Robert A. Erlandson

Peripheral nerve sheath tumors: an electron microscopic study of 43 cases.

To obtain data concerning their histogenesis, 23 benign solitary schwannomas (including five cellular variants), 10 neurofibromas, and 10 malignant peripheral nerve sheath tumors were studied by electron microscopy. The results confirm previous findings that solitary schwannomas (so‐called neurilemomas) are composed principally of cells showing features of differentiated Schwann cells. The principal cells of neurofibromas on the other hand did not resemble differentiated Schwann cells. The predominant cell type in six cases was indistinguishable from normal perineurial cells. Schwann cell‐axon complexes seen in three cases may have represented entrapped normal structures or perhaps one component of a hamartomatous tumor. In contrast to the benign neoplasms the cells of the ten malignant peripheral nerve sheath tumors were in general poorly differentiated. When differentiated, they shared some features with Schwann and perineurial cells. Cell forms intermediate between them and fibroblastic cells were also identified. These findings indicate that schwannoma and neurofibroma are distinct entities. In the authors experience schwannomas rarely undergo malignant change. For this reason and because it is unclear whether malignant tumors of peripheral nerves arise from more than one sheath cell, the designation of malignant peripheral nerve sheath tumor (PNST) is preferable to malignant schwannoma.

Renal oncocytoma: a clinicopathologic study of 70 cases.

We reviewed 954 primary nonurothelial epithelial renal neoplasms with primary resection at Memorial Sloan-Kettering Cancer Center between the years 1980 and 1995 and classified 70 cases (7%) as renal oncocytomas. The study population was composed of 39 men and 31 women, and the mean age was 65 years (range 25 to 86 years). Fifty-six patients (80%) were asymptomatic at presentation, six (4%) had flank pain, six (4%) presented with a mass, and two (3%) had hematuria. Sixty-one were treated with total or radical nephrectomy, nine with partial nephrectomy. The right kidney was involved in 35 cases (50%), the left kidney in 32 (46%). Three cases (4%) were bilateral. Sixty-one cases (87%) were unifocal, nine (13%) multifocal. All the tumors were well circumscribed but unencapsulated. Forty-five (64%) were described as brown or red, whereas the remainder were variously described as tan to yellow. Central fibrosis or scar was described in 23 cases (33%), and gross areas of hemorrhage or cystic changes in 14 (20%). The mean size was 5.2 cm and median 5.0 cm (range 1.5 cm to 14 cm). Histologically, the tumors were characterized by a mixture of architectural patterns: compact cellular nests and acini embedded in a hyalinized, hypocellular stroma were present in 62 cases (89%), a solid nested architecture in 47 cases (67%), and a variable tubular component in 50 cases (71%). Small papillae, pseudopapillae, and intratubular epithelial tufts were seen in 19 cases (27%). Cytologically, the neoplasms also showed a mixture of cell types, the most common being the classic oncocyte, which consisted of round or polygonal cells with moderate to abundant granular, eosinophilic cytoplasm, and small round nuclei with evenly dispersed granular chromatin. Small basophilic nucleoli were visible in many of these cells in all cases. Thirty-one cases (44%) had a variable number of oncocytic cells with pyknotic nuclei and 20 (30%) contained clusters of small cells with a high nuclear/cytoplasmic ratio and dense hyperchromatic nuclei (so-called oncoblasts). Foci of tubules with clear cells embedded in a hyalinized stroma were present in six cases (9%). Cellular atypia was evident in 42 cases (60%) and was marked in 21 (30%). Eleven cases (16%) exhibited mitotic activity, albeit low. No case had atypical mitoses or necrosis. Twenty-two cases (31%) had areas of calcification within the hyalinized stroma, 12 (17%) had calcospherites, and three (4%) had osseous and myeloid metaplasia. Vascular invasion was present in three cases (4%), and invasion of perinephric fat in 14 (20%). One patient presented with liver metastasis. Fourteen cases (20%) were pT1, 42 (60%) pT2, and 14 (20%) pT3. After a mean follow-up of 58 months (range 1 to 181), 62 patients (89%) were alive with no evidence of tumor, six (9%) had died of other causes, one was alive with stable metastatic disease in the liver 58 months after diagnosis, and one died with metastatic disease to bone and liver. We conclude that renal oncocytomas have a varied morphologic appearance and their pathologic diagnosis should be based on a constellation of architectural and cytologic features. The overwhelming majority of cases behave in a benign fashion, although in rare instances they can metastasize. The presence of atypical morphologic features do not alter the excellent prognosis associated with oncocytomas and do not predict an aggressive clinical course.

Pseudoangiomatous hyperplasia of mammary stroma

Grossly circumscribed, nonhemorrhagic breast masses consisting of mammary stromal proliferations that simulated vascular lesions were studied in nine women. Histologically, a striking pattern, which appeared to consist of complex inter-anastomosing channels lined by slender spindle cells, was present in the mammary parenchyma. The importance of this benign lesion, referred to as pseudoangiomatous hyperplasia of mammary stroma, is its distinction from angiosarcoma. The patients ranged in age from 22 to 52 years; all were premenopausal. Each presented with a palpable unilateral mass, measuring up to 7 cm in diameter. The patients were treated by excisional biopsy and remained well for up to 2.5 years after excision. One patient had two local recurrences within one year of the original excision, and a second patient had a local recurrence at 14 months. No patient had another concurrent or metachronous malignant tumor of the breast or other organ, and no abnormal hormonal status was found. Complete local excision appears to be adequate treatment. It remains to be determined whether this is a neoplastic process. However, there is no evidence that it is a precursor of angiosarcoma, and ultrastructural observations demonstrate that the spaces found in the lesion are not true vascular channels. Rather, they appear to arise by a process that involves disruption and separation of stromal collagen fibers. Since small foci of this change are common in hyperplastic breast tissue from premenopausal women, it is likely that the development of a discrete tumor with this pattern represents an exaggerated form of stromal hyperplasia.

Histogenesis of benign pleomorphic adenoma (mixed tumor) of the major salivary glands. An ultrastructural and immunohistochemical study.

Twenty-two benign pleomorphic adenomas of the major salivary glands were studied by transmission electron microscopy and immunohistochemical techniques (three cases) in order to characterize the cell types comprising the epithelial and so-called mesenchymal regions of the tumors. Light- and electron-microscopic studies showed the tumors to consist of variable mixtures of neoplastic ductular epithelial cells, rare acinar cells, and metaplastic myoepithelial cells. Many of the loosely organized “stromal cells” contained structures indicative of their myoepithelial origin, e.g., perinuclear tonofilaments, ectoplasmic actin microfilaments, and remnants of basement membrane. Polyclonal antikeratin antisera strongly stained ductular epithelial and myoepithelial cells, squamoid cell nests, and periductular myoepithelial cells, whereas myxoid and chondroid cells were less intensely stained. Monoclonal cytokeratin antibody AE1 stained only the ductular epithelial cells in both the normal glands and tumors. In contrast, S-100 protein, which is present only in scattered acinar cells and myoepithelial cells in the normal parotid gland, was found in the ductular and periductular myoepithelial cells, isolated myxoid cells, and chondroid and cartilagenous cells in the tumors. Actin was found in all the cell types of the tumor but staining was strongest in the ducts. Double immunofluorescence staining for cytokeratin and vimentin revealed coexpression of both types of intermediate filaments in occasional normal acinar and intercalated duct myoepithelial cells, and in some cells in the myxoid and chondroid regions of the tumors. In the tumors, vimentin was present in occasional periductular myoepitheliai cells, stellate myxoid cells, and especially in chondroid cells and chondrocytes. Our findings indicate that benign pleomorphic adenomas of the major salivary glands are pure epithelial cell tumors. The histologic complexity of these neoplasms is due to the ability of the neoplastic ductular myoepithelial cell to modulate its morphologic appearance and intermediate filament composition, and to produce large amounts of matrix substances. We further postulate that these tumors arise from neoplastically transformed intercalated ducts.

Cellular schwannoma: a variety of schwannoma sometimes mistaken for a malignant tumor.

Fourteen cellular schwannomas, a variety of peripheral nerve sheath tumor showing a predominantly compact cellular growth, no formed cellular palisades or Verocay bodies, but the ultrastructure of schwannomas, are reported. A presumed nerve of origin was identified in three instances. The tumor had no sex predeliction; the mean age was 48. The neoplasm is usually well encapsulated and most commonly presents in the neck, posterior mediastinum, or pelvis. Because of a variety of confusing histologic features, including dense cell bundles and fascicles, storiform areas, a moderate mitotic activity and moderate nuclear atypia, six of 14 cases were mistaken for either fibrous histiocytoma, leiomyoma, malignant peripheral nerve sheath tumor, or sarcoma of uncertain type. In two instances the false impression of a malignant tumor was reinforced by clinical evidence of bony erosion and destruction. Follow-up thus far has shown the tumor to be benign.

Soft-tissue perineurioma. Evidence for an abnormality of chromosome 22, criteria for diagnosis, and review of the literature.

Reported herein are two examples of soft-tissue perineurioma (STP), one arising in the maxillary sinus and the other in subcutaneous tissue of the thigh. Electron microscopy and immunohistochemistry were performed in both cases. Based on our findings and a critical review of the literature, STPs are generally small, well-circumscribed but not encapsulated tumors. Histologically, most STPs resemble fibroblastic tumors, being composed of elongated, wavy cells. The immunohistochemical reactivity for epithelial membrane antigen, the lack of reactivity for S-100 protein, and the presence of ultrastructural features of perineurial cells are typical of this tumor. To explore the possibility that STP, like the intraneural variety of perineurioma, exhibits an abnormality of chromosome 22, we performed fluorescence in situ hybridization with a probe specific for the M-bcr locus, which maps to the chromosome band 22q11. In both our tumors, a high percentage of nuclei having only one M-bcr signal (44 and 96%) was observed. Our findings indicated deletion of part or all of chromosome 22 and support the view that both soft-tissue and intraneural perineurioma are part of a spectrum of perineurial neoplasia.

Cellular schwannoma. A clinicopathologic study of 57 patients and 58 tumors

The cellular schwannoma is a variety of schwannoma with a predominantly cellular growth but no Verocay bodies. Because doubt has been raised about the original assessment of this tumor as benign, the clinical and pathologic characteristics of 58 cellular schwannomas from 57 patients were reviewed. The patients were most often middle aged (63% were female), and their tumors most commonly were painless masses with a predilection for the paravertebral region of the retroperitoneum, pelvis, and mediastinum. Most tumors were solitary and encapsulated, and an associated nerve was identified for 43% of the cases. Electron microscopic and immunohistochemistry studies confirmed the tumors Schwann cell nature. Worrisome features such as bone erosion, hypercellularity, foci of necrosis (four tumors), hyperchromasia, nuclear pleomorphism, and the presence of mitotic figures led to a malignant diagnosis for 28% of the cases. Treatment in all but one case was surgical excision. Two patients also received radiation therapy and chemotherapy. Follow‐up of from 1 year to 24 years, 7 months (median of 6 years and mean of 7 years) for 61% (35 cases) of the cases reveals three patients with a local recurrence but no cases in which the tumor metastasized or the patient died of the tumor. Awareness of this tumor type is important so that the surgeon will avoid unnecessary sacrifice of functionally important nerves attached to these tumors and so that needless adjuvant radiation and chemotherapy will not be instituted.

Extracranial primitive neuroectodermal tumors. The memorial sloan‐kettering cancer center experience

The clinical data of 54 patients (57% males) with extracranial primitive neuroectodermal tumors (PNET) seen over a 20‐year period at Memorial Sloan‐Kettering Cancer Center were reviewed. The age at diagnosis ranged from 1 month to 81 years (median, 17 years). One PNET arose in a previously irradiated site. One patient had an unaffected identical twin. Primary sites were thoracopulmonary (n = 25), pelvis (n = 12), retroperitoneum or abdomen (n = 10), limbs (n = 5), neck (n = 1), and unknown (n = 1). At diagnosis, epidural extension was present in 13 patients with truncal primaries, and 11 patients had distant metastases. All of the latter died with disease. Progression‐free survival (PFS) among the 43 patients with localized tumors (all >5 cm) was 25% at 24 months. Two of 13 patients who relapsed after more than 12 months without therapy were long‐term survivors. Patients with localized PNET who had resection of all gross disease within 3 months of diagnosis had a significantly longer PFS (P = 0.0003). Radiation therapy caused tumor shrinkage but was not curative of measurable disease. A doseresponse effect was evident with the most commonly used drug, cyclophosphamide. Myeloablative regimens using melphalan (n = 8) or thiotepa (n = 1) with autologous bone marrow rescue were not clearly beneficial. The treatment results favor: (1) early surgical removal, (2) dose‐intensive use of drugs active against PNET (especially cyclophosphamide), and (3) radiation therapy to ablate residual microscopic disease.

Subclassification of gastrointestinal stromal tumors based on evaluation by electron microscopy and immunohistochemistry.

Fifty-six gastrointestinal stromal tumors (GIST) were subclassified by ultrastructural examination and by immunophenotypic analysis using a panel of 13 antibodies. Eighty percent of the tumors originated in the stomach and small intestines. The neoplasms were classified as follows: 42.9% smooth muscle tumors (4 leiomyomas, 9 spindle cell and 8 epithelioid leiomyosarcomas, and 3 mixed spindle cell and epithelioid leiomyosarcomas); 37.5% gastrointestinal autonomic nerve tumors (GANT), 47.6% of which arose in the small intestines; 8.9% mixed leiomyosarcoma/neurogenic tumors; and 10.7% undifferentiated GIST, not otherwise specified. The muscle common actin antibody HHF-35, variably reactive with tumor cells composing 23 of 24 smooth muscle tumors, was found to be the most sensitive marker of leiomyocyte differentiation. One immunophenotypically questionable spindle cell leiomyosarcoma was diagnosed by electron microscopy. Since neuron specific enolase positive cells were found in 1/3 of the leiomyosarcoma cases, the ultrastructural demonstration of synapse-like structures and neurosecretory granules was required for diagnosing GANTs. The immunophenotype of the ultrastructurally undifferentiated GIST was vimentin and CD34+. Variable numbers of ultrastructurally undifferentiated cells also we found in all of the tumors except 2 leiomyomas. CD34 was also expressed in smooth muscle (54%) and GAN (62%) tumors. Despite their similar light microscopic appearance, GIST are phenotypically heterogeneous, requiring both ultrastructural and immunohistochemical studies for accurate characterization.

Clinical and Pathobiological Effects of Neoadjuvant Total Androgen Ablation Therapy on Clinically Localized Prostatic Adenocarcinoma

Neodjuvant total androgen ablation therapy leads to involutional changes in prostatic carcinoma and may have the potential to downstage operable prostate cancers. We studied 27 clinically localized prostatic carcinomas after 3 months of combined treatment with a luteinizing hormone-releasing hormone agonist, goserelin acetate, and the antiandrogen flutamide, followed by radical retropubic prostatectomy, for changes in the serum prostatespecific antigen (PSA) level, changes in prostatic volume, therapy-induced histopathologic changes, DNA ploidy, and proliferative activity. Ten hormonally untreated, grade-matched prostatic adenocarcinomas served as controls. The mean pretherapy serum PSA level was 17.5 ng/ml, and posttherapy PSA levels were all < 4.0 ng/ml, with 18 men having undetectable levels. The mean reduction in prostatic volume following hormonal therapy was 37% (range 16–52%). Pathologic staging confirmed 20 pT2NO, six pT3NO, and one pT3N1. All prostates showed residual adenocarcinoma (extremely focal in seven cases [26%] with loss of glandular architecture, cytoplasmic vacuolization, and nuclear pyknosis. High-grade adenocarcinoma was nondiploid in 25% of hormonally treated prostates and 80% of 10 untreated controls. Immunostaining for proliferating cell nuclear antigen showed > 10% nuclear reactivity in 33% of treated carcinomas and 90% of untreated carcinomas. In conclusion, 3 months of neoadjuvant androgen ablation for localized prostatic carcinoma significantly lowers serum PSA and prostatic volume and produces involutional changes in residual carcinomas that mimic high-grade disease. However, pretreated carcinomas have predominantly a diploid DNA content and low proliferative activity as opposed to untreated carcinomas. Thus, grading of pretreated adenocarcinomas by conventional methods may be misleading. Preoperative total androgen ablation has a profound effect on a subset of prostatic carcinoma cells, possibly by facilitating programmed cell death.