Federico Pizzetti

The value of staging laparotomy in non‐Hodgkin's lymphomas. (With emphasis on the histiocytic type)

Laparotomy with splenectomy and multiple tissue biopsies was performed in 106 adult patients with non‐Hodgkins lymphoma (histiocytic—76, lymphocytic—25, and mixed type—5). The histologic pattern at initial biopsy showed nodular lymphoma in 33% and diffuse lymphoma in 67%. Diffuse histiocytic was the most frequently observed histologic type in this series (54%). Before laparotomy, 92% of patients had primary lymphatic and 8% primary extralymphatic involvement. Waldeyers ring involvement accounted for 27% of all patients. Systemic symptoms were present in 7%. Clinical stage (Ann Arbor Classification as proposed for Hodgkins disease) was as follows: I—29%, II—32%, IIs— 2%, III—24%, IIIs—8%, and IV—5%. After staging laparotomy these figures were 25%, 29%, 1%, 20,% 8%, and 17%, respectively (down stage 23%, up stage 4%). Spleen was involved in 23%, liver in 12%, gastrointestinal tract in 5%, and bone marrow in 12%. In 27%, lesions were occult to conventional diagnostic methods. Although not sampled in all patients, splenic hilar, celiac, and mesenteric nodes were the most frequent occult sites of intra‐abdominal lymphoma. With clinical methods, false negative findings for spleen involvement were 12% and for liver 11%. Spleen involvement occurred more often in nodular (29%) than in diffuse lymphoma (19%). There was no appreciable difference in the splenic infiltration among histiocytic (22%), lymphocytic (24%), and mixed (20%) types. With the exception of one case, there were no patients with hepatic involvement without concomitant splenic involvement. Lymphography yielded a 96% accuracy proving once more to be a sufficiently reliable diagnostic method. Two patients died after laparotomy because of acute peritonitis and acute pancreatic necrosis, respectively. Otherwise, the incidence and type of complications were found acceptable. Collectively, our findings indicate that staging laparotomy is a useful procedure in non‐Hodgkins lymphomas to identify occult lesions before planning treatment and to gain more information on the natural history of these diseases.

Classification and Treatment of Hodgkin's Disease

A new clinical classification for Hodgkins disease is proposed by the Committee for the Study of Malignant Lymphomas of the National Cancer Institute of Milan in cooperation with the Institute of Radiology of the University of Milan. The method of treatment of Hodgkins disease adopted in these Institutes is also outlined. The histologic classification includes paragranuloma, nodular sclerosis, granuloma and sarcoma. Stage I: disease limited to a single peripheric lymphatic region. Within this stage two groups can be recognized: a) involvement of one single lymph node or few nodes limited to a small area of the region (unifocal lesions); b) involvement of many nodes spread throughout the region (uniregional lesions). Stage II: disease limited to two contiguous lymphatic regions, or to few deep nodes (mediastinal, retroperitoneal). Stage III: disease limited to two non contiguous peripheric lymphatic regions, or to many peripheric and/or deep (mediastinal, retroperitoneal) regions, provided the involvement is either above or below the diaphragm. Stage IV: generalized disease with involvement of lymph nodes above and below the diaphragm, or involvement of one or more lymphatic regions with concomitant involvement of visceral organs, bones, marrow, nervous system and skin. Systemic symptoms and signs, fatigue, fever, night sweats, loss of weight, itching, anemia, lymphocytopenia, high erythrosedimentation rate) must be recorded in each case to evaluate prognosis and proper treatment, bu are not considered in this classification for lymph node staging. Primary visceral, bone, nervous and cutaneous involvement is exceptional; therefore staging for such lesions is not considered in this classification. In all stages endolymphatic radiotherapy with Lipiodol F 131I is indicated (10 ml in each foot with 2.5 mc/ml, corresponding to a tumor-dose of 15 - 20,000 rads). This is considered as a radical as well as a prophylactic treatment for those lymph nodes adequally filled with the contrast material; in case of non filling or incomplete filling of part of the lymph node chain, treatment will be completed with external radiation therapy. Stage I and II are treated with radical and prophylactic radiotherapy. If systemic symptoms and signs are still present after radiotheraphy, a course with anticancer drugs will be administered. Radiation therapy is given with high voltage or Co60 units. In radical treatments tumor doses of at least 3,000 r within 3–4 weeks are administered to all involved lymphatic regions. Prophylactic radiotherapy is indicated for regions clinically free of disease but contiguous to the involved areas, with tumor doses not less than 3,000 r in 3–4 weeks. In stage II radical radiotherapy follows a course with chemotherapy. In stage IV chemotherapy is the treatment of choice; palliative radiotherapy is given to any bulk of tumors, wherever the location, when specific symptoms can be attributed to the masses. The anticancer drug of choice is methyl-bis-(β-chloro-ethyl)-amine HCl(HN2) 0.4 mg/kg i.v., for those patients who did not receive any previous course of chemotherapy. Otherwise, as well as during the course of the disease, other polyfunctional alkylating agents, vinblastine (alone or in combination with chlorambucil), methylhydrazine, and corticosteroids will be administered according to each clinical situation. Radical surgery followed by radical radiotherapy is reserved for primary lymphatic involvement only in specially selected patients in stage I with unifocal lesions. Primary involvement of the stomach, small bowel or colon is treated by surgical extirpation and radiotherapy. Splenectomy is indicated when this viscus is the only site of involvement. During pregnancy radiation therapy is not administered below the diaphragm. Chemotherapy is not given during the first 4 months of pregnancy. The need for one internationally accepted clinical classification of Hodgkins disease is stressed.

Clinical Staging and Treatment of Lymphosarcoma and Reticulum Cell Sarcoma.

The Committee for the Study of Malignant Lymphomas of the National Cancer Institute of Milano in cooperation with the Institute of Radiology, University of Milano presents a new clinical classification for lymphosarcoma and reticulum cell sarcoma as well as the method of treatment adopted in these Institutes. For primary lymph node lesions the staging is identical to that already proposed for Hodgkins disease. Stage I: disease limited to a single peripheric lymphatic region. Within this stage two groups can he distinguished: a) involvement of one single lymph node or few nodes limited to a small area of the region (unifocal lesions); b) involvement of many nodes spread throughout the region (uniregional lesions). Stage II: disease limited to two contiguous peripheric lymphatic regions, or to few deep nodes (mediastinal, retroperitoneal). Stage III: disease limited to two non contiguous peripheric lymphatic regions, or to many peripheric and/or deep (mediastinal, retroperitoneal) regions, provided the involvement is either above or below the diaphragm. Stage IV: generalized disease with involvement of lymph nodes above and below the diaphragm, or involvement of one or more lymphatic regions with concomitant involvement of visceral organs, bones, marrow, nervous system and skin. For primary pharyngeal lesions the T.N.M. nomenclature has been adopted. T1: unifocal lesion (e.g. nasopharynx, tonsil, uvula); T2: multifocal lesions (e. g. nasopharynx and tonsil, tonsils, tonsil and base of the tongue); T3: unifocal lesion with extension beyond the anatomical confine of the site of origin (e. g. base of the skull, paranasal sinuses, jaw, orbit); T4: multifocal lesions with extension beyond the anatomical confine of the site of origin. N0: no adenopathy; N1: ipsilateral contiguous adenopathy (submental and/or cervical); N2: bilateral contiguous adenopathy; N3: bilateral contiguous and/or supravicular adenopathy (unilateral or bilateral); N4: distant adenopathy. M–-: absence of metastases; M+: presence of metastases (visceral, osseous, nervous, cutaneous). The remaining primary extranodal lesions (visceral, osseous, cutaneous, etc.) are classified as local, regional and diffuse. Systemic symptoms and signs (fatigue, fever, night sweats, more than 10% weight loss, itching, anemia, leukocytosis, lymphocytopenia, high erythrosedimentation rate) must be recorded in each case to evaluate prognosis and proper treatment but are not important for staging the disease. In all stages with primary lymph node lesions endolymphatic radiotherapy with Lipiodol F I131 is indicated (10 ml in each foot with 2–5 mc/ml giving a tissue-dose of 15-20,000 rads). This is considered as radical as well as prophylactic treatment for those lymph nodes adequatelly filled with the contrast medium. In case of non filling or incomplete filling of part of the lymph node chains, treatment will be completed with external radiation therapy. Stage I and II are treated with radical radiation therapy. No prophylactic radiotherapy is given. If systemic symptoms and signs are still present after radiotherapy a course with anticancer drugs will be administered. Radiation therapy is given with high voltage or Co60 units. In radical treatments tumor doses of at least 3,000 rads within 3–4 weeks are administered to all involved lymphatic regions. In stage III radical radiotherapy follows a course of chemotherapy. In stage IV chemotherapy is the treatment of choice. Palliative radiotherapy is given to any bulk of tumors, wherever the location, when specific symptoms can be attributed to the masses. For primary pharyngeal lesions the primary focus (T1, T2, T3, T4) is always treated with radical radiation therapy (Co60 unit) which includes in the whole Waldeyers ring. Prophylactic radiotherapy (Co60 unit with doses not less than 3,000 rads in 3–4 weeks) is given in N0 to the ipsilateral and in N1 to the contralateral submental and cervical lymphatic regions. In N1 and N2 the lymph node bearing areas are given radical radiation therapy. In N3 are irradiated prophylactically also the contralateral submental, cervical and supraclavicular lymphatic regions if clinically free of disease. Endolymphatic radiotherapy is performed only in T1 T2 T3 T4, N3 N4, M–- or M+ cases; otherwise diagnostic lymphangiography is performed and when pathologic nodes are present or suspected they are irradiated with Co60. Chemotherapy is given after the course of radiotherapy in N2 cases only if radical treatment has not been accomplished, while is always administered in combination with radical radiotherapy in N3 cases, and is considered the treatment of choice with palliative radiation therapy in N4 and M+ cases. The drug of choice is methyl-bis-(β-chloro-ethyl)-amine HCl (HN2) 0.4 mg/kg i.v. (single dose) for those patients who did not receive any previous course of chemotherapy. Otherwise, as well as during the course of the disease and in maintenance therapy, other polyfunctional alkylating agents, but chiefly chlorambucil (0.1–0.2 mg/kg/die, p. o.), vinblastine (0.10–0.15 mg/kg/week, i.v.), alone or every two weeks in combination with small daily doses of chlorambucil (5 mg/die, p. o.), methylhydrazine, hydroxyurea, and corticosteroids will be administered according to each clinical situation. Relapses in oropharynx can be treated with intraarterial infusions of amethopterine, vinblastine and cyclophosphamide. Radical surgery followed by a course of radiotherapy is reserved for primary lymphatic involvement only in specially selected patients in Stage I with unifocal lesions. Primary involvement of stomach, small bowel and colon is treated by surgical extirpation and radiotherapy. Splenectomy, lobectomy or pneumonectomy is indicated when these viscus are the only site of involvement. During pregnancy radiation therapy is not administered below the diaphragm and chemotherapy is not given during the first 4 months. The need for one internationally accepted clinical classification for lymphosarcoma and reticulum cell sarcoma is stressed.

Single Agent Sequential Chemotherapy in Non-Hodgkin's Lymphomas

A retrospective analysis of 118 patients with non-Hodgkins lymphomas who received one or more drugs of single agent chemotherapy was conducted to determine the relationship between the histopathologic category of lymphoma, based on the classification proposed by Rappaport et al., and the results (type of regression and survival) of sequential chemotherapy. In 96/118 cases, slides were available for histopathologic reclassification. Patients were selected according to the following criteria: chemotherapy with single agents administered in sequence (e.g. alkylating agents, vincristine, adriamycin, bleomycin); change in drug administration only after an adequate course and either no response or clinical resistance after prior regression; measurable disease; performance status greater than 40. Prior to chemotherapy 66 patients had diffuse (extranodal) disease, 39 adenopathies above and below the diaphragm, and 13 adenopathies only above or below the diaphragm. 49/118 patients were pretreated with radiotherapy. The data were most complete for alkylating agents which were administered as a single agent in 93 patients. Complete remission (CR) plus partial remission (PR) greater than 50% occurred in 39% of patients with lymphocytic lymphoma, in 39% with histiocytic and in 50% with mixed type lymphoma (table 4). This type of response was observed with all drugs in 70% of nodular lymphomas and in 36% of diffuse lymphomas (table 7). The overall response rate to adriamycin was 75% in nodular lymphomas, and 55% in diffuse lymphomas. These data were 40% and respectively 14% after treatment with bleomycin. Median survival of all non-Hodgkins lymphomas was 16.2 months (fig. 1); median survival was 23.4 months for nodular lymphomas and 17.4 months for diffuse lymphomas (fig. 2). Among nodular lymphomas, no significant differences were observed between nodular histiocytic and nodular lymphocytic well differentiated (fig. 3). Diffuse lymphocytic well differentiated lymphomas showed better survival in comparison to diffuse lymphocytic poorly differentiated, diffuse histiocytic and diffuse undifferentiated types (fig. 4). Patients responding to 2 drugs or more showed a better median survival (66 months) than those responding only to one drug (22.4 months) and unresponsive patients (10.2 months) (fig. 5). This study confirms most of the data reported by the Stanford group and emphasizes the need to employ a more deteailed histopathologic classification such as that proposed by Rappaport et al. Although this retrospective analysis has a number of drawbacks, it does provide, in terms of survival, a measurable indication that the responsiveness to at least two drugs is associated with better survival in non-Hodgkins lymphomas than little or no responsiveness.

Il Problema delle Metastasi Tumorali

The authors discuss the biological factors concerned with aggressivity and invasivity of tumor cells. They analyse the data of 1000 autopsies performed at the National Cancer Institute and describe the percentage of lmphatic and hematic spread and the frequency of metastatic deposits to the different organs. The authors emphasize that metastasizability depends upon hydrodynamic factors of the lymphatic and hematic circulation. The hematic spread can be studies through the schemes of Walther. They discuss the possibility that sarcoma cells can go through the lung filter and they point out the significance of the anastomoses between cavae veins and vertebral veinous (Batson) plexus.

Results of Endolymphatic Radiotherapy: Histological Aspects

The histological aspects of lymph nodes after lymphography with radioactive Lipiodol are well known from a previous investigation made by Pizzetti et al. [5]. Such histological experience, however, relates to lymph nodes which either were not invaded by tumors or were infiltrated by metastases of carcinomas, especially from the bladder or uterus or malignant melanoma [1, 4, 6]. So far no extensive reports have been published on the direct action of radioactive Lipiodol on lymph nodes involving malignant lymphomas [2, 3]. With the aim of making a further contribution to this knowledge, we studied the retroperitoneal lymph nodes in patients with lymphoma who have undergone radioactive lymphography, and subsequently, a post mortem examination or a lymphadenectomy.

Occult Carcinoma in Thyroid Adenoma

1111 cases of thyroid adenoma surgically removed at the National Cancer Institute of Milan from 1928 to 1966 were examinated in order to search for areas of occult carcinoma. In each case three to five istological sections were examinated. The diagnosis of malignancy was based upon histological criteria, i. e. infiltration of the tissues, invasion of basal membrane, invasion of venous vessel or of the thyroid capsule; the cytological criteria were considered by themself not sufficient to state the diagnosis of malignancy. Twenty cases (1.8%) showed microscopic areas of carcinoma. This rate does not seem to be higher than the rate of occult carcinoma in clinically normal thyroids as reported in the medical literature.