The Stapes in Otosclerosis: Osteoarthritis of an Ear Ossicle.

Otosclerosis is a pagetoid proliferation of bone remodeling, vascular proliferation, bone resorption and new bone formation in the tympanic region of the temporal bone. The resulting anklyosis of the stapes footplate as it articulates with the oval window is the most common cause of conductive hearing loss in young to middle aged, predominantly Caucasian individuals. The characteristic histologic features have been well documented by autopsy studies of the temporal bone. Although stapedectomy is the surgical treatment for otosclerosis, the stapes specimen may be submitted for gross examination only or not examined at all. A retrospective study of 73 stapedectomy specimens (2008-2019) not including the stapes footplate. Clinical features from the electronic medical record as well as standard histologic sections from surgical specimens were reviewed. Neither the stapedal head nor crura showed histologic features of otosclerosis. There was mild osteoarthritis affecting the head, possibly as a consequence of persistent ossicular vibration superimposed on the ankylosed rigidity. The most common changes were surface fissuring (65%), cartilaginous erosion (49%) and irregularity of the osteochondral interface (51%). An occasional osteophyte (8%) was observed. The ear ossicles, embryologically analogous to long bones of the extremities, develop via endochondral ossification and exhibit articular surfaces of hyaline cartilage. The present observations suggest that a consequence of otosclerotic ankylosis is osteoarthritis of the stapedal head. In this study, the histological features could not be correlated with the severity of hearing loss or duration of clinical disease.

Distinguishing Parathyromatosis, Atypical Parathyroid Adenomas, and Parathyroid Carcinomas Utilizing Histologic and Clinical Features.

Parathyromatosis is displaced parathyroid tissue in the neck and mediastinum related to prior surgery. Parathyromatosis can be difficult to distinguish from atypical adenoma and parathyroid carcinoma. The aim of this study is to evaluate clinical and morphologic features that may differentiate parathyromatosis, atypical adenoma, and parathyroid carcinoma. Cases of parathyromatosis, atypical adenoma, and parathyroid carcinoma were identified. Index cases were reviewed by consensus for histologic features, including stromal, cytologic/architectural, and invasive features. Ki67 was performed on index cases and scored using the Adsay method. Clinical information was gathered from the electronic medical record. 4 parathyromatosis, 17 atypical adenoma, and 6 parathyroid carcinoma were included. Parathyroid carcinomas were more likely to display coarse chromatin with nucleoli (P = 0.04), infiltrative invasion (P < 0.01), and metastasis (P < 0.01). Only parathyromatosis showed circumscribed invasion. Infiltrative invasion was more common in cases with progression (P = 0.046) and metastasis (P < 0.001). Necrosis and perineural invasion were only present in cases with progression and were more frequent in cases with metastasis (P = 0.079 and P = 0.19, respectively). There were no differences in presence of a fibrous capsule, capsular invasion, intralesional fibrous bands, random endocrine atypia, solid growth, Ki67 index, gland size/weight, serum PTH/calcium levels, and locoregional recurrence rates. There is overlap in the histologic features in parathyromatosis, atypical adenoma, and parathyroid carcinoma. While perineural, vascular, and infiltrative soft tissue invasion should remain diagnostic of malignancy, other atypical features such as solid growth, coarse chromatin with nucleoli, and necrosis should raise concern for recurrence and/or metastasis, and can be present in parathyroid lesions with and without recurrence.

Syphilis: A Contemporary Clinicopathologic Assessment.

Syphilis is a sexually transmitted disease caused by the spirochetal bacterium Treponema pallidum that has been of public health concern for centuries. In the United States, it is currently a reportable disease and one which is recently generating increasing case numbers especially in at risk populations of immune deficiency and men who have sex with men. The present series examines biopsies from 13 patients collected over a 12-year period from a general hospital network in north suburban Cook County, Illinois. There were 13 patients (11 male: 2 female) with varied presentations, including primary ulcerated anogenital chancres, mucosal lesions, peculiar rashes, and alopecia. The reason(s) for biopsy were not clear from the clinical record, as a clinical consideration of syphilis was recorded in only 3 cases. Histologic examination of the mucocutaneous lesions encompassed a spectrum of findings including ulceration, psoriasiform hyperplasia, intense mixed band-like inflammation at the dermal-epidermal junction with a prominent plasma cell component. The contemporary availability of an effective immunostain is a valuable diagnostic adjunct. The organisms generally parallel the intensity of the inflammatory infiltrate but the distribution may vary and rarely, organisms may be absent despite serologic confirmation. Previous corkscrew morphology of the organism described ultrastructurally is reflected in the immunostained representation. Although the diagnosis of syphilis remains a clinical one in most cases, some patients will have unusual presentations and biopsies will be done. The awareness of the pathologist will facilitate prompt and effective treatment.

Educational Case: Yolk Sac (Endodermal Sinus) Tumor of the Ovary.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.1.

Atypical Laryngeal Infections: Localized Lesions from Unusual Organisms May Simulate Malignancy.

OBJECTIVE: The identification of rare sources of laryngeal infection in immunocompetent patients. Recovered organisms were Mycobacterium tuberculosis (laryngeal tuberculosis [LTB]), Mycobacterium fortuitum (laryngeal Mycobacterium fortuitum [LMF]), and Blastomyces dermatiditis (laryngeal blastomycosis [LB]). METHOD: Single institution retrospective case series of three patients over a 2.5-year period and review of the literature on laryngeal infections by three atypical organisms. RESULTS: Three patients presented with hoarseness and cough; one additionally had throat pain (LTB). Indirect laryngoscopy demonstrated diffuse laryngeal ulceration (LTB, LMF) and an exophytic, contiguous glottic mass (LB). Direct microlaryngoscopic biopsies and cultures established the diagnoses, including a frozen section in one case (LB), which prevented a simultaneously planned surgical resection. Appropriate antimicrobial therapy yielded dramatic laryngeal and corresponding vocal improvement, for which we provide unique photo and audio documentation. In the last 10 years, fewer than 500 cases of LTB have been reported in the English language medical literature, principally outside the United States. To date, there have been reports of only 34 LB and no cases of LMF. CONCLUSION: Atypical infections of the larynx may be localized and mimic laryngeal cancer on endoscopy. Tissue examination as well as microbiologic samples are diagnostic and complementary.

Histological features and prognostic significance of treatment effect in lymph node metastasis in head and neck squamous cell carcinoma.

AIMS AND OBJECTIVES: Cervical lymph node metastasis in head and neck squamous cell carcinoma (HNSCC) is common. Pre-operative chemoradiotherapy (preCRT) and postoperative chemoradiotherapy (postCRT) is frequently employed in such patients. The prognostic value of viable SCC, treatment effect or no SCC in resected lymph nodes in patients who received or did not receive preCRT and postCRT was investigated. METHODS AND RESULTS: Resected cervical lymph nodes from 146 patients with HNSCC were evaluated for viable SCC, treatment effect or no SCC. Immunostains for Ki67, cyclin D1, caspase 3 and H2AFX were performed on viable SCC or nucleate keratin debris. Clinical and histological data were correlated with tumour recurrence or persistence. Patients with nucleate keratin debris in lymph nodes had outcomes similar to those with diffuse treatment effect and no SCC. Viable tumour in lymph nodes was associated with worse prognosis in patients who received preCRT (P = 0.01). This relative worsening of prognosis was not observed in patients with oropharyngeal SCC or recurrent disease. Lower proliferation index in lymph node SCC was associated with preCRT and with worse outcomes (P = 0.0002). Overall, patients who received preCRT or postCRT had outcomes not significantly different from those who did not. CONCLUSION: The presence of viable SCC in cervical lymph nodes has prognostic import when taken in context with the patient's history. Viable SCC in lymph nodes was significantly associated with worse outcome among patients with non-oropharyngeal SCC who received preCRT. Nucleate keratin debris should not be considered viable SCC in lymph nodes.

Cutaneous Leishmaniasis: Contribution of Routine Histopathology in Unexpected Encounters.

The ulcerated papules of cutaneous leishmaniasis represent an unusual form of granulomatous dermatitis caused by Leishmania species, a protozoan transmitted by sandfly bites. As the disease is not native to North America, clinical suspicion is partially based on a compatible travel history and may result in a biopsy. The key role of standard morphology is the identification of Leishmania organisms, supplemented by Giemsa and/or CD1a immunostaining. Histologically, the organism may be confused with Histoplasma species, which is resolved by staining with methenamine silver or PAS. Four cases of cutaneous leishmaniasis are presented for which organisms were present in 3; polymerase chain reaction and DNA sequencing for speciation done by the Center for Disease Control and Prevention (CDC) was confirmatory in 3 cases, including the one case without histologically identifiable organisms. Rare unexplained cases of cutaneous leishmaniasis without a travel history have been reported outside endemic areas. The present cases emphasize the importance of diagnostic awareness of unusual infections such as this in the context of political unrest, ease of international travel, climate change and the possible expansion of geographic vector distribution. In the morphologic absence of organisms, the diagnosis may require molecular techniques, currently available on a referral basis to pathologists without charge from CDC.

Phyllodes Tumor of the Prostate With Epithelial Intestinal Metaplasia.

Phyllodes tumor of the prostate is a rare mesenchymal tumor conventionally regarded as a stromal tumor of undetermined malignant potential. While the initial presentation is that of urinary obstruction and/or hematuria, the subsequent clinical behavior is thought to be a function of stromal cellularity and cytologic changes of malignancy. Of histologic interest, the epithelial component of this tumor varies, including intestinal metaplasia, as seen in the present case.

Melanotic Translocation Renal Cell Carcinoma With a Novel ARID1B-TFE3 Gene Fusion.

A 36-year-old male was found to have a 7.0 cm left upper pole renal mass on renal ultrasound. Following nephrectomy, the mass was grossly ill-demarcated, friable and red-brown, invading renal parenchyma, hilar fat and the renal vein. Microscopically, the tumor had a nested and papillary architecture. The cells demonstrated abundant clear and eosinophilic cytoplasm and focal intracytoplasmic melanin pigment. Nucleoli were prominent. By immunohistochemistry, the tumor was positive for TFE3; HMB-45 stained approximately 5% of tumor cells corresponding to the histologic melanin pigment, which was confirmed with Fontana-Masson stain with bleach. Immunostains for PAX8, CD10, MiTF, and CAIX were negative; keratins Cam 5.2 and AE1/AE3 were focally positive. Targeted next-generation sequencing revealed an ARID1B-TFE3 gene fusion. Melanotic Xp11 renal cell carcinoma is a rare, pigment containing translocation variant demonstrating overlapping features with melanoma and is usually associated with an SFPQ-TFE3 gene fusion. The patient is alive and without evidence of disease 7 years after his diagnosis. The combination of high grade histopathology, the presence of melanin, absent PAX8, keratin positivity, and relatively indolent clinical behavior with a unique translocation may warrant recognition as a distinct renal cell carcinoma translocation subtype.

Echinococcosis: Unexpected Occurrence and the Diagnostic Contribution of Routine Histopathology.

Echinococcus is the smallest of the major tapeworms. Humans are incidental hosts who become infected by exposure to soil contaminated with ova from the feces of the canine definitive hosts. The major species are E. granulosus (cystic echinococcosis) and E. multilocularis (alveolar or sylvatic echinococcosis), both common worldwide but unusual and not reportable in the United States. Human disease is characterized by slowly growing visceral cystic masses often containing daughter cysts and hydatid sand. In nonendemic areas, the clinical evaluation includes imaging, serology, and surgery; metastatic tumor is a major consideration. The diagnosis depends on the morphologic recognition of scolices and hooklets, albeit degenerated, within the cyst or attached to the cyst wall. Highly suggestive cyst wall features are an acellular hyaline lining surrounded by focally calcific fibrous tissue and chronic inflammation. We report 7 patients encountered in the Chicago area (5 E. granulosus, 2 E. multilocularis) who presented with cystic masses affecting the liver, lung, soft tissue, and spleen. The initial diagnosis was established or suggested by intraoperative evaluation of cyst fluid or cyst wall histopathology. Organism parts were found in 5 cases; 1 patient had a hyalinized cyst wall with a positive IgG (enzyme-linked immunosorbent assay), and 1 had a positive Western blot and a 30-year history of treatment. Treatment included cyst resection, hepatic lobectomy, intraoperative cyst injection, and benzimidazole therapy. There was 1 death. In a nonendemic area, the awareness of the pathologist to the possibility of this disease will exclude a neoplasm and facilitate prompt antihelminthic treatment.

Preservation of Reduced Numbers of Insulin-Positive Cells in Sulfonylurea-Unresponsive KCNJ11-Related Diabetes.

Context: The most common genetic cause of permanent neonatal diabetes mellitus is activating mutations in KCNJ11, which can usually be treated using oral sulfonylureas (SUs) instead of insulin injections, although some mutations are SU unresponsive. In this work, we provide a report of the pancreatic islet endocrine cell composition and area in a patient with an SU-unresponsive KCNJ11 mutation (p.G334D), in comparison with age-matched controls. Case Description: Pancreatic autopsy tissue sections from a 2-year-old female child diagnosed with KCNJ11-related diabetes at 4 days of age and 13 age-matched controls were stained with insulin, glucagon, somatostatin, pancreatic polypeptide, and Ki67 antibodies to determine islet endocrine cell composition and area. ß-cell ultrastructure was assessed by electron microscopic (EM) analysis. The patient's pancreas (sampling from head to tail) revealed insulin-positive cells in all regions. The pancreatic ß-cell (insulin) area was significantly reduced compared with controls: 0.50% ± 0.04% versus 1.67% ± 0.20%, respectively (P < 0.00001). There were no significant differences in α-cell (glucagon) or δ-cell (somatostatin) area. EM analysis revealed secretory granules with a dense core typical of mature ß-cells as well as granules with a lighter core characteristic of immature granules. Conclusions: Our results suggest that mechanisms exist that allow preservation of ß-cells in the absence of insulin secretion. It remains to be determined to what extent this reduction in ß-cells may be reversible.

Unclassified renal cell carcinoma with tubulopapillary architecture, clear cell phenotype, and chromosome 8 monosomy: a new kid on the block.

Accurate subtyping of renal cell carcinomas (RCCs) has become clinically important for therapy and prognostication. RCC subtypes are defined by distinct morphologic and immunohistochemical profiles, and in some instances recurrent cytogenetic and molecular properties. However, some tumors exhibit overlapping morphologic and immunophenotypic features, frequent enough to pose diagnostic dilemmas. This report concerns six histologically unusual RCCs that showed tubulopapillary architecture, clear cell phenotype, and non-diagnostic immunohistochemical profiles. Further investigation of these tumors utilized a single nucleotide polymorphism (SNP) microarray platform (OncoScan®, Affymetrix) that employed molecular inversion probe (MIP) technology to investigate genome-wide chromosomal copy number changes and loss of heterozygosity in formalin-fixed paraffin-embedded sections. The six tumors were assayed in parallel with and in comparison to RCC with typical morphologic or immunohistochemical features for a specific subtype (clear cell, clear cell papillary, and microphthalmia transcription factor (MiT) family translocation RCC). Three of the unusual RCCs showed a molecular signature of clear cell RCC and one of papillary RCC. The remaining two showed monosomy of chromosome 8. Those two cases were tested via next-generation sequencing, and no pathogenic variants were detected, including those in the genes VHL, PBRM1, SETD2, KDM5C, or BAP1. The addition of molecular investigations such as reported here as applied to histologically and immunohistochemically unusual RCC may help to define additional subtypes and contribute to the development of targeted therapy for renal cancer.

Radical Nephrectomy for Renal Cell Carcinoma: Its Contemporary Role Related to Histologic Type, Tumor Size, and Nodal Status: A Retrospective Study.

OBJECTIVES: Staging for renal cell carcinoma (RCC) depends on tumor size and the status of the regional lymph nodes. Although lymph node involvement by tumor yields the most accurate staging and prognostic information in patients with carcinomas of various genitourinary organs, the role of lymph node sampling (LNS) in patients with RCC to definitively establish nodal metastases remains unsettled. METHODS: In this retrospective study of 399 patients with RCC treated by total nephrectomy, 115 cases were subjected to lymph node dissection. RESULTS: The corresponding primary tumors averaged larger than 8 cm. Twenty-nine showed positive lymph nodes (25%). The present review confirms that primary tumor size is a key indicator of nodal involvement. Clear cell and papillary tumors larger than 4 cm involve lymph nodes more commonly than other types of RCC. Sarcomatoid differentiation occurred in all major cell types and existed in numbers too few to predict the likelihood of nodal metastases. CONCLUSIONS: LNS in RCC for staging purposes may be warranted based on tumor size (>4 cm) as determined by imaging as well as histologic cell type, the latter suggesting a selective role for preoperative fine needle aspiration or core biopsy.

Partial nephrectomy for renal tumors: lack of correlation between margin status and local recurrence.

OBJECTIVES: To evaluate the relationship between a positive resection margin in partial nephrectomy (PN) and local recurrence. METHODS: From January 2005 through December 2012, there were 473 PNs in 466 patients at the University of Chicago. A positive margin was defined as tumor extending to the inked specimen edge, either the parenchymal interface or the peripheral fibroadipose tissue. A local recurrence was defined as an ipsilateral tumor of identical histologic type. RESULTS: Renal cell carcinoma (RCC) accounted for 406 tumors: 243 clear cell RCCs (CRCCs), 77 papillary RCCs (PRCCs), and 47 chromophobe RCCs (CHRCCs). Sixty-one RCCs had positive margins: 43 CRCCs, six PRCCs, nine CHRCCs, and three miscellaneous cell types. Of the 61 positive margins, four CRCCs (all originally multifocal) had a local recurrence, two of which occurred in the same patient. One translocation RCC also recurred. Six cases with negative resection margins had a recurrence. CONCLUSIONS: A literature review of 3,803 cases, including our study, shows positive margins in 173, of which 13 recurred; however, 39 with negative margins also recurred. A positive margin in PN seldom correlates with a local recurrence. However, protection from recurrence is not ensured by a negative margin.

Segmental cholangiectasia clinically worrisome for cholangiocarcinoma: comparison with recurrent pyogenic cholangitis.

The aim of this study was to review the clinical, radiographic, and pathologic features of cases of benign segmental cholangiectasia in non-Asian US patients with clinical concern for cholangiocarcinoma and compare these features with cases of recurrent pyogenic cholangitis (RPC) in Asian patients. A total of 10 non-Asian US patients with benign segmental cholangiectasia were included in this study. Nine of them underwent partial hepatic resection due to cholangiographic findings of segmental cholangiectasia with mural thickening and/or proximal biliary stricture. One was found to have markedly dilated and thickened intrahepatic bile ducts at the time of autopsy. Clinical and radiographic findings were reviewed. Elastin stains and immunostains for immunoglobulin G4, cluster of differentiation (CD1a), and Langerin were performed. Six comparison cases of RPC in Asian US patients were also examined. Histologic examination of resection specimens revealed markedly dilated large intrahepatic bile ducts with variable degrees of mural fibrosis, periductal gland hyperplasia, inflammation, and liver parenchymal atrophy. These changes were not associated with a ductular reaction. There was no evidence of biliary dysplasia or biliary cirrhosis in any cases. No gross or microscopic feature definitively separated the Asian from non-Asian patients. The etiology of this disorder in non-Asian US patients is unclear. It does not appear to represent a localized variant of Caroli disease or primary sclerosing cholangitis. The high degree of similarity shared by these cases and classic RPC suggests a common pathogenic mechanism, although the pathologic features tend to be less well developed in the cases from the non-Asian US patients.

Beta-cell destruction and preservation in childhood and adult onset type 1 diabetes.

Previous studies describing the symptomatic onset of type 1 diabetes (T1D) and rate of beta-cell loss (C-peptide) support the notion that childhood onset T1D exhibits more severe beta-cell depletion compared to adult onset T1D. To test this notion, we performed whole pancreas analyses in two T1D cases, one of childhood onset (7-year old, onset at 1.5-year) along with an adult onset case (43-year old with onset at 27-year). Both cases were matched for age and gender with control subjects. Striking regional differences in beta-cell loss were observed in both T1D cases, with severity of loss in the order of tail > body > head regions. In contrast, pancreatic alpha- and delta-cell mass was similar in controls and T1D patients. In the childhood onset T1D case, no intra-islet beta-cells were detected while in the adult onset case, beta-cell containing islets were found, exclusively in the head region. In the latter case, considerable numbers of small cellular clusters negative for three major endocrine hormones were observed, in islets with or without beta-cells. Ultrastructural analysis suggests these cells correspond to degenerating beta-cells, with empty granular membranes and abnormal morphology of nuclei with intranuclear pseudo-inclusions, adjacent to healthy alpha- and delta-cells. These results support a hypothesis that during T1D development in childhood, beta-cells are more susceptible to autoimmune destruction or immune attack is more severe, while beta-cell death in the adult onset T1D may be more protracted and incomplete. In addition, T1D may be associated with the formation of "empty" beta-cells, an interesting population of cells that may represent a key facet to the disorder's pathogenesis.

Natural History and Malignant Transformation in Recurrent Respiratory Papillomatosis: Human Papillomavirus (HPV), Dysplasia and an Autopsy Review.

INTRODUCTION: Recurrent respiratory papillomatosis (RRP) is a human papillomavirus (HPV) related disease in both children and adults, characterized by recurrent benign squamous papillomas of the respiratory mucosa. Malignant transformation is rare. The present report concerns the natural history of RRP in two children. MATERIALS AND METHODS: Clinical records, autopsy material and tissue from previous surgical excisions were reviewed in both cases. Select surgical and autopsy specimens were examined using p16 immunohistochemistry and in-situ hybridization for low and high risk HPV. RESULTS: Both children had pulmonary involvement with incidental invasive keratinizing squamous carcinoma of the lung at autopsy. Low-risk HPV was present in the papillomas and carcinoma at autopsy in both cases. CONCLUSIONS: The autopsy examinations in these two cases emphasize the serious, if uncommon, pulmonary complications of this disease. In conjunction with previously reported autopsies, destructive lung disease may be as frequent a cause of death as disseminated malignancy.