Gastric Carcinomas With Unusual Cytoplasmic Ultrastructural Features

Alterations in tannic acid (TA) binding capacity of cell surface carbohydrates in normal, premalignant, and malignant squamous epithelium of the human uterine cervix have been studied using electron microscopic visualization in combination with microdensitometric evaluation.

While in normal epithelium there is distinct binding in four to five cell layers of the deep intermediate zone, cells of carcinoma in situ and invasive cancer lesions lack TA binding. In moderate dysplasia an intermediate reacting pattern is found.

Deep intermediate cells in areas bordering the carcinoma in situ lesions do not show any binding, although their ultrastructure cannot be distinguished from similar cells in normal tissue.

The TA deposition within the deep intermediate zone is probably related to the presence here of glycoprotein-containing membrane-coating granules.

The finding that TA binding discriminates between cells in normal squamous epithelium and morphologically normal cells in juxtaposition with lesional areas in premalignant and malignant epithelium opens the possibility for a more reliable cytologic diagnosis of cervical epithelial neoplasia.     

Markers for dysplasia of the upper aerodigestive tract. Suprabasal expression of PCNA, p53, and CK19 in alcohol-fixed, embedded tissue.

Recognition of premalignant lesions in the oral epithelium has the potential to increase survival rates for squamous cell carcinoma of the oral cavity. It has previously been reported that cytokeratin 19 (CK19), a 40-kd epithelial cytoskeletal protein within the suprabasal squamous epithelium, is a specific marker of moderate-to-severe dysplasia and carcinoma in situ in oral cavity squamous epithelium. In contrast, normal epithelium and hyperplastic lesions reportedly express CK19 only in the basal layer if at all. The authors chose to test and extend this hypothesis by studying suprabasal CK19 expression and dysplasia of the oral cavity and upper aerodigestive tract in paraffin-embedded specimens that had been fixed in alcohol, a superior fixative for the preservation of cytokeratins. The authors examined 56 alcohol-fixed, paraffin-embedded specimens including 37 from the oral cavity, using two antibodies specific for CK19 (Ks19.1 and 4.62), an antibody to the nuclear proliferation marker, proliferating cell nuclear antigen (PCNA) (19A2), and an antibody to the putative tumor suppressor gene, p53 (pAb1801). The lesions were classified as normal, hyperplasia, mild dysplasia, moderate dysplasia, severe dysplasia/carcinoma in situ, or invasive squamous cell carcinoma, following standard histologic criteria. Immunocytochemically stained sections were scored for the presence or absence of suprabasal CK19, suprabasal PCNA, and p53 positivity, regardless of location. The immunostaining patterns of the two anti-CK19 antibodies were essentially equivalent. Except for one laryngeal specimen, normal epithelium, when positive, showed CK19 expression only in scattered cells throughout the basal layer. Proliferating cell nuclear antigen-positive nuclei were found exclusively in the basal layer. In areas of hyperplasia, CK19 immunostaining was absent or confined to the basal layer in 20 of 38 specimens and was expressed in suprabasal cells in 18 of 38 hyperplastic specimens. Proliferating cell nuclear antigen immunostaining in all cases of hyperplasia was limited to the basal layer. Severe dysplasia and carcinoma in situ showed suprabasal CK19 staining in six of nine specimens and no CK19 staining in three of nine specimens. In contrast, suprabasal PCNA immunostaining was found in all dysplasia and carcinoma in situ cases. p53 expression was detected in three of nine severe dysplasia/CIS specimens and was immunocytochemically undetectable in all normal, hyperplasia, and mild to moderate dysplasia specimens. The authors conclude that suprabasal CK19 expression is neither a sensitive nor a specific marker of premalignancy in oral epithelium and cannot be used to distinguish hyperplasia from dysplasia. In contrast, a strong correlation between suprabasal expression of PCNA, a marker for proliferating cells, and dysplasia/carcinoma in situ was evident.(ABSTRACT TRUNCATED AT 400 WORDS)     

Immunolocalization of cystatin A in neoplastic, virus and inflammatory lesions of the uterine cervix.

Cystatin A was immunohistochemically demonstrated in the normal squamous epithelium of the uterine cervix, particularly in the parabasal and superficial cell layers whereas it was absent or scanty in the basal cells and in areas with parakeratosis. Cystatin A was also found in neoplastic lesions (dysplasia, carcinoma in situ and squamous cell carcinoma), but less abundant than in normal squamous epithelium. The immunoreaction in intraepithelial neoplasia was closely related to the degree of morphological maturation of the squamous cells with more abundant cystatin A in low grade dysplasia and less in high grade dysplasia and carcinoma in situ. In squamous cell carcinoma, cystatin A was often abundant in highly differentiated areas and almost absent in poorly differentiated ones. Cystatin A was found in the squamous epithelium in herpes and in condylomatous lesions. It was also found in the cytoplasm of neutrophils, but not in lymphocytes and plasma cells. In unspecific cervicitis, cystatin A was found extracytoplasmatically as small vesicles in the epithelial-stromal junction. The implications of cystatin A in neoplastic, virus, and inflammatory processes are discussed.     

Expression of keratins 1, 6, 15, 16, and 20 in normal cervical epithelium, squamous metaplasia, cervical intraepithelial neoplasia, and cervical carcinoma.

Expression of keratins 1, 6, 15, 16, and 20 was examined in normal cervical epithelia, squamous metaplasia, various grades of cervical intraepithelial neoplasia, and both squamous cell carcinomas and adenocarcinomas of the cervix with monospecific antibodies. Ectocervical epithelium contains all of these keratins except keratin 20. They show a heterogeneous distribution, with a basally restricted detection of keratin 15. Endocervical columnar cells were found to contain significant amounts of keratin 16, whereas the subcolumnar reserve cells expressed considerable amounts of keratin 15 and 16, and frequently keratin 6. These reserve cell keratins were also found in immature and mature squamous metaplastic epithelium. In the cervical intraepithelial neoplastic lesions they were generally found with increasing intensity as the severity of the lesion progressed. In the keratinizing variety of squamous cell carcinoma of the cervix, these three keratins seem to constitute an important part of the intermediate filament cytoskeleton, whereas in nonkeratinizing squamous cell carcinoma, they occur to a much lesser extent. Surprisingly, these keratins were also occasionally found in adenocarcinomas. From these data we conclude that the keratin phenotype of reserve cells and endocervical columnar cells is more complex than previously suggested. In particular, the keratins occurring in reserve cells are also present in most of the premalignant and in a considerable number of the malignant lesions of the cervix. The differentiation features of the various carcinoma types are, however, reflected in their specific keratin filament composition.     

The Diagnostic Significance of Intracytoplasmic Lumina in Metastatic Neoplasms

The diagnostic significance of intracytoplasmic lumina (ICL) was evaluated in a series of 61 consecutive and unselected metastatic neoplasms in lymph nodes, soft tissues, and bone studied by light and electron microscopy. Their only common denominator was a light microscopic diagnosis of “metastatic tumor of unknown primary site.”

With only rare exceptions, all previous reports of ICL on neoplastic cells deal with glandular organs or organs in which a glandular “metaplasia” may occur. Since primary or metastatic lesions of poorly differentiated squamous carcinomas, melanomas, and lymphomas may often cause problems in the differential diagnosis of poorly differentiated metastases, we also studied a large series of these neoplasms to see if they exhibited ICL.

Our study shows that when ICL are present in a metastatic carcinoma of undetermined primary site, the breast is the most likely site of the primary tumor, but that the clinical context may, and often does, modify the validity of this criterion. Our demonstration of ICL in two adnexal carcinomas of sweat and meibomian glands should discourage pathologists from jumping to a conclusion of a metastatic breast carcinoma whenever ICL are found in a tumor in the skin.

The presence of ICL seems to rule out the possibility of the neoplasm being a squamous carcinoma, a lymphoma, or a malignant melanoma.

Histochemical techniques were useful in diagnosing cases of mesotheliomas and adenomatoid tumors in which ICL are positive with Alcian blue but become negative after hyaluronidase digestion. The notion that mucicarmine positivity might exclude breast carcinoma was not confirmed in our study.     

Lectin binding to normal, dysplastic, and neoplastic cervical epithelium

Avidin-biotin-peroxidase labeling technic was used to localize the binding sites of Concanavalin agglutinin (Con A), Ricinus communis (RCA-I), Ulex europaeus (UEA-I), and Limus flafus (LFA) in the cervical epithelia afflicted with condyloma (2 cases), moderate dysplasia (6), severe dysplasia (3), carcinoma in situ (9), squamous cell carcinoma (18), adenosquamous carcinoma (2), adenocarcinoma (1), and glassy cell carcinoma (1). Normal squamous epithelium displayed binding sites predominantly located on the cellular membranes for all the tested lectins except UEA. Normal glandular epithelium showed cytoplasmic localization of the lectins. Neoplastic transformation of squamous epithelium was associated with an increased intensity of the reaction and the appearance of the binding sites in the cytoplasm. UEA binding has changed from negative in normal epithelium to moderately positive in dysplasia and strongly positive in carcinoma. Invasive squamous carcinomas demonstrated an extremely variable pattern of lectin binding, some with very high intensity, allowing easy recognition of malignant cells even in minute metastatic foci.     

Ultrastructural study of the ciliated cells from renal tubular epithelium in acute progressive glomerulonephritis

Light microscopic examination of the renal tubular epithelium of a female with a rapid progressive glomerulonephritis revealed in several areas the presence of cells bearing ciliumlike structures.

At transmission electron microscopy, normal tubular cells appeared to be partially replaced by epithelial cells showing numerous 9×2 cilia and a normally developed basal apparatus. The cilia showed several ultra-structural details (i.e., outer dynein arms, spokes) such as observed in kinocilia of the respiratory epithelium. In addition, a number of poorly differentiated cells showing cilia with a 9 + 0 pattern and at the same time cilia with a 9 + 2 pattern of microtubular arrangement were also seen.

The possible biologic significance of these cilia is discussed.     

Cytochemistry and Ultrastructure of Normal and Neoplastic Cells Exfoliated from the Human Uterine Cervix

Cells exfoliated from the uterine exocervix from normal women at different stages of the reproductive period and from patients with invasive carcinoma were studied. Cell pellets were fixed in aldehydes and two different concentrations of OsO₄, and embedded in methacrylate or Epon. Semithick sections were used for general light microscopic study and for the visualization of glycogen. Ultrathin sections were used for (1) conventional electron microscopy, (2) high resolution analysis of the plasma membrane, and (3) the demonstration of glycogen and cell surface glycoconjugates by the Thiery method. Semithick sections stained with the Thiery method and viewed under the electron microscope were used for the study of surface projections.

Based on the size, shape, nuclear characteristics, amount and distribution of glycogen, type of surface protrusions, density and distribution of surface glycoconjugates, and plasma membrane fine structure, the cells exfoliated from all normal uterine cervices were grouped into five cell types. It is suggested that these types correspond to cells located in the different layers of the exocervical epithelium and, consequently, represent different degrees of normal differentiation.

The plasma membrane of carcinoma cells shared most of the characteristic of that of the least differentiated normal cells, indicating an early deviation of the differentiation process in carcinoma cells.     

Loss of basement membrane components laminin and type IV collagen parallels the progression of oral epithelial neoplasia

Aims : To determine the immunohistochemical localization of basement membrane components laminin and type IV collagen in premalignant and malignant lesions of the oral epithelium.  

Methods and results

Formalin-fixed tissue sections of 12 epithelial hyperplasias with no dysplasia and 30 dysplasias, clinically diagnosed as leukoplakia and/or erythroplakia, as well as 50 invasive squamous cell carcinomas, were stained with mouse monoclonal antibodies to human laminin and type IV collagen. Statistical analysis showed that there was a linear trend for discontinuous distribution of laminin from epithelial hyperplasia to epithelial dysplasia and invasive squamous cell carcinoma ( P  < 0.001). Laminin staining showed a linear trend for discontinuity with increasing grade of dysplasia ( P  < 0.05) and was more frequently discontinuous in areas of deep tumour invasion than in central or superficial areas ( P  < 0.05). Brush-shaped thickening and reduplication of the basement membrane were also identified.  

Conclusions

Alterations in the distribution of laminin and type IV collagen in oral premalignant and malignant lesions indicate that the loss of continuity of the subepithelial basement membrane parallels the progression of the neoplastic transformation process in oral epithelium.     

Induced expression of syndecan-1 in the stroma of head and neck squamous cell carcinoma.

Syndecan-1 (CD138), a cell-surface heparan sulfate proteoglycan, is involved in cell-cell, cell-matrix interaction and growth factor binding. Loss of expression of syndecan-1 in tumor cells leads to decreased intercellular cohesion, increased potential for tumor invasiveness, and metastatic spread. Furthermore, induction of syndecan-1 expression in the tumor stroma has been postulated to promote tumor angiogenesis via its binding to growth factors such as basic fibroblast growth factor. Although syndecan-1 expression within tumor cells has been investigated in head and neck squamous cell carcinoma, stromal expression has not been studied in detail. We analyzed 38 cases of head and neck squamous cell carcinoma by immunohistochemical staining for syndecan-1 expression within the stroma. The expression of syndecan-1 within tumor cells of various histologic grades of differentiation, squamous cell carcinoma in situ cells, and benign squamous epithelium was also determined. Variable levels of diminished syndecan-1 expression were noted within the dysplastic cells of 9 of 16 (60%) squamous cell carcinoma in situ lesions and in all 38 (100%) invasive squamous cell carcinoma. In general, higher levels of syndecan-1 expression were observed in the well-differentiated tumors, in contrast to significant reduction of expression seen in poorly differentiated tumors. Syndecan-1 expression was observed within the stroma (in fibroblasts) surrounding infiltrating carcinoma cells in 28 of 38 (74%) cases. The intensity of syndecan-1 staining within the stroma showed generally an inverse correlation with the degree of tumor cell differentiation. Syndecan-1 expression was not detected in the stroma beneath normal squamous epithelium or adjacent to areas of squamous cell carcinoma in situ. We conclude that induced expression of syndecan-1 in the stroma surrounding tumor cells of invasive head and neck squamous cell carcinoma is a frequent event. The increased stromal syndecan-1 expression, coupled with its loss from the surface of carcinoma cells, may contribute to tumor cell invasion and the development of metastases.     

Evaluation of p16INK4a and pRb expression in cervical squamous and glandular neoplasia

p16(INK4a) is known to play a critical role as a negative regulator of cell cycle progression and differentiation by controlling the activity of the tumor-suppressor protein pRb. The present study evaluated the expression of p16(INK4a) and pRb in cervical squamous and glandular neoplasia. Immunohistochemical staining was performed for p16(INK4a) and pRb in formalin-fixed, paraffin-embedded tissue sections of the uterine cervix using an indirect immunoperoxidase method. p16(INK4a) staining was detected in 7 of 108 sections (6.5%) of normal squamous mucosa, in scattered ciliated columnar cells in 33 of 88 sections (37.5%) of normal endocervical glands, in 9 of 30 sections (30%) with Nabothian cysts, and in 4 of 4 areas (100%) of tubal metaplasia. In contrast, strong p16(INK4a) staining was found in 13 of 18 cases (72.2%) of cervical intraepithelial neoplasia (CIN) I and in all cases of CIN II/III (n = 46), squamous cell carcinoma (n = 18), endocervical glandular dysplasia (n = 10), adenocarcinoma in situ (n = 23), and invasive adenocarcinoma (n = 12). pRb expression was detected in each diagnostic category; however, the proportion of pRb-positive cells was relatively decreased in high-grade premalignant and malignant lesions of the squamous and endocervical mucosa and showed a generally inverse correlation with the expression of p16(INK4a) at the tissue level. These findings confirm a correlation between the expression of p16(INK4a) and pRb in cervical neoplasias and indicate that p16(INK4a) is a specific marker for premalignant and malignant lesions of the squamous and endocervical mucosa.     

Small Cell Undifferentiated Carcinoma of the Uterine Cervix: Histology, Ultrastructure, and Immunohistochemistry of Two Cases

Two clinical stage IB small cell undifferentiated carcinomas (SCUC) of the cervix were studied by light and electron microscopy and immunohistochemistry. Both cases occurred in women aged less than 31 years. Despite radical hysterectomy and external pelvic radiotherapy, both patients died of recurrent disease within 14 months after initial therapy. The tumors consisted of sheets of closely packed, uniform small, round to oval cells with hyperchromatic nuclei and scant indistinct cytoplasm. One case was associated with cervical squamous cell carcinoma. The neoplastic cells had few organelles and desmosome-like junctions and lacked mucinous or neurosecretory granules or tonofilaments. Immunohistochemistry failed to reveal S-100, CEA, neuropeptides or neuron-specific enolase.

SCUC probably arises either from basal cells of the cervical squamous epithelium, or gland cells of the endocervical epithelium, or still from subcolumnar endocervical reserve cells. Based on ultrastructure and immunohistochemistry, SCUC seems to represent the undifferentiated variant of small cell neuroendocrine tumors of the cervix.     

Impairment of Non-Specific Immunity in Patients in Persistent Vegetative State

In fourtheen patients in persistent vegetative state (PVS) immune responsivenes was investigated. In particular, we studied the relationship between brain lesions following traumatic injury and immune system. In this respect, phagocytosis and killing of Candida albicans by polymorphonuclear cells (PMN) and monocytes were tested. In addition serum levels of Interferon-γ (IFN-γ) were evaluated.

The patients come out fiom PVS by 3-4 month were used as control group.

Data shown a profound impairement of phagocytosis and killing of monocytes and low serum levels of IFNγ when compared with normal values.

Taken together, these findings suggest that brain lesions, may affect non-specific immune response.     

Pseudoneoplastic lesions of the uterine cervix

The differential diagnosis of malignant and premalignant lesions of the uterine cervix includes numerous non-neoplastic conditions which may show overlapping morphological features. Recognizing these mimics is crucial in order to spare the patient unnecessary surgical procedures with potential side effects, as well as the psychosocial consequences associated with the diagnosis of HPV-infection and/or (pre)malignancy. This article reviews benign entities that may be mistaken for neoplastic lesions of the cervix. Conditions of the ectocervical squamous epithelium, the endocervical glandular epithelium and the cervical stroma are systematically discussed in the context of the respective (pre)malignant lesion that they may be confused with, including low and high-grade squamous intraepithelial lesions, invasive squamous cell carcinoma, adenocarcinoma in-situ, various types of invasive adenocarcinomas, and sarcomas. Emphasis is placed on those features that help distinguish pseudoneoplastic lesions from true neoplasms, including clinical information, morphologic findings and ancillary studies.     

Phenotypic alterations of a carbohydrate antigen, blood group A type 3 chain, in neoplastic transformation of uterine cervix

A monoclonal antibody, MRG-1, was established by use of a human ovarian mucinous cyst-adenocarcinoma-derived cell line, RMUG-L, as immunogen. Following its establishment, biochemical analysis revealed that its epitope was blood group A type 3 chain. Using MRG-1 as an immunohistochemical probe, uterine cervical neoplastic lesions including dysplasia, carcinomain situ, and invasive carcinoma were investigated. Light-microscopically, normal squamous epithelium showed a strong positive reaction along the cell surface region exclusively in the intermediate cell layer. On the other hand, intracellular structures were very often strongly stained in squamous cell carcinoma. Under the electron microscope, MRG-1 binding sites in squamous cell carcinoma cells were found to be in intracytoplasmic vesicular structures as well as in the plasma membrane. This marked difference in the antigen distribution was found to be a phenomenon associated with cervical neoplastic transformation.     

Molecular analysis of oral lichen planus. A premalignant lesion?

Oral lichen planus (OLP) is a common mucosal condition that is considered premalignant by some, although others argue that only lichenoid lesions with dysplasia are precancerous. To address the question of whether OLP without dysplasia is premalignant, we used microsatellite analysis to examine 33 cases of OLP for allelic loss at nine loci located on chromosomes 3p, 9p, and 17p. Loss of heterozygosity (LOH) on these three arms occurs frequently in oral tumors, and the presence of these alterations in premalignant lesions suggests that they may play an important role in tumor progression. Results were compared with those observed in oral dysplasias (10 mild, 11 moderate, 16 severe/carcinoma in situ), 22 oral squamous cell carcinomas, and 29 reactive lesions. LOH was present in 6% of OLP, 14% of reactive lesions, 40% of mild dysplasia, 46% of moderate dysplasia, 81% of severe dysplasia/carcinoma in situ, and 91% of squamous cell carcinomas. LOH was detected on only a single arm in OLP and reactive lesions but occurred on more than one chromosome in dysplasia and cancer, and the frequency of this multiple loss correlated significantly with increasing degrees of dysplasia and progression into squamous cell carcinoma (P = 0.0028). Although these findings do not support OLP as a lesion at risk for malignant transformation, such results need to be confirmed by use of other genetic markers as OLP may undergo malignant transformation through genetic pathways different from those of oral dysplasia.     

Overexpression and altered subcellular localization of autophagy-related 16-like 1 in human oral squamous-cell carcinoma: correlation with lymphovascular invasion and lymph-node metastasis

Autophagy is a dynamic process of subcellular degradation, which has recently sparked great interest because it is involved in various developmental processes and various diseases including cancer. Autophagy-related 16-like 1 is a component of a large protein complex essential for autophagosome formation. We previously applied proteomic methods to characterize differentially expressed proteins in oral squamous cell carcinoma cells and detected significantly high expression levels of autophagy-related 16-like 1 in oral squamous cell carcinoma-derived cell lines compared to human normal oral keratinocytes. In the current study, to further determine the potential involvement of autophagy-related 16-like 1 in oral squamous cell carcinoma, we evaluated the state of autophagy-related 16-like 1 protein expression in human oral premalignant lesions and primary oral squamous cell carcinomas, and correlated the results with clinicopathologic variables. Autophagy-related 16-like 1 immunoreaction was predominant in a variety of subcellular components of oral squamous cell carcinoma tissues, including the cytoplasm and plasma membrane of malignant cells (45% and 39%, respectively) and peritumoral and intratumoral stroma (52%), whereas all of the components in normal tissues had no or faint autophagy-related 16-like 1 expression. In addition, high stromal expression of autophagy-related 16-like 1 was associated significantly with lymphovascular invasion of tumor cells (P = .037) and positive lymph node status (P = .015). Furthermore, cytoplasmic and plasma membranous autophagy-related 16-like 1 were also expressed in abundance in the oral premalignant lesion cells (74% and 32%, respectively). Our finding suggests that dysregulation of autophagy-related 16-like 1 protein expression is a frequent and early event during oral carcinogenesis and could affect the malignant behavior of oral squamous cell carcinoma cells.     

Analysis of promoter hypermethylation of death-associated protein kinase and p16 tumor suppressor genes in actinic keratoses and squamous cell carcinomas of the skin.

Death-associated protein kinase is a serine/threonine protein kinase implicated in promoting apoptosis and tumor suppression, whereas p16 is a tumor suppressor gene that inhibits cyclin-dependent kinase 4 and 6 activity and arrests the cell cycle in the G1 phase. Hypermethylation of death-associated protein kinase or p16 gene with resultant gene inactivation has been described in a wide variety of human cancers. Promoter methylation of the death-associated protein kinase and p16 gene has been found in about 55% and 30% cases of head and neck squamous cell carcinoma respectively but has not yet been analyzed in cutaneous premalignant and malignant lesions. A total of 33 cases were examined for evidence of death-associated protein kinase and p16 hypermethylation and these consist of 9 cases of spongiotic dermatitis as nonneoplastic skin control, 9 cases of actinic keratosis, 8 cases of squamous cell carcinoma in situ, and 7 cases of invasive squamous cell carcinoma. Death-associated protein kinase promoter methylation was detected in 1 case of squamous cell carcinoma in situ and 1 case of nonneoplastic skin control but none of the cases of invasive squamous cell carcinoma or actinic keratosis. P16 promoter methylation was detected in 1 case of invasive squamous cell carcinoma and 1 case of nonneoplastic skin control but none of the cases of squamous cell carcinoma in situ or actinic keratosis. Promoter hypermethylation of the death-associated protein kinase and p16 genes does not appear to play an important role in the development of cutaneous squamous cell carcinoma. The data thus suggest that the mechanisms of ultraviolet-induced cutaneous carcinomas differ from those involved in the development of head and neck squamous cell carcinoma, a malignant disease induced by tobacco and alcohol exposure.     

Suprabasal 40 kd keratin (K19) expression as an immunohistologic marker of premalignancy in oral epithelium.

The authors have studied the expression of keratin 19 in normal oral mucosa and in oral lesions exhibiting a range of histopathologic changes that are thought to precede squamous cell carcinoma. Formalin-fixed, paraffin-embedded sections were pretreated with pronase and stained with a K19-specific antibody by the avidin-biotin immunoperoxidase method. In nonkeratinized mucosa, whether normal or benign hyperplastic, K19 was detectable in the basal cell layer. In keratinized mucosa, whether normal or benign hyperplastic, there was no detectable K19. All lesions from any oral site that exhibited atypia diagnosed from hematoxylin and eosin stained sections as moderate-to-severe dysplasia or carcinoma in situ, whether hyperkeratotic or not, stained strongly for K19 in the basal and suprabasal cell layers. The number of cell layers that were K19-positive correlated with the level in the epithelium to which dysplasia persisted. Suprabasal K19 staining tended to occur in regions of the epithelium in which expression of the terminal differentiation protein involucrin was delayed or absent. Thus, K19 expression may be linked to the retention of stem cell character or a state otherwise uncommitted to terminal squamous differentiation. Suprabasal K19 staining is clearly correlated with premalignant change in oral epithelium and therefore promises to be a useful tool in oral histopathologic diagnosis.     

Carcinoma with Multidirectional Differentiation Arising in Barrett's Esophagus

Four cases of esophageal carcinoma arising in metaplastic Barrett's epithelium are presented in which multidirectional differentiation was demonstrated by light and/or electron microscopy and immunohistochemistry. All tumors and adjacent mucosa produced both neutral and acidic mucins, as well as one or more hormones indigenous to the gut, including gastrin, bombesin, substance P, somatostatin, and serotonin. Gastrin and somatostatin were the peptides most frequently identified in the tumors, while somatostatin and serotonin predominated in Barrett's epithelium. Ultrastructurally, neurosecretory-type granules, 80-250 nm in diameter, were present in 2 cases; squamous features also were present in one of these cases. One patient displayed hypertrophic osteoarthropathy, which disappeared after the tumor was resected.

These cases represent the majority of the Barrett-associated carcinomas in our material. Compared to the “pure” esophageal adenocarcinomas not included in this report, these tumors behaved more aggressively, with wider local involvement and nodal and systemic metastases at the time of presentation.

The incidence of multidifferentiation in esophageal carcinomas is not known nor is its possible significance, particularly with regard to tumors arising in metaplastic epithelium. This group may merit further study to detect true differences, if any, between these esophageal carcinomas and their apparently more common counterparts.