The American journal of surgical pathology

Published by Lippincott, Williams & Wilkins
Print ISSN: 0147-5185
: Surgical margin status at prostatectomy is an important predictor of biochemical recurrence (BCR). The current convention is to categorize a margin as negative if tumor cells are not at the inked margin, even if they are within a few cells of the margin. We hypothesized that cancer within 0.1 mm of the margin conferred an increased risk for BCR. We determined the risk for BCR on the bass of surgical margin status in a cohort of 1588 patients who underwent radical prostatectomy for prostate cancer (PCa) between 1998 and 2011. Surgical margins were categorized as positive, close (<0.1 mm from tumor cells), or negative. Multivariate hazard ratios (HRs) for BCR were determined by margin status. We identified 1588 patients, of whom 193 had PCa recurrence. The margin status was negative in 1058 (67%), close in 232 (15%), and positive in 298 (19%). Cancer that was close to the margin was a significant and independent predictor of BCR (HR 1.53; 95% confidence interval, 1.00-2.32) and was not statistically different than a positive surgical margin (HR 2.10; 95% confidence interval, 1.48-2.99). Cancer that is within 0.1 mm of the surgical margin of a prostatectomy is associated with an increased risk for PCa recurrence. Patients with that margin status may be reasonable candidates for adjuvant local therapy.
The authors measured telomerase activity using the telomeric repeat amplification protocol-enzyme-linked immunosorbent assay method in 13 neuroendocrine pulmonary neoplasms and in non-neoplastic frozen lung samples from the same patients. These cases belonged to the complete neuroendocrine neoplastic spectrum: four typical carcinoids, three atypical carcinoids, four large cell neuroendocrine lung carcinomas, and two small cell lung carcinomas. The authors performed the same assay for 52 non-neoplastic lung tissues from the surgical files in their department (negative controls). They verified the presence (or absence) of neoplastic tissue in every case by looking at one frozen section done in the same tissue used for telomerase assay. The telomerase activity level in non-neoplastic tissues (mean, 182 A450nm U) was similar to that obtained in the typical carcinoids (mean, 104.5 A450nm U). All neuroendocrine tumors but the typical carcinoids showed high levels of telomerase activity (mean, 1,750.8 A450nm U). According to the telomerase hypothesis, typical carcinoid cells are mortal pre-M2 stage cells, but atypical carcinoid, large cell neuroendocrine lung carcinoma, and small cell lung carcinoma cells are immortal post-M2 stage cells. This finding may be of important prognostic significance in these kinds of tumors. Measurement of enzyme activity with a good morphologic control could be necessary in telomerase activity assay.
The lymphocytes that accompany thymomas express an immature T-cell phenotype, as usually demonstrated by CD1 or TdT immunoreactivity. Even when thymomas metastasize or occur in ectopic sites, the infiltrating T lymphocytes show this unique immature phenotype, contrasting with thymic and nonthymic carcinomas, in which the infiltrating T lymphocytes typically show a mature phenotype (CD1 and TdT negative). Therefore, the presence of an immature T-cell population in an epithelial tumor strongly supports a diagnosis of thymoma. The availability of an antibody that consistently marks immature T-cells in routine paraffin sections would be of great help in the study of thymic tumors. In this report, we describe the use of MIC2 antibody (013), which has been widely used for the diagnosis of Ewing's sarcomas and peripheral primitive neuroectodermal tumors because it intensely stains thymocytes. Immunohistochemical staining was performed on paraffin sections of normal/hyperplastic thymus (18 cases), thymoma (62 cases), thymic carcinoma (nine cases), tumors showing borderline features between thymoma and thymic carcinoma (three cases), and ectopic hamartomatous thymoma (two cases). T-cell and B-cell antibodies were also applied to aid in the interpretation. In the normal thymus, almost all lymphocytes in the cortex stained with 013, whereas fewer than 5% of those in the medulla were 013 positive. In thymomas, including the three ectopic thymomas and the single case of metastatic thymoma, most lymphocytes were 013 positive, except the spindle-cell foci (medullary thymoma or medullary component of mixed thymoma), in which the percentage of 013-positive lymphocytes was lower (5-30%). Within the pale foci of "medullary differentiation" and the perivascular spaces of lymphocyte-rich thymomas, few lymphocytes showed 013 positivity, indicating that the T lymphocytes in these areas were more mature. None of the thymic carcinomas harbored 013-positive lymphocytes. Among the three cases of borderline thymoma/thymic carcinoma, only one harbored 013-positive lymphocytes. The 013-positive lymphocytes were not seen in the ectopic hamartomatous thymomas. In normal lymph nodes and nonthymic carcinomas studied as controls, there were no or at most small numbers of isolated 013-positive lymphocytes. We conclude that interpreted in the proper context, MIC2 antibody can serve as a useful marker of immature T-cells and thus help in the confirmation of a diagnosis of thymoma in small biopsy specimens, ectopic thymoma, or metastatic thymoma; in the distinction between invasive thymoma and thymic carcinoma; and in the classification of thymomas.
In order to assess the accuracy of the intraoperative consultation, or "frozen section," a retrospective review of 1,000 consecutive intraoperative consultations was performed. We present these data as a quality assurance assessment and as an update to a body of older literature examining the accuracy of the frozen section. The indications for intraoperative consultation and types of specimen submitted have changed in recent years, and these changes are related to the results in the present study. The increasingly important role of intraoperative cytology as an adjunct to and, in many cases, a replacement for frozen section is also emphasized.
The accuracy of intraoperative frozen-section diagnosis of small in situ and invasive breast cancers is uncertain. We reviewed the results of 1,490 consecutive wire-localized breast biopsies from 1,439 patients with nonpalpable mammographically detected abnormalities examined by frozen section at Mayo Clinic over a 3-year period. The mammographic abnormalities included benign calcifications (61 cases), indeterminate calcifications (422 cases), worrisome calcifications (54 cases), well-circumscribed nodules (115 cases), irregular nodules (473 cases), architectural distortions (52 cases), asymmetry (39 cases), well-circumscribed nodules with calcification (12 cases), irregular nodules with calcification (75 cases), architectural distortions with calcification (35 cases), and asymmetry with calcifications (12 cases). We detected 457 carcinomas, including 135 in situ and 322 invasive cancers. The invasive carcinomas had a mean diameter of 1.07 cm (range, 0.1-3.0 cm), including 191 with diameters of 1 cm or less (59.3% of cases). In 77 cases (5.2% of total), the diagnosis was deferred to permanent sections. Frozen-section accuracy was 97.7%. False-negative diagnoses were rendered in 0.5% of cases, and there were no false-positive diagnoses. There was no correlation of infiltrating carcinoma diameter and error rate. These results indicate that intraoperative frozen section of mammographically directed breast biopsies provides accurate and reliable diagnoses.
The literature on the clinicopathologic characteristics of tumoral intraepithelial neoplasms (neoplastic polyps) of the gallbladder (GB) is fairly limited, due in part to the variability in definition and terminology. Most reported adenomas (pyloric gland type and others) were microscopic and thus regarded as clinically inconsequential, whereas papillary in situ carcinomas have been largely considered a type of invasive adenocarcinoma under the heading of "papillary adenocarcinomas." In this study, 123 GB cases that have a well-defined exophytic preinvasive neoplasm measuring ≥1 cm were analyzed. The patients were predominantly female (F/M=2:1) with a mean age of 61 y and a median tumor size of 2.2 cm. Half of the patients presented with pain, and in the other half the neoplasm was detected incidentally. Other neoplasms, most being gastrointestinal tract malignancies, were present in 22% of cases. Gallstones were identified in only 20% of cases. Radiologically, almost half were diagnosed as "cancer," roughly half with polypoid tumor, and in 10% the lesion was missed. Pathologic findings: (1) The predominant configuration was papillary in 43%, tubulopapillary in 31%, tubular in 26%. (2) Each case was assigned a final lineage type on the basis of the predominant pattern (>75% of the lesion) on morphology, and supported with specific immunohistochemical cell lineage markers. The predominant cell lineage could be identified as biliary in 50% (66% of which were MUC1), gastric foveolar in 16% (all were MUC5AC), gastric pyloric in 20% (92% MUC6), intestinal in 8% (100% CK20; 75% CDX2; 50%, MUC2), and oncocytic in 6% (17% HepPar and 17% MUC6); however, 90% of cases had some amount of secondary or unclassifiable pattern and hybrid immunophenotypes. (3) Of the cases that would have qualified as "pyloric gland adenoma," 21/24 (88%) had at least focal high-grade dysplasia and 18% had associated invasive carcinoma. Conversely, 8 of 47 "papillary adenocarcinoma"-type cases displayed some foci of low-grade dysplasia, and 15/47 (32%) had no identifiable invasion. (4) Overall, 55% of the cases had an associated invasive carcinoma (pancreatobiliary type, 58; others, 10). Factors associated significantly with invasion were the extent of high-grade dysplasia, cell type (biliary or foveolar), and papilla formation. Among systematically analyzed invasive carcinomas, tumoral intraepithelial neoplasia was detected in 6.4% (39/606). (5) The 3-year actuarial survival was 90% for cases without invasion and 60% for those associated with invasion. In contrast, those associated with invasion had a far better clinical outcome compared with pancreatobiliary-type GB carcinomas (3-yr survival, 27%), and this survival advantage persisted even with stage-matched comparison. Death occurred in long-term follow-up even in a few noninvasive cases (4/55; median 73.5 mo) emphasizing the importance of long-term follow-up. In conclusion, tumoral preinvasive neoplasms (≥1 cm) in the GB are analogous to their pancreatic and biliary counterparts (biliary intraductal papillary neoplasms, pancreatic intraductal papillary mucinous neoplasms, and intraductal tubulopapillary neoplasms). They show variable cellular lineages, a spectrum of dysplasia, and a mixture of papillary or tubular growth patterns, often with significant overlap, warranting their classification under 1 unified parallel category, intracholecystic papillary-tubular neoplasm. Intracholecystic papillary-tubular neoplasms are relatively indolent neoplasia with significantly better prognosis compared with pancreatobiliary-type GB carcinomas. In contrast, even seemingly innocuous examples such as those referred to as "pyloric gland adenomas" can progress to carcinoma and be associated with invasion and fatal outcome.
Nephrogenic adenoma is a benign lesion that may occur at any site of the genitourinary tract, usually in association with previous urothelial injuries. Although its pathogenesis is still debated, recent studies seem to confirm its derivation from renal tubular epithelium, rather than from a metaplastic process of urothelium. In addition to its uncertain origin, there can be diagnostic difficulty in distinguishing nephrogenic adenoma from prostatic adenocarcinoma, particularly with lesions arising in the prostatic urethra. So far, immunohistochemical stains are often needed to make such a distinction, and several markers have been proposed, often with controversial results. S100A1 is a calcium binding protein that has been recently reported to be expressed in renal tubular cells and in a subset of renal cell neoplasms. Alpha-methylacyl-CoA racemase (AMACR), a recently identified prostate cancer marker, has also been found to be expressed in renal tubules and in some renal epithelial neoplasms. In this study, we investigated the expression of S100A1 and AMACR in 18 nephrogenic adenomas and in 100 prostatic adenocarcinomas. A strong and distinct cytoplasmic or nucleocytoplasmic staining of S100A1 was found in 17 out of 18 cases of nephrogenic adenoma (94%), but never in prostatic adenocarcinoma. In contrast, AMACR expression was detected in 14 of 18 nephrogenic adenomas (78%) and in 96 of 100 prostatic adenocarcinomas (96%). We conclude that (1) S100A1 is a specific and sensitive immunohistochemical marker to differentiate nephrogenic adenoma from prostatic adenocarcinoma; (2) AMACR immunostaining does not seem to be a useful marker in distinguishing between these 2 lesions; (3) given that both S100A1 and AMACR have been reported to be expressed in renal tubular cells and in a subset of renal cell neoplasms, our findings confirm the histogenetic relationship between nephrogenic adenoma and renal tubular epithelium.
In 1951 Haagensen, Stout, and Phillips described a series of patients treated for benign intraductal papillary breast lesions. They emphasized the importance of distinguishing between "microscopic papillomas" and "gross papillomas." While the former tended to be multicentric and potentially precancerous, follow-up of 108 women who had solitary papillomas revealed no subsequent carcinomas. Four women had additional papillomas in the ipsilateral breast and one patient developed a papilloma of the contralateral breast. Review of the literature since 1927 reveals a total of 612 patients who reportedly had a papilloma treated by excision. Subsequent carcinoma was described in 23 cases (11 or 2% ipsilateral; 10 or 2% contralateral; two or 0.3% bilateral). These data indicate that excision of a solitary papilloma from the breast does not indicate that the breast is predisposed to develop carcinoma at a later date.
We report an immunohistochemical study of the distribution and number of interdigitating reticulum cells (IDC) and S-100 beta-positive small lymphocytes (S-100 beta + lymphocytes) in 53 thymomas and 11 thymic carcinomas. All 53 thymomas showed the presence of IDC in the tumor parenchyma. In most cases of predominantly lymphocytic and mixed-type thymoma, IDC clustered in areas, that corresponded to locations that had medullary differentiation and contained accumulated mature lymphocytes. By contrast, in most of the predominantly epithelial-type thymomas, IDC were scattered rather than forming clusters. The distribution and number of IDC were correlation with the histological type of thymoma but not with invasiveness. In thymic carcinomas, IDC were scattered in tumor nests. In 47 of the 53 thymomas (89%), infiltrating S-100 beta + lymphocytes were readily recognized. The remaining six cases without S-100 beta + lymphocytes were noninvasive thymoma. We conclude that the degree of S-100 beta + lymphocyte infiltration is correlated with the stage of thymoma and may be a marker of thymoma malignancy.
Myoepitheliomas and mixed tumors were only recently recognized to occur primarily in soft tissue, and only small case numbers have been described. To characterize these tumors further and to evaluate prognostic parameters, 101 myoepithelial tumors of soft tissue were retrieved from the authors' consult files. Hematoxylin and eosin sections were reexamined, immunohistochemistry was performed, and clinical details were obtained from referring physicians. Fifty-three patients were male and 48 female (mean age 38 years; range 3-83 years). Tumor size ranged from 0.7 to 20 cm (mean 4.7 cm). Most tumors arose in the extremities and limb girdles: 41 in the lower limbs, 35 in the upper limbs, 15 in the head and neck, and 10 in the trunk. Fifty-four tumors were situated in subcutis and 37 in deep soft tissue (depth unstated in 10). Most cases were grossly well circumscribed; 43 showed microscopically infiltrative margins. Histologically, most tumors were lobulated, composed of cords or nests of epithelioid, ovoid, or spindled cells with a variably reticular architecture and a chondromyxoid or collagenous/hyalinized stroma. Eight cases showed a predominantly solid proliferation of spindled or plasmacytoid cells; 17 demonstrated ductular differentiation (mixed tumors). Cartilage was present in 6 cases, 6 contained bone, and 4 others contained both. Mitoses ranged from 0 to 68 per 10 high power fields (mean 4.7 per 10 high power fields). Tumors with benign cytomorphology or mild cytologic atypia (low-grade) were classified as myoepithelioma or mixed tumor, whereas tumors with moderate to severe atypia (high-grade) were classified as myoepithelial carcinoma (epithelioid or spindled cells with vesicular or coarse chromatin, prominent, often large nucleoli, or nuclear pleomorphism) or malignant mixed tumor (cytologically malignant cartilage or bone). Sixty-one cases were myoepitheliomas or mixed tumors, and 40 were myoepithelial carcinomas or malignant mixed tumors. By immunohistochemistry, all cases with available material were reactive for epithelial markers (keratins and/or epithelial membrane antigen): 90 of 97 (93%) expressed keratins (most often AE1/AE3 or PAN-K), 84 of 97 (87%) S-100 protein, 44 of 51 (86%) calponin, 52 of 83 (63%) epithelial membrane antigen, 40 of 87 (46%) glial fibrillary acidic protein, 27 of 75 (36%) smooth muscle actin, 15 of 66 (23%) p63, and 7 of 51 (14%) desmin. Follow-up was available for 64 patients. Among 33 cases with benign or low-grade cytology (mean follow-up 36 months; range 4-168 months), 6 recurred locally (18%) and none metastasized. No clinical or histologic features correlated with recurrence. Among 31 cytologically malignant cases (mean follow-up 50 months; range 4-252 months), 13 recurred locally (42%) and 10 metastasized (32%); so far, 4 patients have died of metastatic tumor. This study expands the spectrum of myoepithelial tumors of soft tissue to include myoepithelial carcinomas and malignant mixed tumors, which pursue an aggressive clinical course. Although the majority of morphologically benign or low-grade myoepithelial neoplasms of soft tissue behave in a benign fashion, there is an approximate 20% risk for local recurrence.
Pseudomyxoma peritonei is a clinical term for gelatinous ascites, usually secondary to an appendiceal tumor. The pathologic classification of pseudomyxoma peritonei and its associated appendiceal tumors has been plagued with controversy and confusing terminology. In an effort to clarify this, we reviewed the pathology of 101 patients, all treated at our institution from 1993 to 2005, with pseudomyxoma peritonei of appendiceal origin. All patients were uniformly treated with our standardized protocol. This is the largest pathologic series solely devoted to appendiceal neoplasia with gelatinous ascites. The cases were assigned, according to previously published criteria, to the categories of disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA), or PMCA with intermediate (well differentiated) features (PMCA-I), with the exception that any case with a signet-ring cell component was considered as PMCA and not PMCA-I. By histologic category, 58 patients had DPAM, 23 were PMCA, and 20 were PMCA-I.One-year, 3-year, and 5-year survival outcomes were not significantly different between DPAM and PMCA-I. DPAM and PMCA-I also exhibited a roughly equal incidence of parenchymal (beyond the serosa) organ invasion. Survival outcomes were significantly worse for PMCA, compared with PMCA-I and DPAM. After reviewing our data and the literature, mucinous carcinoma peritonei-low grade was applied to the low-grade histology of pseudomyxoma peritonei, including those cases referred to by some as DPAM in the same category as PMCA-I. Cases that are moderately differentiated to poorly differentiated are classified as mucinous carcinoma peritonei-high grade.
The occasional finding within the gastric mucosa of unidentified epithelial cells with morphological features closely resembling those of pancreatic acinar cells has prompted us to investigate a retrospective series of 8,430 consecutive gastric biopsies and of 126 surgical specimens of gastric resection and total gastrectomy. The aims of the study were to morphologically and immunocytochemically characterize these cells, to define their actual prevalence in a large series of unselected cases, and to assess the clinicopathologic correlates of their occurrence. Pancreatic acinar-like cells characterized by abundant cytoplasm, which was acidophilic and finely granular in the apical and middle portions and basophilic in the basal compartment, have been identified in 101 cases (84 gastric biopsies and 17 gastrectomies). These cells, arranged in nests or in variably sized lobules among the gastric glands, were morphologically indistinguishable from pancreatic acinar cells, both by light and by electron microscopy. Furthermore, they were consistently immunoreactive for pancreatic lipase and trypsinogen and, in 75% of the cases, for pancreatic alpha-amylase. The appearance of these cells within the gastric mucosa was correlated significantly with chronic gastritis (p = 0.032) and with the simultaneous occurrence of intestinal and pyloric types of gastric metaplasia (p = 0.021). The findings indicate that this is a previously unrecognized pancreatic (acinar) metaplasia of the gastric mucosa, clinically and morphologically distinct from pancreatic heterotopia.
Surgical resection of primary gastric lesions after neoadjuvant or palliative chemotherapy is performed for curative or palliative purpose in locally advanced (LA) or initially metastatic (IM) gastric cancer. We investigated which histomorphologic features were associated with patient prognosis. We examined 143 patients (57 LA and 86 IM) who underwent gastrectomy after chemotherapy between 2000 and 2009. The tumor regression grade (TRG)-determined by examining the residual neoplastic cells and background stromal changes-was evaluated. Progression-free (PFS) and overall survival (OS) were evaluated according to pretherapeutic and posttherapeutic clinicopathologic factors using univariate and multivariate analyses. Because both the LA and the IM groups showed similar trends of PFS and OS according to TRG, the 2 groups were analyzed together. Patients with TRG1 (no residual primary tumor) showed a superior PFS and OS than the remaining TRGs. We defined pathologic complete regression (pCR) as TRG1 with negative lymph nodes (LN) and the others as non-pCR. Sixteen patients (11.1%) had pCR with better PFS (P=0.007) and OS (P=0.006). Initial disease status (LA or IM) remained as independent prognostic factors for PFS (P=0.021) but not for OS (P=0.109). The postoperative negative LN status correlated with good outcome and postoperative diffuse-type histology correlated with poor outcome after multivariate analysis. This study showed that pCR, but not partial regression, provides meaningful prognostic information in gastrectomy after chemotherapy. In addition, postoperative LN positivity and diffuse-type histology were independent poor prognostic factors for PFS and OS.
A workshop jointly sponsored by the University of Hong Kong and the Society for Hematopathology explored the definition, differential diagnosis, and epidemiology of angiocentric lymphomas presenting in the nose and other extranodal sites. The participants concluded that nasal T/natural killer (NK) cell lymphoma is a distinct clinicopathologic entity highly associated with Epstein-Barr virus (EBV). In situ hybridization for EBV an be very valuable in early diagnosis, especially if tissue is sparse. The cytologic spectrum is broad, ranging from small or medium-sized cells to large transformed cells. Histologic progression often occurs with time. Necrosis is nearly always present, and angioinvasion by tumor cells is seen in most cases. Nasal T/NK cell lymphoma has a characteristic immunophenotype: CD2-positive, CD56-positive, but usually negative for surface CD3. Cytoplasmic CD3 can be detected in paraffin sections. Clonal T-cell receptor gene rearrangement is not found. Tumors with an identical phenotype and genotype occur in other extranodal sites, most commonly in the skin, subcutis, and gastrointestinal tract, and should be referred to as nasal-type T/NK cell lymphomas. The differential diagnosis includes lymphomatoid granulomatosis, blastic or monomorphic NK cell lymphoma/leukemia, CD56-positive peripheral T-cell lymphoma, and enteropathy-associated T-cell lymphoma.
In this study, we examine the clinicopathologic features of 104 cases of myxoinflammatory fibroblastic sarcoma (MIFS), a low-grade, inflammatory fibromyxoid tumor with a predilection to distal extremity soft tissue, and attempt to identify factors predictive of aggressive behavior. The study cohort consisted of 49 male and 55 female patients ranging in age from 17 to 83 (mean, 42; median, 39) years. The tumor arose primarily on the dorsal aspect of the distal extremities as a solitary and usually painless mass. Tumors ranged in size from 0.5 to 15 (mean, 3.2; median; 2.4) cm. Microscopically, tumors consisted of variably cellular and inflamed fibromyxoid tissue growing as a lobulated mass or as multiple nodules within subcutaneous tissue or along tendinofascial planes. Tumor cells ranged from plump spindled to more epithelioid cells with enlarged, vesicular nuclei. Characteristic of the process was a strikingly bizarre cell with an inclusion body-like nucleolus (85% of cases) and/or a smudgy hyperchromatic nucleus (51%) present in all but 7 cases. The mitotic rate per 50 high-power field ranged from 0 to 13 (mean, 2,9; median, 2) mitoses. Twenty-two tumors demonstrated 1 or more of the following atypical features: (1) foci with complex sarcoma-like vasculature; (2) hypercellular areas; and (3) increased mitotic activity or atypical mitotic figures. Immunohistochemically, tumor cells demonstrated immunoreactivity for vimentin (100%), D2-40 (86%), CD34 (50%), keratin(s) (33%), CD68 (27%), actin(s) (26%), desmin (9%), S-100 protein (7%), and epithelial membrane antigen (6%). Thirty of 59 patients (51%) with follow-up data suffered (at least) 1 local recurrence, and 1 patient developed metastatic disease after multiple local recurrences. Completeness of initial surgical excision was the only clinicopathologic parameter that statistically correlated with a lower incidence of recurrence (P=0.004). Histologically atypical MIFS recurred more often than conventional tumors (67% vs. 47%), but the difference was not statistically significant (P=0.35). Our study shows that histologic features often associated with more aggressive sarcomas do not substantially impact the morbidity of MIFS, and complete surgical excision provides the best chance for disease-free survival.
Carney triad, as originally described in 1977, was the association of 3 tumors: gastric epithelioid leiomyosarcoma [later renamed gastrointestinal stromal tumor (GIST)], extra-adrenal paraganglioma, and pulmonary chondroma. The disorder affected mostly young women and was not familial. We studied the clinical and pathologic features of the gastric neoplasm in 104 patients with the syndrome. Most (88%) were young women (mean age, 22 y), and the usual presentation was gastric bleeding. The tumors, commonly antral-based (61%), were multifocal, and ranged from 0.2 to 18.0 cm in dimension. Most (86%) featured round and polygonal (epithelioid) cells. Metastasis occurred in 49 patients (47%): to gastric lymph nodes (29%), liver (25%), and peritoneum (13%). Immunopositivity was detected in the tumors tested as follows: KIT, 100%; CD34, 75%; PKCtheta, 21%; PDGFRA, 90%; and smooth muscle actin, 6%. Fourteen patients (13%) died of metastatic GIST at a mean age of 45 years (range, 30 to 69 y). Estimated 10 and 40-year survivals were 100% and 73%, respectively. Median survival time was 26.5 years (range, 16 to 60 y). There was no correlation between the National Institutes of Health tumor risk classification and the tumor behavior. Compared with sporadic gastric GISTs, the gastric stromal tumor in Carney triad showed distinctive features: female predilection, young patient age, epithelioid cell predominance, multifocality, frequent lymph node metastasis, serial tumor occurrence, and unpredictable behavior. Thus, the Carney triad gastric stromal tumor is different clinically, pathologically, and behaviorally from sporadic gastric GIST.
Ossifying fibromyxoid tumor (OFT) is a unique soft tissue tumor of uncertain histogenesis. The majority of reported cases (approximately 220) have pursued a benign clinical course. However, recent literature has emphasized the existence of morphologically atypical and clinically malignant examples of this tumor and proposed guidelines for assessment of biologic potential. In the present study, we evaluated 104 cases of OFT from the Armed Forces Institute of Pathology, accessioned between the years 1970 and 2007. Herein, OFT was strictly defined as a tumor with lobular architecture, predominantly epithelioid cell morphology, a low level of atypia, corded and trabecular growth patterns, moderate amounts of myxocollagenous matrix, and often, focal peripheral metaplastic bone formation. Tumors that lacked conventional morphology were excluded. The exclusion group included cutaneous mixed tumors, low-grade fibromyxoid sarcomas, and extraskeletal osteosarcomas. The OFTs occurred in 64 men and 40 women with a median age of 50 years (range, 21 to 81 y). The tumor size ranged from 0.7 to 17 cm (median, 3 cm). The mitotic rate varied from 0 to 41 mitotic figures per 50 HPFs (median, 2/50 HPFs). Tumor cell nuclei typically contained small, distinct nucleoli, and necrosis was infrequent (11/104). The great majority of tumors (67/71, 94%) were positive for S100 protein, whereas only occasional examples had (focal) positivity for desmin, glial fibrillary acidic protein, and an AE1/AE3 keratin cocktail. Local recurrences were documented in 9 of 41(22%) living patients, usually 10 or more years after primary surgery, but there were no metastases. A mitotic rate of >2 mitotic figures/50 HPFs was a risk factor for local recurrence, but necrosis, tumor size, the presence of satellite nodules, and positive margins were not. When OFT is strictly defined by the criteria noted above, there is potential for local recurrence, but there seems to be little or no risk for metastasis.
Invasive intraductal papillary-mucinous carcinoma (I-IPMC) is a heterogeneous entity with various postoperative outcomes. The aim of this study is to characterize early-stage I-IPMC with nonaggressive characteristics. One hundred and four patients with intraductal papillary-mucinous neoplasm (IPMN) were clinicopathologically investigated. The lesions were classified into 53 noninvasive IPMNs (adenoma, borderline, and noninvasive IPMC) and 51 I-IPMCs on the basis of the WHO classification. I-IPMCs were divided further into 26 minimally invasive IPMCs (MI-IPMCs) and 25 invasive carcinomas originating in IPMC (IC-IPMCs) by new diagnostic criteria proposed in this study. We examined invasiveness of I-IPMC on 4 patterns, and defined simple and practical diagnostic criteria of minimal invasion for each invasive pattern. The disease-specific survival rates after 3, 5, and 10 years were 100%, 100%, and 100% for both noninvasive IPMN and MI-IPMC, and 51%, 38%, and 0% for IC-IPMC. The overall and disease-specific survival rates for MI-IPMC were both significantly better than those for IC-IPMC (P<0.001), but there was no significant difference between noninvasive IPMN and MI-IPMC. Multivariate analysis showed that the factors indicative of poor prognosis were a diagnosis of I-IPMC classified as IC-IPMC and a high level of serum carbohydrate antigen 19-9. The prognosis of IC-IPMC was not significantly different from that of pancreatic ductal carcinoma in each of the corresponding tumor-node-metastasis stages. These findings suggest that a category of MI-IPMC provides more accurate and useful information of the stage and the aggressiveness of I-IPMC.
Sinonasal-type hemangiopericytoma is an uncommon upper aerodigestive tract tumor of uncertain cellular differentiation. We report 104 cases of sinonasal-type hemangiopericytoma diagnosed between 1970 and 1995 from the files of the Armed Forces Institute of Pathology. There were 57 females and 47 males ranging in age from 5 to 86 years (mean 62.6 years). The most common clinical presentation was airway obstruction (n = 57) and/or epistaxis (n = 54), with symptoms averaging 10 months in duration. The tumors involved the nasal cavity alone (n = 47) or also a paranasal sinus (n = 26), were polypoid, and measured an average of 3.1 cm. Histologically, the tumors were submucosal and unencapsulated and showed a diffuse growth with fascicular (n = 37) to solid (n = 50) to focally whorled (n = 7) patterns. The tumor cells were uniform in appearance with minimal pleomorphism and had spindle-shaped (n = 82) to round/oval (n = 18) nuclei with vesicular to hyperchromatic chromatin and eosinophilic to amphophilic to clear-appearing cytoplasm with indistinct cell borders. Multinucleated (tumor) giant cells were identified in a minority of cases (n = 5). Mitotic figures were inconspicuous and necrosis was absent. The tumors were richly vascularized, including staghorn-appearing vessels that characteristically had prominent perivascular hyalinization (n = 92). An associated inflammatory cell infiltrate that included mast cells and eosinophils was noted in the majority of cases (n = 87). The immunohistochemical profile included reactivity with vimentin (98%), smooth muscle actin (92%), muscle specific actin (77%), factor XIIIa (78%), and laminin (52%). Surgery was the treatment of choice for all of the patients; adjunctive radiotherapy was given to four patients. Recurrences developed in 18 patients within 1-12 years from diagnosis. Ninety-seven patients were either alive (n = 51, mean 16.5 years) or dead (n = 46, mean 9.6 years) but free of disease. Four patients had disease at the last follow-up: three died with disease (mean 3.6 years) and one patient is alive with disease (28.3 years). Recurrent tumor (17.8%) can be managed by additional surgery. The majority of sinonasal-type hemangiopericytomas behave in a benign manner with excellent long-term prognosis (88% raw 5-year survival) following surgery alone. Sinonasal-type hemangiopericytomas have a characteristic light microscopic appearance with an immunophenotypic profile resembling that of glomus tumors.
Lymphomas involving the breast account for approximately 2% of extranodal and <1% of all non-Hodgkin lymphomas. Our aim in this study was to classify breast lymphomas using the World Health Organization classification and then compare this classification with clinical, histologic, and radiologic findings as well as survival. The study group included 106 patients with breast lymphoma (105 women and 1 man). The neoplasms were divided into 2 groups based on extent of disease at initial diagnosis: localized disease (n=50) and disseminated disease (n=56). The follow-up period ranged from 4 to 252 months (median, 49 mo). Almost all (97%) patients presented with a palpable breast mass or masses. In the localized group, diffuse large B-cell lymphoma (DLBCL) was most frequent (n=32, 64%). In the disseminated group, follicular lymphoma was most frequent and exclusive to this group (P=0.0004). Mucosa-associated lymphoid tissue lymphomas occurred in both groups without a significant difference in frequency. A variety of other types of B-cell and T-cell non-Hodgkin lymphomas and classical Hodgkin lymphoma involved the breast at much lower frequency; most of these neoplasms involved the breast as part of disseminated disease. The clinical presentation correlated with radiologic findings: localized lymphomas presented as solitary masses, whereas disseminated lymphomas commonly presented as multifocal masses. There was a significant difference in the disease-free survival between patients with localized and disseminated DLBCL (P=0.003). In the disseminated group, patients with DLBCL had a worse disease-free survival compared with patients with mucosa-associated lymphoid tissue lymphoma or follicular lymphoma (P=0.01).
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.
The classification of appendiceal mucinous tumors is controversial and terminology used for them inconsistent, particularly when they lack overtly malignant features but are associated with extra-appendiceal spread. We reviewed 107 appendiceal mucinous neoplasms and classified them as low-grade appendiceal mucinous neoplasm (LAMN) (n = 88), mucinous adenocarcinomas (MACAs) (n = 16), or discordant (n = 3) based on architectural and cytologic features. LAMNs were characterized by a villous or flat proliferation of mucinous epithelium with low-grade atypia. Thirty-nine tumors were confined to the appendix, but 49 had extra-appendiceal tumor spread, including 39 with peritoneal tumor characterized by mucin pools harboring low-grade mucinous epithelium, usually dissecting in a hyalinized stroma. Eight of the 16 MACAs lacked destructive invasion of the appendiceal wall and eight showed an infiltrative pattern of invasion. Extra-appendiceal tumor spread was present in 12 MACAs (four peritoneum, seven peritoneum and ovaries; one ovaries only). In MACAs with an infiltrative pattern, peritoneal tumor consisted of glands and single cells in a desmoplastic stroma. The peritoneal tumor in the remaining cases consisted of mucin pools that contained mucinous epithelium with high-grade atypia and, in some cases, increased cellularity compared with that seen in peritoneal spread in cases of LAMN. Three cases were classified as discordant because the appendiceal tumors were LAMNs but the peritoneal tumors were high-grade. Follow-up was available for 49 LAMNs, 15 MACAs, and 2 discordant cases. None of the patients with LAMNs confined to the appendix experienced recurrence (median follow-up 6 years). LAMNs with extra-appendiceal spread were associated with 3-, 5-, and 10-year survival rates of 100%, 86%, and 45%, respectively. Patients with MACA had 3- and 5-year survival rates of 90% and 44%, respectively (p = 0.04). The bulk of peritoneal disease correlated with prognosis among patients with MACA (p = 0.04) and, to a lesser degree, among patients with LAMNs (p = 0.07). We conclude that: 1) appendiceal mucinous neoplasms can be classified as either low-grade mucinous neoplasms or mucinous adenocarcinoma based on architectural and cytologic features; 2) tumors that can be confidently placed in the low-grade group (which requires rigorous pathologic evaluation of the appendix) and are confined to the appendix are clinically benign in our experience to date; 3) low-grade tumors confined to the appendix are morphologically identical to those with extra-appendiceal spread (except for the usual identification of breach of the wall in the latter cases) and the same designation is appropriate for the appendiceal neoplasia in each situation; 4) the long-term outlook for patients with low-grade tumors and peritoneal spread is guarded with just over half dying of disease after 10 years; 5) appendiceal mucinous tumors with destructive invasion of the appendiceal wall, complex epithelial proliferations, or high-grade nuclear atypia generally pursue an aggressive clinical course and should be classified as mucinous adenocarcinomas; 6) peritoneal tumor can be classified as involvement by LAMN or MACA, and this distinction is of prognostic significance; 7) bulky peritoneal tumor worsens prognosis; and 8) LAMNs associated with high-grade peritoneal tumor behave as adenocarcinoma.
A majority of gastrointestinal stromal tumors (GISTs) carry gain-of-function KIT or platelet-derived growth factor receptor α (PDGFRA) mutations. However, no mutational activation of KIT or PDGFRA has been identified in pediatric gastric GISTs, neurofibromatosis-1-associated GISTs, and a small subset of sporadic GISTs in adults [so-called wild-type (WT) GISTs]. Recently, pediatric gastric GISTs and some adult WT gastric GISTs have been found to have losses of the succinate dehydrogenase (SDH) complex, a Krebs cycle/electron transport chain interface protein, as seen by immunohistochemical loss of SDH subunit B (SDHB) expression. Moreover, recently, expression of the receptor for type I insulin-like growth factor (IGF1R) has been detected in pediatric and WT GISTs, although only a small number of cases have been analyzed. In this study, IGF1R expression was examined immunohistochemically in 1078 well-characterized GISTs representing different clinicogenetic categories and in 103 non-GIST gastrointestinal tumors. IGF1R expression was detected in 71/80 of SDH-deficient GISTs (SDHB-negative GISTs) but only in 9/625 (1%) of the SDHB-positive gastric GISTs. The latter often carried KIT or PDGFRA mutations and generally occurred in older patients. None of the 373 intestinal GISTs was IGF1R positive, whereas many primary intestinal sarcomas, including clear cell sarcomas, leiomyosarcomas, and undifferentiated sarcomas, were IGF1R positive. The consistent lack of IGF1R expression in intestinal GISTs should be considered an additional immunohistochemical marker in the differential diagnosis between GISTs and non-GIST sarcomas. Because inhibition of IGF1R signaling might become a therapeutic target in GISTs, screening for IGF1R expression may become important in the near future.
A review of 256 cases of pathologic Stage I uterine adenocarcinoma treated at Stanford University Hospital revealed 26 cases of uterine papillary serous carcinoma (UPSC), a clinically aggressive and morphologically distinct variant of adenocarcinoma which closely resembles ovarian papillary serous carcinoma. These lesions are easily recognized by microscopic examination and typically feature a high degree of cytologic anaplasia and a papillary growth pattern. Invasion of the lymphatics has been a frequent finding. The relapse rate among patients with pathologic Stage I UPSC was 50% (13/26), five times the rate which would have been predicted by the incidence of UPSC. Patients with Stage I UPSC fared significantly worse than the group of nonpapillary grade II or grade III adenocarcinomas (p less than 0.0001). Forty percent of Stage I UPSC patients had deep myometrial invasion, as compared with 12% of those with all other histologic types of adenocarcinoma (p = 0.001). Women with UPSC deeply invading the myometrium tended to do worse than those with deeply invasive lesions of the more usual endometrioid type as reflected by relapse rates (after surgery alone) of 63% and 30%, respectively. Of seven Stage I corpus carcinoma patients whose initial site of failure was in the upper abdomen, six had UPSC. Thus, UPSC shares the tendency of its ovarian counterpart to spread over peritoneal surfaces. In addition to the original study group of 26 Stage I patients, 34 patients with more advanced stages of UPSC were also reviewed. Of these, 26 have been followed and four survive. Eleven of these women presented or relapsed with abdominal carcinomatosis. UPSC is a clinically aggressive neoplasm which should be distinguished from other types of primary endometrial adenocarcinoma. In cases of invasive UPSC the mode of spread, similar to that of ovarian surface epithelial carcinomas, suggests the need for adjuvant upper abdominal and pelvic irradiation or effective chemotherapy.
Described by Enzinger in 1979, angiomatoid malignant fibrous histiocytoma is a distinctive tumor of adolescence and early adult life characterized by sheets of relatively bland rounded or spindled cells separated by areas of cystic hemorrhage and surrounded by a prominent inflammatory infiltrate and often a fibrous pseudocapsule. On the basis of the original 41 cases, the tumor has been considered a low-grade malignancy. We are reporting the clinicopathologic findings and follow-up information of 108 new cases of angiomatoid malignant fibrous histiocytoma to determine the long-term behavior of this tumor and whether various histologic features (atypia, mitoses, infiltrative borders, and inflammatory infiltrate) are useful in predicting outcome. Follow-up information was obtained in 94 (87%) cases. Local recurrences developed in 11 patients (12%), all of whom were cured by re-excision. The initial excision in all patients developing local recurrence appeared to be incomplete. Local recurrence was statistically associated with irregular tumor border and head and neck location. Five patients developed metastases. Four had only local metastases, which responded to surgery, whereas the fifth patient developed presumed pulmonary and cerebral metastases and died. The development of both local and distant metastases was correlated with invasion into the deep fascia or muscle but not to various histologic parameters such as mitotic rate and pleomorphism. We conclude that angiomatoid malignant fibrous histiocytoma is intrinsically a low-grade tumor, and assessment of various histologic parameters or grading provides little or no additional prognostic information. Because death from disease occurred in only one patient (1%) in our series, it seems reasonable to reclassify angiomatoid malignant fibrous histiocytoma with fibrohistiocytic tumors of intermediate malignancy rather than with the conventional malignant fibrous histocytoma, the majority of which are high-grade sarcomas.
Prox1, a transcription factor important in the regulation and maintenance of the lymphatic endothelial phenotype, is consistently expressed in lymphangiomas and Kaposi sarcoma and has also been reported in Kaposiform hemangioendothelioma. However, information on its distribution in vascular tumors, such as angiosarcoma, is limited. In this study, we examined selected normal tissues and 314 vascular endothelial and 1086 nonvascular tumors to get an insight into the biology of these tumors and on potential diagnostic use of Prox1 as an immunohistochemical marker. In adult tissues, Prox1 was essentially restricted to lymphatic endothelia, with expression in subsets of pancreatic and gastrointestinal epithelia. However, it was also detected in embryonic liver and heart. Prox1 was consistently expressed in lymphangiomas, venous hemangiomas, Kaposi sarcoma, in endothelia of spindle cell hemangioma, Kaposiform hemangioendothelioma, and retiform hemangioendothelioma, and in half of epithelioid hemangioendotheliomas. It was present in most cutaneous angiosarcomas from different sites but was less commonly expressed in deep soft tissue and visceral angiosarcomas. In contrast, Prox1 was generally absent in capillary and cavernous hemangiomas. In positive hemangiomas and angiosarcomas it was coexpressed with podoplanin, another marker of the lymphatic endothelial phenotype. There was an inverse correlation with CD34 expression. The expression in mesenchymal nonendothelial neoplasm was limited. Prox1 was detected in 5 of 27 synovial sarcomas, specifically in the epithelia of biphasic tumors. Four of 16 Ewing sarcomas and 5 of 15 paragangliomas were also positive. All melanomas and undifferentiated sarcomas were negative. Among epithelial neoplasms, Prox1 was detected in 18 of 38 colonic carcinomas and 10 of 15 cholangiocarcinomas and in a minority of pulmonary, prostatic, and endometrial adenocarcinomas. The common Prox1 expression in angiosarcoma and its rare presence in nonvascular mesenchymal tumors make this marker suitable for the diagnosis of angiosarcoma and Kaposi sarcoma. However, the presence of Prox1 in some malignant epithelial tumors necessitates caution in applying Prox1 as a marker for vascular tumors. Common Prox1 expression in angiosarcoma may reflect the lymphatic endothelial phenotype in these tumors. Its patterns of expression in hemangiomas and angiosarcoma may be diagnostically useful and offer a new parameter in the biological classification of vascular tumors.
Pseudomyxoma peritonei (PMP) is a poorly understood condition characterized by mucinous ascites and mucinous implants diffusely involving the peritoneal surfaces. There is considerable debate regarding the definition, pathology, site of origin, and prognosis of PMP. We analyzed the clinicopathologic features of 109 cases of multifocal peritoneal mucinous tumors to develop a pathologic definition of cases characterized by the clinical condition PMP. Cases were separated into two diagnostic categories: disseminated peritoneal adenomucinosis (DPAM) and peritoneal mucinous carcinomatosis (PMCA). Cases classified as DPAM were characterized by peritoneal lesions composed of abundant extracellular mucin containing scant simple to focally proliferative mucinous epithelium with little cytologic atypia or mitotic activity, with or without an associated appendiceal mucinous adenoma. Cases classified as PMCA were characterized by peritoneal lesions composed of more abundant mucinous epithelium with the architectural and cytologic features of carcinoma, with or without an associated primary mucinous adenocarcinoma. Sixty-five of the 109 cases (59.6%) were classified as DPAM consistent with origin from an appendiceal mucinous adenoma. Thirty-seven of the 65 cases (56.9%) had a documented appendiceal mucinous adenoma. Thirty cases (27.5%) were classified as PMCA consistent with origin from an appendiceal or intestinal mucinous adenocarcinoma. Fourteen cases (12.8%) were classified as PMCA with features intermediate between DPAM and PMCA or with discordant features based on the finding of at least focal areas of carcinoma in the peritoneal lesions, whether or not the primary site demonstrated carcinoma. The cases with intermediate features were derived from well-differentiated appendiceal or intestinal mucinous adenocarcinomas and had peritoneal lesions displaying features of DPAM as well as focal areas of mucinous carcinoma. The cases with discordant features were derived from atypical appendiceal adenomas with little or no histologic evidence of a transition from adenoma to carcinoma and had peritoneal lesions uniformly composed of mucinous carcinoma. There was a statistically significant difference in survival between cases classified as DPAM, those classified as PMCA with intermediate or discordant features, and those classified as PMCA (p < 0.0001). The age-adjusted 5-year survival rates were 84% for patients with DPAM, 37.6% for patients with PMCA with intermediate or discordant features, and 6.7% for patients with PMCA. The term DPAM should be used to diagnose the histologically benign peritoneal lesions associated with ruptured appendiceal mucinous adenomas and those that are pathologically identical but lack a demonstrable appendiceal adenoma. Cases with the pathologic features of adenocarcinoma should be designated PMCA because they have recognizably different pathologic features and a significantly worse prognosis.
We present the first report of ovarian dysgerminoma in Cowden syndrome, presenting in a 7-year-old girl. In her second decade, a hamartomatous soft tissue extremity mass and diffuse gastrointestinal hamartomatous polyposis with pathologic features suggestive of either juvenile, Peutz-Jeghers, or Cowden polyps were identified, along with diffuse esophageal glycogenic acanthosis and skin manifestations. During regular thyroid cancer surveillance under the provisional diagnosis of Cowden syndrome, papillary thyroid carcinoma and benign follicular nodules were diagnosed at age 23. PTEN mutational analysis revealed a novel germline nonsense point mutation of Q219X. Loss of PTEN heterozygosity was also present in the ovarian dysgerminoma. Parental mutation testing and phenotype screening were negative. The correct classification of Cowden syndrome is difficult because of its protean manifestations and overlapping phenotypes with other genetic and noninherited pathologies, particularly regarding various gastrointestinal polyposis syndromes. Despite the challenges, correct classification is critical to patient care because of the associated cancer predispositions and necessary surveillance programs. This is the first report of Cowden syndrome presenting with ovarian dysgerminoma, which implicates PTEN in the molecular pathogenesis of dysgerminoma and adds it to the phenotypic manifestations of Cowden syndrome.
Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) is an extraordinarily rare primary tumor in the kidney and can be mistaken for a variety of other round cell tumors, including blastema-predominant Wilms' tumor (WT). Approximately 90% of ES/PNET have a specific t(11;22), which results in a chimeric EWS-FLI-1 protein. Immunohistochemistry for the carboxy-terminus of FLI-1 is sensitive and highly specific for the diagnosis of ES/PNET. WT-1, the WT-associated tumor suppressor gene, is overexpressed in WT but not in ES/PNET. No study has examined FLI-1 or WT-1 expression in renal ES/PNET. The clinicopathologic features of 11 renal ES/PNET were studied along with immunohistochemistry for cytokeratin, desmin, CD99, FLI-1, and WT-1. WT were also immunostained for CD99 (5 cases), FLI-1 (10 cases), and WT-1 (9 cases). The patients (6 men, 5 women) ranged from 18 to 49 years of age (mean, 34 yr). The mean tumor size was 11.8 +/- 3.8 cm (mean +/- standard deviation). Presenting symptoms included abdominal/flank pain and/or hematuria. Grossly, all tumors showed necrosis and hemorrhage, and 4 had cystic change. Microscopically, all tumors showed vaguely lobular growth, primitive round cells, and variable rosette formation. Epithelial, myogenous, or cartilaginous differentiation was not seen. Immunohistochemical results on the renal ES/PNET were cytokeratin (2/8 focal), desmin (0/9), CD99 (8/8), FLI-1 (5/8), and WT-1 (0/8). In comparison, the WT only rarely expressed CD99 (1/5) and did not express FLI-1 (0/10), but were usually WT-1-positive (7/9). Follow-up on 8 cases (mean, 28 mo; range, 6-64 mo) showed 4 lung and pleural metastases, 1 bone metastasis, liver metastasis, 2 local recurrences, and 5 deaths from disease (median time to death, 16.8 mo). No case had distant metastatic disease at presentation. Adjuvant therapy included chemotherapy (8 cases), radiation (3 cases), and bone marrow transplantation (1 case). Our study affirms a unique proclivity of renal ES/PNET for young adults and that it is a highly aggressive neoplasm, with rapid death in many cases, usually after the development of treatment-resistant lung metastases. These tumors must be distinguished from blastema-predominant WT and other primitive renal tumors that require different therapy. FLI-1 and WT-1 immunohistochemistry may be valuable in this differential diagnosis, given the known immunophenotypic overlap between ES/PNET and blastema-predominant WT with regard to CD99, cytokeratin, and desmin. The accurate distinction between these two entities has clear prognostic and therapeutic implications.
The kidney is an important target for mineralocorticoids. Aldosterone, the major endogenously secreted mineralocorticoid, acts by binding to mineralocorticoid receptor (MR) in the distal renal tubule. The enzyme 11beta-hydroxysteroid dehydrogenase type II (11beta-HSD2) prevents the binding of glucocorticoids to the MR by inactivating cortisol to cortisone. Our goal was to determine whether MR and 11beta-HSD2 expression could be used to characterize the major types of renal cell neoplasms. Using immunohistochemistry we analyzed tissue microarray specimens from 132 patients with renal cell neoplasms, stratified into 84 clear cell renal cell carcinomas (CRCC), including 9 cases clear cell carcinoma with predominantly granular cytoplasm; 14 papillary RCC (PRCC); 20 chromophobe RCC (CHRCC); and 14 oncocytomas (OCs). MR and 11beta-HSD2 expression were also quantitated by real-time reverse transcription-polymerase chain reaction. Expression of both MR and 11-betaHSD2 was detected in the distal nephrons of normal kidneys. The CHRCC group stained for 11-betaHSD2 in a membranous and cytoplasmic pattern whereas diffuse cytoplasmic reactivity was seen in OCs. MR and 11beta-HSD2 were coexpressed in most of CHRCC (90% and 95%) and oncocytomas (93% and 100%). No MR staining was detected in CRCC, including clear cell carcinoma with predominantly granular cytoplasm, or in PRCC. Only 2 cases of CRCC (2.6%) showed focal positivity for 11beta-HSD2, whereas all PRCCs were negative. CHRCC and OC demonstrated significantly higher levels of MR and 11beta-HSD2 expression than CRCC and PRCC by real-time polymerase chain reaction. Moreover, CHRCC showed higher expression of MR and 11beta-HSD2, as compared with OC. Our study indicates MR and 11beta-HSD2 are both sensitive and specific markers of the distal nephron and its related neoplasms (CHRCC and OC). Additionally, the staining pattern and the level of MR and 11beta-HSD2 expression seems to be useful in the distinction of CHRCC from OC. MR and 11beta-HSD2 should be considered in the immunohistochemical panel to more accurately subtype renal cell tumors.
Lymphomas with translocations/rearrangements of MYC, BCL2, and BCL6, so-called triple-hit B-cell lymphoma, are rare, and few studies on these tumors are available in the literature. We report 11 cases of triple-hit B-cell lymphoma and characterize their clinicopathologic findings. All patients were men, with a median age of 64 years (range, 45 to 80 y), and 4 patients had antecedent or concurrent follicular lymphoma. Using the 2008 World Health Organization classification, these cases were classified as: 5 B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma; 4 DLBCL; 1 DLBCL with concurrent follicular lymphoma; and 1 low-grade follicular lymphoma. All cases were positive for CD10, BCL2, and FOXP1. Ten of 11 cases were positive for CD20. MYC expression was high in 10/11 (91%), BCL6 was positive in 8/11 (73%), and MUM1/IRF4 was positive in 6/11 (55%) cases. T-cell antigens, TdT, and Epstein-Barr virus-encoded RNA were negative in all cases. Ten of 11 cases showed a high proliferation index-70% to 100%, and the follicular lymphoma had a 30% proliferation rate. Using most algorithms, all cases belonged to germinal center B-cell-like group. All patients received standard or more aggressive immunochemotherapy regimens. Three patients had no response to chemotherapy; 4 patients showed a partial response; 2 patients had complete remission after chemotherapy; and 2 patients had just begun chemotherapy. Three patients underwent a stem cell transplant. The median follow-up time was 5.3 months. Five patients died, and 6 patients were alive at last follow-up. Two patients who underwent stem cell transplant after complete response to chemotherapy were in remission with 16 to 19 months of clinical follow-up. In summary, triple-hit lymphomas are clinically aggressive tumors associated with a poor prognosis. Patients often respond poorly to chemotherapy, but a subset may completely respond to chemotherapy followed by stem cell transplant.
Clinical and pathologic findings in five women and six men with the rare localized form of hyperplastic gastropathy of the mucous cell-(foveolar) or mixed cell-(mucous cell and glandular) type are reported. Upper abdominal discomfort, loss of appetite, loss of weight, and anemia were the principal symptoms. Preoperative hypoproteinemia was documented in two patients. Gross findings consisted of a circumscribed area of giant folds, well demarcated from the surrounding normal-appearing mucosa, located predominantly in the corpus in six patients and predominantly in the antrum in four patients. Histologically they corresponded to an increase in the epithelial cell mass principally of mucous cells with elongated and sometimes cystically dilated foveolae, accompanied by a mild inflammatory infiltrate. This so-called localized form of hyperplastic gastropathy has been known since the first description of the disease but has gained relatively little attention in the literature. However, its recognition seems diagnostically important and pathogenetically interesting. Etiology, pathogenesis, and the natural history are mostly unknown. Five of the 11 patients had concomitant adenocarcinoma of the stomach. In four of them the carcinoma was not located within but outside the area of hyperplasia. Because of that and because of a rather unusual accumulation of other tumors of the gastrointestinal tract in these patients, it is suggested that localized hyperplastic gastropathy could be an indicator of an increased risk for gastrointestinal tumors in general more than a possibly premalignant lesion by itself.
The clinicopathologic features and immunoprofile of 11 cases of an uncharacterized male genital tract tumor with features of vulvovaginal angiomyofibroblastoma (AMF) and spindle cell lipoma (male AMF-like tumor) are described. The lesions presented as a mass involving the scrotum (six cases) or inguinal region (five cases) in males ranging in age from 39 to 88 years (median 57). The tumors were superficially located and well-marginated and ranged in size from 2.5 to 14 cm (approximate mean 7 cm). Microscopically, they were composed of tapered spindled cells proliferating between numerous small to medium-sized vessels. Epithelioid appearing stromal cells were a focal finding in four cases. Mitotic activity was minimal with no abnormal mitotic figures identified. Mild nuclear atypia was identified in two cases. The tumors possessed an acid mucopolysaccharide-rich, finely collagenous stroma. A small quantity of intralesional fat was present in six cases. Tumor cells exhibited immunoreactivity for vimentin (seven of seven cases), progesterone receptor protein (five of seven cases), CD34 (four of eight cases), estrogen receptor protein (three of seven cases), desmin (three of eight cases), muscle-specific actin (three of eight cases), and smooth-muscle actin (two of eight cases) but not for S-100 protein. One of seven patients with follow-up after simple excision had recurrent/persistent disease. The male AMF-like tumor is a soft-tissue neoplasm of the male genital tract that shares clinicopathologic features and a proposed perivascular stem cell derivation with both the female angiomyofibroblastoma and spindle cell lipoma.
Adiaspiromycosis (ad"i-ah-spi"ro-mi-kósis) is a worldwide, noninfectious, nonarthropod transmitted fungal infection of lower vertebrates, most commonly rodents. Humans become an accidental host by inhaling dust-borne spores (conidia) of the saprophytic soil fungus, Emmonsia crescens (recently renamed Chrysosporium parvum variety crescens). We report 11 cases of this unusual deep mycosis from South America, Europe, and the United States. The severity of the disease depends on the number of spores inhaled. In limited inoculum, the disease remains localized (two cases), whereas in heavy inocula the fungus involves both lungs (nine cases) and presents as a diffuse reticulonodular infiltrate. In this disseminated form, patients usually complain of cough, dyspnea on exertion, and low-grade fever mimicking other systemic fungal infections and tuberculosis. It is difficult to unmask the fungus because it is not easily cultured nor is there a reliable serologic test. Therefore, a biopsy is required and the pathologist must recognize the large (ranging in size from 50 to 500 microns), round, Gomori methenamine-silver nitrate and periodic acid-Schiff reagent-positive spherules with a trilaminar wall. The spherules can be surrounded by either suppuration, epithelioid granulomas with or without necrosis, or concentric, hyalinized fibrosis. In the latter chronic stage, the organism may collapse, forming a variety of sizes and shapes thereby resembling other fungi, helminths, mineral particles, or inhaled pollen grains. Clinically, the infection most commonly regresses spontaneously, but may persist, or rarely progress, requiring surgical intervention with limited resection to attain cure.
Within the spectrum of penile squamous cell carcinomas, those that we descriptively refer to collectively as the "verruciform" lesions are particularly difficult to subclassify. In a review of 50 such tumors, we found 11 distinctive neoplasms with condylomatous features conforming to the appearance of so-called "warty (condylomatous) carcinoma." The average patient age was 55 years and the average duration of disease was 19 months. The primary tumor involved multiple anatomic sites (glans, coronal sulcus, and foreskin) in seven cases and a single site (glans or foreskin) in four cases. Grossly, white to gray cauliflower-like tumors typically measuring approximately 5 cm were noted. Histologically the tumors were mainly papillomatous with acanthosis and hyperkeratosis. The papillae had prominent fibrovascular cores. The most conspicuous microscopic findings were striking nuclear atypia of koilocytotic type and clear cytoplasm. The interface between tumor and stroma was irregular in the majority of cases; deep invasion of corpus cavernosum was noted in five cases. The differential diagnosis included verrucous carcinoma, low-grade papillary squamous cell carcinoma, not otherwise specified, and giant condyloma acuminatum. Among other differences, the first two lesions show no koilocytotic changes and the last lacks malignant features and irregular stromal invasion. Metastatic spread occurred in two patients; both are alive with evidence of recurrent disease 12 and 72 months after initial diagnosis. A third patient was alive with recurrent disease 12 months after diagnosis. Five patients were free of disease 8, 12, 24, 52, and 108 months after diagnosis. Three patients were lost to follow up. Warty (condylomatous) carcinomas of the penis are morphologically distinctive verruciform neoplasms with features of human papillomavirus-related lesions and should be distinguished from other verruciform tumors so that differences in behavior, if any, between these tumors will become established.
We report a pulmonary angiocentric immunoproliferative lesion (AIL) in an 11-year-old boy with chronic active Epstein-Barr virus (EBV) infection. The phenotypes of the proliferating lymphoid cells in the biopsied pulmonary lesion were CD2+, CD3+, CD4+, CD5+, CD7+, and HLA-DR+. EBV DNA was detected in the tumorous and the nontumorous tissue by Southern-blotting studies. Dual immunostains and combined immunohistochemistry/in situ hybridization showed the simultaneous presence of EBV-determined nuclear antigen or EBV-encoded small RNAs and T-cell markers in the lymphoid cells. Molecular genetic analysis of the tumorous lesion diagnosed as AIL grade III showed no clonal rearrangement of the T-cell receptor beta gene but a single type of fused terminal band of EBV. No such evidence of monoclonality was identified in the surrounding nontumorous tissue diagnosed as AIL grade I or II. The present case was a rare example of AIL in childhood and provides further histopathologic and molecular biological evidence supporting the concept of AIL as a continuous spectrum from premalignant lymphoproliferative disorders to monoclonal, overt malignant lymphoma.
Top-cited authors
Markku Miettinen
  • National Institutes of Health
Robert H. Young
  • Massachusetts General Hospital
Robert J Kurman
  • Johns Hopkins Medicine
Leslie Sobin
  • National Institutes of Health
Elaine S Jaffe
  • National Institutes of Health