William R. Hart

Perianal Paget's disease: A histologic and immunohistochemical study of 11 cases with and without associated rectal adenocarcinoma

Perianal Pagets disease is rare, and its relationship to an associated internal regional cancer has been ill defined. We analyzed the histologic and immunohistochemical features of perianal Pagets disease in 11 patients to determine the frequency and relationship of associated regional internal carcinoma and to gain insight into its histogenesis. Of five patients with documented rectal adenocarcinoma, it was discovered synchronously with the Pagets disease in four and, subsequently, in one. Pagets cells of signet ring type predominated in four cases. Intraepithelial glands with intraluminal dirty necrosis were present in four cases. The immunophenotype in four cases studied was cytokeratin (CK)7+/CK20+/gross cystic disease fluid protein- (GCDFP) in both the intraepithelial Pagets cells and the invasive rectal adenocarcinoma. Six patients did not have documented rectal carcinoma. The Pagets cells in four were CK7+/CK20-/GCDFP15+. Three of these had purely intraepithelial Pagets disease, and invasive or metastatic disease developed in none after wide local excision. Bilateral inguinal lymph node metastases developed in the fourth patient, and the patient died 8 months after diagnosis of Pagets disease. In two patients, the Pagets cells were CK7+/CK20+/GCDFP15-. Recurrent intraepithelial perianal Pagets disease developed in one patient at 7 months; the patient was alive without disease at 24 months, and the other patient had several intraepithelial recurrences of perianal Pagets disease, and, subsequently, a large perianal tumor of uncertain cell type developed at 108 months, which led to the patients death. We conclude that there are two types of perianal Pagets disease. One type has endodermal differentiation with gastrointestinal-type glands containing intraluminal dirty necrosis, numerous signet ring cells, CK20 positivity, and GCDFP15 negativity. Such cases are especially likely to be associated with synchronous or metachronous rectal adenocarcinoma. The other type is a primary cutaneous intraepithelial neoplasm in which the Pagets cells display sweat gland differentiation, including GCDFP15 positivity; it generally lacks gastrointestinal-type glands, intraluminal dirty necrosis, and CK20 positivity. The CK7 is a sensitive, albeit nonspecific, marker for Pagets cells.

Autoimmune oophoritis: a histopathologic study of involved ovaries with immunologic characterization of the mononuclear cell infiltrate

The ovaries from a patient with autoimmune oophoritis and premature ovarian failure were extensively evaluated by light microscopy and immunohistochemistry. A marked infiltrate of plasma cells and lymphocytes affected developing, cystic and atretic follicles but spared primordial follicles. Immunotyping of the ovarian mononuclear cell infiltrate revealed a mixture of B cells (including plasma cells) and T cells (both T4+ and T8+), as well as numerous macrophages and a few natural killer cells. These findings suggest that a complex immune process with an interplay of humoral and cellular mechanisms is involved in the pathogenesis of autoimmune oophoritis.

Uterine adenomyomas excluding atypical polypoid adenomyomas and adenomyomas of endocervical type: a clinicopathologic study of 30 cases of an underemphasized lesion that may cause diagnostic problems with brief consideration of adenomyomas of other female genital tract sites.

We report 30 uterine tumors composed of an admixture of endometrioid glands, endometrioid stroma, and smooth muscle that lacked the characteristic features of atypical polypoid adenomyoma. The patients ranged from 26 to 64 (median 47) years of age. The usual presenting symptom was abnormal vaginal bleeding, which was “massive” in two patients. Six patients were treated by polypectomy only, with hysterectomy performed in the remainder. Twenty-seven adenomyomas were in the corpus (22 submucosal, two mural, and three subserosal) and three in the cervix. The subserosal and submucosal examples were polypoid. The tumors were 0.3 to 17 cm in greatest dimension, and firm with cystic areas often present on sectioning. Focal hemorrhage was described in five cases. On microscopic examination, the tumors were composed of glands and cysts lined by endometrial-type epithelium separated by endometrial stroma and smooth muscle, with smooth muscle predominating. Minor foci of tubal-type epithelium (14 cases), mucinous endocervical-type epithelium (2 cases), and squamous epithelium (1 case) were present. The smooth muscle component was cellular in three cases and contained occasional bizarre nuclei in three cases. The epithelial cells were uniformly bland. No mitotic activity was observed in the epithelial or mesenchymal elements in 20 cases. In the remainder, up to 5 mitotic figures/10 high-power fields were observed in the epithelium (3 cases), the stroma and smooth muscle (3 cases), or both compartments (4 cases). Follow-up in 14 cases revealed no recurrence or extrauterine spread in any case. A diagnosis of adenocarcinoma or adenosarcoma was entertained by the submitting pathologist in five of 14 consultation cases. Adenomyomas are unusual benign uterine tumors that can be misdiagnosed, in part, because the lesion has not often received attention in the literature. The most realistic considerations in the differential diagnosis are atypical polypoid adenomyoma and adenosarcoma. The former, by definition, has epithelial atypia and the latter a malignant (usually low grade) stromal component with typically absent or inconspicuous smooth muscle. Distinction of adenomyoma from adenosarcoma may have significant therapeutic implications, particularly in young women.

Pagetoid squamous cell carcinoma in situ (pagetoid Bowen's disease) of the external genitalia.

Approximately 5% of cutaneous squamous cell carcinomas in situ (SCCIS) have a nested pattern, referred to as pagetoid SCCIS, or pagetoid Bowens disease. This growth pattern may simulate extramammary Pagets disease (EPD) when the external genitalia are involved. We report two cases of genital pagetoid SCCIS, including the first example affecting the vulva. Using several known cases each of classic (bowenoid) SCCIS of the vulva, primary cutaneous vulvar EPD, and cutaneous melanoma in situ as controls, we performed a battery of immunohistochemical and mucin stains to study the phenotype of pagetoid SCCIS. Both cases of pagetoid SCCIS were strongly positive for cytokeratin (CK) 7, a highly sensitive and popular marker for EPD. Stains with the high molecular weight cytokeratin marker Keratin-903 (34&bgr;E12) showed 4+ immunoreactivity, although not with the intensity seen in the juxtaposed normal keratinocytes or in the cells of classic SCCIS. Immunoreactivity scores were 2+ for CK5/6, 2+ for CK19, and 1+ to 3+ for CK 13. Unlike the Pagets cells of EPD, the nested cells of pagetoid SCCIS were devoid of mucin and were nonimmunoreactive with GCDFP-15, CEA, CAM5.2, and c-erbB2. Stains for CK20, S-100, and Melan A also were negative. Although CK7 is a sensitive marker for the Pagets cells of EPD, this study corroborates the unexpected CK7 positivity in pagetoid SCCIS, precluding its usefulness in distinguishing these two diseases. Combined with mucin stains, a limited immunohistochemical panel may be of diagnostic value in particularly difficult cases.

Peritoneal serous micropapillomatosis of low malignant potential (serous borderline tumors of the peritoneum). A clinicopathologic study of 17 cases.

Primary peritoneal serous micropapillomatosis of low malignant potential, or serous borderline tumor of the peritoneum, is a relatively rare lesion that is histologically indistinguishable from peritoneal “implants” associated with ovarian papillary serous tumors of low malignant potential. We analyzed 17 cases to further define the pathologic features and prognosis of this entity. The ages of the patients ranged from 16 to 67 years (mean, 33 years). Eight patients were symptomatic with chronic pelvic or abdominal pain (five patients), adnexal mass (one patient), small-bowel obstruction (one patient), and possible endometriosis (one patient). In nine cases (53%), peritoneal serous micropapillomatosis of low malignant potential was an incidental finding discovered during evaluation or treatment of other conditions. Grossly, the peritoneal lesions were focal or diffuse. They commonly appeared as miliary granules and often were believed to be peritoneal carcinomatosis. Microscopically, peritoneal serous micropapillomatosis of low malignant potential had all of the patterns seen in superficial (“noninvasive”) peritoneal implants of ovarian serous borderline tumors. Psammoma bodies were a prominent feature of all cases. Twelve patients also had typical endosalpingiosis. Most patients were treated by hysterectomy and bilateral salpingo-oophorectomy. Surgical treatment in seven patients consisted only of biopsy. Ten patients had residual unresected disease at the time of their initial operation. Several patients received adjuvant chemotherapy. Follow-up was available for 14 of the 17 patients. One patient died of metastatic breast carcinoma at 3.8 years; another patient died 7 weeks after operation, possibly as a complication of therapy. The other 12 patients were alive at last known contact after follow-up intervals of 8 months to 16.2 years (mean, 7.5 years). Two of these 12 patients developed multiple episodes of small-bowel obstruction due to persistent peritoneal serous micropapillomatosis of low malignant potential; neither received adjuvant chemo- or radiotherapy. Both were alive without progressive disease 10.9 and 16.2 years after initial diagnosis, respectively. This excellent prognosis supports a regimen of conservative therapy for these patients.

Ovarian serous tumors of low malignant potential (serous borderline tumors). The relationship of exophytic surface tumor to peritoneal "implants".

A series of 98 ovarian serous tumors of low malignant potential (LMP) was studied to test the validity of the implantation theory of extraovarian peritoneal spread of tumor by assessing the association between exophytic tumor on the ovarian surface and synchronous peritoneal implants. Patients ages ranged from 17 to 77 years (mean, 37.8 years). The ovarian tumors were bilateral in 39 cases (40%). Exophytic tumor was present in 47 (48%) cases and involved at least one ovary in 82% of bilateral tumors. Exophytic tumor was found in 29 of 31 patients (94%) with peritoneal implants, but in only 18 of 67 patients (27%) without peritoneal implants. Moreover, 29 of 47 patients (62%) with exophytic tumor had peritoneal implants compared with only 2 of 51 patients (4%) with out exophytic tumor. The utility of exophytic tumor as a marker of synchronous peritoneal implants had a diagnostic sensitivity of 94%, a diagnostic specificity of 73%, and an efficiency of 80%. Because of the strongly positive correlation between exophytic tumor and peritoneal implants, the implantation theory remains as a highly likely explanation for extraovarian spread of ovarian serous LMP tumors. The multicentric “field effect” theory, however, cannot be entirely excluded and may be operative in some cases.

Microcystic Adenomas (Serous Cystadenomas) of Pancreas: A Clinicopathologic Investigation of Eight Cases with Immunohistochemical and Ultrastructural Studies

Microcystic adenomas are rare tumors, which have only recently been distinguished from other cystic pancreatic lesions. This study details eight cases diagnosed at the Cleveland Clinic. Seven occurred in females. The mean age at diagnosis was 66 years. Abdominal or epigastric pain was the most common symptom. A history of extrapancreatic tumors was frequent, and one patient had a concomitant renal carcinoma with adrenal and renal cysts. The adenomas were multicystic, ranging in size from 2 to 14 cm. Cuboidal epithelial cells with vacuolated or clear cytoplasm containing abundant glycogen lined the cysts. The intervening stromal septa were collagenous and hypocellular. The epithelial cells exhibited strongly positive immunostaining for cytokeratins AE1 and AE3, but did not stain with CEA and Uro-2,3, and 4. Ultrastructurally, the epithelial cells rested on well-formed basal lamina and a delicate subepithelial capillary network. They had blunted apical microvilli and contained glycogen, few lipid droplets, and occasional apical secretory granules. Five adenomas were resected, and three had only a diagnostic biopsy. There were no metastases, but one patient died of postoperative complications following local excision. Elderly or high-risk patients may benefit more from biopsy alone than from attempts at total surgical resection of these benign tumors.

Localized fibrous tumor (localized fibrous mesothelioma) of the liver

A case of localized fibrous tumor (LFT) (localized fibrous mesothelioma) of the liver in an 83‐year‐old woman is presented. The tumor was 15 × 9 × 8 cm and was confined to the left lateral segment of the liver. Occasional mitotic figures (MF) (2 to 3 per 50 high‐power fields [HPF]) were present. Strong, diffuse vimentin positivity was demonstrated by immunohistochemistry. Immunoreactivity for cytokeratins (AE1‐3), epithelial membrane antigen (EMA), desmin, and desmosomal proteins (desmoplakin I + II) was absent. Electron microscopic examination showed a mesenchymal appearance of the majority of neoplastic cells, with a few ultrastructural features suggestive of mesothelial differentiation. These findings supported a submesothelial origin of the tumor. After a partial hepatectomy with total gross and microscopic removal of the tumor, the patient was alive without recurrence at 2 years, 5 months later. A review of the English literature showed six additional cases that are probably similar. Currently, all tumors have been clinically benign, although follow‐up information has been limited.

Simple and complex hyperplastic papillary proliferations of the endometrium: a clinicopathologic study of nine cases of apparently localized papillary lesions with fibrovascular stromal cores and epithelial metaplasia.

The clinicopathologic features of nine cases of papillary proliferation of the endometrium devoid of malignant nuclear features were studied. The patients ranged in age from 33 to 71 years (median 57 years). All were postmenopausal, except the youngest. The most common symptom was postmenopausal bleeding. Two patients were receiving hormonal replacement therapy and two were taking megestrol acetate. Two lesions were incidental findings in a hysterectomy specimen. Seven were diagnosed in endometrial biopsy or curettage specimens. In six cases (67%) the lesion involved an endometrial polyp. In all cases the papillae had fibrovascular stromal cores and variable degrees of branching. Two architectural patterns were found. A simple papillary pattern with involvement of only a few glands and little epithelial proliferation occurred in five cases, including three that were entirely intracystic. A complex papillary pattern with more extensive involvement of endometrial glands, a greater degree of branching of the papillae, and cellular tufting occurred in four cases. One or more metaplastic epithelial changes occurred in all cases, including endocervical-type mucinous metaplasia in nine cases (90%), eosinophilic cell change in eight (89%), ciliated cell change in seven (70%), focal squamous metaplasia in two cases (22%), and hobnail cell change in two (22%). Mitotic figures were found in three cases. In four lesions (44%), all with a complex papillary pattern, the proliferating cells had mild nuclear atypia. Three of these patients underwent hysterectomy within 5 months. Simple nonpapillary hyperplasia and two endometrial polyps were found in one patient, complex nonpapillary hyperplasia in one, and atrophic endometrium in the other. Two patients had additional endometrial samplings within 4 months that contained small residual simple papillary lesions. One of these had another biopsy at 16 months that showed only atrophy. One patient had no subsequent diagnostic or therapeutic procedures. One patient was a recent case. Of the three patients with intact uteri and appreciable follow-up, all were alive and well at 14, 96, and 102 months, respectively. We conclude that these papillary proliferations are a form of hyperplasia that is closely associated with endometrial epithelial metaplasia. Polypectomy and/or curettage may be effective in removing them because they often are localized lesions. Although all of our patients had an uneventful outcome, the number of cases is small. Our findings question the validity of diagnosing endometrial lesions as well-differentiated carcinoma solely because of a complex papillary architectural pattern.

Histopathologic findings in 107 uterine leiomyomas treated with leuprolide acetate compared with 126 controls.

The reported histopathologic findings in leiomyomas treated with leuprolide acetate (LA) differ. We examined 233 myomectomy specimens, including 107 myomas from 30 patients (mean age, 34.7 +/- 4.6 years) treated with LA. Their histopathologic findings were compared with those from a control group of 126 myomas from 30 untreated patients (mean age 32.7 +/- 5.3 years). The LA-treated leiomyomas had myxoid change (n = 2; 1.9%), total necrosis (n=4; 3.7%), focal necrosis (n = 5; 4.7%), calcifications (n = 5; 4.7%), hemorrhage (n = 8, 7.5%), vascular changes (n = 12; 11.2%), hydropic degeneration (n = 22; 20.5%), and hyalinization (n = 61; 57.0%). None of these changes differed significantly from the untreated controls. None of the LA-treated leiomyomas had nuclear atypia, whereas nuclear atypia occurred in four (3.2%) of the untreated leiomyomas; this difference was also not significant. Mitotic figures were present in 8.4% of the LA-treated myomas and 8.5% of untreated controls. The number of mitotic figures per 10 high-power fields was slightly higher in the untreated myomas, but the difference was not statistically significant (range, 0-3 for treated, 0-5 for controls). The degree of cellularity did not differ between the two groups. In conclusion, (a) LA-treated myomas do not significantly differ from untreated myomas with respect to nuclear atypia, calcification, total coagulative necrosis, focal coagulative necrosis, hemorrhage, vascular changes, myxoid change, hydropic degeneration, hyalinization, mitotic activity, or cellularity; and (b) the mechanism leading to a reduction in the size of myomas treated with LA is not apparent from routine histologic examination.