Diagnosis of Malignant Melanoma by 5-S-Cysteinyldopa
We have developed a new diagnostic method for malignant melanoma by histo-chemical demonstration and chemical assay of 5-S-cysteinyldopa (5-S-CD) which is a main intermediate product of melanin metabolism. The diagnostic process for the primary lesion of malignant melanoma being performed at our department is as follows:
1. The stage is estimated by measuring urinary 5-S-CD value. 2. As a preoperative diagnostic method if it is an ulcerative lesion, touch-fluorescence method from the surface of the lesion and 5-S-CD value in the exudate in the gauze are made and if it is a non-ulcerative lesion, fine needle aspiration fluorescence method is used. 3. As a quick diagnostic method during operation touch-fluorescence method from the section of the lesion and measurement of 5-S-CD value in the lesion are made. 4. Decision of the morbid type is made from the fluorescence findings from the formalin-fixed and paraffin-embedded unstained specimen. 5. As a tumor marker, measurements are made of urinary and hematic 5-S-CD value with time.

抄録全体を表示

Quality control of patholgy diagnosis
Pathology diagnosis often becomes a final diagnosis for patients with cancer. Important information can be extracted from pathology specimen by pathologists and clinicians use this information as their guidance for clinical decision making. Although pathology diagnosis is important and useful, it suffers from a lack of objective criteria of diagnosis. This fact sometimes causes a significant discrepancy in diagnostic criteria among pathologists and laboratories. It has been demonstrated that the degree of discrepancy is significant enough to cause opposite diagnoses for difficult cases (e.g., benign vs. malignant). In order to minimize the discrepancy, quality control efforts, such as internal and external consultations, postgraduate education and application of objective methods (flow cytometry and image analysis), are necessary. In addition, the author has demonstrated that quality control of pathology diagnosis is required for multi-institutional clinical trials in which cases are collected from several institutions.

抄録全体を表示

Recently, many cases diagnosed as malignant trichilemmoma, or trichilemmal carcinoma, have been reported in Japan, however, the true nature and histogenesis of this bowenoid neoplasm are controversial, and its relationship to malignant proliferating trichilemmal tumor has not been fully elucidated. In this paper, reviewing the literatures, we discussed the concept and criteria of the neoplasm and analysed clinical, histopathological, and prognostic data of the Japanese reported cases. A few critical points regarding this entity were presented.

抄録全体を表示

Cell biological characteristics of the outer root sheath (ORS) of normal human hair follicle have been reviewed. In anagen hair follicle, two cell layers of the ORS are present at the outermost part of hair bulb. The inner one moves up and forms the innermost cell layer of the ORS as a single cell layer, which keratinizes at follicular isthmus after production of keratohyaline granules (KG). While, the outer one suddenly increases its cell number at the suprabulbar level and, above the level of keratogenous zone of hair cortex, these outer cells have clear cytoplasm containing glycogen. At the isthmus, they become longitudinally flattened in cell shape losing glycogen and keratinze toward hair canal without KG production, but with production of many lamellar granules. The basal lamina around the ORS gradually becomes thick up to 1 or 2μm in anagen and degenerated probably by collagenases secreted from retracting ORS in catagen. The ORS cells surrounding the club hair root are not rich in glycogen and show KG-absent keratinization. Stainings of BrdU, involucrin, desmosomes, keratins and lectins for the ORS have been introduced. In conclusion, the cell biological characteristics of trichilemmal tumors are similar in some points to, but different in many points from those of the normal ORS.

抄録全体を表示

Malignant trichilemmoma (MT) is cutaneous adnexal neoplasm of external hair sheath origin, whose histologic feature is often confused with those of malignant proliferating trichilemmal tumor (MPTT) . In order to investigate the possibility that MT might differ from MPTT clinically and histologically, we studied 37 cases of MT and 30 MPTT. MT regarded as the malignant counterpart of trichilemmoma, manifests as solitary keratotic or ulcerated nodules. MT is often misdiagnosed as Bowen disease. Microscopically MT consists of multiple intradermal epithelial lobules in continuity with the epidermis. The tumor is composed of large glycogenrich clear cells with peripheral palisading that exhibit areas of trichilemmal keratinization. Ultrastructurally intracytoplasmic focal dyskeratosis was observed. Despite the frequent presence of histologically malignant features, it has a relatively benign clinical behaviour. MPTT showed clinically ulcerated, teleangiectatic or keratotic nodules. Histologically, MPTT had the presence of cystic configuration that extended from epidermis into reticular dermis. They were more prone to local recurrence and metastasis. We conclude that histologic, ultrastructural, and immunohistochemical studies should be performed to offer a more complete definition and classification of these neoplasms.

抄録全体を表示

1) The histopathological findings of trichilemmal keratinization (TK) and the presence of clear cells are not always diagnostic for “trichilemmal carcinoma”, they are non-specific findings that may be observed in various skin tumors, such as Bowen's disease, Bowen carcinoma, solar keratosis and squamous cell carcinoma.
2) Solar keratosis (bowenoid type) occasionally show the features of “trichilemmal carcinoma”, supporting the concept that at least some percentage of “trichilemmal carcinoma” is just an advanced form of a solar keratosis.
3) Trichilemmal carcinoma, Bowen's disease, Bowen carcinoma and malignant proliferating trichilemmal tumor (MPTT) are related and overlapping tumor concepts, so it is necessary to establish criteria to differentiate among them, if they are indeed different.
4) The diagnosis of MPTT should only be made when malignant transformation is observed in a proliferating trichilemmal cyst (tumor), and should not be used as a synonym for a “trichilemmal carcinoma” or a Bowen carcinoma which occasionally shows cyst-like structures.
5) To establish “trichilemmal carcinoma” as a tumor entity, it is necessary to define what is trichilemmal differentiation histopathologically.

抄録全体を表示

It is a well-established oncologic dogma that there are malignant equivalents of many tumors. This principle applies to putative tumors of the hair follicle. Benign pure epithelial tumors which differentiate into the outer root sheath (ORS) can be classified as trichilemmoma and proliferating trichilemmal tumor. The malignant counterparts of these tumors, if present, are malignant trichilemmoma (mTr) and malignant proliferating trichilemmal tumor, respectively. The criteria used for the histologic diagnosis of mTr have consisted of the presence of clear cells, glycogen-containing cells, and trichilemmal keratinization in the tumor nests. It has been unclear, however, whether these histologic features are specific for the tumors which differentiate into the ORS. We demonstrated that the above histologic features were noted in some cases of Bowen's disease which showed different phenotypes in keratin and involucrin expression from those of the ORS. Further immunohistochemical studies revealed that trichilemmoma and mTr showed similar immunophenotypes to the ORS, especially in the lower hair follicle which had characteristic expression of keratin and involucrin. Therefore, the immunohistochemistry of keratin and involucrin exprssion is useful for the identification and differentiation of mTr. By using immunohistochemical techniques, we should reexamine the diagnosis of the cases which have been diagnosed as mTr.

抄録全体を表示

DNA-flow cytometric analyses were performed on paraffin-embedded sections of trichilemmal carcinoma (TC), proliferating trichilemmal cyst (PTC) and trichilemmal cyst. 12 out of 14 cases of TC and 2 out of 5 cases of PTC showed neuploidy. No aneuploidy was detected in 6 cases of trichilemmal cyst. In one of 6 cases of TC was large enough to investigate regional differences, DNA ploidy heterogeneity was detected. The incidence of aneuploidy of TC was significantly higher than that of squamous cell carcinoma (14%) previously described by us using the same method.

抄録全体を表示

Cytofluorometric analysis were performed on paraffin-embedded sections of hair follicle carcinoma. We classified hair follicle carcinoma as malignant proliferating trichilemmal tumor (MPTT) and malignant trichilemmoma (MT) by Morioka's classification.
In 12 cases of MPTT, ten cases showed aneuploid pattern of the histogram, two showed polyploid pattern. The average nuclear DNA content ranged from 2.81C to 5.11C. There was no significant difference of the average nuclear DNA cotent between non-metastatic MPTT and metastatic MPTT.
In 11 cases of MT, eight cases showed aneuploid pattern, three showed diploid pattern. The average nuclear DNA content ranged from 2.20C to 6.43C. The presence of aneuploid pattern was assumed to be the criteria for malignancy. There was not a significnant correlation between the clinical course and the incidence of aneuploiod pattern in MT.
These results indicate that Cytofluorometric methods are not satisfactory for predicting the behavior of individual cases of malignancy in MPTT and MT.

抄録全体を表示

Author divides the hair follicle carcinoma clinicopathologically into two subtypes, that is the epidermal tumor and the dermo-subdermal tumor. The former group consists of malignant trichilemmoma (MT) and trichilemmomal carcinoma (TCa) in order of malignant potency, whose precursor or prototype is trichilemmoma. The latter group consists of proliferating trichilemmal cyst (PTC) and malignant proliferating trichilemmal tumor (MPTT), whose precursor or prototype is trichilemmel cyst. According to this classification, the principal mode of surgical treatment of hair follicle carcinoma is concluded theoretically. Carcinoma in situ (MT, PTC) could be safely managed with conservative excision but invasive carcinoma should be excised more widely and deeply with lymphnode dissection, if necessary. Besides, dermosubdermal tumors must be handled more carefully and radically than epidermal tumors, because of their deep location and metastasizing capability.

抄録全体を表示

As representative malignant neoplasms of outer root sheath, malignant trichilem-moma (MT) and malignant proliferating trichilemmal cyst (MPTC) are listed in standard classification. Disease names such as trichilemmal carcinoma and malignant proliferating trichilemmal tumor (MPTT) are also used by some authors. Many cases of MT have been recently reported in Japan, however, definition and criteria of MT seem to be different among the authors. To settle this confusion, a consensus symposium on “trichilemmal carcinoma” was held at the 10th Annual Meeting of the Japanese Society for Skin Cancer in June, 1994. In this paper, as a organizer of the symposium, I summarized the 8 speakers' opinions on MT and MPTC/MPTT presented in the symposium. The concept and criteria of these neoplasms were substantially different among speakers and, accordingly, relationship between MT and MPTC/MPTT was controversial. It is important that, to avoid confusion, we clearly define the concept and definition of these neoplasms when we describe them.

抄録全体を表示

We have experienced a patient with intractable mycosis fungoides (MF) who has been treated successfully with recombinant human interferon-γ (IFN-γ) for a period of 7 and half years. This therapy was shown to be a safe alternative to other medications with unacceptable side effects and decreasing the dosage of IFN-γ should be done very slowly in order to maintain complete remission.
In the early stages of disease, T-and B-cell responses are usually unaltered. However, as the disease progresses, T-cell responses to antigens and mitogens, NK cell activity, lymphokine-activated killer cell (LAK) activity, are known to decrease in association with an increase in levels of immunoglobulins IgE and IgA. Recently the peripheral blood cells of patients with MF were shown to exhibit abnormal production of IL-4, as well as a defect in INF-γ release. IL-4 can antagonize the biological activity of INF-γ and can inhibit the production of this cytokine. This lymphokine secretion pattern may help explain the observed immunologic abnormalities present in advanced disease. Interestingly, IFN-γ antagonizes the biologic activity or IL-4. Thus in the initial stages of MF, IL-4 and IFN-γ may be counteracting a portion of each other's activity. Since the reintroduction of IFN-γ exogenously could patially inhibit the enhanced production of IL-4, leading ultimately to augmented NK cell activity and decreased proliferation of tumor cells, thus, the use of IFN-γ may offer therapeutic benefits to patients with MF.
Natural killer cell stimuratory factor (IL-12) is known to induce IFN-γ production by T and NK cells. IL-10 efficiently inhibits a IL-12 production, leading to the decrease in IFN-γ. The reciprocal regulation of these cytokines may result in the abnormal regulation of cellular and humoral immune response in MF. The elucidation of these cytokine interactions will provide highly specific immunotherapeutic approaches to MF.

抄録全体を表示

Angiosarcoma is mainly arising on the scalp of elderly persons and has high malignancy. Its prognosis is very poor and survival term from onset was about one year even though ordinary combination therapies (radical excision, chemotherapy, radiation) have been performed.
We started IL-2 immunotherapy for angiosarcoma from 1987 and twelve patients (10 patients with hemangiosarcoma, 2 patients with lymphangiosarcoma) have been treated. Therapeutic effect of IL-2 is through activation of lymphocyte and induction of LAK-cells. From our experience, we made the plan of IL-2 immunotherapy for hemangiosarcoma, based on clinical and pathological features. Macular lesion that is structured by well-differentiated tumor cells with some lymphocyte infiltration is treated with intra-lesional injection of IL-2 or sometimes IL-2 one-shot intra-arterial injection from external carotid artery. Elevated or ulcerative-nodular lesions that are mostly composed of poorly-differentiated tumor cells without lymphocyte infiltration are treated with combination therapy of one-shot injection of IL-2 and LAK-cells from external carotid artery and small scale surgical excision limited to these lesions. IL-2 immunotherapy by our plan was more effective and valuable for elderly persons with hemangiosarcoma, as compared with ordinary combination therapy, but still insufficient. Moreover, lymphangiosarcoma in our 2 cases that showed different clinical and pathological features from hemangiosarcoma was resistant against IL-2 immunotherapy. At all events, we shall have to discuss to develop IL-2 immunother-apy for the patients with angiosarcoma.

抄録全体を表示

Treatment for metastatic melanoma has not yet been established. Use of biological response modifiers (BRM) have been found to enhance therapeutic benefits. Rosenberg reported the effects of adoptive immunotherapy with lymphokine-activated killer (LAK) cells and with tumor-infiltrating lymphocytes (TIL). We cultured patient's peripheral blood lymphocytes or TIL massively for a short time in the presence of recombinant interleukin 2 and immobilized anti-CD3 antibody. In clinical trials involving 10 cases, the mean number of harvested T cells after 14 days culture was 2.0×10¹⁰, and the mean expansion index was about 2000-fold. We called the acquired lymphocytes “immobilized anti-CD3 antibody-activated T lymphocytes (CD3-AT) ”and studied their clinical efficasy as a part of multidisciplinaly treatment. Of 10 malignant melanoma patients receiving CD3-AT, one had complete response and one had partial response. Moreover we administered CD3-AT to 2 patients of metastatic sweat gland carcinoma and one patient of progressive angiosarcoma, partial response of the angiosarcoma was observed. No side effects of CD3-AT have not yet been observed. Expanded T lymphocytes were infused to the patients with skin malignancies, and safety and feasibility was confirmed.

抄録全体を表示

In this study, I review the newest and attractive technique for the treatment of metastatic melanoma, that is, gene therapy. First, the contents of guide line for gene therapy in Japan was described. Second, the background of gene therapy, for exam ple, the way of gene transfer and advantages and disadvantages of viral vectors and/or nonviral vectors were described. Third, the current status of melanoma gene therapy in USA was described; that is, retroviralmediated gene transduction and/or direct gene transfer with liposome is safe, and feasible gene transductions and treatment with IL-2/TNF and/or HLA B7 gene into TIL and/or melanoma cells are being carried out in USA. Further improvement of efficacy of gene transduction is needed and longterm follow up of patients should be done for safety.

抄録全体を表示

A multicenter late phase II study of recombinant IL-1β derivative (OCT-43) was performed in patients with mycosis fungoides at 37 institutions nationwide. This study consisted of two stages, one to find the optimal dosage and regimen and the other to evaluate clinical efficacy at the optimal dosage and regimen. OCT-43 was administered by the subcutaneous route at a daily dose of 2.5×10⁴ JRU or 7.5×10⁴JRU, twice a week on 2 consecutive days with a 5-day rest, for 6 weeks or longer. The optimal dosage and regimen for the administration of OCT-43 was concluded to besubcutaneous administration once daily at a dose of 2.5×10⁴ JRU or 7.5×10⁴ JRU, adjusting the dose in accordance with the occurrence of adverse reactions and theseverity of the symptoms. Thus, the second stage of the study was performed usingthese dosages and regimen for 6 weeks or longer. Of a combined total of 37 completedcases in both stages of the study, complete response (CR) was observed in 1 case and partial response (PR) in 18 cases, for an overall response rate of 51.4%. The responserates in the individual study phases were 41.2% (7/17) in the dosage and regimen-Finding stage and 60.0% (12/20) in the efficacy-evaluation stage. Major subjectivesymptoms and objective signs consisted of fever (82.1%, 32/39), chills (61.5%, 24/39), and general fatigability (53.8%, 21/39), and clinical laboratory tests showed positiveCRP (93.8%, 30/32), an increase in RBC sedimentation (83.3%, 20/24), and an increasein WBC count (63.2%, 24/38) . Three completed cases were withdrawn at the end of the study due to adverse reactions: 1 case due to worsening of erythema and swelling in rash, 1 due to fever and headache, and l due to diarrhea. These results indicate that although OCT-43 may cause some adverse reactions which require careful attention, this drug is highly useful in the treatment of mycosis fungoides.

抄録全体を表示