Marked Pleomorphism Research Articles

Clinicopathological Characteristics of Pleomorphic High-Grade Squamous Intraepithelial Lesion of the Uterine Cervix: A Single-Institutional Series of 31 Cases.

We investigated the clinicopathological characteristics of 31 cases of pleomorphic high-grade squamous intraepithelial lesions (PHSIL) of the uterine cervix. We reviewed electronic medical records and all available slides to collect clinical and pathological information. PHSILs were histologically characterized by significant nuclear enlargement, marked pleomorphism, hyperchromasia, increased mitotic activity, and frequent atypical mitoses. In the majority of cases (24/31; 77.4%), this striking nuclear atypia involved both the surface epithelium and the endocervical glands. In the remaining seven cases, pleomorphic cells were observed in the surface epithelium only. PHSILs involving both the surface epithelium and glands showed higher mitotic counts and Ki-67 labelling indices than the surface-only PHSILs. Invasive squamous cell carcinoma was present in only one case (3.2%), and none developed recurrent disease. Our observations of striking nuclear atypia in cases of HSIL did not indicate increased aggressiveness. Further investigations are required for confirmation of our data in larger cohorts.

Histological clues to the diagnosis of metastasis to the breast from extramammary malignancies.

The aims of this study were to review the histological features useful for the identification of metastases to the breast and to investigate the impression that this diagnosis has become more common. The histological features of metastases to the breast from 2008 to 2018 were reviewed. Seventy-four biopsies from 66patients were identified: 1% compared with primary carcinoma of the breast. Non-haematological metastases comprised 0.75% compared with 0.3% in a series from 1996 to 2005. The most common tumour types were pulmonary carcinoma (22), lymphoma (15), melanoma (13), gastrointestinal carcinoma (eight) and serous papillary carcinoma (four). In 73% there were histological features that were not typical of primary mammary carcinoma. Some metastases were histologically similar to breast cancer and the history was essential to making the correct diagnosis. Useful histological clues included small-cell morphology for pulmonary carcinoma, glands containing necrosis for gastrointestinal carcinoma, intranuclear inclusions, marked pleomorphism and spindle cells for melanoma, clear cells for renal carcinoma, papillary architecture for serous papillary carcinoma and sheets of centroblasts or nodules of centroblasts and centrocytes for lymphoma. Useful immunohistochemical markers included TTF-1 for pulmonary carcinoma, S100, melan-A and HMB45 for melanoma, CK20 and CDX2 for colorectal carcinoma, PAX8 and WT1 for serous papillary carcinoma and lymphoid markers for lymphomas, in addition to the absence of expression of mammary markers ER, GATA3 and GCDFP-15. The majority of metastases to the breast have histological clues to the diagnosis. Immunohistochemistry is helpful. This diagnosis is being made more frequently.

Clinical Significance of Nucleoli Cytomorphology Assessment in Patients With Uveal Melanoma.

To assess the prognostic significance of nucleolar morphological parameters in a large cohort of patients with uveal melanoma. The presence, size and number of nucleoli of cancer cells were assessed in haematoxylin and eosin (HE)-stained slides of 164 formalin-fixed paraffin-embedded primary uveal melanoma tissue specimens. The results were correlated with clinicopathological features and patient survival. The presence of macronucleoli and multiple nucleoli significantly correlated with the epithelioid type of uveal melanoma, high mitotic rate, and marked pleomorphism. There was a positive correlation between the presence of macronucleoli as well as the number of nucleoli and the largest tumour basal diameter. The increased nucleolus count in tumour cells positively correlated with primary tumour (pT) staging. The presence of both prominent and multiple nucleoli was associated with significantly reduced overall and disease-free survival. Histological assessment of nucleolar morphology in routine HE staining would be a helpful low-cost method to obtain reliable prognostic information.

Ovarian mucinous tumors with mural nodules: immunohistochemical and molecular analysis of 3 cases

BackgroundPrimary ovarian mucinous tumors with mural nodules are very rare. The histogenesis of the mural nodules remains unclear.MethodsWe investigated the clincopathological and molecular features in 3 cases with mural nodules.ResultsPatient 1 was diagnosed as mucinous carcinoma with mural nodules of anaplastic carcinoma that was composed of CK+ and CK7+ spindled cells and polygonal cells with marked pleomorphism. Aberrant p53 staining was found in the mural nodules rather than in the mucinous components. A concordant KRAS mutation (c.35G > A p.G12A) was identified in both mucinous tumors and mural nodules. She died of disease at 44 months. The mural nodule in patient 2 was interpreted as a sarcoma, no other specified. The uniform short spindle cells were separated by abundant myxoid matrix. They were CD10 + , CCND1-, SMA-, and negative for break-apart BCOR, PHF1, and JAZF1 FISH assay. The adenocarcinomatous component harbored LOH at D18S51 and FGA loci while the sarcomatous component had LOH at D19S433. She had lung metastasis at 18 months and was alive without evidence of disease for 40 months. Patient 3 harbored multiple mural nodules that were composed of vimentin+, focal CK+, atypical spindle cells. A diagnosis of sarcoma-like mural nodules was rendered. She was alive with no evidence of disease for 13 months. No hotspot mutant AKT1, KRAS, HRAS, and PI3KCA alleles were found in patients 2 and 3.ConclusionsMural nodules with anaplastic carcinoma or with true sarcomas may represent the dedifferentiation form of mucinous tumors or collision tumors, respectively. The worrisome histology in sarcoma-like mural nodules necessitates meticulous treatment for these patients.

Cytological and Histopathological Correlation of Feline Giant Cell-Rich Osteosarcoma

Background: Primary bone tumours are uncommon and poorly reported in cats but osteosarcoma (OSA) is the most frequent, mostly in elderly animals. Giant cell-rich OSA is considered rare in the literature representing 3% of all OSA in humans. The mitotic index seems to have a significant effect on the survival time of cats affected by this neoplasm as well as the tumour histopathological grade. The objective of this study was to report the cytological and histopathological findings of a giant cell rich OSA in a 4-year old cat with persistent feline leukemia virus (FeLV) antigenaemia.Case: A 4-year-old male neutered cat was referred with a history of persistent FeLV viraemia and pelvic limb lameness with a firm swelling. Previous radiographs of the affected limb revealed bone lysis in the third and fourth metatarsals and increased soft tissue radiopacity in the tarsal region. The referral veterinary assumed it to be osteomyelitis and initiated clinical treatment with antibiotic and anti-inflammatory. The cat was referred after there was no response to medical treatment. The cat was presented with a 5cm diameter ulcerated mass, with putrid odor in the pelvic limb. Complementary exams were performed, and abnormalities were found, including increased urea, creatinine, calcium and potassium, and decreased sodium and phosphorus. A new radiograph showed exuberant bone proliferation, with increased radiopacity involving tarsal, metatarsal, distal third of tarsal I and II, and distal diaphysis of metatarsal V, without compromising the metaphyseal region of distal diaphysis of metatarsal IV. Chest radiographs and abdominal ultrasound were unremarkable. Fine-needle aspiration was performed for cytological analysis, which reavealed a moderate amount of pleomorphic mesenchymal cells with moderate adhesion, cytoplasm with a format ranging from fusiform to stellate, pronounced anisocytosis and cellular pleomorphism, and elevated nucleus:cytoplasm ratio. Nucleus was oval and presented loose chromatin, single to double large and evident nucleolus, frequent karyomegaly, along with marked anisocariosis and nuclear pleomorphism. Multinucleated giant cells were and there was a single mitotic figure in 12 high power fields (0.196 mm2 FN20/400x). Therefore, it was suggestive of malignant mesenchymal neoplasia with possibility of OSA, fibrosarcoma oe undifferentiated sarcoma. Limb amputation with femoral disarticulation was performed uneventfully. The material was conserved in 10% formalin, submitted to macroscopic and microscopic evaluation, which showed a large number of fusiform and stellate cells, with indistinct edges, scarce eosinophilic cytoplasm, high nucleus:cytoplasm ratio and oval nucleus, presenting moderate to marked anisocariosis, loose chromatin, with unique and evident nucleoli, besides of bone trabeculae. Nuclear pleomorphism was moderate and there was four mitotic figures in three random high-power fields (400x). It was observed areas of vascular ectasia, and neoplastic embolization in lymphatic and blood vessels. Among the cells, collagenous stroma was predominant but in some areas there was an eosinophilic amorphous material with the possibility of osteoid matrix or collagen. There was also a large numbers of multinucleated giant cells. The histopathological result was compatible with a grade III giant cell rich OSA.Discussion: Although bone tumours are uncommon in cats, OSA is the most frequent, affecting maingly middle-aged to elderly cats, with a mean age of 10 years, which is different from the present report in a 4-year old cat, with FeLV persistent viraemia. Retroviral status may have influenced the development of the disease at na early onset. FeLV induces uncontrolled cell proliferation through insertional mutagenesis (usually near myc) inducing malignant neoplasias, mainly lymphoma, but also multiple cartilaginous exostosis, which, along with osteomyelitis and bone cyst were included in this patient´s list of differential diagnoses. Despite the macroscopic and radiographical andagressiveness there was no metastasis identified through chest radiographs or abdominal ultrasound, and feline OSA is associated with a lower metastatic rate, if compared to canine OSA. Cytological analysis was compatible with malignant mesenchymal neoplasia, being suggestive of giant cell rich OSA. There is no cytological classification for OSA, however cytological findings of malignancy may be correlated with the patient's clinical course. Cytological features were in agreement with the histopathological findings, compatible with a grade III giant cell rich OSA. Therefore, it is concluded that the characteristics of malignancy presented by cytology were sufficient for the recommendation of amputation of the affected limb, once there was no imaging sign of metastases in the chest or abdomen.

Genomic profiling of pleomorphic and florid lobular carcinoma in situ reveals highly recurrent ERBB2 and ERRB3 alterations.

Pleomorphic LCIS (P-LCIS) and florid LCIS (F-LCIS) are morphologic variants distinguished from classic LCIS by marked nuclear pleomorphism and/or an expansile growth pattern with or without necrosis. Given the rarity of these LCIS variants, little data exist regarding their molecular pathogenesis, natural history, and optimal management. The purpose of this study was to genomically profile LCIS variants to gain further insight into their biology. Nineteen cases of pure LCIS variants (17 P-LCIS, 2 F-LCIS) diagnosed on core needle biopsy at our institution from 2006 to 2017 were included, five of which were upgraded to invasive cancer at excision. Macrodissected lesions were analyzed by a hybrid-capture next generation sequencing assay that surveyed exonic sequences of 447 genes for mutations and copy number variations (CNVs) and 191 regions across 60 genes for structural rearrangements. LCIS variants were all confirmed as E-cadherin negative by immunohistochemistry. Receptor profiles among the 17 P-LCIS cases included HR+/HER2- (nine cases), HR+/HER2+ (three cases), HR-/HER2+ (two cases), and HR-/HER2- (three cases). The two F-LCIS cases were HR+/HER2- and HR+/HER2+. All LCIS variants had genetic alterations consistent with a lobular phenotype including 1q gain (16 cases), 16q loss (18 cases), and CDH1 mutations (18 cases). Highly recurrent ERBB2 alterations were noted including mutations (13 cases) and amplifications (six cases). Other significant alterations included mutations in PIK3CA (six cases), RUNX1 (four cases), ERBB3 (four cases), and CBFB (three cases), as well as amplification of CCND1 (five cases). A TP53 mutation was identified in one case of HR-/HER2+ P-LCIS with signet ring cell features that lacked 1q gain and 16q loss. P-LCIS and F-LCIS contain genetic alterations characteristic of lobular neoplasia; however, these LCIS variants are distinguished from classical LCIS reported in the literature by their highly recurrent ERBB2 alterations.

HPV-positive Squamous Cell Carcinoma of the Larynx, Oral Cavity, and Hypopharynx: Clinicopathologic Characterization With Recognition of a Novel Warty Variant.

Human papillomavirus (HPV) is a principal driver for most oropharyngeal squamous cell carcinomas (OPSCCs), where it is strongly associated with improved survival. HPV is much less frequently detected in squamous cell carcinomas arising in nonoropharyngeal sites (non-OPSCCs), and its pathogenic role and prognostic value in these tumors is unclear. We evaluated the clinicopathologic features of 52 non-OPSCCs considered HPV-positive based upon p16 immunohistochemistry and direct HPV detection using RNA in situ hybridization (ISH), DNA ISH, or real-time DNA polymerase chain reaction. The HPV-positive non-OPSCCs were from the larynx (n=27), oral cavity (n=21), and hypopharynx (n=4). While most cases (n=34, 65%) showed classic histologic features of HPV-positive OPSCC, including endophytic growth, minimal keratinization, and hyperchromatic nuclei without koilocytic changes, a subset (n=13, 25%) were characterized by exophytic growth, exuberant surface hyperkeratosis and parakeratosis, marked nuclear pleomorphism, and prominent koilocytic atypia. These antithetical features were highly reminiscent of the warty variant of HPV-positive squamous cell carcinoma described in anogenital sites. Compared with tumors without warty features, the warty tumors presented at lower stage and were not associated with lymph node metastasis, local recurrence, or distant spread (4 y disease-free survival of 100% vs. 66%, P=0.069). The presence of transcriptionally active HPV as detected by RNA ISH suggests a pathogenic role for HPV in these nonoropharyngeal sites. While most HPV-positive non-OPSCCs are morphologically similar to their tonsillar counterparts, this study highlights a previously unrecognized warty variant that may be associated with a highly favorable clinical outcome.

C6 Cell Injection into the Optic Nerve of Long-Evans Rats: A Short-Term Model of Optic Pathway Gliomas

The optic pathway glioma (OPG) is a slow-growing brain tumor that arises along the optic nerve or its downstream connections and causing vision to gradually worsen with time. This tumor forms in children with a genetic condition called neurofibromatosis type 1 (NF1), causing tumors to grow on nerves. In normal conditions, glial cells are there to support and protect nerve cells but, in NF1-OPG, glial cells have a genetic defect and grow out of control forming a tumor called a glioma. There are no rat models of NF1-OPG that can be used to explore various treatment options, and mouse models make interventional studies difficult due to their small eye size. We have created a model in which to study the progression of tumor growth in the optic nerve and establish the anatomical and functional consequences of the model and determine its suitability to serve as a surrogate for human disease. C6 rat glioma cells were injected into the optic nerve of Long-Evans rats and allowed to proliferate for 2 weeks. The eye clearly showed proptosis and lens opacity was observed, likely due to increased intraocular pressure caused by growing tumors. Hematoxylin–eosin staining showed marked cellularity, with hyperchromatism and pleomorphism. There was prominent area of necrosis with neoplastic cells palisading around the penumbra. Immunostaining with markers such as S100, β-tubulin III, Foxp3, CD45, Vimentin, and Ki67 confirmed low-grade tumor formation, with a mild immune response. Our results show the utility of a surgically induced rat model of OPG that may be used for exploring various treatment options for NF1 ocular tumors.

Vaginal Squamous Cell Carcinoma in a Nelore cow

Background: Skin tumors are the most common neoplasia in veterinary medicine and squamous cell carcinoma (SCC) is the most frequent. In cattle, it is the main tumor besides linfosarcoma and normally affects taurine cattle, but is rare in Nelore cattle. SCC mainly affects mucocutaneous junctions such as the eyelids, sclera, vulva, and perineum, and has already been described in vaginal, eye, and periocular tissues, in addition to the superior digestive tract. The purpose of this paper is to describe a vaginal squamous cell carcinoma in a Nelore cow.Case: A 10-year-old Nelore cow, used as an embryo donor, was submitted to a necropsy procedure. Clinically, the animal had prolonged recumbency, anorexia, weight loss, and vaginal discharge. There was a history of recurrent vaginal prolapses and an intraluminal vaginal mass that had grown over two years. At necropsy, there was diffuse fibrinous peritonitis with marked intestinal adhesions; the vagina was markedly expanded and measured 40 × 20 cm due to the presence of an intraluminal mass occupying the vestibulum and extending up to the cervix. In the vaginal lumen, there was large amount of fibrinonecrotizing malodorous material; the vaginal wall was thickened by an unencapsulated and poorly delimited, firm and white mass composed of sheets and nests of epithelial cells from the squamous layer surrounded by abundant fibrovascular stroma. The neoplastic cells were polygonal with marked pleomorphism, anisokariosis, and anisocytosis; abundant; eosinophilic; and had well-defined cytoplasmic borders. Sometimes it was possible to see desmosomes. The nuclei were rounded to oval with sparse chromatin and one or more nucleoli were seen. Mitotic figures were frequent (at least 3 per higher power field) and there were also a few multinucleated cells. Frequently, there was the formation of distinct keratin “pearls”.Discussion: SCC frequently occurs in the skin, eyes, and vulva in cattle, since these are sites that lack pigment within the epidermis and have prolonged exposed to ultraviolet light. Vaginal SCC has already been described in one cow with recurrent vaginal prolapses that was submitted to follicular aspiration. In a survey of cattle tumors, most genital tract neoplasias affected the uterus, and vaginal tumors normally originated from connective tissue - fibromas, fibropapillomas, and fibrosarcoma - or muscular tissue - leiomyoma and leiomyosarcoma. Irreversible changes in cellular DNA can occur due to physical or chemical carcinogens, and also chronic inflammation. The cow in this paper was frequently submitted to follicular aspiration and this can cause chronic inflammation in the vaginal mucosa after the puncture and, when it’s chronic, can represent one of the main initiating factors for tumor development. This cow’s death was caused by diffuse and marked peritonitis. The same cause was previously described in cows submitted to follicular aspiration and, in one of these animals, there was a rectal perforation caused by mistakes during the procedure. In this animal, we did not find any lesions in the rectum or intestines, however, considering the gravity of the peritonitis, we were not able to exclude this hypothesis. Papillomavirus has previously been found in SCC in sheep and probably acts synergistically with ultraviolet light, however, in this animal, we did not test for the virus. Squamous cell carcinoma in an uncommon tumor in cows’ vaginas, however, this should be included as a possible differential diagnosis, especially in animals submitted to situations that can cause chronic inflammation in the genital tract.

Periocular Sebaceous Carcinoma Masquerading as an Intratarsal Cyst.

A 60-year-old woman with no significant medical history presented to an outside eye care provider for a persistent right lower eyelid lesion. This lesion was diagnosed as a chalazion, and she underwent incision and drainage. Postoperatively, the lesion did not resolve and maintained the same size and appearance. She was referred 6 months later for tarsal cyst excision. Examination was remarkable for an intratarsal cystic lesion involving the margin of the right lower eyelid (Fig. A, B). There was no associated madarosis, ulceration, bleeding, keratinization, or telangiectasia. A wedge excision and reconstruction were performed. Pathologic examination revealed a poorly differentiated sebaceous carcinoma (Fig. C, D). The patient underwent a second resection and conjunctival map biopsies, which showed negative surgical margins and no conjunctival involvement. She subsequently underwent reconstruction, and there was no evidence of recurrence at 6-month follow-up.External photograph demonstrating a right lower eyelid sebaceous cell carcinoma and corresponding histological findings. A,B, The cystic lesion involves the posterior aspect of the tarsus and extends to the margin. C, Lower power photomicrograph demonstrating the cystic growth pattern of the lesion (hematoxylin and eosin; original magnification = ×10). D, High magnification photomicrograph demonstrating that the cyst wall is composed of atypical cells with marked nuclear pleomorphism and vacuolated or foamy cytoplasm in many cells (hematoxylin and eosin; original magnification = ×300).Sebaceous carcinoma is a relatively rare, aggressive malignancy most commonly arising from the periocular tissues including the meibomian glands of the tarsus, and the glands of Zeis of the eyelashes, caruncle, and skin of the eyebrow. Although sebaceous carcinoma accounts for only 0.5% of all eyelid lesions, it is the most concerning because it is associated with increased morbidity and mortality. This periocular malignancy is notoriously difficult to diagnose, masquerading as an assortment of conditions which frequently leads to delays in diagnosis and proper treatment in greater than two thirds of cases. Despite a seemingly benign appearance, any lesion with yellow coloration and thickening of the eyelid or adjacent conjunctiva should cause the clinician to consider sebaceous carcinoma as a possibility with a low threshold for biopsy.

Secondary INI1-deficient rhabdoid tumors of the central nervous system: analysis of four cases and literature review

Atypical teratoid/rhabdoid tumors (AT/RT) are rare, highly malignant neoplasms of the central nervous system that predominantly occur in infants, and are characterized by the presence of rhabdoid cells and inactivation of INI1 or (extremely rarely) BRG1. The vast majority of AT/RT are recognized as primary tumors; however, rare AT/RT or INI1-deficient RT arising from other primary tumors have been reported. To better characterize secondary RT, we performed a histological and molecular analysis of four RT arising from pleomorphic xanthoastrocytoma (PXA), anaplastic PXA, low-grade astrocytoma, or ependymoma. Histologically, although conventional AT/RT are usually not largely composed of rhabdoid cells, three secondary RT were composed mainly of rhabdoid cells, two of which arising from (anaplastic) PXA exhibited marked nuclear pleomorphism reminiscent of that in the precursor lesions. Regarding INI1 alterations, although mutations including small indels are frequent in conventional AT/RT, only in one secondary RT had a mutation. Moreover, together with previously reported cases, biallelic INI1 inactivation in secondary RT was mostly due to biallelic focal and/or broad deletions. Although conventional AT/RT have stable chromosomal profiles, i.e., the frequency of copy number changes involving chromosomes other than chromosome 22 is remarkably low, our array comparative genomic hybridization analysis revealed numerous copy number changes in the secondary RT. In conclusion, secondary RT of the central nervous system are clinicopathologically and molecularly different from conventional pediatric AT/RT, and a nosological issue is whether these secondary RT should be called secondary "AT/RT" as most of the reported cases were.

1863 The Mouth Is More Than Just an Entry Path to the Esophagus: A Rare Site of Breast Cancer Metastasis

INTRODUCTION: The following case highlights a rare site for breast cancer metastasis, as well as demonstrates the importance of careful attention to all structures including the oral cavity, during endoscopy. CASE DESCRIPTION/METHODS: A 53-year-old woman with a history of a recent dental abscess presented with weakness. She reported that 2 weeks before presentation she developed a dental abscess that required drainage. Upon further questioning, she also recalled a 2-month history of right breast pain and swelling. CT abdomen and pelvis obtained raised concern for infiltrative breast cancer with metastases to the liver, lung, bone, and brain. Prior to dedicated breast imaging and biopsy, the patient developed large-volume hematemesis and urgent endoscopy was performed. As the endoscope was advanced into the mouth, a 15 mm soft, friable polypoid mass was seen on the hard palate off the midline, as well as a cratered lesion with rounded walls in the gastric body. These lesions were biopsied with pathology showing poorly differentiated carcinoma composed of nests of malignant cells with marked atypia and pleomorphism, positive for pancytokeratin, GATA3 and CK7. The morphology and immunoprofile supported the diagnosis of metastatic carcinoma of breast origin. DISCUSSION: Breast cancer most often metastasizes to the liver, lung, bone, and brain. Gastric metastases are infrequent, with an estimated incidence rate of approximately 0.3%. Metastasis of malignant tumors to the oral cavity is exceedingly rare and accounts for approximately 1% of all malignant oral tumors. There are insufficient data to account for the true incidence for breast cancer metastasis to the oral cavity. Management of metastatic breast carcinomas of the oral cavity is primarily palliative, as prognosis for patients with these metastatic lesions is generally poor. As gastroenterologists, we are often focused solely on the proximal gastrointestinal tract during upper endoscopy, but we have the ability to fully evaluate and detect abnormalities of a number of other structures, including the oral cavity, oropharynx, and larynx. We should take full advantage of this opportunity to view these structures in an attempt to aid in early detection of what would otherwise be neglected disease. This case not only demonstrates the need for awareness of the oral cavity as a potential site for metastasis of breast cancer and its associated poor prognosis, but it also highlights the key principle of conducting a thorough endoscopic evaluation.

1610 Don't Let Your Past Determine Your Destiny

INTRODUCTION: Synovial sarcoma (SS) is a rare mesenchymal soft tissue sarcoma usually involving extremities close to large joints. SS of the GIT is uncommon; SS of the colon is extremely rare. Recognition and management of SS of the GIT can be very challenging. Here we report a rare case of asymptomatic SS of the rectosigmoid diagnosed as a surprising finding of surveillance colonoscopy. CASE DESCRIPTION/METHODS: A 59-year-old asymptomatic lady with past medical history of diabetes mellitus, morbid obesity, colon polyps was referred for surveillance colonoscopy. Prior colonoscopy six years ago revealed two sigmoid colonic tubular adenomas. Examination was unremarkable except for a BMI of 44. Thorough examination of the musculoskeletal system did not reveal any abnormalities. Colonoscopy revealed a large, 5 cm pedunculated and superficially ulcerated round mass in the rectosigmoid colon, filling most of the lumen with the distal end of the lesion being ∼15 cm above the anal verge. Biopsy demonstrated spindle cells with marked nuclear pleomorphism, high mitotic index rate, positive SS18 (SYT) gene rearrangement testing on FISH. Immunohistochemistry (IHC) was positive for TLE1, OSCAR, MCK, AE1/AE3, CK7 with Ki-67 of 70% and negative for desmin, CD117, DOG1, p63, CK5, CK6, S100, SMA. Findings were consistent with SS. Staging CT and PET-CT did not demonstrate distant spread. Robotic laparoscopic anterior resection with wide surgical resection margins and lymphadenectomy revealed T1N1 LN 2/20 stage 3 monophasic synovial sarcoma, with negative margins, 20% tumor necrosis and high mitotic rate. The patient was started on adjuvant chemotherapy with 5 cycles of Adriamycin 75 mg/m2 and Olaratumab on day 1 and day 8 of a 21-day cycle. A repeat PET-CT and a flexible sigmoidoscopy, six months later, did not reveal any tumor recurrence. DISCUSSION: Increasing number of cases of GIT SS are being reported. The majority of GI SS cases involved esophagus and stomach with pain, obstruction and bleeding being the common presenting symptoms; SS of the large intestine is extremely rare. Diagnosis is established by molecular genetics and IHC. Standardized treatment-guidelines are currently lacking. It is of paramount importance to i) consider SS on the list of differentials of colonic neoplasms, ii) report these unusual cases to better understand the pathophysiology, treatment options and success rates. This would facilitate more targeted and effective treatments for SS of the colon.

Primary Smooth Muscle Tumor of Breast: An Unusual Case Presentation

Abstract Introduction Primary smooth muscle tumors (SMT) of the breast are rare with leiomyosarcomas representing less than 0.1% of all malignant breast tumors. Case Presentation A 58-year-old female with no significant past medical history noted on screening mammography to have a circumscribed 6-mm nodule in the right breast, upper outer quadrant. Core needle biopsy showed a spindle cell neoplasm with smooth muscle differentiation. The excisional biopsy showed a 6-mm lesion composed of atypical hyperchromatic spindle cells in fascicles, marked nuclear pleomorphism, and 5 mitoses per 10 high-power fields. By immunohistochemistry, the spindle cells were positive for smooth muscle actin, desmin, and negative for S-100 and cytokeratin AE1/AE3. Positron emission tomography/computed tomography of head/neck, chest, abdomen, and pelvis did not identify other neoplasms. Despite the lesion size, findings were supportive of a leiomyosarcoma. Discussion Breast SMTs have nonspecific clinical or imaging features. Histologically, these present as spindle cell tumors with smooth muscle differentiation. Initial workup starts with distinction between benign and malignant neoplasms. The malignant SMTs are usually large tumors with cytologic atypia and mitotic activity used as diagnostic criteria. In addition, the distinction between primary and metastasis is important and frequently relies on clinical history and exclusion of other primary origins by radiographic survey. In the current case, although the tumor size is unusually small, the histological features and absence of other primary malignancies support the diagnosis of a leiomyosarcoma. Conclusion Primary leiomyosarcoma of breast is extremely uncommon with less than 70 cases reported in the literature. Although they are usually large tumors, this diagnosis should be included in the differential diagnosis when smooth muscle differentiation, significant atypia, and mitoses are encountered in a spindle cell tumor of the breast.

Metastatic Malignant Paraganglioma: A Case Report

Abstract Objectives Paragangliomas are rare neuroendocrine tumors that arise from chromaffin cells with the ability to secrete catecholamines. The estimated combined prevalence is between 1:6,500 and 1:2,500. Paragangliomas can have a benign or a malignant course with incidence of malignant paraganglioma estimated to be 93/400 million. The majority of paragangliomas are sporadic but may be related to syndromes like multiple endocrine neoplasia type 2, von Hippel-Lindau disease, and neurofibromatosis type 1. Methods We present a unique case of a 25-year-old female who presented with a hepatic mass. Further workup showed an enhancing hypervascular mass along with lesions within the bilateral lungs, liver, spleen, and sclerotic osseous metastatic disease at cervical thoracic lumbar and sacral spine. A liver biopsy was performed, which was consistent with the diagnosis of a metastatic paraganglioma. Results The liver biopsy showed a tumor consisting of epithelioid and polygonal tumor cells with eosinophilic cytoplasm present in a vascularized fibrous stroma in a sinusoidal pattern. In certain areas, the tumor cells show marked pleomorphism with large cells with macronuclei and bizarre shapes. On immunohistochemistry (IHC), the tumor cells were strongly and diffusely positive for CD56 and vimentin and focally positive for synaptophysin and chromogranin. S100 highlighted sustentacular cells. Ki-67 was very low, staining less than 2%. In addition, the tumor cells showed loss of expression of SDHB by IHC. Conclusion Metastatic malignant nonsecretory paraganglioma is an extremely rare disease. The most unique pathological aspect of paragangliomas is that tissue acquired from different organ appears the same histologically and yet different in terms of prognosis. Metastatic hepatic paraganglioma in our patient offers interesting insights to appreciate the rare metastatic nature of paraganglioma to the liver. The elusive nature of the metastatic disease in paraganglioma poses a challenge to clinicians since the diagnosis of metastatic hepatic paraganglioma is usually clinically undiagnosed.

Atypical epithelioid hemangioendothelioma: a clinicopathological analysis of eight cases

Objective: To study the clinicopathological features, diagnosis, and differential diagnosis of atypical epithelioid hemangioendothelioma (EHE). Methods: Eight cases of atypical EHEs were collected from Jiangsu Province Hospital (the First Affiliated Hospital of Nanjing Medical University) between 2010 and 2018. EnVision method and fluorescence in situ hybridization (FISH) were used to detect immunophenotype, WWTR1-CAMTA1 and TFE3 gene rearrangement, respectively. Results: There were 4 males and 4 females, ranging from 42 to 59 years (median 47.5 years). The tumors located in soft tissue (3 cases), lung (3 cases), liver (1 case) and chest wall (1 case). One soft tissue EHE involved also adjacent fibula and pleural involvement was present in all three lung cases at the diagnosis. Regional lymph node metastases were present in two cases (one involving soft tissue tumor and one involving liver). Morphologically, the tumor cells were epithelioid with abundant eosinophilic cytoplasm, moderate to marked nuclear pleomorphism, irregular nuclear membrane, unevenly chromatin, and prominent nucleoli. The cells arranged in cords, small nests or solid pattern. The mitotic rate was 4.3 mitoses/2 mm(2) on average (ranging 2 to 9). Tumor necrosis was seen in every case. Among all 8 cases, blister cells were found upon careful observation. Myxohyaline stroma was present in 6 cases. Immunohistochemically, tumor cells expressed CD31 (8/8), CD34 (7/8), ERG (8/8), CKpan (2/7), and CAMTA1 (4/6). None of the tested cases stained for TFE3 (0/6). WWTR1-CAMTA1 fusion gene by FISH was found in all tested 6 cases and TFE3 gene rearrangement was not detected in any. Available clinical follow-up was obtained in 7 cases and the intervals range from 6 to 55 months (average 19.6 months). Six patients had metastasis and 3 patients died of disease. One patient was alive with no evidence of disease. Conclusions: Atypical EHE is a more aggressive tumor than classic EHE, with histological features including high nuclear grade, increased mitotic activity, the presence of solid growth pattern and tumor necrosis. The differential diagnoses include epithelioid angiosarcoma, carcinoma and epithelioid sarcoma.

Parafibromin immunostainings of parathyroid tumors in clinical routine: a near-decade experience from a tertiary center

The cell division cycle 73 gene is mutated in familial and sporadic forms of primary hyperparathyroidism, and the corresponding protein product parafibromin has been proposed as an adjunct immunohistochemical marker for the identification of cell division cycle 73 mutations and parathyroid carcinoma. Here, we present data from our experiences using parafibromin immunohistochemistry in parathyroid tumors since the marker was implemented in clinical routine in 2010. A total of 2019 parathyroid adenomas, atypical adenomas, and carcinomas were diagnosed in our department, and parafibromin staining was ordered for 297 cases with an initial suspicion of malignant potential to avoid excessive numbers of false positives. The most common inclusion criteria for immunohistochemistry were marked tumor weight (146 cases) and/or fibrosis (77 cases) and/or marked pleomorphism (58 cases). In total, 238 cases were informatively stained, and partial or complete loss of nuclear parafibromin immunoreactivity was noted in 40 cases; 10 out of 182 adenomas (5%), 27 out of 46 atypical adenomas (59%), and 7 out of 10 carcinomas (70%), with positive and negative predictive values of 85 and 90%, respectively for the detection of atypical adenomas/carcinomas versus adenomas, and 18 and 98%, respectively for carcinomas versus atypical adenomas/adenomas. Male patients with high-proliferative tumors were overrepresented among cases with aberrant parafibromin immunohistochemistry, and carcinomas more frequently harbored parafibromin aberrancies than atypical adenomas and adenomas (p < 0.001). We conclude that parafibromin immunohistochemistry is a useful marker in the clinical routine when applied on a pre-selected material of cases, with positive immunoreactivity as a confident rule out marker of malignancy.

Keratinized tumor with aggressive evolution at the orofacial level

Squamous cell carcinoma accounts for 90% of the oral cavity carcinomas. Most commonly affects men over 50, smokers. We present the case of a 77-year-old patient diagnosed in our clinic with a rapidly evolutive, highly aggressive squamous cell carcinoma of the lower lip, with aesthetic and functional consequences. The onset of the tumor was at the lower lip and then rapidly spread to the entire surface of the chin. Dermatological examination revealed a suprainfected tumor, adherent to deep structures. The tumor exhibits numerous bumps at the surface, irregular edges, numerous ulcerations and purse bags. The tumor has invasive character, reaching the mandibular bone and was evolving for the last 3 months. The histopathological examinations showed squamous cells, intense nuclear tachycromasia, marked pleomorphism, hight nuclear and cytoplasmic ratio and frequent mitosis, thus being conclusive for the diagnosis of moderately differentiated squamous cel carcinoma. The bacteriological examination revealed bacterial infection with Proteus vulgaris and beta hemolytic Streptococcus. Computer tomography showed the partially necrotic tumor, located on the soft parts of the right mandibular region and submandibular adenopathies. There were no secondary disseminations. This case highlights the need for complete surgical excision of a rapidly evolving tumor with increased size, perineural and perivascular invasion, diagnosed at an early stage where appropriate treatment can be done.

Micropapillary adenocarcinoma of lung: Morphological criteria and diagnostic reproducibility among pulmonary pathologists

ContextInvasive micropapillary adenocarcinoma (MPC) is an aggressive variant of lung adenocarcinoma, frequently manifesting with advanced stage lymph node metastasis and decreased survival. ObjectiveIdentification of this morphology is important, as it is strongly correlated with poor prognosis regardless of the amount of MPC component. To date, no study has investigated the morphological criteria used to objectively diagnose it. DesignHerein, we selected 30 cases of potential MPC of lung, and distributed 2 digital images per case among 15 pulmonary pathology experts. Reviewers were requested to diagnostically interpret, assign the percentage of MPC component, and record the morphological features they identified. The noted features included: columnar cells, elongated slender cell nests, extensive stromal retraction, lumen formation with internal epithelial tufting, epithelial signet ring-like forms, intracytoplasmic vacuolization, multiple nests in the same alveolar space, back-to-back lacunar spaces, epithelial nest anastomosis, marked pleomorphism, peripherally oriented nuclei, randomly distributed nuclei, small/medium/large tumor nest size, fibrovascular cores, and spread through air-spaces (STAS). ResultsCluster analysis revealed three subgroups with the following diagnoses: “MPC”, “combined papillary and MPC”, and “others”. The subgroups correlated with the reported median percentage of MPC. Intracytoplasmic vacuolization, epithelial nest anastomosis/confluence, multiple nests in the same alveolar space, and small/medium tumor nest size were the most common criteria identified in the cases diagnosed as MPC. Peripherally oriented nuclei and epithelial signet ring-like forms were frequently identified in both the “MPC” and “combined papillary and MPC” groups. ConclusionsOur study provides objective diagnostic criteria to diagnose MPC of lung.

Clinico-Histomorphological and Immunohistochemical Profile of Anaplastic Pleomorphic Xanthoastrocytoma: Report of Five Cases and Review of Literature

Background: Pleomorphic xanthoastrocytoma is a rare tumour of children and young adults, particularly for those with features of anaplasia. Materials and Methods : This retrospective study comprises five cases of anaplastic pleomorphic xanthoastrocytomas diagnosed over a period of 4years in a tertiary care institute. A detailed clinicopathological and immunohistochemical profile of the tumours were noted from the hospital database. Results: Five cases of anaplastic pleomorphic xanthoastrocytomas were evaluated for their clinicoradiological, histomorphological as well as immunohistochemical findings, which included 3 females and 2 males, with age range of 11-40 years and a mean age at presentation of 22 years. Histologically a solid cystic biphasic tumour with moderate to high cellularity, spindled pleomorphic astrocytes, hyperchromatic nuclei showing moderate to marked atypia, intranuclear inclusions, ≥5 mitoses per 10 high power fields, with evidence of necrosis and atypical mitoses was noted. One of the cases showed transformation into glioblastoma with evidence of spinal metastasis on follow-up. The tumours expressed both glial as well as neuronal markers with expression of CD34 with increased Ki 67 ranging between 5-20%. Conclusion: It was concluded that PXA, a low-grade glioneuronal tumour, can show odd site presentation, marked pleomorphism, increased mitosis, atypical mitoses and increased Ki 67 when associated with features of anaplasia. An appropriate panel of immunohistochemical markers in conjunction with a detailed evaluation of histomorphological features and clinicoradiological information are useful for its diagnosis.