associated with systemic lupus erythematosus (SLE) have been described previously; analyses of their fibrillar amyloid proteins were not reported. We present herein, a patient with SLE and amyloidosis. Histochemical staining of our patient's renal tissue with Congo red demonstrated that the amyloid deposits contained amyloid A protein, as defined by permanganate sensitivity. In addition, the patient's serum contained increased concentrations of serum amyloid A proteins. In review, each of the previously described patients with amyloidosis associated with SLE had renal amyloid deposits, with diagnosis in three during evaluation of proteinuria. Thus, although rare, amyloidosis should be considered in the differential diagnosis of proteinuria in patients with SLE.

Clinical usefulness of 67gallium scanning in the malignant lymphomas.

To determine the clinical usefulness of 67 gallium (Ga) scanning in the evaluation of patients with lymphomas, we reviewed 142 total body Ga scans performed on 44 patients with Hodgkin's disease and 53 patients with non-Hodgkin's lymphoma. Fifty-two per cent (123 of 236) of known disease sites were detected on scan. The false-positive rate was less than 5 per cent. The accuracy of detecting lymphoma varied in individual anatomic areas from 33 per cent in the axilla to 73 per cent in the thorax. In eight patients with bone involvement, all bone lesions were detected on scan. The size of the lesion appeared to influence accuracy, since tumors greater than 3 cm in diameter were more often positive.

Technical considerations in the immunohistochemical demonstration of intermediate filaments.

The intermediate filaments represent an important group of differentiation markers that have proven to be useful for the diagnosis and classification of human neoplasms. The immunohistochemical demonstration of these proteins is subject to numerous technical variables that include specificities and patterns of reactivities of polyclonal antisera and monoclonal antibodies, cross-reactivities of "specific" monoclonal antibodies with other intermediate filaments and other classes of antigens, masking of certain epitopes due to physiologic or pathologic changes in cells, effects of tissue fixation and subsequent tissue processing, and the sensitivity of the particular immunohistochemical detection system employed. Moreover, a wide variety of microenvironmental signals may affect the patterns of expression of intermediate filament proteins in different pathological conditions. For accurate interpretation of intermediate filament immunoreactivity, the pathologist must be familiar with the various sources of error relating to false positive or negative results. This requires the availability of optimally fixed tissues, a well-characterized set of antibodies to intermediate filament antigens and access to the results of extensive performance testing.

Hyperplastic lesions of the gastrointestinal endocrine cells.

A substantial body of knowledge is presently available on the morphologic, histochemical, ultrastructural, and functional characteristics of both the normal endocrine cell population of the gut and their related endocrine tumors. In contrast to this, we have only recently begun to recognize the existence of hyperplastic proliferations of various endocrine cell types, and information is therefore steadily accumulating on the morphologic criteria for their recognition, their clinicopathologic correlates and the clinical relevance of this morphologic finding. Hyperplastic proliferations of various endocrine cell types most often develop as a secondary phenomenon in a variety of clinical situations, and may modify the clinical course of the associated condition in a manner that underscores the functional interrelationships these endocrine cells have not only with each other but with other cell types as well. However, similar proliferations may also occur as a primary event (e.g. primary antral G-cell hyperplasia) and give rise to clinical and biochemical features attributable to the overproduction of their specific hormonal product (e.g. Zollinger-Ellison Syndrome, type I). This communication provides a broad overview of the current state of our knowledge of hyperplastic lesions of a variety of gut endocrine cell types in humans, their pathophysiologic significance, their relationship (if any) to the subsequent development of endocrine tumors (i.e. the hyperplasia-neoplasia sequence), and the utility of certain experimental models for the study of such proliferations in a variety of animal species.

Mucinous tumors of the ovary with argyrophil cells. An immunohistochemical analysis.

Forty-five cases of mucinous tumors of the ovary were studied for argyrophilia. Argyrophil cells were identified in seven of the 22 cystadenomas (32%), five of the 11 borderline tumors (45%), and two of the 12 carcinomas (17%). These 14 tumors and two additional mucinous tumors known to contain argyrophil cells were studied further by immunohistochemical methods for the localization of calcitonin, gastrin, somatostatin, adrenocorticotropin (ACTH), serotonin, neurotensin, and lysozyme. Serotonin immuno-reactivity was identified in 15 of the 16 cases. Among the peptide hormones, there was a high frequency of positivity for ACTH, gastrin, and somatostatin. Despite the demonstration of reactivity for these hormones, there was no clinical evidence of syndromes of hormone excess in the patients. Lysozyme was present in all but one of the benign and borderline tumors, but was not identified in the carcinomas. Lysozyme was also found in normal and neoplastic gastric and endocervical epithelium, indicating that its presence is not useful in differentiating gastrointestinal and müllerian-type epithelium. The results of this study confirm the previously recognized intestinal characteristics of the epithelium of many mucinous tumors, but also raise the question whether the simple, uniformly mucinous epithelium that is most common within these tumors and is generally regarded as endocervical in type may occasionally be gastric in nature.

Intramammary lymphatic invasion in breast carcinomas. Evaluation using ABH isoantigens as endothelial markers.

Recent studies indicate that intramammary lymphatic invasion represents an important prognostic parameter in breast carcinomas. However, the identification of intramammary lymphatic invasion in tissue sections is a subjective procedure, frequently hampered by factors such as fixation artefacts and interobserver variations. In this study, monoclonal antibodies to ABH isoantigens were applied on formalin-fixed, paraffin-embedded breast carcinoma tissue by using the avidin-biotin-peroxidase complex technique. In addition, the H antigen was localized using the Ulex europeus agglutinin I lectin binding technique. Isoantigen localization provided excellent delineation of lymphatics and blood vessels, in general unhampered by the retention of isoantigen expression in some breast carcinomas. In comparison, Factor VIII-related antigen localization required prior trypsin enhancement and was less sensitive and less consistent. The staining for isoantigens was more intense in vascular than in lymphatic endothelium. ABH isoantigen localization of lymphatic channels identified lymphatic tumor emboli peripheral to and within the carcinomas, and distinguished bona fide intramammary lymphatic invasion from tissue shrinkage artefacts. The applicability to routinely processed tissue permits retrospective studies and renders the identification of intramammary lymphatic invasion a more objective procedure. Further studies are needed to assess the role of this technique in evaluating the prognostic value of intramammary lymphatic invasion; the technique may be extended also to the study of other neoplasms.

Small cell carcinoma of the breast: a clinicopathologic and immunohistochemical study of nine patients.

Small cell carcinoma of the breast is an uncommon neoplasm that has been reported rarely in the literature. The aim of this study was to characterize better the pathologic and immunohistochemical features of this neoplasm. Nine examples of mammary small cell carcinoma were retrieved from the authors' consultation files and reviewed. The patients ranged in age from 43 to 70 years. Two patients had a previous history of cutaneous malignant melanoma and one had prior lobular carcinoma in situ and atypical duct hyperplasia in the same breast as the small cell carcinoma. Eight patients presented with a mass in the breast; one patient had an axillary tumor. Tumor size ranged from 1.3 to 5.0 cm (mean, 2.6 cm). Histologically, the nine tumors had characteristics of small cell carcinoma with high mitotic activity and necrosis. A dimorphic histologic appearance was observed in four tumors. In one instance, this consisted of small cell carcinoma merging with invasive lobular carcinoma. In three cases, small cell carcinoma was present together with invasive, poorly differentiated duct carcinoma; invasive carcinoma with "lobular and gland-forming elements"; and focal squamous differentiation, respectively. Lymphatic tumor emboli were identified in four instances. An in situ component was seen in seven tumors; five were of the small cell type in ducts and two were of the ductal type with high nuclear grade. Immunohistochemical analysis showed consistent staining for cytokeratin markers but variable staining with neuroendocrine markers. Sixty-six percent of the tumors (six of nine) were reactive for chromogranin, synaptophysin, or peptide hormones, including four positive for chromogranin and synaptophysin, one positive for synaptophysin and calcitonin, and one positive for calcitonin alone. One tumor that was reactive for chromogranin and synaptophysin also contained calcitonin immunoreactive cells, whereas gastrin-releasing peptide was present in two other tumors that were also positive for chromogranin. Leu 7 was positive in three cases that were reactive for either chromogranin or synaptophysin. Five tumors were estrogen and progesterone receptor-positive. All tumors were positive for bcl-2 and negative for HER2/neu. Patients were treated by mastectomy (n = 3) or lumpectomy (n = 6). Eight underwent an axillary dissection that revealed metastatic carcinoma in four patients. Seven patients received adjuvant chemotherapy and four patients received radiation. Two patients also received tamoxifen treatment. Metastases developed in two patients (22%) with a follow-up period of 11 and 32 months. All patients were alive at last follow up 3 to 35 months after treatment. When compared with published reports of mammary small cell carcinoma, our results show that the prognosis in these patients may not be as poor as previously suggested.

Leu-enkephalin-like immunoreactivity in proliferative lesions of the human adrenal medulla and extra-adrenal paraganglia.

Leu-enkephalin, a potent, endogenous, opiate-like regulatory peptide, is present in a subpopulation of normal adrenal medullary cells and in a spectrum of proliferative lesions of adrenal and extra-adrenal chromaffin cell origin. The presence, extent, and intensity of leu-enkephalin-like immunoreactivity is variable in normal and pathological states. While areas of diffuse medullary hyperplasia consistently exhibited leu-enkephalin-like immunoreactivity, approximately 50% of hyperplastic medullary nodules, pheochromocytomas, and paragangliomas were positively stained. Tumors of neuroblastic origin, on the other hand, did not contain leu-enkephalin-like immunoreactivity. Variations in leu-enkephalin-like immunoreactivity may be related to aberrations of feedback mechanisms, multicentric origins of lesions from chromaffin cells with or without the capacity for leu-enkephalin synthesis, or to a variety of other mechanisms, including defective innervation of hyperplastic and neoplastic chromaffin cells. The results of these studies indicate that leu-enkephalin-like immunoreactivity is a useful tissue marker for the demonstration of chromaffin cell hyperplasia and neoplasia and may also prove to be an important clinical marker for the assessment of chromaffin cell hyperfunction.

Duodenal carcinoids in patients with and without neurofibromatosis. A comparative study.

Nine duodenal carcinoids from patients with von Recklinghausen's neurofibromatosis (VRNF) were investigated for their morphologic, immunocytochemical, and ultrastructural characteristics, and were compared with seven similar tumors from patients without VRNF. Strong similarities were found between tumors in each group. Irrespective of their association with VRNF, duodenal carcinoids arose in adults and usually produced jaundice, upper intestinal bleeding, or obstruction. Tumors larger than 2.0 cm had already metastasized when first detected. All tumors showed a mixed architectural pattern; five tumors associated with VRNF were of the psammomatous type, as opposed to two of those without VRNF. While no tumors showed argentaffinity, stray argyrophil cells were present only in the three tumors not associated with VRNF. All of the tumors showed immunocytochemical evidence of somatostatinomas, and only one VRNF-associated tumor showed immunoreactivity for an additional regulatory substance, as opposed to three of those not associated with VRNF. Thus, while VRNF-associated duodenal carcinoids are not otherwise distinctive, they tend to be pure somatostatinomas (eight of nine cases), whereas similar tumors unassociated with VRNF are frequently multihormonal (three of seven cases). While many more duodenal carcinoids need to be investigated systematically for their immunocytochemical profile, detection of a pure somatostatinoma in the duodenum should alert one to the possibility of coexistent VRNF.

Adenoma malignum (minimal deviation adenocarcinoma) of the uterine cervix. A clinicopathological and immunohistochemical analysis of 26 cases.

We reviewed 26 examples of the rare variant of cervical adenocarcinoma that has been designated "adenoma malignum." The patients, three of whom had Peutz-Jeghers syndrome, ranged in age from 25 to 72 years (average, 42 years). The most common presenting symptom was menometrorrhagia, followed by vaginal discharge, postmenopausal bleeding, and abdominal swelling in decreasing order of frequency. In 12 of the patients, the diagnosis was established on the basis of the examination of a cervical biopsy specimen, endocervical curettage specimen, or both. In three of these cases, however, up to four biopsies were performed before the diagnosis was established. In the remaining 14 patients, the diagnosis was not made until the time of operation or pathologic examination of a hysterectomy specimen. On gross examination, the cervix usually appeared abnormal, but occasional specimens were considered unremarkable. The cervix was typically described as firm or indurated. Microscopic examination showed glands that were irregular in size and shape and lined predominantly by mucin-containing columnar epithelial cells with basal nuclei. The tumors typically exhibited deep invasion of the cervical wall, and a portion of the infiltrating tumor was associated with a stromal response in most cases. Minor foci of tumor with a less well-differentiated appearance were present in 15 of the 26 tumors. Argyrophil cells were present in six of 15 tumors. Five of the six tumors containing argyrophil cells stained immunohistochemically for serotonin and peptide hormones. Positive staining for serotonin was seen in four tumors; one of these also contained a few cells positive for neurotensin. Cytoplasmic staining of the tumor cells for carcinoembryonic antigen (CEA) was seen in five of six cases. CEA reactivity was very focal in two of the positive tumors. Microscopic features that were most helpful in distinguishing adenoma malignum from normal endocervix or benign endocervical glandular proliferations were the presence of markedly irregular, abnormally shaped glands; invasion of the cervical wall; a loose edematous or desmoplastic stromal response; foci of less well-differentiated tumor; vascular invasion; perineural invasion; and positive staining for CEA. Despite radical therapy in most of the cases, the prognosis was poor. Follow-up data were available for 22 patients. Thirteen of them died of recurrent tumor, four were alive with recurrent tumor at the time of last follow-up examination, and only three patients were disease free for 2 years or more.4+ tumor of the

Psammomatous somatostatinomas of the duodenum.

The presence of psammoma bodies in carcinoid tumors of the gastrointestinal tract is a rare occurrence; it has also been reported to be associated with features of somatostatin production by the tumor cells. The morphologic features of three such tumors arising in the duodenum were studied by a combination of histochemical, immunocytochemical, and ultrastructural techniques in an effort to delineate their secretory profile and further subclassify them. All tumors showed a mixed architectural pattern with prominent areas of glandular differentiation. The psammoma bodies were almost exclusively located within the glandular lumina. In each instance, the majority of tumor cells showed histochemical and immunocytochemical features of somatostatin-containing cells, and one tumor studied ultrastructurally showed numerous large- and small-sized intracytoplasmic secretory granules, both of which contained somatostatin. In contrast to other endocrine tumors of the duodenum that frequently have a multihormonal secretory profile, psammomatous duodenal carcinoids are associated with the exclusive presence of somatostatin within tumor cells. While many more of such examples of this uncommon tumor need to be systematically investigated for their immunocytochemical and ultrastructural characteristics, duodenal somatostatinomas need to be included in the differential diagnosis of psammomatous tumors.

Alpha-lactalbumin as an immunohistochemical marker for metastatic breast carcinomas.

Alpha-lactalbumin (ALA), a milk protein, was demonstrated by immunohistochemistry with polyclonal antisera from three different sources in primary and metastatic breast carcinomas, and mammary Paget's disease. ALA localization was observed in 67% of mammary carcinomas, and in 62% of their metastases to sites which included lymph nodes, lung, bone, liver, pericardium, skin, and subcutaneous tissue. There was close correlation between primary and metastatic breast carcinomas in ALA positivity, but no correlation between ALA positivity and histologic differentiation. A variety of nonmammary neoplasms were examined for ALA immunoreactivity. In contrast to ALA immunoreactivity of breast tissue, which was removed by preabsorption of antiserum with ALA antigen, a number of skin appendage tumors, salivary gland tumors, and mesotheliomas demonstrated positive staining which was not abolished by preabsorption and was most likely due to the presence of cross-reacting antibodies. One commercial ALA antiserum also reacted with pancreatic islet cells in a distribution similar to glucagon. Our results demonstrate the presence of ALA in breast carcinomas and its potential value to the surgical pathologist in the workup of metastatic carcinomas of unknown primary sites. However, the staining encountered in some nonmammary tumors necessitates caution in its interpretation.