QA CONFERENCE #2, May 30, 2012 Dr. Esther Ravinsky

Case 1 60 year old female Ultrasound guided right breast core biopsy Palpable nodule, UOQ Query reactive lymph node R/O carcinoma Magnification x 2

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Case 1 DIAGNOSIS Pathologist or resident Mammary carcinoma pending stains. There is some spindling ?metaplastic ca 1 pathologist Probably invasive carcinoma. Need immunostains 1 resident; 1pathologist Epithelioid and spindled neoplasm. Do testing Does not look like invasive ca. Needs immuno Does not look malignant. Needs immunostains 1 resident Sclerosing adenosis. Needs IHC to confirm and R/O carcinoma Infiltrative tumour. Needs IHC (possibly myoepithelial, possibly metastatic possibly invasive carcinoma) 2 pathologists Spindle cell neoplasm Do IHC (?myofibroblastoma) 1 Myofibroblastoma vs granular cell tumour Myofibroblastoma

Case 1 Immunohistochemical stain for desmin

The answer is: Case 1 Neoplasm with stromal differentiation Differential diagnosis includes: Myofibroblastoma with epithelioid features Metaplastic carcinoma Sarcoma (e.g. leiomyosarcoma)

Case 1 Mastectomy was performed The nodule which had been biopsied was described as a pinkish-grey encapsulated nodule ?lymph node ?tumour nodule, 1.8 cm in dimension

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Myofibroblastoma Rare benign breast tumour arising from myofibroblasts Radiologically, the tumours are homogeneous, lobulated, well circumscribed and lack microcalcifications The excised mass is firm and rubbery with a lobulated external surface The cut surface consists of homogeneous, bulging, gray to pink whorled tissue

Myofibroblastoma Microscopically, the classic type of myofibroblastoma is devoid of mammary ducts and lobules, with compressed breast parenchyma forming a peripheral pseudocapsule The tumour consists of bundles of slender bipolar uniform spindle shaped cells typically arranged in clusters which are separated by broad bands of hyalinized collagen distributed throughout the tumour In a minority of cases, fat cells are present in the tumour, reflecting invasion of the surrounding tissue

Myofibroblastoma, variant forms The epithelioid variant features polygonal or epithelioid cells arranged in alveolar groups Epithelioid cells may be mixed with more classical variants or they can constitute the predominant growth pattern Because of the epithelioid growth pattern, the tumour may be mistaken for an infiltrating lobular carcinoma, especially in the limited material of a needle core biopsy Other variants which may be mistaken for malignancy are the cellular variant, the infiltrative variant and the deciduoid variant

Myofibroblastoma, variant forms By immunohistochemistry, myofibroblastomas stain positive for actin and desmin and negative for cytokeratin Noticing a spindle cell component can raise a red flag for the pathologist considering a diagnosis of carcinoma and result in the ordering of appropriate immunohistochemistry The absence of mitotic figures should raise a red flag if the diagnosis of metaplastic carcinoma or sarcoma is considered

Infiltrating myofibroblastoma

Myofibroblastoma No recurrences have been reported after follow-up of 3 to 126 months Excision with wide margins is recommended when myofibroblastoma is identified in a needle core biopsy

Case 2 65 year old female Endometrial biopsy History of post menopausal bleeding Magnification x 4

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Case 2 DIAGNOSIS Endometrioid adenocarcinoma Pathologist or resident Endometrioid adenocarcinoma 1 pathologist; 2 ? Endometrioid adenocarcinoma in a background of complex hyperplasia with atypia 1 pathologist Complex hyperplasia with atypia 1 resident; 1? High grade: Serous papillary carcinoma vs. endometrioid adenocarcinoma FIGO 2. Do p53 and deepers to R/O MMMT 2 pathologists;1 resident Endometrioid adenoca with focal serous features. Do p53; Serous carcinoma 1 pathologist; 1 resident Endometrioid carcinoma with area showing high grade nuclei. Do p53 to R/O serous carcinoma Adenocarcinoma (illegible) – To Pat

Case 2 Immunohistochemical stain for p53

Case 2 The answer is: Serous carcinoma of endometrium

Case 3 76 year old female Endometrial curettage performed at diagnostic hysteroscopy Post menopausal bleeding Atypical glandular cells on Pap Magnification x 2

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Case 3 Immunohistochemical stain for p53

Case 3 DIAGNOSIS Gyne consult Serous carcinoma Pathologist or resident 2 pathologists: 1 resident 2 ? High grade endometrioid adenocarcinoma vs. serous carcinoma. 3 pathologists; 1 resident; 1 ? Moderately differentiated endometrial adenocarcinoma 1 resident Endometrioid adenocarcinoma; p53 expression – not over-expressed Endometrioid adenocarcinoma. Ignore p53 – To Pat

Case 3 Immunohistochemical stain for ER

Case 3 The answer is: Endometrioid adenocarcinoma, FIGO grade 2

Differential diagnosis of villoglandular (endometrioid) adenocarcinoma and serous carcinoma of endometrium Serous carcinoma It is defined by a discordance between its architecture which appears well differentiated; papillary or glandular and its nuclear morphology which is high grade Papillary architecture is complex with short thick papillae though thin papillae may also be present. The cells covering the papillae and lining the glands form small papillary tufts, many of which are detached and float freely in spaces between the papillae and in the gland lumens

Differential diagnosis of villoglandular (endometrioid) adenocarcinoma and serous carcinoma of endometrium The cells are cuboidal or hobnail shaped and contain abundant epsinophilic cytoplasm The cells tend to be loosely cohesive The cells show marked cytologic atypia with marked nuclear pleomorphism, hyperchromasia and macronucleoli Multonucleated cells, giant nuclei and bizarre forms can occur Mitotic activity is high and abnormal mitotic figures are easily identified

Differential diagnosis of villoglandular (endometrioid) adenocarcinoma and serous carcinoma of endometrium Villoglandular carcinoma is characterized by the presence of long delicate papillary fronds that do not show papillary tufting The cells are columnar, resembling the cells in endometrioid adenocarcinoma The glands in endometrioid adenocarcinoma have a smooth luminal border and are lined by columnar cells with nuclei which are grade 1 or 2. Endometrioid adenocarcinomas with grade 3 nuclei are almost always solid

Differential diagnosis of villoglandular (endometrioid) adenocarcinoma and serous carcinoma of endometrium Immunohistochemical findings: Serous carcinoma 75% of serous carcinomas are strongly and diffusely positive for p53 The typical serous carcinoma lacks diffuse ER and PR expression. Carcinomas with hybrid endometrioid/serous features and admixtures of endometrioid and serous components can express ER Diffuse strong p16 staining is characteristic of serous carcinomas The Ki67 labelling index is extremely high (50%-75% of tumour nuclei)

Differential diagnosis of villoglandular (endometrioid) adenocarcinoma and serous carcinoma of endometrium Immunohistochemical findings: Villoglandular/endometrioid carcinoma The preponderance of grades 1 + 2 and half of the grade 3 endometrioid carcinomas strongly express ER and PR P53 expression is not identified in FIGO 1 carcinomas. It is identified in a minority of FIGO 2 carcinomas and in a significant number of FIGO 3 carcinomas However, when p53 staining is prominent, serous carcinoma, clear cell carcinoma or undifferentiated carcinoma should be considered Overexpression characteristic of serous carcinoma is defined as diffuse and strong expression in more than 50-75% of tumour cells Low-grade expression of p53 in less than 50% of tumour cells is commonly found in endometrioid carcinomas Endometrioid carcinoma can show patchy expression of p16

Differential diagnosis of villoglandular (endometrioid) adenocarcinoma and serous carcinoma of endometrium Immuno stain Serous carcinoma Endometrioid carcinoma, grades 1 + 2 ER/PR Weakly positive or negative Strongly and diffusely positive P53 Negative or low level expression P16 Negative or patchy positivity Ki-67 index Extremely high (more than 50-75% of cells) Less than the index of serous carcinoma

Case 4 74 year old female Open cholecystectomy Calculi identified Magnification x 2

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Case 4 DIAGNOSIS Pathologist or resident Suspicious for adenocarcinoma. Lining epithelium dysplastic. Small irregular glands in deeper tissue 1 Pathologist Suspicious for malignancy 1 Resident Adenocarcinoma or invasive adenocarcinoma 1 Pathologist; 1 ? Severely dysplastic glandular cells. Suspicious for invasion ?invasion 1 pathologist; 1Resident Gastric/intestinal metaplasia. Adenocarcinoma in situ Acute/acute and chronic cholecystitis or benign glandular proliferation 3 Pathologists; 2 ?

Case 4 The answer is: Low grade dysplasia High grade dysplasia Focus suggestive but not diagnostic of invasive adenocarcinoma

Case 4 Low grade dysplasia Suggestive of invasive adenocarcinoma High grade dysplaisa

Dysplasia of gallbladder Dysplastic changes, mostly low-grade have been reported as an incidental finding in 1% to 3.5% of cholecystectomies This frequency varies significantly between patient populations and generally parallels the incidence of adenocarcinoma Dysplasia is detected in 40%-50% of adenocarcinomas Most patients with high grade dysplasia have associated invasive carcinoma

Dysplasia of gallbladder Dysplasia of gallbladder is characterized by a disorderly proliferation of atypical columnar or cuboidal cells Low-grade dysplasia shows cells with mild stratification and nuclear enlargement with only minimal nuclear enlargement High grade dysplasia shows marked nuclear enlargement and irregularity, hyperchromasia and significant loss of polarity Prominent tufting of of irregularly shaped nuclei and apoptosis are also characteristic of high-grade dysplasia An abrupt transition from abnormal to normal epithelium is characteristic of both grades of dysplasia

Dysplasia of gallbladder The differential diagnosis of dysplasia is marked reactive/degenerative changes Biliary epithelium has the capacity to develop marked cytologic atypia secondary to injury which, at times, may be difficult to distinguish from true neoplastic changes Also, neoplastic transformation is often related to chronic inflammatory conditions

Dysplasia of gallbladder Lesions that show marked nuclear stratification, enlargement, hyperchromasia, and irregularity in the absence of inflammation or ulceration favour dysplasia, especially high-grade Reactive atypia does not show all of these features at once Reactive epithelium often shows a peculiar moulding pattern of the cells and reveals maturation towards the surface of the epithelium Nuclear polarity is usually maintained in reactive epithelium One should be cautious about making a definative diagnosis of dysplasia in areas of acute inflammation or ulceration

Reactive atypia

Reactive atypia

Reactive atypia

Low grade dysplasia

High grade dysplasia

High grade dysplasia

Differential diagnosis of invasive adenocarcinoma and reactive changes There are difficulties in distinguishing the cytologic changes of invasive adenocarcinoma from reactive changes Carcinoma cells may be deceptively bland and regenerative cells may show a marked degree of atypia At the architectural level: Well differentiated adenocarcinoma often have well organized gland formation which may be difficult to distinguish from Rokitansky-Aschoff sinuses or Luschka’s ducts (Benign biliary-type ducts commonly present in the perimuscular tissue at the hepatic surface of the gallbladder

Differential diagnosis of invasive adenocarcinoma and reactive changes Lushka’s ducts are composed of uniform, evenly sized tubules, all arranged parallel to the surface Rokitansky-Aschoff sinuses are continuous, oriented perpendicularly to the mucosa, show undulating contours and may appear flask-shaped Invasive adenocarcinoma consists of smaller and more variably sized glands arranged in a haphazard fashion Malignant glands have open round lumina and angulated contours and are more densely packed Nuclear enlargement, nuclear irregularity, hyperchromasia, loss of polarity, apoptotic cells, intraglandular necrosis with neutrophils, open lumina, perineural or vascular invasion are in favour of carcinoma when present Subtle nuclear grooves can be helpful in recognizing an extremely well differentiated adenocarcinoma

Well differentiated adenocarcinoma

Case 5 71 year old female Core biopsy cervical lymph node left neck Patient had lumpectomy for infiltrating duct carcinoma in 2010 FNAB had been performed and showed malignant cells with no cellular material available for ancillary techniques Magnification x 4

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Case 5 DIAGNOSIS Metastatic carcinoma Pathologist or resident Squamous cell carcinoma/ favour squamous cell carcinoma/ ?squamous cell carcinoma (do immunos) 2 Pathologists; 2 ? Positive for carcinoma. Poorly differentiated carcinoma, DDX: Metastatic IDC vs. other primary 1 pathologist; 1 Resident Metastatic carcinoma 1 ? Carcinoma. Will do ER, PR, CK7, CK20 1 Pathologist;1 Resident High grade non-lymphoid malignancy. Do immunos 2 Pathologists Malignant. Needs immuno 1 Resident Adenoca c/w ductal ca, pending stains 1 Pathologist

Case 5 Immunohistochemistry was performed and the tumour cells stained positive for P63 and negative for ER and Brst2 The report of the previous breast carcinoma was reviewed and was a low grade infiltrating duct carcinoma which was strongly ER positive

Case 5 The answer is: Squamous cell carcinoma

Case 5 Patient subsequently had a total thyroidectomy and left modified radical neck dissection Thyroid masses: Papillary carcinoma, tall cell variant, with extrathyroidal extension into muscle. Cervical lymph nodes: Metastatic papillary carcinoma to several lymph nodes. Matted together lymph nodes in neck: Anaplastic (undifferentiated) thyroid carcinoma, epithelioid pattern, with tumor giant cells and stromal eosinophilia associated with tall cell papillary carcinoma with extra-nodal extension Part of the undifferentiated component appeared squamoid