Visceral Carcinomas Research Articles

Is Metformin Use Associated with Prolonged Overall Survival in Patients with Soft Tissue Sarcoma? A SEER-Medicare Study.

Metformin, an oral drug used to treat patients with diabetes, has been associated with prolonged survival in patients with various visceral carcinomas. Although the exact mechanisms are unknown, preclinical translational studies demonstrate that metformin may impair tumor cellular metabolism, alter matrix turnover, and suppress oncogenic signaling pathways. Currently used chemotherapeutic agents have not been very successful in the adjuvant setting or for treating patients with metastatic sarcomas. We wanted to know whether metformin might be associated with improved survival in patients with a soft tissue sarcoma. In patients treated for a soft tissue sarcoma, we asked: (1) Is there an association between metformin use and longer survival? (2) How does this association differ, if at all, among patients with and without the diagnosis of diabetes? The Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) database was used to identify patients with a diagnosis of soft tissue sarcoma from 2007 to 2016. Concomitant medication use was identified using National Drug Codes using the Medicare Part D event files. This database was chosen because of the large number of captured sarcoma patients, availability of tumor characteristics, and longitudinal linkage of Medicare data. A total of 14,650 patients were screened for inclusion. Patients with multiple malignancies, diagnosis at autopsy, or discrepant linkage to the Medicare database were excluded. Overall, 4606 patients were eligible for the study: 598 patients taking metformin and 4008 patients not taking metformin. A hazard of mortality (hazard ratio) was analyzed comparing patients taking metformin with those patient groups not taking metformin and expressed in terms of a 95% confidence interval. Cox regression analysis was used to control for patient-specific, disease-specific, and treatment-specific covariates. Having adjusted for disease-, treatment-, and patient-specific characteristics, patients taking metformin experienced prolonged survival compared with all patients not taking metformin (HR 0.76 [95% CI 0.66 to 0.87]). Associated prolonged survival was also seen when patients taking metformin were compared with those patients not on metformin irrespective of a diabetes diagnosis (HR 0.79 [95% CI 0.66 to 0.94] compared with patients with a diagnosis of diabetes and HR 0.77 [95% CI 0.67 to 0.89] compared with patients who did not have a diagnosis of diabetes). Without suggesting causation, we found that even after controlling for confounding variables such as Charlson comorbidity index, tumor grade, size, stage, and surgical/radiation treatment modalities, there was an association between metformin use and increased survival in patients with soft tissue sarcoma. When considered separately, this association persisted in patients not on metformin with and without a diabetes diagnosis. Although metformin is not normally prescribed to patients who do not have a diabetes diagnosis, these data support further study, and if these findings are substantiated, it might lead to the performance of multicenter, prospective clinical trials about the use of metformin as an adjuvant therapy for the treatment of soft tissue sarcoma in patients with and without a preexisting diabetes diagnosis. Level III, therapeutic study.

Tumor-Suppressive miR-192-5p Has Prognostic Value in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by fast tumor progression and diagnosis at advanced, inoperable stages. Previous studies could demonstrate an involvement of miR-192-5p in epigenetic regulation of visceral carcinomas. Due to contradictory results, however, the clinical utility of miR-192-5p in PDAC has yet to be determined. MiR-192-5p expression was analyzed by RT-qRT-PCR in human PDAC and benign tissue (n = 78), blood serum (n = 81) and serum exosomes (n = 74), as well as in PDAC cell lines (n = 5), chemoresistant cell clones (n = 2), and pancreatic duct cell line H6c7. Analysis of EMT-associated (epithelial-to-mesenchymal transition) proteins was performed by immunohistochemistry and Western blot. MiR-192-5p was deregulated in PDAC as compared to healthy controls (HCs), with downregulation in macrodissected tissue (p < 0.001) and upregulation in blood serum of PDAC UICC (Union for International Cancer Control) stage IV (p = 0.016) and serum exosomes of PDAC UICC stages II to IV (p < 0.001). MiR-192-5p expression in tumor tissue was significantly lower as compared to corresponding peritumoral tissue (PDAC UICC stage II: p < 0.001; PDAC UICC stage III: p = 0.024), while EMT markers ZEB1 and ZEB2 were more frequently expressed in tumor tissue as compared to peritumoral tissue, HCs, and chronic pancreatitis. Tissue-derived (AUC of 0.86; p < 0.0001) and exosomal (AUC of 0.83; p = 0.0004) miR-192-5p could differentiate between PDAC and HCs with good accuracy. Furthermore, high expression of miR-192-5p in PDAC tissue of curatively resected PDAC patients correlated with prolonged overall and recurrence-free survival in multivariate analysis. In vitro, miR-192-5p was downregulated in gemcitabine-resistant cell clones of AsPC-1 (p = 0.029). Transient transfection of MIA PaCa-2 cells with miR-192-5p mimic resulted in downregulation of ZEB2. MiR-192-5p seems to possess a tumor-suppressive role and high potential as a diagnostic and prognostic marker in PDAC.

450 Sun exposed individual normal keratinocytes tolerate multiple cancer-causing mutations in vivo

The burden of somatic mutation in sun-exposed normal skin has been described to be as high as visceral carcinomas using bulk DNA sequencing approaches. Mutations in so called keratinocyte carcinoma “driver genes”, such as TP53 and NOTCH1, are also frequently detected. Here we use a single colony sequencing approach to determine the mutation profiles of individual normal keratinocytes isolated from the periphery of multiple separate patient squamous cell carcinomas (SCC). We find the burden of mutation in individual normal sun-exposed keratinocytes ranges orders of magnitude, from 0.3 single nucleotide variants (SNV) per mega-base (Mb) of exome-captured DNA to 30.9 SNV / Mb, similar to those reported in keratinocyte carcinomas (ranging 1 to over 100 SNV / Mb). Forty-five percent of single sun-exposed keratinocytes harbored mutations in at least one known SCC driver gene: NOTCH1 (30% of cells), TP53 (15%), NOTCH2 (10%), NOTCH3 (5%), and FAT1 (5%). Surprisingly some single cells harbored mutations in up to three separate driver genes, a number not often identified in keratinocyte carcinomas for these defined driver genes. Although multiple single cell derived colonies were sequenced from individual patients, we found no evidence of clonal expansion of cells harboring NOTCH or TP53 mutations as reported from bulk sequencing approaches. In contrast, we found that a high proportion of single colony clones sequenced from normal laryngeal keratinocytes adjacent to a laryngeal SCC were populated by three separate clones, providing evidence of so-called “field cancerization” in larynx but not in skin. Mutation signature analysis demonstrated presence of UV mutation in sun-exposed skin and presence of tobacco mutation in larynx. Collectively these data have implications on both keratinocyte stem cell biology in the skin and larynx as well as the differential ability of normal stratifying epithelia to tolerate somatic mutation.

Extraocular well‐differentiated sebaceous tumors with overlying cutaneous horns: four tumors in three patients

Sebaceous tumors are adnexal neoplasms showing sebocytic differentiation. They range from benign to malignant and are associated with Muir-Torre syndrome (MTS). Several clinical and histopathological features associated with MTS have been described. Sebaceous tumors with an overlying cutaneous horn are extremely rare. Hematoxylin and eosin-stained slides were retrospectively reviewed to identify sebaceous tumors with marked hyperkeratosis, a condition that is often associated with cutaneous horns. Clinical correlation and mismatch repair protein immunohistochemical studies were then conducted. Four tumors from three patients were identified in our archive. Three were classified as sebaceous adenomas, and the fourth was considered as a borderline sebaceous tumor favoring well-differentiated sebaceous carcinoma. All cases showed loss of expression of mismatch repair proteins (three tumors from two patients exhibited lost expression of MSH2 and MSH6, and the fourth exhibited lost expression of MLH1 and PMS2). Additionally, one patient presented characteristic clinical manifestations of MTS, including multiple sebaceous adenomas and visceral carcinomas. We suggest that extraocular well-differentiated sebaceous neoplasms with overlying cutaneous horns may be an indication of underlying mismatch repair protein deficiency and potential MTS. This distinctive morphology might be an exaggerated combination of other features associated with MTS, i.e. keratoacanthoma-like architecture and extensive holocrine secretion.

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A 50 year old female presented with complaints of asymptomatic, raised skin lesion over left leg for the past two years, which on local examination revealed a single, localized, well defined, rounded plaque of 4 cm. Clinically Bowen's disease was not suspected because of its rarity and also occurred in the unusual site. Biopsy was taken and sent for histo-pathological examination. In histo- pathological examination Bowen's disease was diagnosed. This case is highlighted to show the pathologist's help in making a proper diagnosis when atypical skin lesions are seen at unusual sites. INTRODUCTION: Most of the overt malignant conditions actually originate as microscopic lesions, which are designated as in-situ carcinomas. These in-situ carcinomas are typically noticed as intra- epithelial lesions, most often seen in squamous cell epithelial lined tissue eg. oral mucosa, genitals, cervix and skin. In skin, the intra-epithelial carcinoma-in situ lesions may be Bowen's disease, Bowenoid papulosis or Erythroplasia of Queyrat. In the same way gastrointestinal and urinary system also can show in-situ malignancies. Bowen's disease was first described by an American dermatologist John T Bowen in the year 1912. It is most commonly reported in sun exposed sites. It rarely occurs in patients with darkly pigmented skin. Bowen's disease is observed in skin and external genitals and is sometimes associated with arsenic poisoning and visceral carcinomas. Bowen's disease is a rare, persistent, progressive, intra-epithelial carcinoma, 8% of which will develop into an invasive squamous cell carcinoma. Treatment options are topical 5-fluorouracil, cryotherapy or surgical excision. Further a detailed clinical examination is needed along with supportive diagnostic aids to exclude the possibility of any internal malignancy. A wide excision is to be done to prevent invasive malignant tumor.

Ovarian Basaloid Carcinoma with Shadow Cell Differentiation

So-called shadow cell differentiation (SCD) is typical for pilomatrixoma and other skin lesions with follicular differentiation, but it was rarely described also in some visceral carcinomas. We report a case of ovarian basaloid carcinoma with SCD. The tumor presented as a 14 cm ovarian mass in a 45-year-old woman, and therefore the adnexectomy and hysterectomy were performed. The tumor was of high stage. Multiple metastases were found in the liver, retroperitoneal and mediastinal lymph nodes, and the lung. Histologically, the tumor showed a pattern of high-grade basaloid carcinoma with numerous shadow cells. Extensive histologic examination did not reveal any glandular or preexisting teratoma component. Immunohistochemically, the tumor expressed markers of squamous cell differentiation, such as p63, cytokeratin 5/6, and high-molecular-weight keratin. Cytokeratin 7 and CA125 were positive in scattered cells of the lesion. Estrogen and progesterone receptor, vimentin, and p53 were negative. Beta-catenin showed nuclear and cytoplasmic positivity, indicating possible tumor proliferation/differentiation via Wnt signaling pathway. To our knowledge, SCD in basaloid carcinoma of the ovary was not described before. In addition to the description of the case, we review the literature on SCD in visceral carcinomas.

Muir-Torre-Syndrom mit bisher nicht beschriebener Frameshift-Mutation im MSH2-Gen

Muir-Torre syndrome (MTS) is a rare phenotypic variant of hereditary non-polyposis colorectal carcinoma (HNPCC, Lynch syndrome), in which patients, in addition to visceral carcinomas, develop skin tumors. Multiple keratoacanthomas and basal cell carcinomas with sebocytic differentiation are characteristic as well as multiple benign and malignant tumors of the sebaceous glands, such as sebaceous adenoma, sebaceous epithelioma (sebaceoma) and sebaceous carcinoma. Particularly Cystic tumors of the sebaceous glands are especially suggestive of MTS. In genetically predisposed persons, cutaneous and visceral tumors are diagnosed at an average age of 53 years. Here we present an interesting case of a 65-year-old man in whom molecular genetic tests revealed a novel mutation in the MSH2 gene, leading to a frame shift within the gene.

Prevalence of Known and Unknown Primary Tumor Sites In Spinal Metastasis Patients

Study Design: A retrospective study.Objectives: Three objectives have been designated for this study: (1) to determine the prevalence of identifiable and non-identifiable primary tumor sites in patients with spinal metastasis, (2) to identify the most common site of the known primary tumor sites, and (3) to identify the factors associated with survival time.Summary of Background Data: The spine is the third most common metastatic site for several primary visceral carcinomas. The primary tumor site could not be identified in 15% to 20% of patients who had been diagnosed of with a skeletal metastasis. Most of the previous studies on skeletal metastasis have not been limited to spinal metastasis alone.Methods: Between January 2007 and July 2011 reviews were done for 82 patients with spinal metastasis who had not received a previous diagnosis of carcinoma. The assessment parameters included the following: general demographic data, Karnofsky score, Frankel score, number of spinal vertebra affected, region of the spine affected by metastasis, other skeletal metastasis site, visceral metastasis, known or unknown primary sites of metastasis, histological cell type of metastasis, and the survival period. The log-rank test and Cox proportional hazard model were used to study the survival analysis.Results: Of the 82 patients included in the study, 56 were male. The mean age was 57 years. 86.6% had a known primary carcinoma site while the remaining 13.4% had none. The two most common known carcinoma sites were the lung and biliary systems. Among the 11 unknown primary sites, the most common histological finding was adenocarcinoma. The mean survival period was 8.7 ± 11.7 months. The survival analysis revealed two statistically significant factors: the primary tumor site’s aggressiveness (P<0.005) and the presence of visceral metastasis (P<0.05).Conclusion: The prevalence of identifiable primary site was 86.6% and the most common site was the lungs followed by the biliary system. The primary carcinoma site’s aggressiveness and the presence of visceral metastasis were the factors associated with patient survival.

Distinct expression pattern of claudin‐6, a primitive phenotypic tight junction molecule, in germ cell tumours and visceral carcinomas

This study aimed to clarify claudin-6 expression patterns in cancers. We surveyed claudin-6 expression by immunohistochemistry using tissue microarray in 860 tumours, including germ cell tumours and major carcinomas. Claudin-6 was expressed consistently in germ cell tumours (28 of 28, 100%), whereas only 64 (8%) of 832 non-germ cell tumours demonstrated claudin-6 expression. Further immunohistochemical study in full tissue sections demonstrated diffuse claudin-6 staining in all seminomas (n=14), embryonal carcinomas (n=10), yolk sac tumours (n=12) and mononuclear trophoblastic cells of choriocarcinomas (n=3), and focal staining in immature epithelial components of immature teratomas (n=6). Additionally, because alpha-fetoprotein (AFP)-producing gastric adenocarcinomas and pulmonary high-grade fetal adenocarcinomas were among the claudin-6 expressing non-germ cell tumours in the microarray studies, we predicted that claudin-6 may be a biomarker for them and studied additional tumours in full sections, which showed claudin-6 expression in AFP-producing gastric adenocarcinomas (18 of 20, 90%) and pulmonary high-grade fetal adenocarcinomas (four of five, 80%). Only one of 11 hepatoblastomas demonstrated focal claudin-6 staining. This study demonstrated that claudin-6 is a novel diagnostic marker for primitive germ cell tumours and is also expressed frequently in some cancers with a primitive phenotype.

Pilomatrix Carcinoma of the Clitoris

Pilomatrix carcinoma, a malignant counterpart of pilomatrixoma, is a rare skin neoplasm composed of basaloid and shadow cells that characterize differentiation toward the hair matrix. The authors present a case of pilomatrix carcinoma of the clitoris, a very unusual location not previously reported. Diagnostic criteria and differential diagnoses are discussed. Pilomatrix carcinoma should be differentiated from benign pilomatrixoma and other carcinomas with shadow cells, including basal cell carcinoma with matrical differentiation and metastases of visceral carcinomas with shadow cells.

Stereotactic radiotherapy using Novalis for skull base metastases developing with cranial nerve symptoms

Skull base metastases are challenging situations because they often involve critical structures such as cranial nerves. We evaluated the role of stereotactic radiotherapy (SRT) which can give high doses to the tumors sparing normal structures. We treated 11 cases of skull base metastases from other visceral carcinomas. They had neurological symptoms due to cranial nerve involvement including optic nerve (3 patients), oculomotor (3), trigeminal (6), abducens (1), facial (4), acoustic (1), and lower cranial nerves (1). The interval between the onset of cranial nerve symptoms and Novalis SRT was 1 week to 7 months. Eleven tumors of 8-112 ml in volume were treated by Novalis SRT with 30-50 Gy in 10-14 fractions. The tumors were covered by 90-95% isodose. Imaging and clinical follow-up has been obtained in all 11 patients for 5-36 months after SRT. Seven patients among 11 died from primary carcinoma or other visceral metastases 9-36 months after Novalis SRT. All 11 metastatic tumors were locally controlled until the end of the follow-up time or patient death, though retreatment for re-growth was done in 1 patient. In 10 of 11 patients, cranial nerve deficits were improved completely or partially. In some patients, the cranial nerve symptoms were relieved even during the period of fractionated SRT. Novalis SRT is thought to be safe and effective treatment for skull base metastases with involvement of cranial nerves and it may improve cranial nerve symptoms quickly.

Paget's disease of the anal margin.

A follow-up study of 22 patients with Paget's disease of the anal margin was conducted to determine the prevalence of invasive disease and coexisting visceral carcinomas, cure and survival rates. Seventy-three per cent of the patients suffered from persistent pruritus ani. Seven (32 per cent) patients had malignancy (invasive Paget's disease (n = 5) and coexisting visceral carcinoma (n = 2] and six (27 per cent) developed malignancy (invasive Paget's disease (n = 4) and coexisting visceral carcinoma (n = 2] during follow-up, giving an overall occurrence of malignancies of 59 per cent (95 per cent confidence limits: 36-79). The median follow-up period was 9 (range 0.5-25) years. No difference in length of history could be found between patients with or without malignancy. The estimated cure rate by actuarial analysis among radically treated patients was 64 per cent (95 per cent confidence limits: 43-91) at 1 year and 45 per cent (95 per cent confidence limits: 18-72) at 8 years after primary treatment. The 5- and 10-year crude survival rates of 54 per cent and 45 per cent, respectively, were significantly lower than the corresponding values of 84 per cent and 60 per cent for the normal population (P less than 0.01). Patients with persistent pruritus ani and a perianal skin lesion should be biopsied frequently. If Paget's disease is diagnosed, physical examination of the patient and anorectal region must be done carefully and repeatedly.

Immunolocalization of the Epstein-Barr nuclear antigen-1 in conjunctival squamous carcinomas and dysplasias

Epstein-Barr virus (EBV) has been linked etiologically to infectious mononucleosis, some non-Hodgkin as well as Hodgkin lymphomas, and lymphoepithelioma-like carcinomas. Moreover, various EBV antigens have been identified by a variety of techniques in a number of visceral carcinomas including breast, prostate, colon and lung primaries. We have now demonstrated by immunohistochemistry the presence of EBV nuclear antigen-1 (EBNA-1) in 4 of 15 cases of conjuntival squamous carcinomas and related dysplasias. At present, there is no significant evidence linking etiologically EVB to this type of tumor and dysplasia. However, our findings merit further investigation given the growing evidence that EBV may enhance proliferation and aggressiveness of tumor systems as well as the immortalization of non-neoplastic cells.

Numerous Sebaceous Neoplasms in a Patient without Visceral Carcinomas

We present a 58‐year‐old Caucasian man who spawns sebaceous neoplasms with a widely varying histopathologic pattern, the true nature of which were difficult to determine in some of the cases. In a 10‐year period, the patient developed over 20 lesions that varied in size, shape, and location. The patient denied a family history of either similar cutaneous lesions or internal malignancies that would fulfill the criteria of Hereditary Nonpolyposis Colorectal Cancer (HNPCC). Vigilant screening failed to reveal visceral carcinomas. The histopathologic findings of the neoplasms as well as the results of tests for microsatellite instability(MSI) in various tumors and the immunohistochemical staining for the mismatch repair genes (MMR) MSH2 and MLH1 will be discussed. Our patient has been maintained on low‐dose isotretinoin since 1995.

Study of “de novo” malignancies among greek renal transplant recipients

The incidence of malignancy was estimated in 1055 renal transplant recipients, engrafted between 1983 and 2001 including 611 grafts from living and 444 from cadaveric donors. The meoplasms were 22 skin cancers, 18 Kaposi’s sarcomas, 10 lymphomas nine non-Hodgkin’s and one Hodgkin’s lymphoma) and 24 visceral carcinomas. Skin cancers were completely excised. Patients with Kaposi sarcoma were treated by tapering the immunosuppression with cessation of cyclosporine. In addition, four patients received chemotherapy, and one of them received local radiotherapy. All patients with lymphomas were treated by cessation of calcineurin inhibitors with modulation of the immunosuppression to levels that were safe for the graft. Furthermore, five patients underwent first line chemotherapy, two patients radiotherapy and two patients, surgical removal of the tumor. The patients with visceral tumors were treated surgically with excision of the lesions when possible, without severe modification of the immunosuppressive regimen. Chemotherapy or radiotherapy was added accordingly. Disease-related mortality rate in patients with skin cancer was 4.5%; in Kaposi’s Sarcoma cases 11.11%; in lymphomas 50%; and in all the other instances, 45.8%. This study shows the increased incidence of certain malignancies in transplant recipients, illustrating the importance of cancer surveillance following kidney transplantation. A substantial reduction or even cessation of immunosuppressive therapy may be necessary to achieve patient survival.

Visceral Carcinoma With Shadow Cell Differentiation Can Mimic Pilomatrix Carcinoma

We appreciate the interest of Drs. Zamecnik, Michal, and Mukensnabl in our recent publication on pilomatrix carcinoma (1). In their letter, these authors challenge the specificity of shadow cells in the diagnosis of pilomatrical neoplasms. Shadow cells are cornified cells in which, as a consequence of karyolysis, nuclei have faded but vague outlines of them still can be recognized. According to the latest edition of Ackerman's book Neoplasms With Follicular Differentiation, these cells represent faulty attempts at differentiation toward hair and are found only in conditions in which some follicular matrical cells are present (2). Although shadow cells are most commonly seen in pilomatricoma and its malignant variant, the pilomatrix carcinoma, it is well known that other lesions with follicular differentiation may have shadow cells on rare occasions. These include trichoepithelioma, desmoplastic trichoepithelioma, proliferating trichilemmal tumor, and panfolliculoma (3). Additionally, the occurrence of shadow cells has already been reported in keratoacanthoma, chondroid syringoma, and in some odontogenic tumors, notably the calcifying odontogenic cyst and the complex odontoma (4–6). Recently, Dr. Zamecnik et al. have described the presence of shadow cells in extracutaneous locations, namely in adenosquamous carcinomas of the colon and uterus (7). This has led these authors to suggest that the pathologist should be aware that shadow cell differentiation may occur in visceral carcinomas and that it is not diagnostic of matrical tumors. There are unquestionable morphologic similarities between the cells they describe and folliculosebaceous matrical shadow cells, although they are not quite identical to the shadow cells seen in matrical neoplasms. In this regard, we agree with the opinion of Drs. Hitchcock and Ellington (8) in that the cells that Zamecnik et al. describe show much less regular distribution of the clear zone previously occupied by the nucleus and a more filamentous cytoplasm than matrical shadow cells. In our cases, the diagnosis of pilomatrix carcinoma was made because the tumors showed architectural features that implied malignancy coupled with cytologic characteristics of matrical differentiation. In the cases presented by Zamecnik et al. the shadow cells were present in isolation, without demonstrating the classic findings of matrical tumors. Obviously, it cannot be assumed that the superficial morphologic appearance between true shadow cells and the cells described by Zamecnik et al. is per se indicative of a tumor with matrical differentiation. Whether tumors previously interpreted as pilomatrix carcinoma could have represented cutaneous metastases from poorly differentiated visceral carcinomas with shadow cell differentiation remains, in our opinion, speculative. In such cases it could be of interest to perform immunohistochemical studies of follicle-associated keratins to identify further differences (9). Finally, the differential diagnosis between pilomatrix carcinoma and the cutaneous metastases from an undifferentiated visceral carcinoma has also important prognostic considerations. Pilomatrix carcinomas are locally aggressive tumors that have a tendency to recur, especially when they are incompletely excised. Metastasis and death have resulted from these tumors but are rare. On the other hand, the prognosis for patients with cutaneous metastasis from a visceral carcinoma is ominous, and their life expectancy from the appearance of the metastases is on average less than one year. David Hardisson, M.D. Félix Contreras, M.D. Jesús Cuevas-Santos, M.D. M. Dolores Linares, M.D.

Pleural mesotheliomas have an integrin profile distinct from visceral carcinomas

Cryosections of epithelial, sarcomatoid, and biphasic malignant mesotheliomas (EMM, n = 11; SMM, n = 5; BMM, n = 6) of the pleura were immunostained with monoclonal antibodies to integrin subunits α 1–6 and v, and β 1–4. Localization patterns were compared with those known to occur in pulmonary and other adenocarcinomas (PADC, ADC). EMM and the epithelial component of BMM (ecBMM) expressed α 1,3,5,6, and v and β 1 and 4 . SMM and the sarcomatoid elements of BMM (scBMM) reacted variably for α 1,3,5,6 and v and β 1. Reactions for α 3, found in all tumors, were strongest in EMM, ecBMM, and PADC. Our findings indicate that EMM and ecBMM parallel PADC and most ADC in their expression of α 6 β 4, underscoring that this laminin integrin receptor is intimately associated with these neoplastic epithelial phenotypes. Also, our observations on α 3 β 1 suggest that this cell-cell adhesion-mediating integrin is related to the epithelial phenotype. Notably, all malignant mesotheliomas (MM), including those with distinct glandular structures, expressed the α 5 β 1 fibronectin receptor, thus paralleling most sarcomas and differing from PADC and most other ADC. We conclude that irrespective of architectural and cytologic variants, transformed mesothelial cells possess an integrin repertory that differs significantly from that of most ADC, including those of the lung. These findings set mesothelium apart from epithelia and may prove helpful as adjunct tools for the differential diagnosis between EMM and AD.

Ultrastructural localization of carcinoembryonic antigen (CEA) glycoproteins and epithelial membrane antigen (EMA) in normal and neoplastic sweat glands.

Glycoproteins of the carcinoembryonic antigen family (CEA) and epithelial membrane antigen (EMA) are established markers for glandular and mucosal tissues. However, their precise ultrastructural distribution in sweat glands has not been determined as yet. Therefore, normal human skin, 19 cases of various sweat gland neoplasms, Paget's disease, and cutaneous metastases of visceral carcinomas were stained with well-defined antibodies using a postembedding immunogold technique. In some cases, a new method of re-embedding paraffin material for immunoelectron microscopy was applied. In normal sweat glands, immunoreactivity of the endoplasmic reticulum and vesicles indicated biosynthesis and processing of CEA and EMA. Along the luminal surfaces both CEA and EMA represented an integral part of microvilli. However, a differential expression of CEA and EMA was demonstrated in apocrine epithelia, mucous cells of eccrine glands, and sweat ducts. In fetal glands, CEA was associated with formation of secretory and ductal lumina. The overall cellular distribution of CEA and EMA was highly preserved in benign sweat gland neoplasms whereas malignant neoplasms were characterized by loss of protein targeting and cellular polarity. In conclusion, these immunoelectron microscopical findings suggest a role of CEA and EMA for cell differentiation and secretory mechanisms of sweat gland epithelia.

Diffuse nodular regenerative hyperplasia of the liver (DNRH). A clinicopathologic study of 24 cases.

The authors report 24 cases of diffuse nodular regenerative hyperplasia of the liver (DNRH) seen in a General Hospital during the last 9 years (prevalence: 3'1/100,000, incidence: 0'34/100,000). DNRH was diagnosed in 0.52% of the liver biopsies and 0.72 of the autopsies. These results suggest that DNHR is probably more frequent than suspected, and 1 DNRH was seen for each 39 biopsied cases of liver cirrhosis. Fourteen patients did not have hepatic symptoms. Portal hypertension was present in 9 cases. The biochemical disturbance most frequently found was a moderate elevation of GGT and APh, associated with slight elevation of SGOT, SGPT and bilirubin levels. Normal liver function tests could be seen (3 cases). Previous exposure to potentially hepatotoxic drugs or chemicals was discovered in 15 cases (62.5%). Diseases associated were circulatory disturbances (6 cases), autoimmune disease (5 cases), hemopathies (5 cases), and visceral carcinomas (4 cases). Two patients were recipients of renal transplant. Nodules distributed through the whole liver tissue were found in 16 cases, while 8 patients showed areas of normal parenchyma in their livers. Impairment of small hepatic vessels was detected in 16 cases. Some uneven cytologic findings were discovered: clusters of small basophilic cells (4 cases), large clear cells (8 cases), and dysplastic hepatocytes (10 cases), which suggests that DNRH could be a preneoplastic condition.

Sebaceous Adenoma in a Patient With Acquired Immunodeficiency Syndrome

To the Editor.— Sebaceous adenomas are uncommon, benign tumors of sebaceous glands. 1 They may be single or multiple, and are usually slow-growing, asymptomatic tumors that appear most commonly on the head, neck, and trunk as discrete, smooth, yellow or flesh-colored papules of less than 1 cm in diameter. 2 Solitary or multiple sebaceous adenomas may be associated with visceral carcinomas in the Muir-Torre syndrome. 1,2 We describe a patient with acquired immunodeficiency syndrome (AIDS) with an unusual presentation of a solitary sebaceous adenoma, without evidence of visceral neoplasia. This association has not been made previously. Report of a Case.— A 39-year-old homosexual man with AIDS, based on a two-year history of Kaposi's sarcoma without opportunistic infection, presented to the dermatology clinic with a three-month history of a rapidly growing nodule on his right nostril. On examination, there was a friable hemorrhagic nodule, 7 mm in diameter. The rest of