Digital pathology for reporting histopathology samples, including cancer screening samples - definitive evidence from a multisite study.

AIMS: To conduct a definitive multicentre comparison of digital pathology (DP) with light microscopy (LM) for reporting histopathology slides including breast and bowel cancer screening samples. METHODS: A total of 2024 cases (608 breast, 607 GI, 609 skin, 200 renal) were studied, including 207 breast and 250 bowel cancer screening samples. Cases were examined by four pathologists (16 study pathologists across the four speciality groups), using both LM and DP, with the order randomly assigned and 6 weeks between viewings. Reports were compared for clinical management concordance (CMC), meaning identical diagnoses plus differences which do not affect patient management. Percentage CMCs were computed using logistic regression models with crossed random-effects terms for case and pathologist. The obtained percentage CMCs were referenced to 98.3% calculated from previous studies. RESULTS: For all cases LM versus DP comparisons showed the CMC rates were 99.95% [95% confidence interval (CI) = 99.90-99.97] and 98.96 (95% CI = 98.42-99.32) for cancer screening samples. In speciality groups CMC for LM versus DP showed: breast 99.40% (99.06-99.62) overall and 96.27% (94.63-97.43) for cancer screening samples; [gastrointestinal (GI) = 99.96% (99.89-99.99)] overall and 99.93% (99.68-99.98) for bowel cancer screening samples; skin 99.99% (99.92-100.0); renal 99.99% (99.57-100.0). Analysis of clinically significant differences revealed discrepancies in areas where interobserver variability is known to be high, in reads performed with both modalities and without apparent trends to either. CONCLUSIONS: Comparing LM and DP CMC, overall rates exceed the reference 98.3%, providing compelling evidence that pathologists provide equivalent results for both routine and cancer screening samples irrespective of the modality used.

Low-grade Neuroendocrine Tumor of the Cervix: Report of 3 Cases of a Rare Neoplasm With Review of the Literature.

Neuroendocrine neoplasms are uncommon in the cervix with almost all representing neuroendocrine carcinomas (NECs), either small cell or large cell type. Cervical low-grade neuroendocrine tumors (NETs) are extremely rare with few recent reports using contemporary modern diagnostic criteria. We report 3 cases of cervical NET in patients aged 32 to 57 yr and undertake a review of the literature. The first case was a pure grade 2 NET with pelvic lymph node metastasis (FIGO stage IIIC1). In the second case, a grade 1 NET was associated with high-grade squamous intraepithelial lesion, adenocarcinoma in situ and human papillomavirus (HPV)-associated adenocarcinoma and was FIGO stage IA1. The third patient underwent chemoradiotherapy following a biopsy diagnosis of a high-grade NEC which was radiologically FIGO stage IIIC1 and salvage hysterectomy revealed residual tumor with features of a grade 1 NET. In all cases, the NET was diffusely positive with at least 2 of the neuroendocrine markers chromogranin, synaptophysin, and CD56. The first tumor was p16 negative and the third exhibited block-type immunoreactivity. Molecular tests revealed high risk HPV types 18 and 51 in the third case but no HPV in the first case. p16 immunohistochemistry and HPV molecular testing was not available in the second case. The patients remain disease free with follow-up ranging from 2 to 8 yr. Since a combination of NET and NEC is extremely rare at all sites due to a different pathogenesis, we speculate that in the third case, the NET developed out of the NEC as a "maturation" phenomenon secondary to chemoradiotherapy.

Low-grade Serous Carcinoma Arising in Inguinal Nodal Endosalpingiosis: Report of 2 Cases and Literature Review.

We report 2 cases of low-grade serous carcinoma probably arising from endosalpingiosis within inguinal lymph nodes. The neoplasms occurred in 51- and 58-yr old women in the absence of tumor within the adnexa, peritoneum or elsewhere. These represent the first reported examples of low-grade serous carcinoma arising within and confined to inguinal nodes. We review the pertinent literature regarding primary nodal low-grade serous carcinoma.

Ovarian Combined Brenner Tumor, Mucinous Cystadenoma and Struma Ovarii: First Report of a Rare Combination.

Brenner tumors are uncommon ovarian neoplasms which occasionally occur in combination with a mucinous tumor. Rarely, the combination of Brenner tumor and thyroid tissue (struma ovarii) has been reported. We report an ovarian neoplasm with components of Brenner tumor, mucinous cystadenoma and struma ovarii. As far as we are aware, this combination has not been previously reported. We speculate on the possible histogenesis of this combination of elements.

Validation of digital pathology imaging for primary histopathological diagnosis.

AIMS: Digital pathology (DP) offers advantages over glass slide microscopy (GS), but data demonstrating a statistically valid equivalent (i.e. non-inferior) performance of DP against GS are required to permit its use in diagnosis. The aim of this study is to provide evidence of non-inferiority. METHODS AND RESULTS: Seventeen pathologists re-reported 3017 cases by DP. Of these, 1009 were re-reported by the same pathologist, and 2008 by a different pathologist. Re-examination of 10 138 scanned slides (2.22 terabytes) produced 72 variances between GS and DP reports, including 21 clinically significant variances. Ground truth lay with GS in 12 cases and with DP in nine cases. These results are within the 95% confidence interval for existing intraobserver and interobserver variability, proving that DP is non-inferior to GS. In three cases, the digital platform was deemed to be responsible for the variance, including a gastric biopsy, where Helicobacter pylori only became visible on slides scanned at the ×60 setting, and a bronchial biopsy and penile biopsy, where dysplasia was reported on DP but was not present on GS. CONCLUSIONS: This is one of the largest studies proving that DP is equivalent to GS for the diagnosis of histopathology specimens. Error rates are similar in both platforms, although some problems e.g. detection of bacteria, are predictable.

Florid vulval Paget disease exhibiting p16 immunoreactivity and mimicking classic VIN.

The diagnosis of vulval Paget disease is generally relatively straightforward but may be difficult, especially when the Paget cells are few in number. We report 2 cases of the opposite scenario where the Paget cells were present in such large numbers and formed confluent sheets such that they effaced the residual keratinocytes. There were associated epidermal hyperplastic changes in the form of acanthosis, papillomatosis, and hyperkeratosis, and the overall morphology resulted in close mimicry of classic (undifferentiated/human papillomavirus-related) vulval intraepithelial neoplasia. There was focal intraepidermal clefting in both cases, resulting in an acantholytic appearance. In both cases, the Paget cells were strongly positive with p16 that further heightened the mimicry of vulval intraepithelial neoplasia. The Paget cells were diffusely positive with cytokeratin 7, CAM5.2, carcinoembryonic antigen, and epithelial membrane antigen and with mucin stains, and molecular tests for human papillomavirus were negative. The p16 immunoreactivity, which has not previously been reported in vulval Paget disease, prompted us to stain a small number of additional cases of more typical vulval Paget disease with this marker. Four of 5 additional cases were positive with varying degrees and patterns of immunoreactivity. Florid vulval Paget disease may morphologically mimic vulval intraepithelial neoplasia, and this mimicry may be exacerbated by p16 immunoreactivity.

Ovarian Signet-ring Stromal Tumor: A Morphologic, Immunohistochemical, and Molecular Study of 7 Cases With Discussion of the Differential Diagnosis.

Signet-ring stromal tumor (SRST) is a rare ovarian stromal neoplasm characterized by a population of bland signet-ring cells, devoid of mucin or lipid, in a generally cellular fibromatous stroma. Previous reports have described heterogenous immunohistochemical and molecular genetic findings, including occasional nuclear ß-catenin expression and/or CTNNB1 mutations. We report 10 ovarian stromal neoplasms originally diagnosed as SRST. All but 1 tumor underwent detailed immunohistochemical analysis (including ß-catenin) and 5 of 10 had CTNNB1 mutation analysis performed. All tumors contained a population of morphologically bland signet-ring cells that ranged from 15% to 95% of the neoplasm, characterized by a single large empty intracytoplasmic vacuole, mostly with nuclear indentation. Six of the 10 tumors contained cellular fibroma-like areas, comprising from 10% to 85% of the neoplasm. Three of the 10 tumors were reclassified as microcystic stromal tumor with signet-ring cells on the basis of the microcyst formation and hyalinized stroma, beta-catenin and cyclin D1 nuclear expression and/or CTNNB1 mutation, CD10 staining and largely absent expression of inhibin and calretinin. In the remaining 7 tumors, the diagnosis of SRST remained, constituting the largest series of SRST reported in the literature to date. The results of our study suggest that a subset of tumors diagnosed as ovarian SRST, especially those which show ß-catenin nuclear positivity and/or CTNNB1 mutation, likely represent microcystic stromal tumor with variant morphology. We also suggest that at least a subset of SRSTs without evidence of Wnt/ß-catenin pathway abnormalities may be related to ovarian fibromas. We discuss the differential diagnosis of ovarian neoplasms containing signet-ring cells.

Multisystem amyloidosis as the unifying diagnosis for constipation, collapse and cardiomyopathy.

Amyloidosis a rare disorder characterised by the deposition of amyloid protein aggregates in different organ systems throughout the body with resulting functional impairment of affected organs. It can present with localised or multisystemic deposits. Diagnosis is often delayed due to the non-specific nature of the symptoms. We present the case of a 59-year-old man with a 12-month history of non-specific symptoms. Investigations revealed Helicobacter pylori positive gastritis. Blood tests showed only a normocytic anaemia and thrombocytopaenia. CT scan showed proximal sigmoid thickening. Biopsies were unremarkable. Echocardiogram and cardiac MRI scan showed restrictive cardiomyopathy. Congo red staining of gastric biopsies showed amyloid deposition. The patient had elevated serum kappa light chains and a bone marrow biopsy confirmed multiple myeloma and he was subsequently diagnosed with systemic light chain (AL) amyloidosis secondary to this. He was started on chemotherapy and parenteral nutrition; however, he deteriorated rapidly and so was started on palliative treatment and discharged home.

Diagnostic value of fine needle aspiration cytology in gouty tophi: a report of 7 cases.

UNLABELLED: BACKGROUND The diagnosis of gout can be problematic when the presentation is atypical and serum uric acid is borderline elevated. Demonstration of monosodium urate (MSU) crystals in fine needle aspiration (FNA) smears from nodular masses clinically suspected to be tophi establishes the diagnosis unequivocally. CASES: Of the 7 cases in this study, 4 were suspected clinically to have gouty tophi. Giant cell tumor of tendon sheath, giant cell tumor of bone and metastatic tumor with multicentric involvement of bone were the clinical diagnoses in 1 case each. Serum uric acid levels high enough to be in the diagnostic range for gout were reported in 3 cases, within normal limits in 3 cases and low in 1 chronic alcoholic patient. Bright field microscopy of FNA smears revealed singly scattered or stacks of MSU crystals with variable number of inflammatory cells, with or without foreign body giant cells in 6 cases. In 1 patient, FNA showed stacks of MSU crystals only. Characteristic birefringence of MSU crystals was observed on polarizing microscopy. CONCLUSION: FNA demonstration of MSU crystals on polarizing microscopy can easily establish the nature of the nodules in and around the joints and in soft tissue as gouty tophi and is thus an investigation differentiating this lesion from other masses clinically simulating it.

Enterobius vermicularis causing symptoms of appendicitis in Nepal.

This study set out to determine the prevalence of Enterobius vermicularis in surgically removed appendices and to assess the possible relation of the parasite to acute appendicitis. All 624 surgically removed appendices received in the Department of Pathology, BPKIHS, Dharan, Nepal during 2(1/2) years (August 1999-January 2002) were examined. E. vermicularis was identified in nine (1.62%) appendices from the patients with a clinical diagnosis of appendicitis. The parasite was most frequently seen in histologically normal appendices (6/71) and was rarely associated with histological change of acute appendicitis (3/539). No cases of E. vermicularis infestation occurred in appendices showing chronic inflammation or removed during the course of other surgical procedures. E. vermicularis was found more frequently in uninflamed and histologically normal appendices (8.45%) than those which were inflamed with histopathologic changes of acute appendicitis (0.56%). It may be a cause of symptoms resembling acute appendicitis although the mechanism for this does not involve mucosal invasion by the parasite.

A Detailed Immunohistochemical Analysis of a Large Series of Cervical and Vaginal Gastric-type Adenocarcinomas.

Adenocarcinomas exhibiting gastric differentiation represent a recently described and uncommon subtype of non-human papillomavirus (HPV)-related cervical adenocarcinoma. They comprise a spectrum from a well-differentiated variant (adenoma malignum/mucinous variant of minimal deviation adenocarcinoma) to a more poorly differentiated overtly malignant form, generally referred to as gastric-type adenocarcinoma. Rarely, such tumors have also been described as primary vaginal neoplasms. Gastric-type adenocarcinomas exhibit considerable morphologic overlap with adenocarcinomas originating outside the female genital tract, especially mucinous adenocarcinomas arising in the pancreas and biliary tract. Moreover, they often metastasize to unusual sites, such as the ovary and peritoneum/omentum, where they can be mistaken for metastatic adenocarcinomas from other, nongynecologic sites. There is little information regarding the immunophenotype of gastric-type adenocarcinomas, and knowledge of this is important to aid in the distinction from other adenocarcinomas. In this study, we undertook a detailed immunohistochemical analysis of a large series of cervical (n=45) and vaginal (n=2) gastric-type adenocarcinomas. Markers included were cytokeratin (CK)7, CK20, CDX2, carcinoembryonic antigen, CA125, CA19.9, p16, estrogen receptor, progesterone receptor, MUC6, PAX8, PAX2, p53, hepatocyte nuclear factor 1 beta, carbonic anhydrase IX, human epidermal receptor 2 (HER2), and mismatch repair (MMR) proteins. All markers were classified as negative, focal (<50% of tumor cells positive), or diffuse (≥50% tumor cells positive) except for p53 (classified as "wild-type" or "mutation-type"), HER2 (scored using the College of American Pathologists guidelines for gastric carcinomas), and MMR proteins (categorized as retained or lost). There was positive staining with CK7 (47/47-45 diffuse, 2 focal), MUC6 (17/21-6 diffuse, 11 focal), carcinoembryonic antigen (25/31-12 diffuse, 13 focal), carbonic anhydrase IX (20/24-8 diffuse, 12 focal), PAX8 (32/47-20 diffuse, 12 focal), CA125 (36/45-5 diffuse, 31 focal), CA19.9 (11/11-8 diffuse, 3 focal), hepatocyte nuclear factor 1 beta (13/14-12 diffuse, 1 focal), CDX2 (24/47-4 diffuse, 20 focal), CK20 (23/47-6 diffuse, 17 focal), and p16 (18/47-4 diffuse, 14 focal). Most cases were negative with estrogen receptor (29/31), progesterone receptor (10/11), PAX2 (18/19), and HER2 (25/26). p53 showed "wild-type" and "mutation-type" staining in 27 of 46 and 19 of 46 cases, respectively. MMR protein expression was retained in 19 of 20 cases with loss of MSH6 staining in 1 patient with Lynch syndrome. Molecular studies for HPV were undertaken in 2 tumors, which exhibited diffuse "block-type" immunoreactivity with p16, and both were negative. This is the first detailed immunohistochemical study of a large series of gastric-type adenocarcinomas of the lower female genital tract. Our results indicate immunophenotypic overlap with pancreaticobiliary adenocarcinomas but suggest that PAX8 immunoreactivity may be especially useful in distinguishing gastric-type adenocarcinomas from pancreaticobiliary and other nongynecologic adenocarcinomas, which are usually negative. Diffuse "block-type" p16 immunoreactivity in a cervical adenocarcinoma is not necessarily indicative of a high-risk HPV-associated tumor.

Fine needle aspiration of lymphadenopathy in visceral leishmaniasis.

OBJECTIVE: To illustrate the cytomorphologic features of Leishmania lymphadenitis associated with visceral leishmaniasis (V/L) and post-kala-azar dermal leishmaniasis (PKDL) and to highlight the fact that Leishmania lymphadenitis must he included in the differential diagnosis of patients presenting with lymphadenopathy, particularly in areas endemic for the disease. STUDY DESIGN: Fine needle aspiration (FNA) was routinely done in 21 cases of lymphadenopathy in VL (18 cases) and PKDL (3 cases), and the detailed cytomorphologic features were correlated with the respective histopathologic findings. RESULTS: Amastigote forms of Leishman-Donovan (LD) bodies were seen in 19 cases both intracellularly, in histiocytes and multinucleate giant cells, and extracellularly. The FNA smears revealed a polymorphous population of cells composed of lymphocytes, histiocytes, plasma cells, giant cells and tingible body macrophages. In a few cases, epithelioid cell granulomas were also seen. The cytomorphologic features were confirmed and correlated on histopathology. CONCLUSION: Not all lymphadenopathy in VL and PKDL is due to Leishmania lymphadenitis. Demonstration of LD bodies on FNA smears helps with the early diagnosis of VL and PKDL with lymphadenopathy where the diseases are endemic.

Pyomyoma in a postmenopausal woman: a case report.

Pyomyoma (suppurative leiomyoma of the uterus) is a rare condition associated with a high fatality rate. Only surgical intervention is lifesaving. It usually develops in association with either recent pregnancy or in postmenopausal patients who have underlying vascular disease. Since 1945 only 15 cases of pyomyoma have been reported in the literature. We present a rare case of pyomyoma in a 64-year-old woman with a brief review of the literature.

Oculosporidiosis in eastern Nepal: a report of five cases.

Rhinosporidiosis is endemic in India, Sri Lanka, and parts of East Africa and South America; sporadic cases are reported in other countries. We report on five patients from eastern Nepal with oculosporidiosis. The conjunctiva was involved in two patients and the lacrimal sac was involved in three patients; treatment was by simple total excision of the conjunctivalgrowth (patients with conjunctival involvement) and by dacryocystectomy (patients with lacrimal sac involvement). This is the second case report from Nepal.

Choroidal melanoma with secondary glaucoma.

The case of a 40-year-old female patient with choroidal melanoma with secondary glaucoma presenting as a painful blind right eye is reported. Liver metastasis was detected by ultrasonography. The choroidal tumor measured 2 x 2.1 x 1.5 cm; histopathology showed that it was of the spindle cell (spindle A) variety. Such tumors are rare in non-white races and secondary glaucoma is an uncommon presentation.

Visceral leishmaniasis in two cases of leukemia.

Two cases of visceral leishmaniasis (VL), one in a 51-year-old man with accelerated-phase chronic myeloid leukemia and another in a 35-year-old woman with acute myeloblastic leukemia, are reported. Incidental finding of Leishman-Donovan (LD) bodies in patients with leukemia highlights VL as a potent opportunistic infection in immunosuppressed patients.

Diffuse hyperplastic oncocytosis of parotid gland: a case report.

Oncocytic tumors of salivary glands are rare. Diffuse oncocytosis is the rarest lesion among 3 principal groups of oncocytic lesions as classified by WHO. Only seven cases have been previously reported in the literature. We report a case of diffuse hyperplastic oncocytosis of the parotid gland in a 63-year-old male with a brief review of literature. To the best of our knowledge this is the first case from Indian subcontinent.

Inflammatory fibroid polyp of the jejunum presenting as intussusception.

Inflammatory fibroid polyp (IFP) of jejunnum is a rare nonneoplastic lesion of gastrointestinal tract. We report a case of a 45-year-old man presenting with small bowel obstruction due to jejuno-jejunal intussusception of an inflammatory fibroid polyp. To the best of our knowledges, this is the eighth reported case with such a presentation in English medical literature. Segmental resection of the jejunum was performed and histopathology confirmed the diagnosis.

Mucinous carcinoma of rectosigmoid in a 15-year-old child: a case report.

A 15-year-old girl with Duke's B mucinous carcinoma of the rectosigmoid was treated with surgical resection and adjuvant chemotherapy. The patient is alive and has been disease-free for 15 months. Colorectal carcinoma is extremely rare in children and adolescents. Adenocarcinoma of colon is a virulent disease in children and has a poor prognosis. This is because of the poor histological characteristics and difficulty in diagnosis.