Lester D. R. Thompson

Pheochromocytoma of the adrenal gland scaled score (PASS) to separate benign from malignant neoplasms: A clinicopathologic and immunophenotypic study of 100 cases

No comprehensive series has evaluated the histologic features of pheochromocytoma to separate benign from malignant pheochromocytoma by histomorphologic parameters only. Fifty histologically malignant and 50 histologically benign pheochromocytomas of the adrenal gland were retrieved from the files of the Armed Forces Institute of Pathology. The patients included 43 females and 57 males, with an age range of 3–81 years (mean 46.7 years). Patients usually experienced hypertension (n = 79 patients). The mean tumor size was 7.2 cm (weight was 222 g). Histologically, the cases of malignant pheochromocytomas of the adrenal gland more frequently demonstrated invasion (vascular [score = 1], capsular [score = 1], periadrenal adipose tissue [score = 2]), large nests or diffuse growth (score = 2), focal or confluent necrosis (score = 2), high cellularity (score = 2), tumor cell spindling (score = 2), cellular monotony (score = 2), increased mitotic figures (>3/10 high power fields; score = 2), atypical mitotic figures (score = 2), profound nuclear pleomorphism (score = 1), and hyperchromasia (score = 1) than the benign tumors. A Pheochromocytoma of the Adrenal gland Scaled Score (PASS) weighted for these specific histologic features can be used to separate tumors with a potential for a biologically aggressive behavior (PASS ≥4) from tumors that behave in a benign fashion (PASS <4). The pathologic features that are incorporated into the PASS correctly identified tumors with a more aggressive biologic behavior. Application of these criteria to a large cohort of cases will help to elucidate the accuracy of this grading system in clinical practice.

Mucinous cystic neoplasm (mucinous cystadenocarcinoma of low-grade malignant potential) of the pancreas : a clinicopathologic study of 130 cases

Mucinous cystic neoplasms (MCNs) of the pancreas are uncommon tumors. The classification and biologic potential of these neoplasms remain the subject of controversy. Attempts to classify these tumors in a similar manner to ovarian MCNs remains controversial, as even histologically benign-appearing pancreatic MCNs metastasize and are lethal. One hundred thirty cases of MCNs were identified in the files of the Endocrine Pathology Tumor Registry of the Armed Forces Institute of Pathology from the years 1979 to 1993. The pathologic features, including hematoxylin and eosin staining, histochemistry, immunohistochemistry (IHC), cell cycle analysis, and K-ras oncogene determination were reviewed. These findings were correlated with the clinical follow-up obtained in all cases. There were 130 women, aged 20-95 years (mean age at the outset, 44.6 years). The patients had vague abdominal pain, fullness, or abdominal masses. More than 95% of the tumors were in the pancreatic tail or body and were predominantly multilocular. The tumors ranged in size from 1.5 to 36 cm in greatest dimension, with the average tumor measuring >10 cm. A spectrum of histomorphologic changes were present within the same case and from case to case. A single layer of bland-appearing, sialomucin-producing columnar epithelium lining the cyst wall would abruptly change to a complex papillary architecture, with and without cytologic atypia, and with and without stromal invasion. Ovarian-type stroma was a characteristic and requisite feature. Focal sclerotic hyalinization of the stroma was noted. This ovarian-type stroma reacted with vimentin, smooth muscle actin, progesterone, or estrogen receptors by IHC analysis. There was no specific or unique epithelial IHC. K-ras mutations by sequence analysis were wild type in all 52 cases tested. Ninety percent of patients were alive or had died without evidence of disease (average follow-up 9.5 years), irrespective of histologic appearance; 3.8% were alive with recurrent disease (average 10 years after diagnosis); and 6.2% died of disseminated disease (average 2.5 years from diagnosis). Irrespective of the histologic appearance of the epithelial component, with or without stromal invasion, pancreatic MCNs should all be considered as mucinous cystadenocarcinomas of low-grade malignant potential. Pancreatic MCNs cannot be reliably or reproducibly separated into benign, borderline, or malignant categories.

Monoclonal origins of malignant mixed tumors (carcinosarcomas). Evidence for a divergent histogenesis.

Malignant mixed tumors (carcinosarcomas) are examples of unusual neoplasms whose occurrences have been observed in increasingly diverse sites but whose pathogenesis remains a complete mystery. Two antithetical hypotheses that have been advanced to explain the histogenesis of these tumors include the convergence hypothesis, which proposes an origin from two or more stem cells (multiclonal hypothesis), and the divergence hypothesis, which proposes an origin from a single totipotential stem cell that differentiates into separate epithelial and mesenchymal directions (monoclonal hypothesis). To test these hypotheses, a novel strategy for the determination of clonality from as few as 100 tumor cells obtained by enzymatic digestion of either fresh or formalin-fixed, paraffin-embedded tissues and cell sorting was used that exhibited the polymerase chain reaction (PCR) in amplifying a 511-bp region located within the first intron of the human hypoxanthine phosphoribosyl transferase gene, a site that contains inactive X chromosomal obligately methylated HpaII/MspI sites and single-base allelic polymorphisms in 5% females. Carcinoma cells gated on the basis of fluorescein isothiocyanate (FITC)-anti-cytokeratin and sarcoma cells gated on the basis of FITC-antivimentin or FITC-anti-desmin were sorted to homogeneity on FACSTAR and then subjected to genomic DNA extraction and Hpa II digestion before PCR amplification and subsequent analysis of the product on denaturing gradient gel electrophoresis. The comigrations of the single homoduplexes generated from both the carcinoma cells and sarcoma cells in six different malignant mixed tumors obtained from four different organs indicated clonal identity and monoclonality in all cases. These findings of monoclonality were confirmed independently by two other methods of clonality determination. The findings of a monoclonal origin of carcinosarcomas support the single totipotential stem-cell-divergence hypothesis.

Replication of HIV-1 in dendritic cell-derived syncytia at the mucosal surface of the adenoid.

Human immunodeficiency virus-type 1 (HIV-1) replicates actively in infected individuals, yet cells with intracellular depots of viral protein are observed only infrequently. Many cells expressing the HIV-1 Gag protein were detected at the surface of the nasopharyngeal tonsil or adenoid. This infected mucosal surface contained T cells and dendritic cells, two cell types that together support HIV-1 replication in culture. The infected cells were multinucleated syncytia and expressed the S100 and p55 dendritic cell markers. Eleven of the 13 specimens analyzed were from donors who did not have symptoms of acquired immunodeficiency syndrome (AIDS). The interaction of dendritic cells and T cells in mucosa may support HIV-1 replication, even in subclinical stages of infection.

Malignant lymphoma of the thyroid gland: a clinicopathologic study of 108 cases.

We report a retrospective clinicopathologic study of 108 primary thyroid gland lymphomas (PTLs), classified using the REAL and proposed WHO classification schemes. The patients included 79 women and 29 men, with an average age of 64.3 years. All patients presented with a thyroid mass. The PTLs were classified as marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) or MZBL (n = 30), diffuse large B-cell lymphoma (DLBCL) with MZBL (n = 36), DLBCL without MZBL (n = 41), and follicle center lymphoma (FCL; n = 1). Excluding the FCL, features of lymphomas of MALT-type were identified in all groups, despite a follicular architecture in 23% of cases. Lymphocytic thyroiditis (LT) was identified in 94%. Ninety-one percent of patients presented with stage IE or IIE disease, whereas 69% had perithyroidal soft tissue infiltration. All patients were treated with surgical excision followed by adjuvant therapy (76%): chemotherapy (15%), radiation (19%), or a combination of radiation and chemotherapy (42%). Disease-specific survival was 82% at last follow up (mean, 82.8 mos) and 79% at 5 years. Statistically, stages greater than IE, presence of DLBCL, rapid clinical growth, abundant apoptosis, presence of vascular invasion, high mitotic rate, and infiltration of the perithyroidal soft tissue were significantly associated with death with disease. No patients with MZBL or stage IE disease died with disease. In summary, PTLs typically occur in middle- to older-aged individuals as a thyroid mass, with a predilection for females. Despite their histologic heterogeneity and frequent simulation of other lymphoma subtypes, virtually all PTLs are lymphomas of MALT-type arising in the setting of LT. Mixed DLBCL and MZBL are common. Overall, PTLs have a favorable outcome with appropriate therapy, but prognosis depends on both clinical stage and histology. MZBL and stage IE tumors have an excellent prognosis, whereas tumors with a large cell component or DLBCL or stage greater than IE have the greatest potential for a poor outcome.

Sinonasal tract and nasopharyngeal melanomas: a clinicopathologic study of 115 cases with a proposed staging system.

&NA; Primary sinonasal tract mucosal malignant melanomas are uncommon tumors that are frequently misclassified, resulting in inappropriate clinical management. A total of 115 cases of sinonasal tract mucosal malignant melanoma included 59 females and 56 males, 13–93 years of age (mean 64.3 years). Patients presented most frequently with epistaxis (n = 52), mass (n = 42), and/or nasal obstruction (n = 34) present for a mean of 8.2 months. The majority of tumors involved the nasal cavity (n = 34), septum alone, or a combination of the nasal cavity and sinuses (n = 39) with a mean size of 2.4 cm. Histologically, the tumors were composed of a variety of cell types (epithelioid, spindled, undifferentiated), frequently arranged in a peritheliomatous distribution (n = 39). Immunohistochemical studies confirmed the diagnosis of sinonasal tract mucosal malignant melanomas with positive reactions for S‐100 protein, tyrosinase, HMB‐45, melan A, and microphthalmia transcription factor. Sinonasal tract mucosal malignant melanomas need to be considered in the differential diagnosis of most sinonasal malignancies, particularly carcinoma, lymphoma, sarcoma, and olfactory neuroblastoma. Surgery accompanied by radiation and/or chemotherapy was generally used. The majority of patients developed a recurrence (n = 79), with 75 patients dying with disseminated disease (mean 2.3 years), whereas 40 patients are either alive or had died of unrelated causes (mean 13.9 years). A TNM‐type classification separated by anatomic site of involvement and metastatic disease is proposed to predict biologic behavior.

Spindle cell (sarcomatoid) carcinomas of the larynx: A clinicopathologic study of 187 cases

Laryngeal spindle cell (sarcomatoid) carcinomas are uncommon tumors, frequently misdiagnosed as reactive lesions or mesenchymal malignancies. The records of 187 patients with tumors diagnosed as laryngeal spindle cell (sarcomatoid) carcinoma were retrieved from the files of the Otorhinolaryngic Tumor Registry of the Armed Forces Institute of Pathology. There were 174 men and 13 women, 35–92 years of age (average, 65.6 years). Nearly all patients experienced hoarseness (n = 165 [88%] patients) for a mean duration of 11.0 months. Patients admitted to smoking (n = 162 [87%] patients) and/or alcohol use (n = 90 [48%] patients). Most tumors were glottic (n = 132 [71%]), T1 (n = 111 [59%]), 1 and polypoid (n = 185 [99%]), with a mean tumor size of 1.8 cm. Histologically, squamous cell carcinoma (n = 157 [84%]) was noted, ulcerated, and blended with the spindle cell component, which was most frequently arranged in a storiform pattern (n = 92 [49%] tumors). Foci of benign or malignant cartilage and/or bone (n = 13 [7%]) were noted in the spindle cell component. All patients were treated with surgery (n = 90 [48%] patients) or surgery with radiation (n = 97 [52%] patients). Recurrences developed in 85 (45%) patients. Overall, T1 glottic tumors managed by complete surgical eradication had the best outcome (mean follow-up, 7.8 years).

Polymorphous Low-Grade Adenocarcinoma

Polymorphous low grade adenocarcinomas (PLGA) are minor salivary gland neoplasms with a predilection for intraoral sites.

Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients.

Adrenal cortical neoplasms in pediatric patients (<20 years) are rare. The clinical manifestations and biologic behavior of these lesions can be quite distinct from their histologically similar counterparts in the adult population, making pathologic criteria for distinguishing benign from malignant tumors equivocal. We undertook a study of 83 adrenal cortical neoplasms to determine if adult clinical and histologic features can be applied to pediatric patients in an outcome-based analysis. Most of the patients (50 girls and 33 boys) presented with hormone-related symptoms present for a mean of 6.8 months. The tumors ranged in size from 2 to 20 cm (mean 8.8 cm). Histologic parameters examined included capsular and/or vascular invasion, extraadrenal soft tissue extension, growth pattern, cellularity, necrosis, cytoplasmic eosinophilia, nuclear pleomorphism, nuclear-to-cytoplasmic ratio, prominent nucleoli, mitotic figures, atypical mitotic figures, bands of fibrosis, and calcifications. Immunophenotypically, there was reactivity with inhibin, vimentin, CK5, and focally with p53 and Ki-67. All patients underwent adrenalectomy, and 20 patients received adjuvant therapy. All patients with tumors classified as adenomas (n = 9) were alive, without evidence of disease (mean 14.7 years), whereas 21 patients with carcinomas had died with disease (mean 2.4 years). Only 31% of histologically malignant tumors behaved in a clinically malignant fashion. Features associated with an increased probability of a malignant clinical behavior included tumor weight (>400 g), tumor size (>10.5 cm), vena cava invasion, capsular and/or vascular invasion, extension into periadrenal soft tissue, confluent necrosis, severe nuclear atypia, >15 mitotic figures/20 high power fields, and the presence of atypical mitotic figures. Vena cava invasion, necrosis, and increased mitotic activity (>15 mitotic figures/20 high power fields) independently suggest malignant clinical behavior in multivariate analysis.

Kimura disease: a clinicopathologic study of 21 cases.

Kimura disease is a rare form of chronic inflammatory disorder involving subcutaneous tissue, predominantly in the head and neck region and frequently associated with regional lymphadenopathy and/or salivary gland involvement. This condition has a predilection for males of Asian descent and may clinically simulate a neoplasm. Kimura disease is sometimes confused with angiolymphoid hyperplasia with eosinophilia, which occurs in the superficial skin of the head and neck region. Although sporadic cases have been reported in non-Asians, there is no large, comprehensive study of Kimura disease in the United States. We report 21 cases with nodal involvement that, histologically, are consistent with Kimura disease. There were 18 males and 3 females (male/female ratio 6:1), 8 to 64 years of age (mean, 32 years), and included 7 Caucasians, 6 Blacks, 6 Asians, 1 Hispanic, and 1 Arabic. Anatomic sites of involvement included posterior auricular (n = 10), cervical (n = 6), inguinal (n = 3), and epitrochlear (n = 2) lymph nodes, with two patients having associated salivary gland involvement. Most (n = 16) cases had peripheral blood eosinophilia. Consistent histologic features were follicular hyperplasia, eosinophilic infiltrates, and proliferation of postcapillary venules. Follow-up data on 18 patients revealed that 13 were alive without disease (3 had recurrence), mean follow-up, 10.9 years; 4 were alive with disease (2 had a recurrence), mean follow-up, 8.8 years; and 1 died with disease (12.7 years). Kimura disease has been described more often in Asians, but it does occur in non-Asians with a similar clinicopathologic presentation. It is a distinctive entity with no known etiology. Kimura disease has characteristic histologic features that are important to recognize and can be used to differentiate it from hypersensitivity and drug reactions and infections.