Lymphatic Tumor Emboli Research Articles

Uterine papillary serous carcinoma following radiation therapy for carcinoma of cervix: a case report.

Uterine papillary serous carcinoma (UPSC) is a clinically aggressive and morphologically distinctive variant of endometrial carcinoma that has been recognized recently as a distinct entity. The association between radiation therapy (RT) and UPSC is rarely described in the literature. We describe the clinicopathologic features of a 71-year-old patient with UPSC that developed 15 years after radiation therapy for squamous cell carcinoma of cervix, stage IIB. In the subtotal hysterectomy specimen the endometrium was irregular with multifocally raised masses. Microscopically, the tumor was composed of high-grade papillary serous carcinoma focally admixed with solid transitional cell carcinomatous areas and multifocal intraepithelial carcinoma in adjacent atrophic endometrium. The tumor exhibited diffuse infiltrative growth with frequent lymphatic tumor emboli in the myometrium. Immunohistochemical staining for p53 and c-erbB-2 were positive in about 70% of the tumor cells. Carcinoembryonic antigen (CEA) was focally positive. Ki-67 positive cells were present in about 60% of the tumor cells. The tumor directly extended to the cervix and perirectal soft tissue and metastasized to the omentum. Intraoperative pelvic washing cytology was positive for papillary adenocarinoma cells. The possible etiologic role of radiation is discussed, and the literature on endometrial carcinomas developing after RT is reviewed.

Mutation Analysis of BRCA1 and BRCA2 in Italian Hereditary and Sporadic Forms of Breast and Ovarian Cancers: Tumor Genotype‐Phenotype Correlation in Breast Cancer BRCA‐Mutation Carriers

Predisposition to breast and ovarian cancer has been attributed to mutant BRCA1 alleles in 90% of hereditary combined tumors and in 45% of hereditary breast cases, whereas mutations in BRCA2 gene are thought to account for about 35% of inherited breast cancers. On the other hand, the presence of mutations in the sporadic forms of these tumors is an infrequent event. This suggests that tumors arising in BRCA mutation carriers may differ from BRCA negative hereditary and sporadic cancer in genetic and biological features as well as in clinical behaviour. We undertook our study to evaluate the frequent of BRCA mutations in patients with hereditary and sporadic breast and/or ovarian tumors in order to explore if specific pathological and clinical features of tumors are associated with BRCA1 and BRCA2 mutations. Mutational analysis was also performed for exon 11 by PTT complemented by SSCP for the remaining entire coding region and exon-intron splice boundaries. Direct sequence analysis was used to identify the genetic alterations. DNA germline mutations were detected in 22 out 76 (29%) families; 15 probands (20%) showed BRCA1 mutations; 7 patients (9%) presented mutations in the BRCA2 gene. About 50% (11/22) BRCA-mutations were detected in families with three or more affected relatives most of which (8/11) occurred in BRCA1; 27% (6/22) BRCA-mutations were observed in families with two affected relatives; 18% (4/22) in families with one affected relative and one BRCA-mutation (5%; 1/22) was identified in a borderline family. No hot spot of mutations was found in the two genes, but almost 50% occurred in exon 11 of BRCA1 and BRCA2. The BRCA-mutational analysis, performed on 30 primary early onset breast cancers (” 36 yrs.) and 18 ovarian carcinomas (” 50 yrs.), revealed the presence of: a) one somatic point mutation, an 5382insC, in one ovarian cancer patient, b) a rare sequence variant in exon 15 in one case of breast cancer, c) four different common polymorphisms (one in intron 8 in breast and ovarian tumors, one in intron 7 in breast carcinomas and one in exon 13 and in exon 16 in ovarian neoplasm). The specific pathological and clinical features of breast-tumors associated with BRCA1 and BRCA2 mutations were explored (histological type, pathological grade, lymph node status, tumor size, lymphatic and blood vessel tumor emboli, tumor necrosis, presence of other lesions in the parenchyma collateral to invasive carAbstract

Predicting Axillary Nodal Positivity in 1,787 Patients with Invasive Breast Carcinoma

Abstract: Axillary lymph node status continues to be the single most important prognostic variable regarding breast cancer survival in spite of the development of numerous new tumor markers. All patients with invasive breast cancer who underwent axillary lymph node dissection as part of their treatment were stratified by the primary lesion's T category (TNM staging system) and whether or not the lesion was clinically palpable. Laboratory parameters and breast cancer specific survival were stratified by palpability and T category. Six hundred and forty-two of 1,787 (36%) axillary node dissections contained metastases. Overall, the probability of axillary node involvement was higher for all palpable lesions versus all nonpalpable lesions (42% versus 13%, p = 0.00001). Palpable lesions were less likely to be ER or PgR positive. They had a lower percentage of favorable histologic patterns, were less likely to be diploid, and were more likely to overexpress HER2/neu, have a high S-phase, exhibit high nuclear grade, and microscopically reveal lymphatic tumor emboli or vascular invasion. When tumors were stratified by size, the probability of nodal involvement was higher within each T category for palpable lesions when compared with nonpalpable lesions. The 10-year Kaplan-Meier survival for patients with palpable invasive breast cancer was 75% compared with 90% for patients with nonpalpable lesions (p = 0.00001). Palpability is a poor prognostic sign.

Prognostic factors in resectable breast cancer.

The traditional unfavorable clinicopathologic features in operable breast cancer are large tumor size, number of axillary node metastases, poorly differentiated grade, presence of lymphatic tumor emboli near to the primary malignancy, blood vessel invasion, tumor necrosis, intense lymphoplasmocytic reaction around the tumor and perimenopausal status. Current multidisciplinary approach is still based on two major clinico-pathologic findings such as tumor size and number of infiltrated axillary nodes. Only in recent years the presence or absence of estrogen receptors was taken into consideration to administer adjuvant tamoxifen or adjuvant chemotherapy, respectively. Since the fundamental prognostic indicators in breast cancer are the total tumor cell number and its inherent biological aggressiveness, it is important to assess the clinical role of the proposed new determinants as a guide to prognosis in series of consecutive patients staged and managed according to uniform treatment programs. Properties such as hormone receptor status, ploidy and tumor cell kinetics (3H-TdR labeling index and percent of S-phase cell) as well as oncogenes should be evaluated also as expression of tumor cell burden and/or indicators of clinical aggressiveness. Recent results from retrospective case series strongly suggest that tumor cell proliferative activity, in particular labelling index, is a prognostic factor independent of axillary nodes, tumor size, and receptor status for the relapse-free survival of node-positive and node-negative tumors. This new prognostic factor should be taken into consideration in the selection of candidates for adjuvant chemotherapy.

Topographic criteria in the diagnosis of tumor emboli in intramammary lymphatics

Topographic relationships to adjacent structures were used as criteria to identify intramammary lymphatics with tumor emboli in breast cancer patients, in addition to conventional morphologic criteria. Patterns of relationship to blood vessels, non-neoplastic lobules and ducts, and empty lymphatics were defined. Ninety-five cases were independently reviewed by two observers. Interobserver reproducibility of the diagnosis of lymphatic vessel invasion (LVI) was 82% (kappa 0.60). The observers agreed on the presence of LVI in 23 patients (24%), of whom 21 (91%) had positive lymph nodes. Only among patients in whom more than ten emboli were identified was the frequency of positive lymph nodes markedly higher than in the total material. The location of tumor emboli relative to the invasive tumor was of little significance. LVI was a more powerful predictor of lymph node status than tumor size, margin contour, histologic grade and histologic type, and was highly significant also when controlled for these features.

Factors Influencing Survival and Prognosis in Early Breast Carcinoma (T1N0M0–T1N1M0): Assessment of 644 Patients with Median Follow-up of 18 Years

That there is probably a significant proportion of "cured" patients, particularly in the T1N0 group, is an important observation when one considers the proper role of adjuvant therapy, especially for patients with stage I disease. Analysis of this series indicates that patients with T1N0 disease can be subdivided into different prognostic groups. Factors associated with an especially favorable prognosis in T1N0 cases are a primary tumor size of 1 cm or less; special tumor type such as tubular, medullary, papillary, or colloid carcinoma; and low-grade tumor. Relatively unfavorable tumor characteristics are size greater than 1.0 cm (especially the group 1.7 to 2.0 cm), the presence of lymphatic tumor emboli in the breast, blood vessel invasion, high-grade tumor or poor differentiation, and intense peritumoral lymphoplasmacytic reaction. The T1N0 patients whose tumors manifest the latter features may have longer disease-free survival as a result of adjuvant therapy. On the other hand, women in the T1N0 group with an especially favorable prognosis usually can be spared adjuvant therapy.

Pathological prognostic factors in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma: a study of 644 patients with median follow-up of 18 years.

Prognostic factors have been examined in 644 patients with tumor-node-metastasis (TNM) stage T1 breast carcinoma treated by mastectomy and followed for a median of 18.2 years. Overall, 148 patients (23%) died of recurrent breast carcinoma. Eighteen (3%) were alive with recurrent disease and 478 (74%) were alive or died of other causes without recurrence. Unfavorable clinicopathologic features were larger tumor size (1.1 to 2.0 cm v less than or equal to 1 cm), perimenopausal menstrual status, the number of axillary lymph node metastases, poorly differentiated grade, presence of lymphatic tumor emboli (LI) in breast tissue near the primary tumor, blood vessel invasion (BVI), and an intense lymphoplasmacytic reaction around the tumor. Median survival after recurrence for the entire series was 2 years. This was not significantly influenced by tumor size, the number of axillary nodal metastases, the type of treatment for recurrence, or the interval to recurrence. The proportions surviving 5 and 10 years after recurrence were 17% and 5%, respectively. Among T1N0M0 cases, the chance of a local recurrence was 2.8% within 20 years. Median survival of T1N0M0 cases after local recurrence (4.5 years) was significantly longer than after systemic recurrence (1.5 years). A similar trend (3.7 v 2.0 years), not statistically significant, was seen in T1N1M0 patients, who had a 6.5% chance of local recurrence within 20 years. Median survival following systemic recurrence detected 10 or more years after diagnosis in T1N0M0 and in T1N1M0 patients was significantly longer than the median survival for systemic recurrences found in the first decade of follow-up. This difference did not apply following local recurrence in either T1N0M0 or T1N1M0 cases. It is evident that patients with T1 breast carcinoma can be subdivided into differing prognostic groups and this must be taken into account when considering the role of adjuvant chemotherapy for stage I disease. Systemic adjuvant treatment may prove to be beneficial for patients with unfavorable prognostic factors, while women with an especially low risk for recurrence (eg, T1N0M0 tumor 1.0 cm or less) might be spared such treatment.

Cancer cell emboli in the pectoral lymphatics of patients with breast cancer.

In order to investigate the possibility of local recurrence in the pectoral muscles of patients who undergo modified radical mastectomies, the cancer cell involvement of the lymphatics associated with the pectoralis major muscle was studied in 39 patients who underwent a standard radical mastectomy for Stage I-III breast cancer. Cancer cell emboli were found in the transpectoral lymphatics of 2 patients (2/39 = 5.1 per cent) and in the pectoral fascial lymphatics of 6 patients (6/39 = 15.4 per cent). Two patients with fascial lymphatic cancer cell emboli were from a group of 14 patients with intramammary lymphatic tumor emboli of a low degree (ly 1). The other 6 patients with cancer cell emboli in either the pectoral fascia or the transpectoral lymphatics were from a group of 11 patients with intramammary lymphatic tumor emboli of a moderate degree (ly 2). There was a significant relationship between the intramammary and the pectoral lymphatic cancer cell emboli (Chi square test: (p less than 0.05). The results of this study therefore indicate that lymphatic cancer cell emboli in the pectoral fascia and muscle are an important risk factor for patients who undergo a modified radical mastectomy.

Ras p21 Expression in the progression of breast cancer

The differential expression of the ras oncogene product p21 in the primary tumor, regional nodes, and distant metastatic sites in patients with disseminated breast cancer was examined to define the biologic and clinical significance of the ras oncogene in the progression of breast cancer. The avidin-biotin peroxidase complex method was used on formalin-fixed, paraffin-embedded tissues from 16 patients with metastatic disease. The primary antibody used in this protocol was RAP-5, an anti-p21 murine monoclonal IgG2a. p21 antigen staining was similar in the primary tumor and regional nodes from the same patient (P less than 0.05), but the staining of distant metastases was more variable. Expression of ras p21 was consistently increased in invasive components of the primary tumor as compared with intraductal tumor. In addition, a high level of p21 expression was seen in tumor emboli in lymphatics and blood vessels as compared with contiguous tumor in parenchymal tissue. Although p21 staining is present in aggressive primary breast cancers and most metastatic sites, our findings indicate that markedly enhanced p21 expression is associated with the earlier stages (invasion and dissemination) of aggressive breast cancers.

The application of immunohistochemical stains to identify endothelial-lined channels in mammary carcinoma

The identification of lymphatic and vascular channels with immunohistochemical reagents directed against antigens of the endothelial cells was undertaken in formalin-fixed breast tissues from 100 women with infiltrating mammary duct carcinoma. Fifty women had had lymphatic tumor emboli identified in the original review of their slides. Each case was matched with a control of similar size and laterality. From each case one section containing tumor and normal tissue was stained with antibodies directed against Factor VIII-related antigen, blood group antigen A, blood group antigen B and with Ulex europaeus I agglutinin. All specimens with a reaction displayed variation in the intensity of the stain as well as in the propensity of a given endothelial lined channel to stain at all. Factor VIII-related antigen was identified in 96 tissue samples and Ulex europaeus I agglutinin reacted with 75 specimens. Reactivity of endothelium to blood group antigens either A, B, or both was found in 63 samples. Twenty-one of 26 (81%) samples with endothelial-lined channels which contained tumor emboli in the hematoxylin and eosin (H & E) section showed a reaction to one or more of the reagents. In six other cases involvement of endothelial-lined channels was detected only in the specially stained sections, but in three of these, the tumor emboli appeared only in these deeper sections and could have been detected by serial sections stained with H & E. The results of this study indicate that examination of H & E sections is a reliable method of identifying tumor involvement of endothelial-lined channels. Immunohistochemical stains may be of assistance in occasional cases, but with the reagents currently available this methodology is subject to false-positive and false-negative results.

Intramammary Lymphatic Invasion in Breast Carcinomas Evaluation Using ABH Isoantigens as Endothelial Markers

Recent studies indicate that intramammary lymphatic invasion represents an important prognostic parameter in breast carcinomas. However, the identification of intramammary lymphatic invasion in tissue sections is a subjective procedure, frequently hampered by factors such as fixation artefacts and interobserver variations. In this study, monoclonal antibodies to ABH isoantigens were applied on formalin-fixed, paraffin-embedded breast carcinoma tissue by using the avidin-biotin-peroxidase complex technique. In addition, the H antigen was localized using the Ulex europeus agglutinin I lectin binding technique. Isoantigen localization provided excellent delineation of lymphatics and blood vessels, in general unhampered by the retention of isoantigen expression in some breast carcinomas. In comparison, Factor VIII-related antigen localization required prior trypsin enhancement and was less sensitive and less consistent. The staining for isoantigens was more intense in vascular than in lymphatic endothelium. ABH isoantigen localization of lymphatic channels identified lymphatic tumor emboli peripheral to and within the carcinomas, and distinguished bona fide intramammary lymphatic invasion from tissue shrinkage artefacts. The applicability to routinely processed tissue permits retrospective studies and renders the identification of intramammary lymphatic invasion a more objective procedure. Further studies are needed to assess the role of this technique in evaluating the prognostic value of intramammary lymphatic invasion; the technique may be extended also to the study of other neoplasms.

Prognostic factors in adenocarcinoma of the uterine cervix

A group of 136 female patients with adenocarcinoma of the uterine cervix, treated at Memorial Sloan-Kettering Cancer Center between 1949 and 1981, with slides available for review, formed the basis for this study. They ranged in age from 10 to 91 years. Most (73%) had abnormal bleeding, either alone or in combination with other symptoms; 15% were asymptomatic. Eighty percent had a visible abnormality, most commonly an exophytic mass. Clinical stages were: 0 (3%), IB (61%), IIA (14%), IIB (10%), III (4%). There were four major histologic subtypes: mucinous (47%), endometrioid (24%), adenosquamous (15%), and clear cell (9%) carcinoma. Of the many clinicopathologic variables evaluated for prognosis, the most significant was stage of disease (P less than 0.0001). Those with Stage IB disease had a survival probability of 76% at 5 years compared with 49% for those with Stage IIA and 34% with Stage IIB. The endometrioid pattern was associated with a more favorable prognosis than any other histologic subtype (P = 0.02). The presence of lymphatic tumor emboli and/or metastatic carcinoma in any lymph node group was associated with a less favorable prognosis for patients with Stage IB and IIA disease (P less than 0.0001).

Histopathologic high risk factors influencing the prognosis of patients with early breast cancer (T 1N 0M 0)

A retrospective study of 78 women with early breast cancer was undertaken with the aim of detecting histopathologic risk factors that would influence the prognosis of these patients. Histologic tumor type, nuclear grade of tumor, tumor margin, and lymphoid infiltration near the tumor as well as blood vessel invasion and lymphatic tumor emboli were evaluated. The overall 10 year survival rate was 79.2 percent. In correlating the aforementioned criteria against survival rate, it was found that the patients without any of the histopathologic risk factors had a 100 percent rate, whereas those with one risk factor had a 79 percent rate and those with two or more risk factors a 66 percent rate. Nuclear grade and lymphoid infiltration were found to have the highest significance in regard to recurrence and the mortality rate. The findings of this study suggest that in patients classified as having T 1N 0M 0 disease without any of the histopathologic risk factors, operation is the only treatment indicated. Patients with one or more positive risk factors should receive adequate adjuvant therapy in order to increase their survival rate.

Occult axillary lymph node metastases from breast cancers with intramammary lymphatic tumor emboli.

Serial sections were performed on the axillary lymph nodes from 28 women with mammary carcinoma and intramammary lymphatic tumor emboli. Occult metastases were demonstrated in nine women (32%), all less than 2 mm in diameter. During the 10 years of follow-up, no difference in recurrences was found between this group (33%) and those without occult metastases (37%). Serial sectioning of lymph nodes in this group of patients does not appear to be helpful in prognosis.

Predictors of recurrence in stage I (T1N0M0) breast carcinoma.

A ten-year follow-up study of 382 women with Stage I (T1N0M0) breast carcinoma revealed recurrence and/or death due to cancer in 16% of the patients. Among 134 patients (35%) with a primary tumor 1.0 cm or less in diameter (Group A), 7% had recurrences and 5% died of breast carcinoma. Recurrences were observed in 21% of the 248 women with a tumor 1.1-2.0 cm in diameter (Group B), and 15% died of disease. These differences in recurrence and mortality rates were statistically significant. All recurrences were due to infiltrating duct or lobular carcinoma which accounted for 91% of the 382 carcinomas. Most strongly linked to recurrence was the finding of tumor emboli in lymphatics of the breast. This was found in 23 Group B patients and ten of them (43%) died of disease. No recurrences were observed among the seven Group A patients with lymphatic emboli. Other features associated with a significantly increased risk of recurrence were poorly differentiated carcinoma, marked lymphoid reaction to tumor, and menarche before age 12 years or after age 14 years. No combination of variables proved to identify a subset of patients with an especially increased or low risk of recurrence. Stage I patients with lymphatic tumor emboli in the breast surrounding a carcinoma 1.1-2.0 cm in diameter have a sufficient risk for recurrence to warrant consideration of adjuvant systemic therapy. A very low risk of recurrence was observed for the following: any tumor 1.0 cm or smaller; and tubular, medullary or colloid carcinoma up to 2.0 cm.

Neoplastic involvement of nipple and skin flap in carcinoma of the breast

This study was carried out to determine the frequency of neoplastic involvement of the nipple and of the skin flap in 1,000 mastectomy specimens with primary breast carcinomas. Nipple involvement (Paget's, and carcinoma in ducts or stroma or in lymphatics) was encountered in 23.4% of the cases and appeared to be more frequently associated with tumors of large size or located in the central sector of the breast, and with the intraductal and small cell carcinomas. The skin flap was invaded by the underlying tumor in 101 cases, particularly when the tumors were over 2 cm in diameter and when the nipples were involved. In 12 additional cases, tumor emboli in dermal lymphatics were discovered microscopically in random sections of the skin flap. The neoplastic involvement could not be recognized grossly in 58% of the involved nipples, in 28.7% of the skin flaps directly invaded by an underlying tumor, and in nine of the 10 cases with microscopic emboli dermal lymphatics and in which the gross appearance of the skin was recorded. A high incidence of axillary metastases was found in association with nipple and skin involvement.

Prognostic significance of tumor emboli in intramammary lymphatics in patients with mammary carcinoma.

Approximately 20% of patients with invasive mammary carcinoma who do not have axillary metastases develop recurrent carcinoma within 10 years of initial therapy. There is clearly a need to identify those patients most likely to develop recurrences in this group since they may benefit from adjuvant therapy. This study was undertaken to evaluate the prognostic significance of intramammary lymphatic tumror emboli in patients with invasive breast carcinoma who did not have lymph node metastases. Twenty-three such patients treated in 1974 and 15 from 1964 were compared with matched groups of control patients who did not have lymphatic emboli. About 43% of patients with lymphatic emboli and 4% of those without emboli followed for 5 or more years in the 1964 group developed distant metastases (p less than 0.001). Local recurrences were found in only one study patient and one control in the entire series of 1964 and 1974 patients. The results suggest that among patients without axillary metastases, the finding of tumor cells in lymphatic spaces within the breast is associated with a substantial risk of distant metastases but not local recurrence.

Pathologic findings from the National Surgical Adjuvant Breast Project (protocol no. 4). I. Observations concerning the multicentricity of mammary cancer.

Microscopic foci of multicentric cancer were detected in 121 of 904 breasts surgically removed for a clinically overt, invasive cancer. This incidence of 13.4% is regarded as a conservative estimate since examples of such lesions occurring in the same quadrant as the dominant mass, except in those instances in which the latter was present within the tail of the breast or beneath the nipple, were excluded from the analysis. Further, this data was obtained from only one randomly selected block of the quadrants, and in 41% of the cases only one or two were available for study. Multiple multicentric cancers were found in the same breast in two and three quadrants in 11.6% and 5.8% of the cases respectively. In 9.3% of the cases the multicentric cancers were designated as noninvasive (lobular in situ and/or intraductal) and in 4.1% invasive. An attempt to correlate the occurrence of multicentric cancers with a large number of pathologic and some clinical features disclosed a statistically significant association between multicentricity and grossly nonencapsulated dominant cancers with maximum diameters greater than 5 cm, the presence of a moderate or marked intraductal component and noninvasive cancer in its vicinity, and tumor involvement of the nipple. In addition, it was noted that there was a greater likelihood that the primary tumor was of the lobular invasive type and that the overlying skin was involved when the multicentric cancer was invasive rather than noninvasive. Lymphatic tumor emboli were observed in quadrants in 18 or 2.0% of the cases. Although the number of examples is small, nevertheless positive associations were noted with the occurrence of primary tumors that were in the left breast or beneath the nipple and were not grossly circumscribed, but exhibited a nuclear grade of 1, intralymphatic and blood vessel invasion, calcium, and involvement of the overlying skin as well as nipple. In addition, patients with such intralymphatic extension were more likely to have clinically detectable lymph nodes of which four or more contained metastases. The relationship of these findings to the rationale of such procedures as segmental resection in the surgical treatment of breast cancer is discussed.

Inflammatory carcinoma of the breast. A pathologic definition.

We examined the pathologic material and/or reports of all but one patient reported free of disease at least 5 years following radical mastectomy for inflammatory carcinoma of the breast. None of these patients had dermal lymphatic metastases. In addition, no patient with erythema of the breast or clinical inflammatory carcinoma who survived without recurrence 5 years following radical mastectomy (performed from 1950 to 1960 at the Barnes Hospital) had dermal lymphatic metastases. Inflammatory carcinoma is a poorly defined and confusing term which should be discarded. The histologic hallmark of surgically incurable carcinoma of the breast is tumor emboli in the dermal lymphatics. We propose the name “dermal lymphatic carcinomatosis of the breast” for this entity and stress the necessity of a palliative approach toward patients with this disease.

Malignant melanomas of the skin: A study of the Origin, Development, Ætiology, Spread, Treatment, and Prognosis

Summary The study is based on a series of 226 malignant melanomas of the skin in 220 cases examined and treated by a single team during the period 1947 to 1960. The general policy has been outlined and the surgical technique described. The origin of the malignant melanoma has been traced from the melanocytes in the basal layer of the epidermis, and the relationship between the malignant tumour and its benign counterpart has been discussed. Some clinical and histological diagnostic pitfalls have been outlined. Three stages of malignant melanoma have been defined, according to the degree of invasion of the dermis and of tumour formation. Stages 1and 2 are superficial melanomas and have a much better prognosis than Stage 3. Ulceration is a bad prognostic sign. Survey of this series has given the opportunity to discuss most of the ˦tiological aspects of malignant melanomas. There is a two-to-one female preponderance, mainly due to the prevalence of the melanomas on the faces of elderly women and on the legs of women under the age of 50. Such tumours are less malignant than the average, so that the prognosis for women as a whole is better than that for men. Melanomas of the foot are relatively common and have a worse than average prognosis, possibly because of trauma. Melanomas of the trunk have a relatively poor prognosis, as they are usually seen in a more advanced state. Five cases had multiple primary melanomas, and in three of these the two tumours were bilaterally symmetrical. The question of hormonal dependence of melanoma is discussed, particularly with reference to the influence of pregnancy on the eruption of malignancy. Two cases of spontaneous regression of malignant melanoma are described. The evidence that trauma causes malignant melanoma is not good, but the evidence that it may make the prognosis worse is strong. The methods of spread of malignant melanoma are described. The pigmented flare or halo in which the tumour appears is all malignant and seems to spread by the communication of malignant potential to neighbouring epidermal melanocytes. The manifestation of this process is less than its real extent and the process may be discontinuous, giving rise to satellites. Satellites may also be produced by the permeation of the lymphatics in the papillary layer of the dermis. They are of bad prognostic significance. When obvious permeation of dermal lymphatics is seen microscopically near a malignant melanoma the prognosis is much worse. The regional lymph nodes to which tumours of different sites may metastasise are described. The problem of lymphatic spread to the skin of a graft donor area is discussed. Lymphatic tumour emboli may give rise to skin metastases on the route of lymphatic drainage, particularly if there is lymphostasis. A particular study has been made of these lymphatic skin metastases, with reference to their development by chain reaction and also with reference to the need for adequate primary excision. The problem of prophylactic lymph node dissection is discussed, and it is concluded that this treatment can be of use, provided it is done after an interval of two to three weeks from excision of the primary. This tends to allow lymphatic tumour emboli to reach the regional nodes. If simultaneous prophylactic lymph node dissection and excision of the primary are carried out, the block excision should be all in one piece, as otherwise lymphatic skin metastases are likely to develop in the intervening part. The therapeutic removal of lymph node metastases is a marginally useful operation. The experience gained in this study has been embodied in a number of recommendations. When the clinical diagnosis is in doubt, excision biopsy is recommended. Incision biopsy and all forms of deliberate trauma are condemned. The margin of excision of a primary tumour will depend on its site, on its stage of development, and on the age of the patient. After an interval of two to three weeks the regional lymph nodes should be removed if the primary is not a superficial melanoma, and in all cases where lymphatic permeation of the dermis has been histologically observed. In this series every single case has been followed up, and the five-year successful results in the ninety-three determinate cases is 51·6 per cent., which is better than in any other published series, even when allowance is made for selection of cases. Malignant melanoma is not a rare tumour (Table I), and its prognosis is better than for most of the common forms of cancer (Table II).