Cutaneous malignant melanoma in Swedish children and teenagers 1973-1992: a clinico-pathological study of 130 cases.

To assess whether there has been a change in histological features and prognostic factors of primary cutaneous malignant melanoma (CMM) in young individuals in Sweden, an unselected, population-based study was undertaken; 177 cases of primary CMM in persons below 20 years of age were reported to the Swedish National Cancer Registry between 1973 and 1992. In 87% of the cases, original tumor tissue was available for histo-pathological review. The original diagnosis was verified in 88% (n = 126) of these cases. All tumors had histological features similar to adult CMM; 17% had an associated precursor lesion. Superficial spreading melanoma (SSM) was the most common sub-type, constituting 20/36 cases in the first decade and 59/90 in the second. Corresponding figures for nodular melanoma (NM) were 11/36 and 23/90. Only 5 melanomas in situ were diagnosed. In girls, the mean thickness of SSM decreased from 1.5 to 0.6 mm (p < 0.001). Overall mortality was 10%, 22% in the group with CMM diagnosed 0-15 years of age and 8% in individuals 15-19 years. Fatal CMM cases diagnosed below 15 years of age (n = 4) were NM > 1.6 mm thick and in subjects 15-19 years (n = 9) 44% of fatal tumors were NM with a mean thickness of 2.2 mm. Breslow index was the single most important prognostic factor. However, when known prognostic factors were adjusted for in a Cox regression analysis, young age remained an independent risk factor, with a relative death rate of 0.21 for individuals aged 15-19 compared with children < 15 years of age.

Increasing incidence of cutaneous malignant melanoma in children and adolescents 12-19 years of age in Sweden 1973-92.

One-hundred-and-seventy-seven cases of cutaneous malignant melanoma were reported to the Swedish National Cancer Registry in subjects below the age of 20 during the period 1973-92. One-hundred-and-fifty-four (87%) were re-examined histologically, and the original diagnosis of primary cutaneous malignant melanoma was verified in 88%. The age-specific mean annual incidence rate increased to 0.5/100,000 in 1983-92 from 0.2/100,000 in 1973-82. Cutaneous malignant melanoma remained extremely rare in children below the age of 12, where only two cases were found. In subjects aged 12-19, the incidence doubled to 93 cases in the second 10-year period compared to 41 in the first. In boys, most of the melanomas occurred on the trunk, and, in girls, on the legs. Sixty-three percent of the melanomas were of the superficial spreading type, which also was the most rapidly increasing type of melanoma. These results emphasize the importance of surveillance and intensified preventive measures in protecting children and adolescents from the harmful effects of excessive exposure to the sun.

Ovarian endometrioid carcinomas simulating sex cord-stromal tumors: a study using inhibin and cytokeratin 7.

We have investigated the use of inhibin and cytokeratin-7 (CK-7) in distinguishing endometrioid ovarian carcinomas (both typical and sex cord-like) form granulosa cell and Sertoli cell-containing ovarian tumors. Immunohistochemical staining with inhibin, CK-7, and epithelial membrane antigen (EMA) was performed on 6 endometrioid carcinomas simulating sex cord-stromal tumors, 5 typical endometrioid carcinomas, 14 adult granulosa cell tumors (AGCTs), 3 Sertoli-Leydig cell tumors (SCLTs), and 1 sex cord tumor with annular tubules (SCTAT). All AGCTs and SLCTs as well as the SCTAT were inhibin-positive. In contrast, all of the endometrioid carcinomas (both typical and those mimicking sex cord-stromal tumors) were inhibin-negative. CK-7 expression was not observed in the granulosa cell tumors and it was noted only in retiform areas in SLCTs. All 5 typical endometrioid carcinomas and 5 of the 6 sex cord-like endometrioid carcinomas were CK-7 positive. EMA was positive in all carcinomas but negative in the SCTAT, AGCTs, and SLCTs. Inhibin can distinguish between sex cord-stromal tumors (whether granulosa or Sertoli-Leydig type) and endometrioid carcinomas. CK-7 is also helpful in differentiating between AGCTs and most endometrioid carcinomas, and may also aid in separating SLCTs from sertoliform carcinomas. The addition of inhibin to an antibody panel is important because it provides a positively-staining marker for sex cord-derived cells.

Mucinous tumors of the vermiform appendix and ovary, and pseudomyxoma peritonei: histogenetic implications of cytokeratin 7 expression.

Cytokeratin 7 (CK-7) has been shown to be uncommonly expressed in colonic epithelial tumors, as opposed to ovarian epithelial tumors, which are always CK-7 positive. The authors investigated the expression of CK-7 in 17 appendiceal cystadenomas and carcinomas, 20 mucinous borderline tumors of the ovary, 10 cases of simultaneous mucinous tumors of the appendix and ovary, three so-called high-stage mucinous borderline tumors of the ovary, and three cases of pseudomyxoma peritonei (PP) of unknown origin. Nine appendiceal cystadenomas were CK-7 negative; two of these were associated with PP, and the peritoneal lesions were negative as well. Three cystadenomas were CK-7 positive. Three appendiceal carcinomas were CK-7 negative, and in one case the metastases were also negative. Two carcinomas were CK-7 positive. All 20 ovarian borderline tumors were CK-7 positive. Six cases of simultaneous mucinous tumors of the ovary and appendix were CK-7 negative, as were their peritoneal mucinous deposits. Four cases showed a positive reaction in both appendiceal and ovarian sites. Two of three so-called high-stage ovarian borderline tumors were CK-7 negative. All three cases of PP of unknown origin were CK-7 negative. In conclusion, appendiceal cystadenomas are often CK-7 negative, whereas ovarian mucinous borderline tumors are always CK-7 positive. The concordant staining pattern for CK-7 of simultaneous mucinous tumors involving the appendix and ovary (60% of which were CK-7 negative) supports an appendiceal origin for these tumors. Our results also support an appendiceal (or colonic) source for any CK-7-negative mucinous tumor involving the ovary or the peritoneum. Furthermore, our findings are in agreement with the assumption that mucinous borderline-like tumors in the ovary associated with PP are not ovarian in origin but are often, if not always, metastatic from an appendiceal (or other) mucinous tumor.

Infiltration of mononuclear inflammatory cells into primary colorectal carcinomas: an immunohistological analysis.

Local immunoregulation mediated by mononuclear tumour-infiltrating cells is considered of importance for tumour progression of colorectal cancer, although the balance between immunosuppressor and cytotoxic activities is unclear. Colorectal cancers from 26 patients were investigated using a panel of monoclonal antibodies in order to identify subsets of mononuclear inflammatory cells and to study their pattern of distribution in relation to tumour stage and cytotoxic immune reactivity against the tumour. In all but five tumours, mononuclear cells, lymphocytes or monocytes were present in fairly large numbers, particularly in the stroma. The infiltration of CD4+ mononuclear cells predominated over the CD8+ subset. Infiltration near the tumour cells was found in four cancers only. Stromal infiltration of CD11c+ macrophages was found in all but eight tumours. Small regressive areas, in which the histological architecture of the tumours was broken down, were found in 17 tumours with intense or moderate infiltration by CD4+ lymphocytes or CD11c+ macrophages. Probably this destruction of tumour tissue was caused by cytotoxic activity of the tumour-infiltrating mononuclear cells. In Dukes' class A and B tumours, CD4+ lymphocytes predominated over CD4+ cells with macrophage morphology, but the latter were increasingly found in Dukes' class C and D disease. The occurrence of MHC II-positive macrophages and lymphocytes in different Dukes' classes was similar to that of CD4+ cells. In contrast to this, CD11c+ and CD11a+ cells were more frequent in Dukes' A and B class tumours compared with Dukes' C and D. Four out of nine tumours of the latter stages showed a poor inflammatory reaction. The interpretation of our results is that the subsets of tumour-infiltrating mononuclear cells change with advancing Dukes' class and that the local immune control is gradually broken down in progressive tumour growth, even if some cytotoxic activity is still present.

Occurrence and prognostic importance of micrometastases in regional lymph nodes in Dukes' B colorectal carcinoma: an immunohistochemical study.

OBJECTIVE: To evaluate the incidence and prognostic importance of micrometastatic disease in regional lymph nodes from Dukes' B colorectal carcinomas. DESIGN: Retrospective study. SETTING: University hospital, Sweden. SUBJECTS: 100 patients operated on for primary colorectal carcinoma, classified as Dukes' B lesions. INTERVENTIONS: The regional lymph nodes were re-examined immunohistochemically using monoclonal antibodies against cytokeratin. OUTCOME MEASURES: Incidence and prognostic importance of micrometastases. RESULTS: Micrometastases were found in 39% (39/100) of the patients. The number of positive cells in the lymph nodes examined varied from 1 to over 100. They appeared as single cells or small clusters of cells located within the capsule or in the peripheral sinus of the lymph node. At least three sections from each of three lymph nodes had to be examined to identify 95% of the patients with lymph node micrometastases. The outcome of the patients with micrometastases was not significantly different from that of patients with no epithelial cells in the lymph nodes. CONCLUSION: Micrometastases in regional lymph nodes are a interesting phenomenon but clinically seem to be of only weak prognostic value.

Tumor necrosis factor-alpha expression in human primary malignant malanoma and it relationship to tumor infiltration by CD3+ cells.

Optimal conditions for immunohistochemical staining of tumor necrosis factor-alpha (TNF-alpha) in paraffin-embedded tissue sections were established to investigate TNF-alpha expression in human primary malignant melanomas. Seventeen malignant melanomas of the nodular (NMM) and superficially spreading (SSM) subtypes were analyzed. Twelve of these were TNF-alpha+, while 5 did not stain for the cytokine. To evaluate how TNF-alpha expression affected the immune response to the tumors, infiltration by CD3+ and mac387+ cells was investigated in NMM. TNF-alpha expression seemed to selectively affect the capability of T cells to infiltrate the tumors since TNF-alpha+ tumors were found to have significantly lower levels of infiltrating CD3+ cells, while there was no difference in numbers of mac387+ cells. These results demonstrate that TNF-alpha is variably expressed in primary malignant melanoma in vivo and that the T-cell response to TNF-alpha-expression NMM is inhibited.

Correlations of Ki-67 and PCNA to DNA ploidy, S-phase fraction and survival in uveal melanoma.

In 79 patients with uveal melanoma, the tumours were investigated by DNA flow cytometry and immunohistochemical staining of PCNA and Ki-67. S-phase as a continuous variable was significantly correlated with Ki-67 (P = 0.033), but not with PCNA. DNA ploidy was not correlated with either of the two antigens. Ki-67 was significantly correlated with histopathological type (P < 0.001) and tumour size (P < 0.001). Large tumours and epithelioid cell type were associated with a high frequency of Ki-67 positive cells. A high level of Ki-67 positivity (> or = 6.5%) was also associated with a shorter survival (P = 0.0037), and when adjusted for DNA ploidy, histopathological type and tumour size, Ki-67 in the multivariate analysis remained an important prognostic factor (P = 0.017).

Correlation of DNA ploidy and S-phase fraction with chemotherapeutic response and survival in a randomized study of disseminated malignant melanoma.

DNA ploidy and S-phase fraction were measured by flow cytometry in the tumour tissue of 87 patients with disseminated malignant melanoma, who had been classified either as responders or with progressive disease in a study of the effects of 2 chemotherapeutic regimens. The patients had been randomized to receive treatment with dacarbazine (DTIC) and vindesine (Eldesine) with or without addition of cisplatin (Platinol). Tumour tissue was obtained from both the primary tumours and the last histologically verified metastases, but in some cases only the primary tumours or the last metastases could be evaluated. There was a significantly higher mean S-phase value in melanoma metastases from patients with complete or partial responses compared with patients with progressive disease. Neither the S-phase fraction of the primary tumour, nor the DNA ploidy of the primary tumour or of the last histologically verified metastases taken before inclusion into the study were associated with therapeutic response. In the multivariate analysis, both the anatomical location of the metastases and the S-phase fraction measured on the last metastases remained significant prognostic factors of response. In the univariate survival analysis, there was an association between high S-phase fractions of the metastases and longer survival. In the multivariate survival analysis, the S-phase fraction, the number of involved metastatic sites and the treatment response were independent predictive factors. We conclude that, in disseminated melanoma treated with chemotherapy, a high S-phase fraction measured in the last histologically verified metastases is associated with a higher response rate and a longer survival. Our results clearly support the role of S-phase measurement as a potential tool for selecting patients for treatment.

Interrelations of clinicopathologic variables and their prognostic value in colorectal adenocarcinoma.

We analyzed the interrelations of sex, age, tumor site, Dukes' stage, growth pattern and differentiation, and their prognostic value in 293 patients with primary colorectal adenocarcinoma. Simultaneously, growth pattern, differentiation, DNA and S-phase fraction (SPF) in paired primary tumors and lymph node metastases from 97 colorectal cancer patients were compared. The results revealed that poorly differentiated and mucinous tumors, as against well/moderately differentiated tumors, were frequently located in the proximal colon, and their frequencies were increased as Dukes' stage advanced (p=0.03). Tumor differentiation was usually identical in primaries and corresponding metastases (p=0.002), but this was not true of tumor growth pattern, DNA ploidy or SPF. In multivariate survival analyses, Dukes' stage provided strongly prognostic information (p<0.001) and mucinous tumors tended to predict worse survival (p=0.08).

Expression of cytokeratin 7 in simultaneous mucinous tumors of the ovary and appendix.

Cytokeratin 7 (CK-7) is a simple epithelial keratin that may be used to investigate the site of origin of adenocarcinomas. In fact, CK-7 is present in ovarian epithelial neoplasms but is generally absent in colonic carcinomas. This pattern of CK-7 expression may aid in elucidating the genesis of mucinous tumors occurring simultaneously in the ovary and appendix, accompanied by psuedomyxoma peritonei. Five such cases were immunostained with anti-CK-7, and all showed a concordant staining pattern of the appendiceal, ovarian, and peritoneal lesions. Two cases showed a negative reaction for CK-7 and thus would appear to represent ovarian and peritoneal metastases from an appendiceal primary tumor. Three cases were CK-7 positive, and the nature of these mucinous lesions remains open to debate; they may either represent independent primary tumors or originate from the appendix. For comparison, five Stage I mucinous borderline tumors of the ovary and their normal appendices were also stained with anti-CK-7. These ovarian tumors were all CK-7 positive, whereas the appendices were negative. It is concluded that CK-7 is capable of distinguishing a group of tumors that can reliably be classified as primary appendiceal neoplasms metastatic to the ovaries and peritoneum.

Salivary duct carcinoma.

Twelve cases of salivary duct carcinoma were examined clinically, pathologically and by flow cytometry to quantify their histological features as well as attempt to identify factors predictive of patient outcome. All of the tumours arose in the parotid gland. Eight of the twelve patients were male. Four patients died of disease (median survival 12.5 months); three are alive with disease; and five are alive with no evidence of disease (mean follow-up of 50 months). Two tumours arose in a pre-existing pleomorphic adenoma. Positive lymph nodes were present in eight of ten patients sampled; patients with two or more positive lymph nodes tended to die of their disease or be alive with metastases. Comedo necrosis, perineural invasion and vascular invasion were common findings by light microscopy. Ten of the twelve tumours were aneuploid. Neither clinical stage, tumour size, aneuploidy nor histological features correlated with patient outcome. This study confirms the aggressive nature of salivary duct carcinoma.

DNA ploidy and S-phase fraction as prognostic factors in patients with uveal melanomas.

In 96 patients with uveal malignant melanomas the tumours were investigated by DNA flow cytometry. Thirty-eight per cent of the melanomas were aneuploid. By univariate analysis significant correlations with survival were found for histological type, tumour size, DNA ploidy, evidence of 'blind eye' and S-phase fraction. By multivariate analysis, significant prognostic variables were found to be histological type (P = 0.0008), tumour size (P < 0.0001) and DNA ploidy (P = 0.0038). Evidence of 'blind eye' was not significantly correlated with survival after adjustments for the other variables mentioned above. The S-phase fraction could be estimated in all 60 diploid tumours and in 12 of 36 aneuploid melanomas. By univariate analysis this variable was found to be a significant prognostic factor, but did not remain so after adjustment for ploidy, histological type and tumor size. We further conclude that patients with small DNA diploid uveal melanomas of spindle cell type have a rather favourable prognosis.

Experience with distant pathology demonstrations for clinicians in hospitals without local pathologists through the Swedish telepathology work station.

Conferences between pathologists and clinicians are routinely important at each hospital which has its own department of pathology. With the aid of telepathology, such conferences can be facilitated to provide results similar to those in hospitals with their own pathological service. Our Department serves the hospital in Motala, which is located 50 km west of Linköping. We now have telepathology conferences every second week with the surgeons and every second week with colleagues in internal medicine. The equipment we use is LabEye, which is produced by Innovativ Vision AB in Linköping. This equipment includes mouse pointers at both stations which are always visible in the images at both ends of the system. The quality of images received in Motala is very good, allowing discussion of details regarding the specimens, especially the cytological ones. Our experiences with these conferences have been very good.

Elective lymph node dissection in stage I cutaneous malignant melanoma of the head and neck. A report from the Swedish Melanoma Study Group.

The effect of elective lymph node dissection in patients with cutaneous malignant melanoma of the head and neck was investigated in a retrospective study. Of 517 patients in clinical stage I, 84 underwent elective dissection of the ipsilateral neck lymph nodes. In six of these patients, lymph node metastases were demonstrated at histopathological examination. There was a slight reduction in the incidence of recurrent disease in the regional lymph nodes in the group of patients who had undergone elective lymph node dissection, but this difference was not statistically significant. No significant differences were seen between the two groups regarding overall survival of disease-related survival.

Mucinous borderline and malignant tumors of the ovary. A clinicopathologic and DNA ploidy study of 92 cases.

BACKGROUND: The morphologic spectrum of ovarian mucinous tumors is well known, but the features that predict aggressive behavior are still controversial. METHODS: Ninety-two cases of primary ovarian mucinous tumors with atypical epithelial proliferation and/or stromal invasion were analyzed histologically and by DNA flow cytometry, and the results were correlated with clinical findings. RESULTS: The authors reviewed 57 intestinal mucinous borderline tumors (IMBT), 3 endocervical-like mucinous borderline tumors (EMBT), 21 noninvasive mucinous carcinomas (NIMC), and 11 invasive mucinous carcinomas (IMC). The 5-year survival rate for Stage I tumors was: IMBT 100%, EMBT 100%, NIMC 94% and IMC 60%. The 5-year survival of Stage II-IV tumors was: IMBT 50%, NIMC 33% and IMC 0%. Forty-four IMBTs were diploid, and 4 were aneuploid. All six high stage IMBTs were diploid. Two EMBTs were diploid, and one was aneuploid. There were seven diploid, four polyploid, and six aneuploid NIMCs. Two of the three lethal NIMCs were aneuploid. Four IMCs were diploid, and four were aneuploid. Of these, only the diploid Stage I IMCs were nonlethal. All NIMCs that recurred or presented with metastases had been sampled inadequately. High stage tumors with pseudomyxoma peritonei (PP)-type lesions often were associated with pseudomyxoma ovarii of the cellular type. CONCLUSIONS: Mucinous tumors with stromal invasion or presenting with PP had a definite malignant behavior. All other atypical mucinous tumors, when confined to the ovary and optimally sampled, had an excellent prognosis. DNA ploidy analysis may prove useful in determining the risk of progression, especially in Stage I IMCs.

DNA ploidy and S-phase fraction in primary melanomas and their regional metastases.

Flow cytometric analysis of DNA ploidy and S-phase fraction was performed on the primary melanomas and the first metastases from 55 melanoma patients with regional lymph node metastases or in transit metastases. The frequency of aneuploidy was significantly higher in metastases than in the primary tumour (p = 0.009), suggesting a higher growth potential in melanoma metastases than in the primary tumours. In 18 patients with reliable S-phase determinations from both primary tumour and metastasis there was no significant difference in mean S-phase fraction between primary melanomas and metastases. Skin metastases localized in dermis and subcutis had a significantly (p = 0.012) higher mean S-phase fraction than lymph node metastases.