Henry J. Norris

The behavior of endometrial hyperplasia. A long‐term study of “untreated” hyperplasia in 170 patients

Endometrial curettings from 170 patients with all grades of endometrial hyperplasia, who did not undergo a hysterectomy for at least 1 year were evaluated in order to correlate the histopathologic features with behavior. Follow‐up ranged from 1 to 26.7 years (mean, 13.4 years). Cytologic and architectural alterations were analyzed separately in order to assess their respective roles in predicting the likelihood of progression to carcinoma. Classification of proligerative lesions based solely on the presence of cytologic atypia revealed that atypia was a discriminant factor. Proliferations lacking cytologic atypia were designated hyperplasia and those displaying atypia were designated atypical hyperplasia. Only 2 (1.6%) of 122 patients with hyperplasia progressed to carcinoma compared with 11 (23%) of women with atypical hyperplasia (P = 0.001). Subclassification of the two forms of hyperplasia (those with cytologic atypia and those without) was performed using the degree of architectural abnormalities. Hyperplasia and atypical hyperplasia displaying marked glandular complexity and crowding producing a back‐to‐back appearance were designated complex hyperplasia (CH) and complex atypical hyperplasia (CAH), respectively. Hyperplasia and atypical hyperplasia with lesser degrees of glandular complexity and crowding were designated simple hyperplasia (SH) and simple atypical hyperplasia (SAH), respectively. Progression to carcinoma occurred in 1 (1%) of 93 patients with SH, in 1 (3%) of 29 patients with CH, in 1 (8%) of the patients with SAH, and in 10 (29%) of the patients with CAH. The differences between the four subgroups suggest a trend but are not statistically significant. The findings in this study provide a rationale for classifying noninvasive endometrial proliferations primarily on the basis of cytologic atypia since this is the most useful criterion in predicting the likelihood of progression to carcinoma. In addition, the presence of concommitant architectural alterations appears to identify a particularly high‐risk subgroup.

Mesenchymal Tumors of the Uterus

This chapter deals with neoplasms of the uterus in which there is mesenchymal differentiation. Purely mesenchymal tumors, such as those derived from smooth muscle and endometrial stroma, are considered, as are benign and malignant neoplasms in which there are mixtures of epithelium and connective tissue.

Immature (malignant) teratoma of the ovary. A clinical and pathologic study of 58 cases

Fifty‐eight immature ovarian teratomas were studied. Neoplasms with other germ cell elements (endodermal sinus tumor, choriocarcinoma, and dysgerminoma) were excluded so that the clinical and pathologic features of “pure” immature teratomas could be defined and correlated with the prognosis. The primary tumors and their metastatic growths were graded from 0 to 3. Forty were stage I; nine, stage II; and nine, stage III. The size and stage of teratomas were related to survival, but it was the grade of the primary tumor that best determined the likelihood of extraovarian spread, and it was the grade of the metastases that related best to the subsequent course. Actuarial survival was 63% at 5 years and also at 10 years. Regardless of the grade of the primary tumor, only one of six with grade 0 metastases progressed, and that neoplasm may not have been adequately sampled. Two of five neoplasms having grade 1 metastases did not progress, and two of six patients with grade 2 metastatic growths were living after relatively long intervals. All seven patients with grade 3 metastases died with tumor, none surviving more than 2.1 years. Survival of patients with grade 1, 2, and 3 neoplasms was 81, 60, and 30%, respectively. The importance of adequate sampling of primary tumor and metastases for estimating prognosis and determining therapy is stressed.

Endodermal sinus tumor of the ovary. A clinical and pathologic analysis of 71 cases

The clinical and pathologic features of 71 endodermal sinus tumors of the ovary were studied in an effort to delineate the histogenesis and biologic behavior of this neoplasm and to evaluate the efficacy of different forms of treatment. Alpha‐fetoprotein (AFP) was identified in hyaline droplets, cell cytoplasm, and intercellular spaces of all 15 tumors examined by an immunoperoxidase technique; this supports the view that the neoplasm simulates yolk sac endoderm. There were only nine survivors among 65 patients on whom follow‐up information was available; the actuarial survival was 13% at 3 years. Of the neoplasms that recurred, 93% did so within 1 year, and of those patients who died, 93% did so within 2 years. The size and stage of the tumor had prognostic significance, but the patientapos;s age, the mitotic activity, and histologic pattern did not. Although 71% of the patients had Stage I tumors at the time of diagnosis, subclinical metastasis was present in 84% of Stage I patients. Triple chemotherapy (vincristine, actinomycin D, and cyclophosphamide (VAC)) employed after unilateral salpingo‐oophorectomy in four patients with Stage I tumors resulted in three long‐term survivals (75%). In contrast, there were only five survivors among 27 patients (19%) with Stage I neoplasms treated by surgery alone, and no survivors among 12 Stage I patients treated with combined surgery and radiation. The finding of AFP in all tumors in which this was evaluated suggests that serum radioimmunoassay might be useful to monitor response to therapy.

A comparison of the results of long‐term follow‐up for atypical intraductal hyperplasia and intraductal hyperplasia of the breast

Follow‐up information was obtained on 199 women with breast biopsy specimens containing intraductal epithelial proliferation. The proliferations were divided into regular or ordinary intraductal hyperplasia (IDH) (117 cases) and atypical intraductal hyperplasia (AIDH) (82 cases). The average length of followup was 14 years for the patients with IDH and 12.4 years for the patients with AIDH. Of the 117 patients with ordinary IDH, carcinoma subsequently developed in six (5%); three of these were invasive carcinomas (2.6%). All three invasive carcinomas were in the ipsilateral breast, but of the three intraductal carcinomas (IDCa), two were in the contralateral breast. Of the 82 patients with AIDH, invasive carcinoma subsequently developed in eight (9.8%); six of these were located in the ipsilateral breast and two in the contralateral breast. One of these six patients died of disseminated carcinoma. The average interval to the subsequent carcinoma (intraductal and invasive carcinoma) was about the same in the two groups (8.3 years for AIDH and 8.8 years for IDH lacking atypia). When considering only subsequent invasive carcinomas, the interval was 8.3 years for the AIDH and 14.3 years for the IDH lacking atypia. Of the 14 patients with IDH and a family history of breast carcinoma, invasive carcinoma subsequently developed in one (7%) as compared with two (2%) of the 91 with a negative family history. Among patients with AIDH, invasive carcinoma subsequently developed in two of the 13 (15%) of those with a family history of breast carcinoma as compared with one of 57 (1.8%) of the women with a negative family history. The presence of atypia in epithelial hyperplasia is a significant factor in increasing the likelihood of the development of subsequent invasive carcinoma (P = 0.03; two‐tailed test). Of women with AIDH, invasive carcinoma subsequently developed in 17% of those with sclerosing adenosis (SA) as compared with 4.2% of those without it. Therefore, SA may be a contributing factor to increased risk. A positive family history also appears to increase the likelihood of the subsequent development of invasive carcinoma, particularly in patients with AIDH.

Borderline and malignant mucinous tumors of the ovary. Histologic criteria and clinical behavior

The tremendous variation in length of survival of patients with mucinous cystadenocarcinoma of the ovary largely reflects the lack of uniform histologic criteria for the diagnosis. Evaluation of the efficacy of therapy for patients with Stage I carcinoma is especially difficult, since borderline tumors have been included that are histologically and clinically intermediate between a cystadenoma and a cystadenocarcinoma. A review of 688 primary mucinous tumors confined to one or both ovaries at the time of initial surgery indicated 80% were benign cystadenomas. The remaining 20% (136 neoplasms) were characterized by a proliferation of atypical epithelium that had features suggestive of malignancy. By analyzing the depth of stratification of the atypical cells and the presence or absence of stromal invasion, 97 Stage I borderline tumors (71%) were delineated from 39 Stage I cystadenocarcinomas (29%). Typically, the borderline tumor was a large, multilocular neoplasm that had papillary infoldings and two to three layers of atypical epithelial cells, but no invasion of the stroma. The “true” carcinoma had a greater degree of cellular stratification and/or unequivocal stromal invasion. An infiltrative growth pattern was identified in 56% of the carcinomas. Only 3 (4%) of 87 patients followed with a borderline tumor died with neoplasm compared to 9 (33%) of 27 patients followed with a cystadenocarcinoma. Rupture of tumor with spillage did not adversely affect the prognosis. Since the prognosis of the borderline mucinous tumor is vastly superior to that of a cystadenocarcinoma, the two should be separated if meaningful data on frequency, behavior, and therapeutic results are to be obtained. Our findings substantiate the rationale for preserving the contralateral uninvolved ovary in a young woman with a borderline mucinous ovarian tumor.

Relationship of histologic features to behavior of cystosarcoma phyllodes. Analysis of ninety-four cases

The clinical and pathologic findings in 94 patients with cystosarcoma phyllodes were studied to determine which pathologic characteristics were related to clinical behavior. The neoplasm recurred in 28 patients and 15 patients (17%) died of metastatic cystosarcoma. Most recurrences occurred within 2 years of initial surgery and all patients who died of cystosarcoma did so within 6 years. No tumor less than 4 cm in diameter or having fewer than 3 mitotic figures per 10 hpf in the areas of greatest mitotic activity proved fatal. Other microscopic features associated with a low risk of recurrence or of death were pushing margins (one death in 39 examples) and minimal cytologic atypism of the stromal cells (two deaths in 30 examples). No one feature was wholly reliable and a clearcut separation of benign from malignant tumors could not be made. Although axillary lymph nodes were enlarged in 17% of patients, metastasis to them occurred in not more than three instances (one histologically proved) and therefore radical mastectomy or routine axillary lymph node dissection is not worthwhile. Wide local excision for small cystosarcomas and simple mastectomy for larger ones is recommended. In addition, low axillary dissection should be considered in patients having clinically enlarged axillary lymph nodes and tumors larger than 4 cm if there is marked atypism of stromal cells or high mitotic activity, as determined by microscopic evaluation of the cystosarcoma.

Evaluation of criteria for distinguishing atypical endometrial hyperplasia from well‐differentiated carcinoma

Endometrial curettings from 204 patients containing severe forms of atypical hyperplasia, carcinoma in situ, and well‐differentiated carcinoma were compared with subsequent hysterectomy specimens to evaluate and identify the most useful histologic criteria for predicting the presence of invasive carcinoma. Endometrial stromal invasion, increased degrees of nuclear atypism, mitotic activity, cellular stratification, and epithelial necrosis in curettings were associated with a greater likelihood of carcinoma in the uterus. Of these, stromal invasion was the most significant feature. When stromal invasion was absent, carcinoma was present in the uterus in only 17%, and the carcinomas were well differentiated and confined to the endometrium or only superficially invasive. When stromal invasion was present in curettings, residual carcinoma was present in the uterus in half, and of these, one third were moderately or poorly differentiated and a quarter invaded deeply into the myometrium. The criteria for invasion are 1) an irregular infiltration of glands associated with an altered fibroblastic stroma or desmoplastic response; 2) a confluent glandular pattern in which individual glands are uninterrupted by stroma and merge to form a cribriform pattern of stromal replacement; 3) an extensive papillary pattern; and 4) replacement of stroma by masses of squamous epithelium. To qualify as invasion, items 2, 3, and 4 must occupy at least one half (2.1 mm) a low power field 4.2 mm in diameter. Because of the important role of stromal invasion in predicting prognosis, future classifications of endometrial neoplasia should utilize this feature in distinguishing atypical hyperplasia from well differentiated adenocarcinoma.

Metaplastic carcinomas of the breast. II. Spindle cell carcinoma

The clinical and pathologic features of 100 examples of spindle cell carcinoma (SpCC) of the breast are reported. Eighty-three neoplasms contained overt carcinoma; 72 had infiltrating ductal or intraductal carcinoma and in 11 the carcinomatous component was purely squamous. Seventeen neoplasms lacked overt carcinoma, but were identified as SpCC by immunoreactivity for keratin and the typical bland spindle cell proliferation forming a variable complex of fibrocollagenous stroma with feathered, myxoid, angioid, and storiform patterns. Areas of epithelium merging imperceptibly with the spindle cell component were commonly observed. Sixty neoplasms were studied by immunohistochemistry for the presence of keratin, epithelial membrane antigen (EMA), vimentin, S-100, and actin. The spindle cell component in 98% of SpCC was immunoreactive for keratin. Most were also immunoreactive for vimentin and actin, and in approximately one half, S-100 immunoreactivity was noted. These findings, in conjunction with histopathologic features, and ultrastructural observations from three cases, support myoepithelium as an integral component of SpCC. The cumulative 5-year survival rate for SpCC was 64%, better than survival rates usually reported for metaplastic carcinomas. Of 47 patients with axillary dissection, only 6% had metastases to axillary lymph nodes. Development of metastasis was an ominous sign as 29 of the 30 patients who developed metastases died from tumor. Local recurrence was not as ominous as only 29% who had only local recurrence subsequently died from tumor. The difference in size between tumors that recurred (mean, 5.0 cm) and those that did not (mean 3.7 cm), and the presence or absence of complete microscopic circumscription, were both significant prognostic factors.

Myofibroblastoma of the breast. Sixteen cases of a distinctive benign mesenchymal tumor

The clinical and pathologic findings of 16 examples of a distinctive stromal tumor of the breast designated as“myofibroblastoma” are reported. Eleven of the 16 patients were men, and the average age at presentation was 63 years. Fourteen were treated by local excision and two by simple mastectomy. None of the lesions recurred or metastasized. The tumors were grossly nodular and welldemarcated from the surrounding mammary tissue. Ducts and lobules were not engulfed by the neoplasm. Microscopically, the lesions were formed by uniform, slender, bipolar spindle cells haphazardly arranged in fascicular clusters separated by broad bands of hyalinized collagen. Ultrastructural examination of four lesions identified a predominance of myofibroblasts. Immunoreactivity for S-100 protein and cytokeratin was absent in the 10 tumors examined, but desmin immunoreactivity was focally present in three lesions. The differential diagnosis of myofibroblastoma includes reactive processes and benign neoplasms such as nodular and proliferative fascititis, fibromatosis, spindle-cell lipoma, neurofibroma, neurilemmoma, and leiomyoma. Malignant neoplasms such as stromal sarcoma, malignant fibrous histiocytoma, and spindle-cell or metaplastic carcinoma should not be confused with a myofibroblastoma. The clinical significance of this entity lies primarily in its recognition as a distinctive benign neoplasm.