Spotlight – pathology

Case 5: Challenges of treating incidental synchronous bilateral breast cancer with differing tumour biology

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Q1: Breast carcinoma is defined as bilateral when a primary carcinoma develops in each breast. What pathological properties are seen in synchronous bilateral breast carcinoma (BBC)?

Synchronous BBC tends to be more often of lobular histological type, lower histological grade and hormone-receptor positive than unilateral breast cancer. 

However, substantial differences may exist in hormone receptor and HER2 status between the tumours in BBC in individual cases. Separate assessment of these parameters is recommended in routine practice. 

Source: MacGrogan G, Tot T, Rakha E, Morrow M; Bilateral breast carcinoma and non-synchoronous breast carcinoma, in WHO classification of tumours of the breast, 4th ed.,IARC, Lyon, 2012, p. 69-70

Q2: Nearly all invasive breast carcinomas enhance on gadolinium contrast-enhanced MRI. The sensitivity of breast MRI for breast carcinomas is between 88 and 100 percent. However, there are controversies in the use of MRI in breast cancer patients. What are the major problems in regard to the diagnostic use of MRI?

A major disadvantage is the limited specificity due to enhancement of benign breast lesions. In a meta-analysis of 44 studies evaluating patients with breast lesions, pooled specificity was 72 percent. Even using optimal MRI techniques, specificity is still insufficient to obviate the need for biopsy confirmation of an MRI abnormality. 

Available data has shown that preoperative breast MRI has not improved outcomes, overestimates the extent of disease, and has overall limited value. Additionally, the role of MRI to assess the contralateral breast is controversial and cannot be routinely recommended for the majority of women with a newly diagnosed breast cancer. 

Source: Esserman LJ, Joe BN ; Diagnostic evaluation of women with suspected breast cancer, Literature review current through: Aug 2016, this topic last updated: Mar 21, 2016 (accessed as of September 21, 2016) 

Q3: In which clinical scenarios is it appropriate to use breast MRI prior to therapy to assess contralateral disease?

High risk women — A contralateral breast MRI is reasonable for women with newly diagnosed breast cancer who are high risk for contralateral breast cancer, such as being carrier of a breast cancer gene mutation in BRCA 1 or BRCA 2 or is a first-degree relative of a known BRCA 1 or BRCA 2 mutation carrier or the patient was previously treated with radiation to the chest wall. In addition, if the patient has a personal history or a first-degree relative with Li-Fraumeni syndrome or one of the PTEN hamartoma tumour syndromes such as Cowden syndrome or the patient has an estimated lifetime risk of breast cancer of 20 percent or higher, as estimated using the BRCA-PRO model, used to identify women for breast cancer genetic testing, assessment with MRI could be considered. 

Issues related to breast reconstruction — Some surgeons prefer a preoperative MRI to assess the opposite breast in a woman undergoing significant reconstructive procedures such as a partial mastectomy with contralateral breast reduction or mastectomy with flap reconstruction. Surgical decisions should not be based on MRI findings alone. MRI findings alone should not be used to change surgical planning and conversion from breast conservation to mastectomy. All suspicious findings on MRI require pathologic confirmation.

Case 4: Inflammatory bowel disease-like colitis pathology in a patient with common variable immune deficiency

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Q1: Common variable immunodeficiency (CVID) can affect any level of the gastrointestinal tract. Which pathological features may be helpful in differentiating CVID from coeliac disease?

CVID and coeliac disease share a similar pattern of damage; villous blunting, crypt hyperplasia, and increased intraepithelial lymphocytes may be present. However, in CVID there is a lack of plasma cells, and there is no histological response to a gluten-free diet.

Coeliac disease is characterised by the presence of abundant plasma cells in the small intestinal mucosal biopsies, as well as improvement in response to a gluten free diet.

Source: Greenson JK, Lamps LW, Common Variable Immunodeficiency, in Diagnostic pathology. Gastrointestinal, [edited by] Joel K. Greenson, 2nd edition. Elsevier, 2016, p.244-47. 

Q2: A phenotypic approach to categorising common variable immunodeficiency (CVID) has been proposed, based upon the type of complications the patient develops. What are these five proposed phenotypic categories?

These proposed phenotypic categories are: 

  1. Patients with no complications
  2. Patients with autoimmune disease
  3. Patients with lymphocytic organ infiltration (i.e., lymphocytic enteropathy, granulomas, unexplained hepatomegaly, persistent lymphadenopathy, splenomegaly, and/or lymphoid interstitial pneumonitis); 
  4. Patients with predominant enteropathy
  5. Patients with lymphoid malignancy. 

Analysis of mortality showed a considerable reduction in the last 15 years, and that different phenotypes were associated with different survival times. 

Types of complications and clinical phenotypes varied significantly between countries, indicating the need for large, international registries. The only clinical predictor was polyclonal lymphocytic infiltration, which was associated with a 5-fold increased risk of lymphoid malignancy. There was widespread variation in the levels of serum immunoglobulin isotypes as well as in the percentages and absolute numbers of B cells, confirming the heterogeneity of these conditions. 

Source: Chapel H, Lucas M, Lee M, Bjorkander J, Webster D, Grimbacher B, Fieschi C, Thon V, Abedi MR, Hammarstrom L; Common variable immunodeficiency disorders: division into distinct clinical phenotypes., Blood. 2008;112(2):277. 

Q3: Gastrointestinal disease is identified in approximately 10 to 20 percent of CVID patients and may be the presenting disorder in some. Diarrhoea is the most common symptom, with malabsorption and weight loss also reported. Vitamin and electrolyte deficiencies may be seen in severe cases. What are the major gastrointestinal disorders in adult patients with CVID (in decreasing order of prevalence)?

  • Inflammatory bowel-like disease, which may resemble ulcerative colitis, ulcerative proctitis, Crohn’s like disease, or microscopic colitis
  • Celiac-like illness with flat villi
  • Nodular lymphoid hyperplasia
  • Pernicious anaemia
  • Bacterial overgrowth
  • Protein-losing enteropathy
  • Nonspecific malabsorption
  • Gastrointestinal lymphoma. 

Source: Ahn S, Cunningham-Rundles C, ; Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults, Literature review current Aug 2016, this topic last updated: Apr 25, 2016, (accessed as of September 21, 2016)

Case 3: Mistaken identity: endometrial or rectal cancer?

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Q1: Which types of endometrial cancers are biologically more aggressive and ‘high grade’?

Endometrial carcinomas defined as serous or clear cell are high grade cancers. Pathologic features of these aggressive carcinomas are absence of oestrogen and progesterone receptors, but having p53 positivity. These cancers are often aneuploid with c-myc gene amplification.

Endometrial carcinoma is graded pathologically in a three tier system; i.e. grade 1 to 3, depending on microscopic features. The presented case had an endometrial adenocarcinoma of grade 2 following microscopic pathologic assessment.

Source: Bitterman P., Reddy V.B. ; Female reproductive system, in Differential Diagnosis in Surgical Pathology, 3rd edition, Elsevier, 2015, p. 627.

Q2: The presented case emphasises the importance of clinicopathologic cooperation. In addition to the clinical findings and histopathologic appearances, what immunostains may help in differentiating a colorectal carcinoma from endometrial adenocarcinoma?

In primary endometrial carcinoma, vimentin, cytokeratin 7, oestrogen receptors are often positive, CDX2 may be positive in a small number of cases, CEA and cytokeratin 20 are negative.

In colorectal carcinoma, vimentin, cytokeratin 7 are negative, cytokeratin 20, CDX2 and CEA are often positive in colorectal carcinomas.

Source: McCluggage W,G.; My approach to and thoughts on the typing of ovarian carcinomas. J Clin Pathol 61:152-163, 2008.

Q3: How might an endometrial adenocarcinoma be pathologically differentiated from an endocervical adenocarcinoma infiltrating the uterine cavity?

Morphological differences are helpful but a precise differential diagnosis is also supported by immunostains.

Vimentin is often positive and CEA is negative in endometrial adenocarcinomas (except for the mucinous variant) whereas endocervical adenocarcinomas have the vice versa. Additionally, p16 is generally positive in cervical adenocarcinomas reflecting their HPV related origin.

CDX2 is also a marker commonly positive in cervical adenocarcinomas but in small number of cases in endometrial adenocarcinomas.

Source: Bitterman P., Reddy V.B. ; Female reproductive system, in Differential Diagnosis in Surgical Pathology, 3rd edition, Elsevier, 2015, p. 619, 627

Case 2: Malignant gastric lymphoma with spontaneous perforation

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Q1: What is the “biological agent” recognised as a causative agent in both gastric adenocarcinomas and lymphomas?

First discovered as causing peptic ulcers, Helicobacter pylori is also a carcinogenic agent implicated in the genesis of both gastric adenocarcinomas and gastric lymphomas. 

In gastric cancers, the pathogenesis of H. pylori is multifactorial; which includes chronic inflammation and reparative gastric cell proliferation. H. pylori pathogenicity genes, such as CagA, also may contribute by stimulating growth factor pathways. 

Chronic H. pylori infection leads to polyclonal B-cell proliferations that may give rise to a monoclonal B-cell tumour (lymphoma) of the stomach, as a result of accumulation of mutations. 

Source: Kumar V., Abbas AK., ASter J.C., Robbins and Cotran Pathologic Basis of Disease, 9th edition, Elsevier, 2015, p.329 

Q2: In this case, a gastric diffuse large cell B lymphoma is presented. What is the other type of lymphoma commonly observed in the stomach that has a better prognosis?

The other type of lymphoma commonly seen in the stomach is extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (also known as MALToma, MALT-type lymphoma, or MALT lymphoma). It accounts for 38-48% of gastric lymphomas, and is classified as a type of low-grade B cell lymphoma. 

Source: Freedman, A.S., Lister, A., Connor R.F. ; Clinical presentation and diagnosis of primary gastrointestinal lymphomas,, Literature review current through: Aug 2016. | This topic last updated: May 21, 2015., (accessed as of September 9, 2016) 

Q3: Is there any pathological finding which differentiates extranodal marginal zone lymphoma of gastric mucosa from its counterpart nodal marginal zone B cell lymphoma of lymph nodes

Cytogenetic analysis demonstrating the presence of t(11;18)(q21;q21) can help in differentiating low-grade gastric MALT lymphomas from their nodal counterparts (marginal zone lymphomas). They are otherwise identical in their morphology and immunophenotype. 

Such a differentiation is currently not possible with regard to many other forms of gastrointestinal lymphomas, for example, diffuse large B cell gastric lymphoma from a nodal diffuse large B-cell lymphoma (DLBCL).

Source: Rosenwald A, Ott G, Stilgenbauer S, et al. Exclusive detection of the t(11;18)(q21;q21) in extranodal marginal zone B cell lymphomas (MZBL) of MALT type in contrast to other MZBL and extranodal large B cell lymphomas. Am J Pathol. 1999;155(6):1817–1821.

Case 1: Dual pathology of the submandibular gland: plasmacytoma and pleomorphic adenoma

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Q1: What are pleomorphic adenomas also known as, and what is the reason for this?

Pleomorphic adenomas are also known as mixed tumours. This is because they are characterised by the proliferation of ductal (epithelial) cells and myoepithelial cells within a varied stroma.

It has also been suggested that a single cell with the capacity of differentiation toward either epithelial or myoepithelial cells may be responsible for these tumours.

Reference: Oral Pathology, Clinical Pathologic Correlations, 7th Edition, JA Regezi, JJ Sciubba, RCK
Jordan p.349, Elsevier.

Q2: Why is enucleation not a recommended treatment for pleomorphic adenomas within the parotid gland?

Enucleation within the parotid gland is not recommended as it carries a high risk of disease recurrence. This is because the tumour can extend through the defects in its own pseudocapsule, making complete removal difficult.

Superficial parotidectomy (lateral lobectomy) is the most appropriate management for tumours arising within the parotid. Resection of the submandibular gland is the preferred treatment in this location. Tumours located in the palate or gingiva often involve or abut periosteum or bone, making complete removal difficult, unless some bone is removed.

Reference: Oral Pathology, Clinical Pathologic Correlations, 7th Edition, JA Regezi, JJ Sciubba, RCK
Jordan p.349, Elsevier.

Q3: This case presents a patient with an extramedullary plasmacytoma within the parotid gland. Comment on the prognosis, with respect to this finding.

A plasma cell tumour within a soft tissue (as was presented in this case) is known as an extramedullary plasmacytoma. They typically carry a good prognosis – wide dissemination is rare and they typically show no preference for active hematopoietic sites.

In contrast to solitary plasmacytoma of bone, it is very uncommon for extramedullary plasmacytomas to progress to myeloma. Extramedullary plasmacytomas are also radiosensitive, and regional control rates of 80% can be achieved.

Reference: Oral Pathology, Clinical Pathologic Correlations, 7th Edition, JA Regezi, JJ Sciubba, RCK
Jordan p.399, Elsevier