TREATMENT OF INTRAORAL CARCINOMA—Combined Resection of the Jaw and Radical Dissection of the Neck

Intraoral carcinomas first occur as primary growths. From these sites they spread by the lymphatics to the regional nodes. In the past, treatment of these lesions has consisted of radiation therapy for the primary lesion, followed by radical neck dissection. The results of this treatment have not been satisfactory. On the other hand, for carcinoma elsewhere in the body the results of surgical extirpation of the primary lesion, of the intervening lymphatics and of the regional nodes at the same operation has given much better results.In the past few years an attempt has been made to improve the results of treatment of intraoral carcinoma by removal in continuity of the primary lesion, intervening lymphatics and regional nodes. The improvement in anesthesiology, electrolytes and fluid balance, blood replacement, and the development of the antibiotics, in conjunction with the realization that the cosmetic deformity is not as great as might be expected, has led to this development. In those centers where it has been possible to apply this principle of treatment to intraoral carcinoma the results have been very encouraging.     

PLANNED RESECTION OF THE REGIONAL LYMPH NODES IN PNEUMONECTOMY FOR CARCINOMA

Although there has been a reluctance to include the regional lymph nodes in pneumonectomy for cancer because of the supposed inaccessibility of the nodes, radical removal of the nodes within the thorax is a feasible procedure.Failure to include the regional nodes in pneumonectomy for cancer violates the accepted principle of inclusion of the regional lymphatics in operations for cancer. If pneumonectomy is indicated for removal of a malignant lesion, then removal of the regional nodes is also indicated. Injection of a dye helps the surgeon in identification of lymphatics to be excised.     

A Statistical Review of Carcinoma of the Lip

Among 3166 patients with microscopically confirmed squamous cell carcinoma of the lip registered at The Ontario Cancer Treatment and Research Foundation''s Regional Clinics in 1938-1955, the five-year crude survival rate was 65%, and the five-year net survival rate 89%. Survival was influenced by age, site and size of primary lesion, local and regional invasion, long delay, and treatment method. The initial treatment appeared to control the primary lesion in 84% of cases and involved lymph nodes in 58%. The net survival rates improved over the survey period. Findings confirm the usefulness of the proposed TNM staging.     

Brugia pahangi: infections and their effect on the lymphatic system of Mongolian jirds (Meriones unguiculatus)

Brugia pahangi has been found to be primarily a lymphatic-dwelling parasite in jirds when infections are induced by the subcutaneous injection of infective larvae or by allowing infected Aedes aegypti to feed.Migration to the regional lymphatics occurred as early as 1–4 days. Although some injected larvae remained in the skin for as long as 30 days and some became localized in the heart, lungs, pleural cavity, or peritoneal cavity, about three-fourths of the recovered filariae were found in the regional lymphatics. In contrast, when larvae were injected peritoneally they remained largely in the peritoneal cavity for at least 30 days.The relevant lymphatics and their drainage patterns in jirds have been described.The major pathological changes noted in jirds involved the regional lymphatic vessels and nodes, which were severely affected when they contained dead worms. Pulmonary granulomas due to dead microfilariae and occasionally to dead larvae or adult worms were noted.Observations are included on the susceptibility and course of B. pahangi infections in jirds.     

Carcinoma of the Vulva

A series of 127 patients presenting at two London hospitals with carcinoma of the vulva during the period 1948-70 is reviewed. Patients with intraepithelial carcinoma or rodent ulcer are excluded, but the series includes two cases of malignant melanoma, one of adenocarcinoma of Bartholin''s gland, and two of basal cell carcinoma. In the remainder the pathological diagnosis was squamous cell carcinoma.Leucoplakia was present in only 30 cases (24%) and it is therefore concluded that this condition is probably not so dangerous as a precursor of cancer as has been stated in the past, though an association with cancer of the vulva is undeniable.In only three cases was no form of treatment practicable. Of the remaining 124, two were treated by radiotherapy, 37 by simple vulvectomy, 12 by vulvectomy followed by separate inguinal lymphadenectomy, and 73 by radical vulvectomy combined with bilateral lymphadenectomy en bloc, pelvic lymphadenectomy being included whenever the superficial lymph nodes appeared to be involved or when Cloquet''s node was shown by frozen-section examination to be invaded. Excellent results, with an absolute five-year survival rate of 66%, were obtained with this last procedure, especially when primary skin cover was provided by the delayed technique (five-year survival 73%). The results of simple vulvectomy were also surprisingly good, with an absolute five-year survival rate of 65%, and this operation may be a wise choice for the very old or infirm patient.     

Bacterial infections of skin and soft tissues in filariasis

Adenolymphangitis is a common occurrence in filarial lymphedema. Damage to the lymphatics and lymph nodes by F. bancrofti is followed by obliteration of lymph vessels and lymph stasis. Obstruction of lymphatics prevents the bacteria penetrating skin to be evacuated with lymph stream to regional lymph nodes. Colonization of dermis, subcutis and lymphatics evokes clinical symptoms of adenolymphangitis. The question arises which strains of bacteria are responsible for the acute and chronic types of adenolymphangitis. The most probable strains responsible for this condition belong to the cocci and probably the bacillus strains.     

Effect of time and therapy on the hormone receptor status of breast carcinomas.

To determine whether the hormone receptor status of a breast carcinoma can change during the course of the disease or its treatment, the results of estrogen receptor assays in two or more biopsy specimens from 68 patients were examined; progesterone receptors had been assayed in approximately 40% of the specimens, too few to permit statistical analysis of the results. The patients fell into four groups: A, those with at least two primary breast carcinomas, and B to D, those with at least two breast carcinomas, at least one of which was a secondary tumour (usually of lymph node, skin or soft tissue) excised on the same occasion (B), 1 to 76 months later, after no intervening therapy (C), or 3 to 73 months later, after intervening chemotherapy (usually adjuvant), regional irradiation or hormonal therapy, or a combination of these (D). The small numbers in the subgroups precluded statistical analysis of the results for groups A and D. The degree of concordance of the hormone receptor status of the primary and secondary tumours in groups B and C was significant, at 87% (P less than 0.01) and 80% (P congruent to 0.01) respectively. Chemotherapy and regional irradiation did not appear to reduce the degree of concordance. All primary tumours in the same breast removed on the same occasion had the same hormone receptor status, but bilateral primary tumours appeared to have an independent status, which suggests that local tissue factors, as well as the systemic hormonal environment, play a role in establishing the hormone receptor status of breast carcinomas.     

Carcinoma of the Larynx: Results of Therapy

Prognosis of laryngeal carcinoma varies considerably, depending on its site and stage of development. In the past, laryngectomy was considered the treatment of choice for all but very early lesions. Results of therapy and five-year survival rates were relatively good, but the patient deprived of his larynx frequently presented difficulties in rehabilitation.Recent advances in radiotherapy techniques have permitted treatment of a greater proportion of patients with laryngeal carcinoma by this means, with encouraging results. Results of a survey in the Toronto area suggest that radiotherapy should be used as primary treatment in early and intermediate stages of the disease; radical excision combined with radiotherapy is indicated for treatment failures among early cases and for those with far-advanced disease or carcinoma outside the larynx proper. With this program five-year survival rates are comparable to those achieved when laryngectomy is the primary treatment used, and two-thirds of those who survive maintain laryngeal function.     

Cutaneous melanoma: a twenty-year retrospective study with clinicopathologic correlation.

The survival of melanoma patients is directly related to the involvement of regional nodes and to the microscopic level of invasion of the tumor. During the past 10 years, with the increased use of aggressive surgical therapy (wide local excision or re-excision of the primary tumor and prophylactic dissection of predictably involved regional nodes) the 5-year survival rate has more than doubled. The 5-year survival has doubled in those patients with regional lymph node involvement who were infused for 5 days with L-phenylalanine mustard. Perfusion of the lower extremities with L-phenylalanine mustard has been abandoned at Vanderbilt. The potential aggressiveness of a specific melanoma can be predicted, and thus an appropriate treatment may be planned.     

Treatment of lymphedemas by microsurgical lymphatic grafting: what is proved?

Lymphedemas due to a local blockade of the lymphatic system can be treated by bridging the defect with autologous lymphatic grafts. Under the microscope, grafts are anastomosed to peripheral lymphatics distal to and central lymphatics proximal to the regional blockade. In this way, the diminished transport capacity can be restored. In the case of unilateral blockade at the groin or pelvis, the grafts connect the lymphatics of the thigh of the affected leg with lymphatics in the contralateral healthy groin. Between June of 1980 and December of 1986, 55 patients with lymphedemas have been treated by lymphatic grafting. The effect of lymph vessel transplantation has been evaluated by volume measurements and lymphatic scintiscans, showing a persistent patency of grafts, improvement of the transport index, and a persistent reduction in volume of the affected limbs. The reduction reached a level of 80 percent in patients with a follow-up of at least 3 years. The transport index showed an improvement of 30 percent. Autologous lymph vessel transplantation has been shown to be a fundamental step toward the microsurgical treatment of lymphedema.     

Lymph node localization of non-specific antibody-coated liposomes

Subcutaneously injected small unilamellar liposomes are drained into the lymphatics and localized in the regional lymph nodes, and thus they can be used for the detection of metastatic spread in breast cancer patients and for delivery of drugs to diseased lymph nodes (1-8). An aqueous phase marker, [125I]-polyvinylpyrrolidone, and a lipid phase marker, [3H]-cholesterol, were used to study the lymph node localization of IgG-coated liposomes injected subcutaneously into mouse and rat footpads. The results show that human immunoglobulin G (IgG) coated liposomes are rapidly removed from the site of injection and are localized in the regional lymph nodes to a greater extent than control liposomes (i.e. liposomes without IgG). Free IgG was found to inhibit the uptake of IgG-coated liposomes by the lymph nodes. The localization of IgG-coated liposomes in the regional lymph nodes is influenced by charge of the liposomes. The results presented here suggest that antibody-coated liposomes may provide a more efficient way of delivering therapeutic agents to the lymph nodes in the treatment of diseases such as breast cancer with lymph node involvement. Similarly, monoclonal antibody-coated liposomes containing lymphoscintigraphic material may improve the detection of lymph node metastases.     

Role of lymphangiogenic factors in tumor metastasis

Nearly four centuries after the discovery of lymphatic vessels, the molecular mechanisms underlying their development are beginning to be elucidated. Vascular endothelial growth factor C (VEGF-C) and VEGF-D, via signaling through VEGFR-3, appear to be essential for lymphatic vessel growth. Observations from clinicopathological studies have suggested that lymphatic vessels serve as the primary route for the metastatic spread of tumor cells to regional lymph nodes. Recent studies in animal models have provided convincing evidence that tumor lymphangiogenesis facilitates lymphatic metastasis. However, it is not clear how tumor-associated lymphangiogenesis is regulated, and little is known about how tumor cells escape from the primary tumor and gain entry into the lymphatics. This review examines some of these issues and provides a brief summary of the recent developments in this field of research.     

Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis

Metastasis is a frequent and lethal complication of cancer. Vascular endothelial growth factor-C (VEGF-C) is a recently described lymphangiogenic factor. Increased expression of VEGF-C in primary tumours correlates with dissemination of tumour cells to regional lymph nodes. However, a direct role for VEGF-C in tumour lymphangiogenesis and subsequent metastasis has yet to be demonstrated. Here we report the establishment of transgenic mice in which VEGF-C expression, driven by the rat insulin promoter (Rip), is targeted to beta-cells of the endocrine pancreas. In contrast to wild-type mice, which lack peri-insular lymphatics, RipVEGF-C transgenics develop an extensive network of lymphatics around the islets of Langerhans. These mice were crossed with Rip1Tag2 mice, which develop pancreatic beta-cell tumours that are neither lymphangiogenic nor metastatic. Double-transgenic mice formed tumours surrounded by well developed lymphatics, which frequently contained tumour cell masses of beta-cell origin. These mice frequently developed pancreatic lymph node metastases. Our findings demonstrate that VEGF-C-induced lymphangiogenesis mediates tumour cell dissemination and the formation of lymph node metastases.     

Lymphangiogenesis and its role in cancer

In many tumour types, lymphatic vasculature serves as a major route for tumour metastasis. The dissemination of malignant cells to the regional lymph nodes is an early step in the progression of many solid tumours and is an important determinant of prognosis. Lymphangiogenesis (formation of new lymphatic vessels) is thought to be crucial for cancer cells to metastasise to the regional lymph nodes. However research in this important process has been neglected largely due to the lack of molecular markers specific to the lymphatic endothelium. Recently, several specific markers have been identified including LYVE-1, podoplanin and prox-1. Although the biology of lymphangiogeneis, particularly its regulation, is still far from clear, it is now well established that tumours are lymphangiogenic i.e. they could induce the generation of their own lymphatics and metastasise to the regional lymph nodes. It is thought that the interruption of the main signalling pathways involved in this process could help to prevent lymphatic spread of many tumours. Furthermore, understanding the molecular mechanisms in lymphangiogenesis might help to develop new therapeutic strategies against cancer lymphatic spread. Here, we reviewed the literature in regards to the biology of lymphangiogenesis, its molecular regulation, lymphatic markers and the significance in human solid tumours.     

Lymphoscintigraphic monitoring of the lower limb lymphatic system response to bone fracture and healing

Closed bone fractures, and torn muscles and tendons are "internal wounds". What kind of reaction do they evoke in the local and systemic immune system? Cellular debris of damaged tissue and extravasated blood cells are removed by scavenger cells. They are transported via lymphatics to the lymph nodes. There elimination of self antigens takes place. Clinically, no enlargement of lymph nodes is observed after closed fractures and soft tissue damage. The question arises whether there is really no enlargement of regional lymph nodes, in other words, no reaction to damaged cell antigens. This question was studied by using lymphoscintigraphy to visualize lymphatics and lymph nodes draining the site of closed bone fracture. The lymphoscintigraphic pictures of two groups of patients, those with a rapid noncomplicated healing of leg fractures, and those with protracted healing and undergoing surgical reconstructions, were evaluated. The surface area of lymphatic pathways and inguinal lymph nodes on the injured and contralateral normal limb were measured. Enlarged superficial lymphatics and inguinal lymph nodes were found in limbs with healed bone fractures, and decreased inguinal lymph nodes and visualization of deep lymphatics and popliteal nodes in the majority of patients with nonhealing fractures. There was a lack of correlation between age of patients, duration of healing, and surgical interventions and the lymphoscintigraphic changes. These findings suggest that the fracture gap tissue is a dominant source of signals to the lymph nodes, releasing cellular and humoral regulatory factors. Taken together, there is a strong immune reaction of lymph node to the fracture, although it cannot be recognized clinically.     

Treatment of melanoma; success or failure?

The treatment of melanoma should be by radical surgical excision of the primary lesion and dissection of the regional nodes. Where possible this should be done in anatomic continuity; otherwise in physical discontinuity but at the same time. If maximum salvage is to be achieved the nodal dissection must be effected before there is clinical evidence of involvement by metastasis. Amputation of extremities should be reserved for cases in which there is evident metastasis between the original focus and the regional lymph node areas.     

TREATMENT OF MELANOMA—SUCCESS OR FAILURE?

The treatment of melanoma should be by radical surgical excision of the primary lesion and dissection of the regional nodes.Where possible this should be done in anatomic continuity; otherwise in physical discontinuity but at the same time.If maximum salvage is to be achieved the nodal dissection must be effected before there is clinical evidence of involvement by metastasis.Amputation of extremities should be reserved for cases in which there is evident metastasis between the original focus and the regional lymph node areas.     

Colloid carcinoma of the breast with concomitant metastasis and a tuberculous lesion in the axillary lymph nodes. A case report.

A 30-year-old woman presented with a lump in the left breast and left axillary lymphadenopathy that, on fine needle aspiration cytology (FNAC), proved to be duct cell carcinoma with metastasis. Histology of the radical mastectomy specimen showed a mixed colloid carcinoma. Axillary lymph nodes revealed a variety of pathologic changes consisting of reactive hyperplasia, tuberculosis and metastasis. A combination of a tuberculous lesion and metastasis in the same lymph nodes was also found. During follow-up, after radiotherapy, the patient developed left supraclavicular and right cervical lymphadenopathy that, on FNAC, revealed a tuberculous lesion and metastasis, respectively. The rarity of this condition with double pathology is highlighted, and the reason behind the limitations of FNA in subtyping the primary malignancy and its failure to detect the tuberculous lesion in the axillary lymph node are discussed.     

Debridement increases survival in a mouse model of subcutaneous anthrax

Anthrax is caused by infection with Bacillus anthracis, a spore-forming gram-positive bacterium. A major virulence factor for B. anthracis is an immunomodulatory tripartite exotoxin that has been reported to alter immune cell chemotaxis and activation. It has been proposed that B. anthracis infections initiate through entry of spores into the regional draining lymph nodes where they germinate, grow, and disseminate systemically via the efferent lymphatics. If this model holds true, it would be predicted that surgical removal of infected tissues, debridement, would have little effect on the systemic dissemination of bacteria. This model was tested through the development of a mouse debridement model. It was found that removal of the site of subcutaneous infection in the ear increased the likelihood of survival and reduced the quantity of spores in the draining cervical lymph nodes (cLN). At the time of debridement 12 hours post-injection measurable levels of exotoxins were present in the ear, cLN, and serum, yet leukocytes within the cLN were activated; countering the concept that exotoxins inhibit the early inflammatory response to promote bacterial growth. We conclude that the initial entry of spores into the draining lymph node of cutaneous infections alone is not sufficient to cause systemic disease and that debridement should be considered as an adjunct to antibiotic therapy.     

Tumor draining lymph nodes,immune response,and radiotherapy: Towards a revisal of therapeutic principles

The tumor-draining lymph nodes (TDLNs) are the primary sites of the development of anti-tumor immunity. Primary tumor irradiation promotes ‘radio-vaccination’ by enhancing the release of tumor antigens and activating the interferon type-I pathway. Activated intratumoral dendritic cells (DCs) enter the lymphatics to reach the TDLNs. The adaptive anti-tumor immune responses are developed, as DCs will present tumor-related antigens to activate CD4+ and CD8+ T-cells. Strong experimental evidence suggests that post-irradiation tumor clearance is strongly dependent on the accumulation of such cytotoxic T-cells in the tumors. However, TDLNs are heavily irradiated during Radiotherapy to eradicate the clinical and subclinical metastatic disease. At the same time, irradiation depletes the critical immune cell population residing in TDLNs and primary tumors, blocking immune response and compromising the effectiveness of immuno-stimulatory interventions. Since TDLNs are essential for T-cell activation by inbound dendritic cells previously activated in the tumor environment, the practice of TDLN-irradiation demands re-evaluation. Interventions to preserve and handle the functional state of regional TDLNs or remote nodes, during or after Radiotherapy, may have great therapeutic importance. TDLNs represent the main playground for educating and expanding tumor-specific cytotoxic immune cells and controlling a delicate balance between immune surveillance and tumor spread. Their activation state may define the outcome of Radiotherapy and the manifestation of abscopal effects. In this critical review, we present the biological and clinical role of TDLNs and propose strategies to include in the design of immuno-radiotherapy trials aiming to eradicate cancer at a local and distant level.