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Perinuclear dot-like cytokeratin 20 staining in small cell neuroendocrine carcinoma of the ovary (pulmonary-type).

Primary ovarian small cell carcinomas are rare tumors that are subclassified into the hypercalcemic (HT) and the pulmonary type (PT), and each tumor type has different clinicopathologic characteristics. However, overlapping morphologic features can make the distinction between these lesions difficult. The PT small cell carcinoma is very rare, with only one series and a few case reports published. The authors report two additional cases of this entity and also report for the first time the immunohistochemical finding of perinuclear dot-like staining with cytokeratin 20. This staining pattern has been reported only for Merkel cell carcinoma and salivary gland small cell carcinoma. The authors suggest that the punctate CK20 staining is a useful tool in the diagnostic distinction of PT small cell carcinoma from HT small cell carcinoma, from other primary ovarian tumors such as granulosa cell tumors, and from metastatic neuroendocrine tumors originating at primary sites such as the lung. Since the authors' conclusions are based on two cases of this rare entity, additional cases will need to be studied in the future.

Adult↗

Cutaneous cysts of Gardner's syndrome are similar to follicular stem cells.

Cutaneous cysts from a patient with Gardner's syndrome were histopathologically studied in detail. The cysts were, by and large, indistinguishable from ordinary epidermal cysts. However, several distinctive features were found: 1) epidermal or trichilemmal keratinization, 2) mature sebaceous glands connected with the cyst wall, 3) hair matrix-like structures associated with dermal papilla cells, 4) pilomatricoma-like changes, 5) intraluminal masses or pericystic deposits of shadow cells variably accompanied with foreign body reaction, 6) foreign body reaction or masses of shadow cells lining completely eroded cysts, 7) the presumptive bulge area, and 8) epithelial islands adjacent to the cyst. Each cutaneous cyst showed a variable combination of the findings described above. Foci of the basal layer of some cyst walls or epithelial islands were immunohistochemically stained with CK19, where CK20-reactive Merkel cells were also present. These findings were consistent with those of the bulge area. Unexpectedly, desmin-reactive muscle bundles, presumably indicating arrector pili muscle, were observed along the cyst wall. Our observations suggest that Gardner's cysts may be derived from putative follicular stem cells which reside in the bulge area.

Adult↗

The value of cytometric DNA analysis as a prognostic tool in neuroendocrine neoplastic diseases.

In several traditionally non-endocrine, common, human, neoplastic diseases, it has become well established during the last few years, that cytometric analyses of the DNA distribution pattern of the nuclei of tumour cells can be an excellent supplement to the conventional prognostic tools, (such as clinical staging and histopathologic malignancy assessments). When analogous studies of the value of DNA analysis by means of flow cytometry and/or image cytometry are made in neuroendocrine (NE) neoplastic diseases, the ensuing results often become rather disappointing. Thus, clear-cut aneuploid DNA histograms can be found in the neoplastic cell nuclei of clinically and histopathologically completely benign NE adenomas (and even hyperplastic nodules). In contrast, highly aggressive NE carcinomas not seldom reveal themselves to be composed of tumour cells with nuclei, displaying an euploid, i.e. normal, DNA pattern. Statements of this kind have been based on the results of comprehensive investigations in several laboratories, analysing such NE tumours as insulomas/insular carcinomas, bronchial/gastrointestinal carcinoids, phaeochromocytomas, paragangliomas, neuroblastomas, adenomas of the anterior pituitary gland, parathyroid adenomas, medullary carcinoma of the thyroid and Merkel-cell tumours of the skin. Thus, the prognostic value of the cytometric DNA ploidy pattern of the nuclei of neoplastic parenchymal cells is definitely lower in NE tumours than in most of the traditionally non-endocrine carcinomas and sarcomas. Data from published and unpublished series of these kinds of NE tumours, and those of prostatic and breast carcinomas with NE differentiation, are given. By means of a new, consecutive double staining technique, it was shown that in idiopathic nesidioblastosis, the hyperinsulinism is caused by beta cells with a nuclear DNA ploidy pattern of euploid type. By the same technique, it can be shown that in the pathogenesis of the hypergastrinaemia-induced ECL-cell carcinoids of the stomach, a switch from an euploid to an aneuploid nuclear DNA distribution pattern occurs in the ECL-cells when they pass from a state of hyperplasia to that of a genuine neoplasia. In neuroblastomas, a triploid (i.e. aneuploid) DNA pattern is part of an algorithm capable of predicting a 96% survival rate, whereas a diploid/tetraploid (i.e. euploid) DNA pattern predicts a 0% survival.

DNA, Neoplasm↗

Immunohistochemical studies in endocrine carcinoma of the skin.

Twenty-two endocrine carcinomas of the skin were examined immunohistochemically for the presence of several polypeptides and serotonin. Eight tumors contained one or more polypeptides. Occasional cells containing calcitonin were found in several tumors. Rare cells with substance P, somatostatin, and ACTH were present in only one tumor each. None of the patients presented a clinical syndrome associated with any of these polypeptides. Met-enkephalin and serotonin were negative in all tumors. The lack of demonstration of met-enkephalin in these tumors makes their relationship to the Merkel cell uncertain.

Adenocarcinoma↗

Fine-structural characterization of the somatic innervation of the tympanic membrane in normal, sympathectomized, and neurotoxin-denervated rats.

The pars tensa of the rat tympanic membrane (TM) consists largely of a lamina propria of specialized unbanded collagen bounded on the outer surface by an unusually thin epidermal layer and on the inner surface by a flat, single-cell mucosal layer. The mucosal layer is innervated solely by unmyelinated (C) axons, whereas the cutaneous layer is supplied by both myelinated and C axons. The outer surface differs from general body skin, lacking dermal papillae, hairs, sweat glands, and distinctive dermal corpuscular structures. Epidermal innervation includes distinctive terminals in the basal layer, unassociated with Merkel cells, and deeper intraepidermal smaller endings containing accumulations of mitochondria and vesicles. The sensory nature of these endings can be inferred by their extensive, but not total, elimination following neonatal capsaicin treatment (a potent neurotoxin for thin sensory fibers) and their preservation following surgical or neurotoxin sympathectomy. The thin mucosal epithelium displays capillaries and beaded axons close to the free surface of the middle ear. The unmyelinated terminals contain predominantly large, dense-core vesicles (LDCVs). Capsaicin treatment results in extensive elimination of terminals containing LDCVs in surface epithelia. A possible small trophic influence of sensory thin-fiber supply was noted on the development of the epidermal layers. The sensory modalities elicited by natural stimulation of the TM is considered in relation to the pattern of innervation.

Animals↗

Primary small cell carcinoma of skin. Histogenetical study.

Four cases of primary small cell carcinoma of the skin (PSCCS) are presented (ages ranging from 60 to 68 years). Ultrastructurally, two cell types were identified, with both presenting electron-dense secretory granules and paranuclear intermediate filaments. Argyrophylia was positive in one case. Intense solar elastosis in two cases and actinic keratosis in one case suggest a possible role from solar damage in the pathogenesis of this tumor. According to comparative ultrastructural features, different histogenetic possibilities in Merkel cells (MC), peripheral neuroblastic tissue, and totipotential cells are discussed. Some neurosecretory-like granules were observed in basal cell carcinoma (BCC). We consider that PSCCS reproduces cells similar to MC and probably originates in stem cells with totipotential capacity.

Aged↗

[Tumors of the eyelids in the elderly].

The clinical aspect of tumors of the eyelids is polymorphous; however, the most frequent are benign tumors such as papillomas, basal cell carcinoma, squamous cell carcinoma, meibomian gland carcinoma, and melanomas. An important step in the management of the malignant types is to try to establish clear margins through histopathologic techniques: the Mohs technique, the rapid fixation technique, and the frozen section method are the most frequent technical tools used today. For the most malignant tumors such as malignant melanoma and Merkel cell tumor, lymph sentinel biopsy is a recent, valuable tool, but its benefit needs to be confirmed in large series.

Aged↗

Skin cancers in organ transplant recipients.

Organ transplant recipients on immunosuppressive therapy are prone to skin cancers, especially squamous cell carcinomas developing on sun-exposed areas. Their frequency increases with time after transplantation reaching 40-70% of the patients after 20 years. Squamous cell carcinomas tend to be multiple and may have a life-threatening course. Most studies concern kidney transplant recipients but new data are now available on recipients of other organs. Carcinogenic factors include mainly immunosuppressive treatments, UV light and human papillomaviruses; the role of genetic factors is more equivocal. Melanomas and other rare tumors such as Merkel cell tumors or sarcomas are also increased. Surgical excision with histological examination represents the treatment of choice. When lesions become multiple and/or aggressive, additional therapeutic methods are necessary, such as topical or oral retinoids and in some cases, reduction of the immunosuppressive treatment. Radiotherapy should be reserved to limited cases. Prevention must be undertaken by a regular dermatological examination and sun protection.

Carcinoma, Squamous Cell↗

[Cutaneous tumors in organ transplant recipients].

THE CONTEXT: With the improvement in transplant in surgery, organ storage techniques and immunosuppressive treatments, the number of organ transplant recipients is regularly increasing. To preserve the activity of the graft, immunosuppressive treatment is required for life in most cases, leading to prolonged immunodeficiency. These patients exhibit an increased risk of cancer, notably of tumors associated with viruses such as carcinomas, Kaposi's sarcoma and lymphomas. THE DIFFERENT CANCERS CONCERNED: Cutaneous cancers, notably squamous cell carcinomas, are the predominant cancers encountered in transplant recipients and affect around half of the patients within 20 years following the transplant. Squamous cell carcinomas tend to be multiple, may be life-threatening, and appear to predict the onset of other cancers. Exposure to UV, immunosuppression, the relatively old age at the time of the transplant, light skinned phototype, genetic factors and papillomavirus infections are all factors of risk. Other photo-induced tumors, such as melanoma, some sarcomas or Merkel cell carcinomas also appear increased and of severe prognosis. MEASURES OF PREVENTION: The prevalence of these tumors could be reduced by educating the patients on strict sun-protection measures following the transplant. The factors enhancing Kaposi's sarcoma associated with the HHV8 virus remain to be defined. The possibility of transmission of the infection through the graft must lead to the systematic search for this virus in the donors.

Carcinoma, Squamous Cell↗

Target-derived BMP signaling limits sensory neuron number and the extent of peripheral innervation in vivo.

The role of target-derived BMP signaling in development of sensory ganglia and the sensory innervation of the skin was examined in transgenic animals that overexpress either the BMP inhibitor noggin or BMP4 under the control of a keratin 14 (K14) promoter. Overexpression of noggin resulted in a significant increase in the number of neurons in the trigeminal and dorsal root ganglia. Conversely, overexpression of BMP4 resulted in a significant decrease in the number of dorsal root ganglion neurons. There was no significant change in proliferation of trigeminal ganglion neurons in the noggin transgenic animals, and neuron numbers did not undergo the normal developmental decrease between E12.5 and the adult, suggesting that programmed cell death was decreased in these animals. The increase in neuron numbers in the K14-noggin animals was followed by an extraordinary increase in the density of innervation in the skin and a marked change in the pattern of innervation by different types of fibers. Conversely, the density of innervation of the skin was decreased in the BMP4 overexpressing animals. Further Merkel cells and their innervation were increased in the K14-noggin mice and decreased in the K14-BMP4 mice. The changes in neuron numbers and the density of innervation were not accompanied by a change in the levels of neurotrophins in the skin. These findings indicate that the normal developmental decrease in neuron numbers in sensory ganglia depends upon BMP signaling, and that BMPs may limit both the final neuron number in sensory ganglia as well as the extent of innervation of targets. Coupled with prior observations, this suggests that BMP signaling may regulate the acquisition of dependence of neurons on neurotrophins for survival, as well as their dependence on target-derived neurotrophins for determining the density of innervation of the target.

Animals↗

The promise of molecular targeted therapies: protein kinase inhibitors in the treatment of cutaneous malignancies.

A new revolution in cancer therapy has arrived with the development of agents targeting cancer-related protein kinases, critical regulators of malignant behavior. These drugs are selective inhibitors of protein kinases, which mediate most signal transduction pathways in malignant cells and result in increased proliferation, evasion of apoptosis, invasion, and metastasis. Protein kinases are the second largest group of drug targets and they account for 20% to 30% of the drug discovery programs of many biotechnology and pharmaceutical companies. A critical review of the literature is performed, highlighting selective inhibitors of signal transduction molecules involved in nonmelanoma skin cancer, melanoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, Kaposi's sarcoma, and systemic mastocytosis. Clinical studies were identified by searches of the Proceedings of the American Society of Clinical Oncology Annual Meetings, MedLine, and www.clinicaltrials.gov. Clinical trials of kinase inhibitors in study populations are illustrated, highlighting early results, side effects, and potential improvements in outcomes. Case series and case reports were included for rare diseases. These drugs will have important implications in clinical dermatology, based on their expected frequent use in the treatment of dermatologic malignancies, and their associated cutaneous side effects.

Clinical Trials as Topic↗

[Cutaneous complications after organ transplant].

FREQUENT DIVERSE COMPLICATIONS: Skin problems in organ recipients mainly result from the induced immunosuppression but also from specific adverse effects of immunosuppressive drugs. The degree of extension and gravity of the clinical manifestations are often proportional to the intensity and/or duration of the immunosuppressive therapy. Immunodepression mainly leads to infectious and neoplastic complications. INFECTIONS: Viral and fungal infections are the most frequently encountered. Herpes simplex and zoster infections require treatment to prevent visceral involvement. Human papillomavirus infections occur in 80% of patients 5 years after transplantation and can lead to malignant transformation. Fungal infections include pityriasis versicolor and often extensive dermatophytosis. CANCER: Increased rate of cancer occurs especially in patients with viral disease. Skin cancers involving papillomavirus are the most frequent cancers observed in transplant recipients, occurring in half of the long-term survivors. Squamous cell carcinoma of exposed areas are the most common; they are often more aggressive than in non-immunodepressed patients (multiple sites, recurrence). Exposure to sun is a proven inducer. There is a 500-fold higher risk of Kaposi disease linked to HHV8 virus. This disease can regress simply after reducing the immunosuppressive treatment. Other more uncommon tumors such as lymphomas, melanomas, sarcomas and Merkel cell tumors also appear to occur at an increased rate in transplant recipients. PREVENTION: Most malignant skin tumors are the expression of marked immunodepression and their prognosis is improved with reduction in immunosuppressive therapy. Prevention requires regular dermatology work-ups and counseling about strict protection from sun exposure.

Graft Rejection↗

Keratin expression in taste bud cells of the circumvallate and foliate papillae of adult mice.

The patterns of keratin expression of taste buds in murine oral mucosa were examined using a panel of antibodies with various specificities for cytokeratins. The patterns for taste buds differed markedly from those of the surrounding epithelium but no regional differences in the staining patterns of the taste buds themselves were detected. The taste buds and the ducts of von Ebner's glands were strongly stained by monoclonal antibodies (mAbs) against cytokeratins (K) 8, 18 and 19, those typically expressed by simple epithelia. Merkel cells, which are also present in the oral epithelium and may correspond to the type III cells in taste buds, stained for K8 and K18 but not K19. None of the mAbs against simple epithelial keratins stained the stratifying epithelium of the trench wall or of the oral mucosa. Antibodies with specificity for keratins that are expressed as differentiation products of the mucosal epithelium did not stain taste buds. The staining pattern of the epithelium of the trench wall indicated that it expressed some keratins typical of stratifying epithelia but lacked the full pattern of differentiation of the adjacent mucosal epithelia. Staining within the taste buds was not homogeneous but no clear differences of keratin staining could be directly related to the subtypes of cells constituting them. The markedly differing patterns of keratin expression between taste buds and the adjacent epithelium raises questions about the type of inductive signals that produce and maintain these patterns.

Animals↗

Cytokeratins in the histological diagnosis of malignant tumors.

Cytokeratins, which comprise a multigene family of 20 related polypeptides (CKs 1-20), are constituents of the intermediate filaments of epithelial cells, in which they are expressed in various combinations depending on the epithelial type and the degree of differentiation. Of these, CK 19 (400 amino acids; 44.1 kilodaltons) is an example of a widely distributed CK, being expressed in various epithelia, including many simple epithelia. In contrast, the recently identified CK 20 (424 amino acids; 48.6 kilodaltons) is essentially confined to gastrointestinal epithelia, the urothelium and Merkel cells. The differential expression of individual CKs in various types of carcinomas makes them useful markers for histopathological carcinoma subtyping, providing relevant information concerning the differentiation and origin of carcinomas, especially when tumors first present as metastases. The CKs that are of particular value for differential diagnosis include CK 20, as it is mainly expressed in carcinomas derived from CK 20-positive epithelia; it is also found in bile-tract, pancreatic and mucinous ovarian adenocarcinomas, being absent in most other carcinomas. In certain carcinoma types, the changes in the expression of individual CKs that may occur during tumor progression could be of prognostic relevance. It remains to be established whether the serological detection of fragments of not only widely distributed but also more restrictedly expressed CKs may provide useful serological tumor markers in the future.

Antibodies, Monoclonal↗

Immunohistologic localization of corticotrophin-releasing hormone in human tumors.

The authors investigated formalin-fixed, paraffin-embedded human tissues for the presence of corticotrophin-releasing hormone (CRH) using the avidin-biotin-peroxidase technic. Immunopositivity was demonstrated in nontumorous hypothalami, 1 of 8 hypothalamic gangliocytomas, 3 of 9 bronchial endocrine tumors, 1 of 30 small cell lung carcinomas, 1 of 8 ileal endocrine neoplasms, 2 of 20 pancreatic endocrine tumors, 2 of 10 medullary thyroid carcinomas, and 1 of 3 small cell prostate carcinomas. Of the tumors containing immunoreactivity, most were associated with Cushing's syndrome; the ileal and thyroid tumors were not. Adrenocorticotrophic hormone was immunohistochemically localized in two bronchial and one pancreatic tumor, which contained CRH-like immunoreactivity. No CRH was detected in nontumorous extrahypothalamic tissues from which the CRH-containing tumors derived, two mediastinal endocrine carcinomas, six endocrine tumors of the stomach/duodenum/appendix, eight pheochromocytomas, one Merkel cell tumor, and 32 squamous and adenocarcinomas of the lung/gut. CRH-like immunoreactivity may be found in tumors composed of peptide-hormone-producing endocrine cells; hypersecretion of CRH by those neoplasms may be significant in the development of Cushing's syndrome.

Adolescent↗

Radiation therapy for skin tumors.

Radiation therapy is an acceptable alternative for the treatment of many malignancies of the skin. Results are gratifying, and long-term sequelae are few. In basal cell and squamous cell carcinomas, radiation is often the best treatment when surgery is expected to cause excessive morbidity or mortality or require extensive reconstruction. Radiation should be considered as first-line treatment for tumors in the midfacial triangle. It is also very acceptable treatment for Kaposi's sarcoma and mycosis fungoides. Radiation can be used for melanoma, although it is not standard first-line therapy. Radiation is probably the treatment of choice for Merkel cell carcinoma.

Facial Neoplasms↗

Localization of the expressed human p58 protein kinase chromosomal gene to chromosome 1p36 and a highly related sequence to chromosome 15.

The gene for the human p58 protein kinase, a cell division control-related gene, has been mapped by somatic cell hybrid analyses, in situ localization with the chromosomal gene, and nested polymerase chain reaction amplification of microdissected chromosomes. These studies indicate that the expressed p58 chromosomal gene maps to 1p36, while a highly related p58 sequence of unknown nature maps to chromosome 15. Assignment of a p34cdc2-related gene to 1p36 may have implications for numerous tumors that involve deletion of this region, including neuroblastoma, ductal carcinoma of the breast, malignant melanoma, Merkel cell carcinoma, and endocrine neoplasia.

Animals↗

[Undifferentiated salivary gland carcinomas].

Undifferentiated salivary gland carcinomas may be divided into small cell and large cell types. Among large cell undifferentiated carcinomas, lymphoepithelial carcinomas have to be distinguished, the latter of which are endemic in the Arctic regions and southern China where virtually all cases of these tumors are associated with the Epstein-Barr virus (EBV). Association with EBV may also be observed in sporadic cases, and detection of EBV gene products may aid their diagnosis. Immunohistology may be employed to resolve the differential diagnosis of undifferentiated salivary gland carcinomas, comprising malignant lymphomas, amelanotic melanomas, Merkel cell carcinomas, and adenoid cystic carcinomas, in particular in small biopsy materials. Because of the rarity of undifferentiated salivary gland carcinomas, the differential diagnosis should always include metastases of undifferentiated carcinomas arising at other primary sites, particularly when expressing the thyroid transcription factor-1 (TTF-1).

Cell Differentiation↗