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How to Screen for Hereditary Cancers in General Pathology Practice.

Five percent to 10% of cancer has an inherited basis.1 This can generally be identified through phenotypic analysis and other medical history regarding age of onset, number and type of tumors, and family history. In assessment of a patient's tumor for the possibility of an inherited basis, the pathologist may play an essential role. Although clinical characteristics and family history are often unavailable, the pathologist is a point of contact for all patients with newly diagnosed cancer to tertiary care. Pathologists have access to cancer histories that span multiple, often disparate, specialties and often back through several decades and thus are uniquely situated to recognize suspicious cancer histories. The role of the pathologist in diagnosing patients and families with potential hereditary cancer syndromes cannot be understated.

Regardless of the clinical context in which a tumor arose, clear genotype-phenotype relationships that can be recognized as harbingers for potential underlying cancer predispositions should flag the consideration for genetic assessment (Table). The discussion presented herein is not exhaustive of tumor types that are associated with hereditary cancer syndromes. Furthermore, there are situations in which the a priori likelihood of a hereditary cancer syndrome is increased, as in cases with multiple primaries known to be associated with a syndrome, such as endometrial cancer and colon cancer in the same patient, in individuals with rare tumors such as pheochromocytoma, or paraganglioma, or otherwise common malignancies such as basal cell carcinomas when present in strikingly elevated numbers, or those with uncharacteristically early ages of onset. In general a flag should be raised whenever there is a reasonable likelihood of an inherited or constitutional genetic association or when the genetic information may impact treatment choices or management. In the past this threshold has been greater than 10%; however, if there is treatment utility, an argument can be made for always raising the awareness for a potential association. This can aid the primary care physician as a reminder to further assess other important phenotypic elements that may, or may not, be cancer related in the personal or family history, but may provide supportive evidence for an underlying inherited predisposition.

With the advent of massively parallel (next-generation) sequencing, there has been an opportunity to understand the molecular landscapes of tumors. Furthermore, studies examining tumor evolution have allowed the elucidation of the early and late genomic aberrations that act as drivers in tumorigenesis. These studies have been particularly illuminating in the recognition of recurrently mutated pathways acting in the early stages of tumorigenesis, which demonstrate overlaps between the known hereditary cancer genes and early driver mutations, revealing aberrant molecular pathways important with regard to development of both hereditary and sporadic cancer.

Recognition of recurrently mutated genes and pathways that can be associated with particular tumor phenotypes is important. It not only aids in targeted clinical assessment of an underlying genetic predisposition but may also help direct research candidate gene assessment and identification of the molecular basis of disease, and consideration for targeted therapies in trials directed toward underlying molecular lesions as compared with those targeting histologic phenotypes. Critical to this understanding is the concept that the development of cancer occurs on a continuum. Within this continuum, hereditary cancer exists on one end of the spectrum with the patient being born with the first mutation, which was either inherited or that occurred postzygotically, very early on in embryogenesis and therefore is present in all or a portion of all nucleated cells of the body. On the other end of the spectrum is a cancer arising from a mutation in the same gene that was acquired later in life and therefore is only found within that cell and its descendants.

Herein we provide a brief review of several tumor types, which should ideally trigger consideration for genetic assessment for an underlying tumor predisposition. We briefly review the genetics and the key features and highlight the importance of the observation and documentation by the pathologist to flag these considerations for the primary care physician.


Ovarian High-Grade Serous Carcinoma

Genes: BRCA1 and BRCA2 Chromosome: 17q21.31 and 13q13.1 Mode of inheritance: Autosomal dominant Syndrome: Hereditary breast and ovarian cancer

Hereditary breast and ovarian cancer is characterized by a predisposition to premenopausal breast cancer in females, with the triple-negative (estrogen receptor/progesterone receptor negative [ER-/PR-] and human epidermal growth factor receptor 2 negative [HER2/neu-]) phenotype more commonly associated with germline mutations in BRCA1 than BRCA2, although both can be seen (2); ovarian cancer; male breast cancer (3); prostate cancer (4); pancreatic cancer (5); and risks of other less commonly associated cancers. (6)

Rate of Somatic Mutations in Unselected Tumors.--In 2011, The Cancer Genome Atlas Project reported germline and somatic mutation frequencies in 316 cases of high-grade serous ovarian cancer as 8.5% (27 of 316) and 3.5% (11 of 316), and 7.9% (25 of 316) and 3.2% (10 of 316), for BRCA1 and BRCA2, respectively. (7) Further analysis of the 287 overlapping cases and an additional 142 cases revealed germline truncating variants and large deletions across Fanconi pathway genes in 20% of cases. (8)

Key Histologic Features.--High-grade serous (HGS) is the most common histologic subtype of ovarian carcinoma. Many different histologic patterns exist; immunohistochemistry for mutated p53 (strong uniform, or total loss of expression) may be helpful in establishing a diagnosis (Figure 1).

Genetic Heterogeneity.--Studies of germline genetic assessment of individuals with epithelial ovarian cancer have revealed a high underlying rate of germline BRCA1 and BRCA2 mutations, which is even higher if only considering the rate in HGS subsets. (9-11) Reports of large patient cohorts have demonstrated that germline BRCA1 and BRCA2 mutation status is not restricted to ovarian cancer reported as HGS. (9) Thus, the National Comprehensive Cancer Network (NCCN) recommends that all women diagnosed with invasive ovarian cancer, including fallopian tube and primary peritoneal, be referred for genetic assessment. (12) This is also important considering that endometrioid and clear cell ovarian carcinoma subtypes have been associated with Lynch syndrome and should also raise suspicion in this regard. (13-15) Genetic predisposition to ovarian cancer has also been shown to extend beyond these aforementioned genes, to BARDI, BRIP1, CHEK2, MRE11A, MSH6, NBN, PALB2, RAD50, RAD51C, and TP53,11 the extent and clinical significance of which continues to be investigated. Validation case-control studies suggest that there may be benefit in undertaking genetic assessment for RAD51D, RAD51C, and BRIP.16,17

Clinical Utility.--Beyond the classical cancer prevention and early disease detection reasoning as to why it is important to diagnose cancer susceptibility, there are potentially more immediate treatment implications. The genetic lesions that lead to defective DNA repair can be targeted by use of platinum-based therapies and poly ADP-ribose polymerase (PARP) inhibitors, which act by means of synthetic lethality in the cancer cells. (18) PARP inhibitors have been approved for use in patients with advanced ovarian cancer with germline BRCA1 and BRCA2 mutations after studies showed improved progression-free survival. (19) Furthermore, it is proposed that cancers associated with other genes implicated in DNA repair may also respond to the same targeted treatment strategies. (20) In addition there is utility in identification of ovarian cancer related to Lynch syndrome, which has potential implications with regard to immune modulator therapies currently being investigated in tumors with mismatch repair deficiencies. (21)

In summary, without knowing additional clinical information, a pathologist could flag the consideration of genetic assessment in the following groups related to hereditary breast and ovarian cancer: all invasive epithelial ovarian cancers, all male breast cancers, and triple-negative breast cancer diagnosed in patients younger than 60 years, in line with current NCCN guidelines (12) that recommend consideration for BRCA1 and BRCA2 genetic testing in these settings.

Medullary Thyroid Carcinoma

Gene: RET Chromosome: 10q11.21 Mode of inheritance: Autosomal dominant Syndrome: Multiple endocrine neoplasia type 2

Activating germline mutations in RET predispose to multiple endocrine neoplasia type 2 (MEN 2), which is characterized by a high risk for development of medullary carcinoma of the thyroid. The syndrome is subdivided into 3 subtypes: MEN2A, familial medullary thyroid carcinoma (FMTC), and MEN2B. (22) There are also additional risks for pheochromocytoma (MEN2A and MEN2B) and parathyroid adenoma or hyperplasia (MEN2A). Genotype-phenotype correlations exist that help predict potential onset of disease and guide recommendations for surveillance and total thyroidectomy risk-reduction surgery. (23) Risk for medullary thyroid carcinoma (MTC) occurs as early as the first year of life. Thus, recognition of this syndrome is critical; therefore, genetic testing of RET is recommended in patients with a history of MTC, primary C-cell hyperplasia, or clinical features of MEN2 or FMTC. (23)

Germline mutations occur in 20% to 30% of medullary thyroid cancers, (24) with implications for the patient and family. Offering genetic testing on the basis of a family history consistent with MEN2A, MEN2B, or FMTC does not detect all hereditary cases, emphasizing the importance of recognition of the association. Germline mutations in RET were identified in 6% and 7.7% of cases of apparently sporadic MTC. (25,26) Dvorakova et al (25) found that 48% of nonhereditary cases were accounted for by somatic RET mutations, indicating the specificity of the tumor phenotype for underlying genotype.

Key Histologic Features.--These tumors show neuroendocrine nuclear features. The cells can be somewhat spindled to plasmacytoid. Immunohistochemistry for calcitonin may be helpful in diagnosis (Figure 2).

Clinical Utility.--Tyrosine kinase inhibitors have shown utility in treatment of this disease, indicating that peridiagnostic molecular testing for germline and somatic RET mutation status has important implications for both treatment and preventative management for the patient and family. (27)

Choroid Plexus Carcinoma

Gene: TP53 Chromosome: 17p13.1 Mode of inheritance: Autosomal dominant Syndrome: Li-Fraumeni syndrome

Li-Fraumeni syndrome (LFS) is associated with a high lifetime risk of multiple primary cancers including soft tissue sarcoma, osteosarcoma, premenopausal breast cancer, brain tumors, adrenocortical carcinoma (ACC), and leukemias. (28) There is a significant risk for childhood and young adult cancer. Recent focus has been on establishing the utility of investigational cancer screening protocols that use whole-body magnetic resonance imaging. (29-31)

Key Histologic Features.--Typical choroid plexus carcinomas (CPCs) show variable morphology with a syncytial or solid arrangement. Focal papillary architecture may be present. These tumors exhibit frankly malignant histologic features with marked cytologic atypia, nuclear pleomorphism, and hyperchromasia, and high mitotic activity (Figure 3, A and B).

Choroid plexus carcinoma is associated with germline mutations in TP53.32 Tabori et al (33) identified somatic TP53 mutations in 18 of 36 CPCs (50%), and germline TP53 mutations in 8 of 18 patients with CPC (44%), all of whom had an LFS-suggestive family history. (33) Gozali et al (34) conducted a retrospective review of choroid plexus tumors managed over a 20-year period at a single center and found that 6 of 42 patients (14.3%) had conditions suggestive of LFS on history, with a 36.4% mutation detection rate in those tested for germline mutations. Becherini et al (35) identified a paternally inherited germline TP53 mutation associated with CPC in a 3-month-old boy, with no significant family history. In light of these and other data, the 2009 Chompret criteria for germline TP53 mutation screening were revised to reflect the association, such that patients with ACC or choroid plexus tumor are screened for germline mutations in TP53, irrespective of family history. (36)

Adrenocortical Carcinoma

As noted in the Li-Fraumeni testing criteria, ACC is another Li-Fraumeni syndrome-associated tumor that should alert the pathologist to relay the significant underlying risk for a TP53 mutation. Varley et al (37) found the rate of germline mutations in TP53 to be greater than 80% (9 of 11) for pediatric patients with ACC. Raymond et al (38) found that patients with ACC unselected for age or family history had a TP53 mutation detection rate of 7.5% (n = 4 of 53 who had consented to genetic testing).

Key Histologic Features.--The diagnosis of ACC can often be challenging. The presence of metastasis may be the only feature of malignancy. These tumors can often feature bizarre, anaplastic-appearing tumor giant cells.

Genetic Heterogeneity.--Adrenocortical carcinoma can also occur in patients with Lynch syndrome. Raymond et al (39) found the prevalence of Lynch syndrome among adult patients with ACC to be 3.2%. Analysis of 4 ACC tumors with known germline mutations showed that they were microsatellite stable but demonstrated abnormal immunohistochemistry (IHC) consistent with the germline mutations. (39) These data indicate the potential utility in IHC assessment of ACC to screen for Lynch syndrome.

Subependymal Giant Cell Astrocytomas

Gene: TSC1 and TSC2 Chromosome: 9q34.13 and 16p13.3 Mode of inheritance: Autosomal dominant Syndrome: Tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is a multisystem tumor predisposition syndrome resulting from abnormal mammalian target of rapamycin (mTOR) signaling. Tuberous sclerosis is characterized by developmental abnormalities and tumors of the skin, central nervous system, kidney, heart, and lungs. (40) Seizures are common and half of individuals may have intellectual disability or developmental delay. (40) Clinical diagnosis of TSC can be made on the presence of major and minor clinical features. (40) Subependymal giant cell astrocytomas (SEGAs) are a major feature of TSC. They are generally slow-growing glioneuronal tumors that occur in 10% to 15% of individuals with TSC and arise from subependymal nodules, found in 80% of individuals with TSC. (40)

Key Histologic Features.--Subependymal giant cell astrocytomas are characterized by the presence of small, spindle-shaped or elongated cells often arranged in fascicles admixed with intermediate-sized polygonal or "gemistocyte-like" cells and globoid or "ganglion-like" cells. Occasional mitoses, moderate atypia, focal necrosis, or vascular hyperplasia do not portend a worse prognosis (Figure 4, A and B).

Clinical Utility.--Targeting the underlying molecular defect in SEGA with mTOR inhibitors has revolutionized care for patients with TSC and is now included as an option in the current management guidelines. (41) Recent data suggest everolimus is safe and effective in the long-term treatment of SEGAs associated with TSC. (42)

Multiple Hemangioblastomas

Gene: VHL Chromosome: 3p25.3 Mode of inheritance: Autosomal dominant Syndrome: von Hippel-Lindau syndrome

von Hippel-Lindau (VHL) syndrome is a tumor predisposition syndrome characterized by retinal, brain, and spinal cord hemangioblastomas; clear cell renal cell carcinoma; pheochromocytoma; neuroendocrine tumors; endolymphatic sac tumors; and epididymal cysts and cysts of the kidneys, pancreas, and broad ligaments. (43) Screening for VHL-associated tumors and manifestations begins in childhood.

Key Histologic Features.--Hemangioblastomas are highly vascular tumors. The neoplastic component corresponds to stromal cells found between the vascular channels lined by a single layer of endothelium. These stromal cells exhibit bland, sometimes bizarre and degenerative-appearing nuclei and ample, vacuolated, and clear cytoplasm containing mainly lipids (Figure 5, A and B).

Hemangioblastomas are benign tumors that are a canonical feature of VHL and occur in most patients, (44) such that individuals with 2 or more hemangioblastomas of the retina, spine, or brain, or a single hemangioblastoma in association with other visceral VHL manifestations, should be offered genetic assessment. (43)

Combined Nevus

Gene: BAP1 Chromosome: 3p21.1 Mode of inheritance: Autosomal dominant Syndrome: BAP1 tumor predisposition syndrome

BAP1 tumor predisposition syndrome has been recently identified and is yet to be fully elucidated. Thus far, it is associated with a significantly increased risk for multiple primary cancers including uveal melanoma, renal cell carcinoma, malignant mesothelioma, and cutaneous melanoma. (45) Benign pigmented skin lesions similar to atypical Spitz tumors are seen on the head and neck, trunk, and limb in 72% of mutation carriers. (45,46)

Key Histologic Features.--Atypical Spitz tumors resemble intradermal epithelioid tumors, usually with atypical melanocytes with nuclear pleomorphism and hyperchromatic nuclei similar to nevoid melanomas; however, unlike Spitz nevi, the nuclei of atypical Spitz tumors are more hyperchromatic and do not contain Kamino bodies, epidermal hyperplasia, or clefting around junctional melanocytic nests. (47) Atypical Spitz tumors are characterized by biallelic inactivation of BAP1 and frequent BRAF V600E mutation; therefore, IHC forBAP1 and mutant BRAF V600E may be of utility. (46) Figure 6, A and B, demonstrates a melanocytic proliferation with 2 distinct appearances suggestive of a combined nevus.

On review of the clinical features of families identified to date, Rai et al (45) conclude that genetic assessment and testing for BAP1 mutations should be considered in patients with 2 or more of the associated tumors in themselves and/or first-or second-degree relatives.

Sebaceous Cell Carcinoma

Gene: MSH2, MLH1, MSH6 Chromosome: 2p21-p16, 3p22.2, 2p16.3 Mode of inheritance: Autosomal dominant Syndrome: Muir-Torre syndrome, variant of Lynch syndrome

Lynch syndrome is associated with an increased risk for colon cancer and cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, urinary tract, brain, and skin.48 It is caused by mutations in, or affecting expression of, the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM [through loss of expression of MSH2]). Lynch syndrome-associated tumors exhibit loss of corresponding mismatch repair (MMR) proteins and microsatellite instability.

Muir-Torre syndrome is a variant of Lynch syndrome, characterized by the combination of sebaceous neoplasms of the skin and 1 or more internal malignancies. Most patients harbor germline mutations in the MSH2 gene, less than 10% have germline mutations in the MLH1 gene, and there are several reports of patients with Muir-Torre syndrome and germline mutations in the MSH6 gene. (49)

Key Histologic Features.--Sebaceous carcinoma features nuclear atypia and frequent mitotic activity with identifiable sebaceous differentiation (Figure 7).

Everett et al (50) conducted a review of tumor IHC testing and germline genetic testing in 86 patients with sebaceous neoplasms to determine the clinical utility of IHC testing in diagnosis of Lynch syndrome and found IHC to correctly identify 13 of 16 MMR mutation carriers, resulting in an 81% sensitivity. Fifty-two percent of MMR mutation carriers did not meet clinical diagnostic criteria for Lynch syndrome, and 11 o (f 25 (44%) did not meet the clinical definition) of Muir-Torre syndrome, suggesting potential utility in universal IHC screening of sebaceous neoplasms. This view is in contrast to previous studies that concluded that screening for Lynch syndrome, using IHC on sebaceous neoplasms, may not be effective owing to the common occurrence of aberration of the MMR pathway in sebaceous neoplasms (42%). (51-53) In light of the collective data, Everett et al (50) suggested that clinical genetics evaluation should be undertaken for patients with abnormal IHC test results, normal IHC test results with personal or family history of other Lynch syndrome-associated neoplasms, and/or multiple sebaceous neoplasms. (50)

Medulloblastoma With Extensive Nodularity

Gene: PTCH1 Chromosome: 9q22.32 Mode of inheritance: Autosomal dominant Syndrome: Nevoid basal cell carcinoma syndrome/Gorlin syndrome

Nevoid basal cell carcinoma syndrome (NBCCS) is characterized by multiple jaw keratocysts, basal cell carcinomas, macrocephaly, facial milia, skeletal anomalies, and ectopic calcification of the falx. (54) Medulloblastoma of the desmoplastic subtype occurs in approximately 5% of all children with NBCCS. More recently, Smith et al (55) reported SUFU mutations in families with classic Gorlin syndrome, without odontogenic jaw keratocysts. The authors reported a risk for medulloblastoma up to 20 times higher in SUFU mutation-positive individuals. Brugieres et al (56) reported SUFU germline mutations in 7 of 10 patients with medulloblastomas who were younger than 3 years of age at diagnosis, with desmoplastic/medulloblastoma with extensive nodularity.

Key Histologic Features.--Medulloblastomas with extensive nodularity are tumors recognized primarily by their overall primitive, embryonal appearance and an expanded lobular architecture made of nodules composed of cells with a uniform neurocytic appearance and reduced nuclear to cytoplasmic ratio, embedded in a fibrillary neuropil-like matrix. The internodular component is made of densely packed, mitotically active primitive-appearing cells and may be focally absent in this histologic variant of medulloblastoma.

Identification of germline status is important with regard to anticipatory guidance, screening recommendations, avoidance of radiation and with regard to utility of sonic hedgehog inhibitors such as vismodegib to treat basal cell carcinomas in germline PTCH1 mutation carriers.


Within recent years molecular tumor phenotyping has erupted on the oncology scene and has, in some cases, redefined tumor classifications and our understanding of the driving molecular events related to pathogenesis. An example has been the reclassification of gastric cancer with the elucidation of the relationship with Epstein-Barr virus. (57) There has been a movement toward molecular tumor phenotyping to identify targetable driver lesions. Identification of targeted therapies can potentially improve cancer treatment by specifically targeting the aberrant pathways driving the tumors.

With a greater understanding of the germline pathogenic, genetic, and genomic changes and the association of tumor histology with these changes, we have been able to select cohorts that have a higher likelihood of being associated with a germline predisposition. This is important because it has implications for the patient with regard to secondary cancers and also with regard to primary prevention in family members, such that cascade carrier testing for the familial mutation can be undertaken. More recently, new therapeutic options have shown benefit in groups such as the hereditary cancers associated with germline mutations in BRCA1 and BRCA2 and in applying immune modulator therapy to tumors that have mismatch repair deficiency, (21) thus the benefits of identifying these individuals peridiagnostically has become apparent.

Institutions are now conducting tumor sequencing to identify targetable genetic lesions peridiagnostically. In some cases, institutions are also conducting germline DNA sequencing alongside tumor sequencing to aid in their ability to accurately assign variants as being only tumor specific as opposed to inherited in the germline. (58,59) This is important to note, as TP53 mutations are some of the most common mutations identified in somatic cancers. Even though they are less frequently identified in the germline DNA, tumor-only analysis raises the potential for an inherited susceptibility that can really only be dismissed if analysis of normal tissue is undertaken. Likewise, an assessment for inherited cancer risk can only be undertaken with normal tissue. Thus, patients are being consented accordingly. As a secondary outcome, it is possible to detect previously unrecognized associations that may have therapeutic relevance but would certainly have potential preventative implications for the patients and their family. As tumor sequencing has also become available in the pediatric setting, it has challenged previous paradigms with regard to the avoidance of testing adult-onset conditions in childhood, as this information is potentially available for return. Furthermore, it has revealed previously unrecognized associations, with potential therapeutic implications for the child with the tumor, that broaden our understanding of the classically understood syndromes. (60) Care will need to be taken with regard to revealing the mutation status of adult-onset conditions in children when not of immediate need or treatment relevance to the child. Of critical importance will be the consent for such analyses. Thus, these studies will broaden the molecular landscape of known hereditary cancer genes and phenotypes; however, the role of the pathologist to phenotypically characterize the tumors will continue to be vital.

Assignment of pathogenicity to somatic variants is challenging, let alone consideration of the assignment of pathogenicity to germline variants. Tumors vary in the number of somatic mutations per case; however, in general the most highly mutated cancers relate to ultraviolet exposure, such as skin cancer or those that have developed in the setting of clear DNA damaging agents or carcinogens. Germline genetic variation is vast and remains largely unique to individuals. Several public efforts are ongoing to amass sequencing data in order to understand the full spectrum of "normal" variation; however, apart from the 1000 Genomes Project, (61) these are still developing and other factors relating to access to genomewide sequencing is variable and not fully representative of ethnicities beyond those represented by mainly Western countries. Tumor sequencing invariably identifies variants of uncertain significance. Generally, the best way to sort out variant pathogenicity is to understand the phenotypic context. This is where the role of pathology will always remain critical to the characterization of tumor phenotype. Tools that can assess protein expression and cellular localization, RNA splicing and expression, and histologic architecture all remain critical to help infer variant pathogenicity. Retention of the variant and loss of heterozygosity for the wild-type allele or second somatic hits can theoretically provide support for pathogenicity of variants of uncertain significance. Furthermore, segregation of the variants in individuals with cancer within a family is particularly useful. For example, a variant of uncertain significance seen in multiple individuals with cancers with signet ring cell phenotypes with loss of E-cadherin on immunohistochemistry and not in a significant proportion of unaffected controls, may help infer potential pathogenicity of a CDH1 variant of uncertain significance. This is in accord with the most recent standards and guidelines for the interpretation of sequence variants from the American College of Medical Genetics and Genomics, which provide weight to the phenotypic context and the frequency of variants in cases as compared to controls, in addition to other measures of variant pathogenicity. (62) With this in mind, care must be taken not to overinterpret the pathogenicity of a variant of uncertain significance only because it is seen in the context of a particular tumor type, in consideration of any potential ascertainment biases from sequencing tumor cohorts. An exciting area of study is the potential to infer variant pathogenicity from understanding the functional readouts or biologic effects of established pathogenic variants. In future, this area of study combined with somatic analysis of the wild-type allele and generalized mutational signatures, may help determine whether a variant of uncertain significance is actually pathogenic. For example, an MMR-deficient profile of the tumor by immunohistochemistry or microsatellite instability testing may support evidence for pathogenicity of a variant of uncertain significance in an MMR gene.

It is important to understand that tumor sequencing is not infallible and can miss mutations, that is, it has a false-negative rate and therefore it is important to consider the phenotype as being the harbinger for an underlying aberration of a pathway in which the actual germline or somatic mutation has not yet been identified, but for which treatment of that molecular pathway may have utility. This is also extremely important with regard to the germline aspect and the degree to which mutational analysis of known genes is undertaken to try to define a genetic basis, an example being newly defined mutations in previously untested genomic regions that account for portions of familial adenomatous polyposis cases, such as promoter 1B deletions in the APC (adenomatous polyposis coli) gene. (59)

The a priori likelihood of an underlying germline mutation may be high depending on the histologic phenotype of a tumor or may increase with further investigations that demonstrate loss of protein or function of a particular pathway. Regardless, the possibility of an underlying hereditary cancer syndrome associated with 5% to 10% of cancers should be raised with every patient at the time of initial assessments and family history gathering. Further education of patients as to this potential possibility is an increasingly important aspect of a discussion regarding cancer and potential outcomes of tumor assessment (including histopathologic assessment with the potential of further ancillary tests). As our ability to determine the actual genomic architecture of tumors becomes more widespread, communication of these risks will be an essential part of the consent for tumor sequencing, with regard to potential treatment options and eventually future risk of cancer and implications for family members.

Finally, although tumor sequencing may eventually become more widely accessible, it is not currently available at all institutions and therefore in the setting of hereditary cancer, the task is for the pathologist to recognize suspicious phenotypes that can be associated with particular hereditary cancer syndromes in order to flag these cases to be referred on for genetic assessment by a genetic counselor, geneticist, or physician experienced and specialized in hereditary cancer predisposition. Communication of the potential need for further genetic assessment will need to be carefully worded so as not to imply diagnosis of an underlying genetic syndrome, but rather, that further evaluation is appropriate based on the known association of the particular tumor type and the syndrome. This is important for reasons of accuracy and to also not preempt a diagnosis for an individual, which may have discriminatory repercussions.


Participation of the pathologist in hereditary cancer screening is vital. There are 2 main ways that a pathologist can assist in the detection of hereditary cancers. First, by recognizing and drawing attention to the association between rare tumor types and predisposition syndromes--several of which are highlighted above. Second, by performing ancillary studies such as MMR IHC with specific screening value. Typically, when a laboratory is prepared to engage in a screening program such as MMR IHC, this will be associated with a reflex referral to a hereditary cancer program when an event such as MMR deficiency is encountered. Screening by morphology alone is less structured and will have more variation from practice to practice.

The intention of this article is to raise awareness regarding the benefit of a comment suggesting hereditary cancer referral (regardless of whether or not the actual referral takes place). Pathologists should be encouraged to raise this possibility whenever they have a concern, particularly in the settings described above. Pathologists are uniquely positioned with an overview of a patient's illness and have a responsibility to use this position to direct care to the best of their abilities. Raising the possibility of an inherited cancer predisposition is just one of the ways that pathologists can make a difference in patient care on a daily basis.


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Brandon S. Sheffield, MD; Veronica Hirsch-Reinshagen, MD; Kasmintan A. Schrader, MBBS, PhD, FRCPC

Accepted for publication May 18, 2016.

From the Departments of Laboratory Medicine and Pathology (Drs Sheffield and Hirsch-Reinshagen) and Medical Genetics (Dr Schrader), University of British Columbia, Vancouver, British Columbia, Canada.

The authors have no relevant financial interest in the products or companies described in this article.

Portions of this work were presented at the Canadian Anatomic and Molecular Pathology Conference; January 29-30, 2016; Whistler, British Columbia, Canada.

Reprints: Kasmintan A. Schrader, MBBS, PhD, FRCPC, Department of Medical Genetics, The University of British Columbia, 614-750 W Broadway, Vancouver, BC V5Z 1H5, Canada (email: ischrader@

Please Note: Illustration(s) are not available due to copyright restrictions.

Caption: Figure 1. Ovarian high-grade serous carcinoma. Typical hematoxylin-eosin appearance of high-grade serous carcinoma (original magnification X200). Photo courtesy of A. Karnezis, MD, PhD, FRCPC, (British Columbia Cancer Agency).

Caption: Figure 2. Medullary thyroid carcinoma. Typical appearance of a medullary thyroid carcinoma invading thyroid parenchyma (hematoxylin-eosin, original magnification X200).

Caption: Figure 3. Choroid plexus carcinoma. A, Low-power view of a choroid plexus carcinoma shows focal papillary areas admixed with sheetlike architecture. Necrosis is present. B, Neoplastic cells in this case show mild to moderate pleomorphism and very high mitotic activity (hematoxylineosin, original magnifications X100 [A] and X400 [B]).

Caption: Figure 4. Subependymal giant cell astrocytomas. A, Low-power magnification shows a mass composed of gemistocytic-like cells arranged in nests separated by dense fibrillary septae. B, On higher magnification, the neoplastic cells show abundant glassy cytoplasm with large vesicular nuclei and prominent nucleoli (hematoxylin-eosin, original magnifications X100 [A] and X400 [B]).

Caption: Figure 5. Hemangioblastoma. A, Low-power view of a hemangioblastoma shows a highly vascular tumor with thin-walled vascular channels and intervening neoplastic stromal cells. B, Neoplastic stromal cells exhibit a characteristically vacuolated, clear, and ample cytoplasm associated with bland nuclei (hematoxylin-eosin, original magnifications X100 [A] and X400 [B]).

Caption: Figure 6. Nevus with absent BAP1 staining. A, Melanocytic proliferation with 2 distinct appearances suggestive of a combined nevus. B, BAP1 immunohistochemical stain showing loss of nuclear staining in 1 component of the nevus, with retained staining in the other component and background cells (hematoxylin-eosin, original magnification X100 [A]; original magnification X100 [B]).

Caption: Figure 7. Sebaceous carcinoma showing mitotic activity and residual sebaceous differentiation (hematoxylin-eosin, original magnification X200).
A Selection of Cancer Predisposition Syndromes and Related Tumors

Strongly Associated Tumors      Gene          Cancer Syndrome

Vestibular schwannoma          NF2       Neurofibromatosis type 2

Rhabdoid tumor (renal,         SMARCB1   Rhabdoid predisposition
  extrarenal)                              syndrome

Retinoblastoma                 RB1

Medulloblastoma with           PTCH1     Nevoid basal cell
  extensive nodularity                     carcinoma syndrome
                                         Gorlin syndrome
Medulloblastoma                SUFU
Subependymal giant cell        TSC1      Tuberous sclerosis 1

Subependymal giant cell        TSC2      Tuberous sclerosis 2

Hemangioblastoma (central      VHL       von Hippel-Lindau
  nervous system, retina)                  syndrome

Cylindroma                     CYLD      Familial cylindromatosis
                                         Brooke-Spiegler syndrome
                                         Familial multiple
Medullary thyroid cancer       RET       Multiple endocrine
                                           neoplasia 2A/2B
                                         Familial medullary thyroid
Neuroendocrine tumor           MEN1      Multiple endocrine
  (gastroenteropancreatic                  neoplasia type 1

Pleuropulmonary blastoma       DICER1    DICER1 syndrome

Pheochromocytoma               TMEM127
Paraganglioma                  MAX       Familial paraganglioma-
Pheochromocytoma                           pheochromocytoma
Paraganglioma                  SDHAF2    Familial paraganglioma-
Pheochromocytoma                           pheochromocytoma
Paraganglioma                  SDHB      Familial paraganglioma-
Pheochromocytoma                           pheochromocytoma
Paraganglioma                  SDHC      Familial paraganglioma-
Pheochromocytoma                           pheochromocytoma
Paraganglioma                  SDHD      Familial paraganglioma-
Pheochromocytoma                           pheochromocytoma
Renal cell cancer, type II     FH        Hereditary
  papillary                                leiomyomatosis and
Leiomyosarcoma (uterus)                    renal cell cancer
Leiomyomata (cutaneous,
Renal cell cancer, type I      MET
  papillary carcinoma
Renal oncocytoma               FLCN      Birt-Hogg-Dube syndrome
Adrenal cortical hyperplasia   PRKAR1A   Carney complex
  (primary pigmented nodular
  adrenocortical disease)

Sebaceous adenoma,             MSH2      Lynch syndrome
carcinoma, epithelioma

Colorectal cancer, hamartoma   BMPR1A    Juvenile polyposis
Colorectal cancer, hamartoma   SMAD4     Juvenile polyposis
Malignant peripheral nerve     NF1       Neurofibromatosis type 1
sheath tumor

Ovarian cancer (epithelial,    STK11     Peutz-Jeghers syndrome
sex cord-stromal tumor)

Adrenocortical carcinoma       TP53      Li-Fraumeni syndrome

Strongly Associated Tumors            Tumor Spectrum

Vestibular schwannoma          Vestibular schwannoma
Rhabdoid tumor (renal,         Rhabdoid tumor (renal,
  extrarenal)                    extrarenal)
                               Choroid plexus
                               Central primitive
Retinoblastoma                 Retinoblastoma
Medulloblastoma with           Basal cell carcinoma
  extensive nodularity
Medulloblastoma                Medulloblastoma
Subependymal giant cell        Renal cell cancer,
  astrocytoma                    angiomyolipoma
                               Subependymal giant
                                 cell astrocytoma
                               Rhabdomyoma (cardiac)
                               Hamartoma (retinal,
                                 gastrointestinal tract)
Subependymal giant cell        Renal cell cancer,
  astrocytoma                    angiomyolipoma
                               Subependymal giant
                                 cell astrocytoma
                               Rhabdomyoma (cardiac)
                               Hamartoma (retinal,
                                 gastrointestinal tract)
Hemangioblastoma (central      Renal cell cancer
  nervous system, retina)      Pheochromocytoma
                               Neuroendocrine tumor
                                 (central nervous
                                 system, retina)
Cylindroma                     Cylindroma

Medullary thyroid cancer       Medullary thyroid

Neuroendocrine tumor           Parathyroid adenoma
  (gastroenteropancreatic      Pituitary adenoma
tract)                         Neuroendocrine tumor
                               Carcinoid tumor
                               Adrenocortical carcinoma
Pleuropulmonary blastoma       Pleuropulmonary
                               Cystic nephroma
                               Ovarian sex cord tumor
Pheochromocytoma               Pheochromocytoma
Paraganglioma                  Paraganglioma
Pheochromocytoma               Pheochromocytoma

Paraganglioma                  Paraganglioma
Pheochromocytoma               Pheochromocytoma

Paraganglioma                  Paraganglioma
Pheochromocytoma               Pheochromocytoma
                               Renal cell cancer
Paraganglioma                  Paraganglioma
Pheochromocytoma               Pheochromocytoma

Paraganglioma                  Paraganglioma
Pheochromocytoma               Pheochromocytoma

Renal cell cancer, type II     Renal cell cancer
  papillary                    Leiomyosarcoma (uterus)
Leiomyosarcoma (uterus)        Leiomyomata (cutaneous,
Leiomyomata (cutaneous,          uterus)
Renal cell cancer, type I      Renal cell cancer (papillary
  papillary carcinoma          carcinoma)
Renal oncocytoma               Renal oncocytoma
Adrenal cortical hyperplasia   Myxoma (cardiac/
  (primary pigmented nodular     cutaneous/breast)
  adrenocortical disease)      Thyroid cancer, adenoma
                               Pituitary adenoma
                               Testicular cancer (sex
                                 cord-stromal tumor)
                               Psammomatous melanotic
                               Adrenal cortical
                                 hyperplasia (primary
                                 pigmented nodular
                                 adrenocortical disease)
Sebaceous adenoma,             Colorectal cancer
carcinoma, epithelioma         Endometrial cancer
                               Ovarian cancer
                                 (endometrioid, clear cell
                               Sebaceous adenoma,
                               carcinoma, epithelioma
Colorectal cancer, hamartoma   Colorectal cancer,
Colorectal cancer, hamartoma   Colorectal cancer,
Malignant peripheral nerve     Glioma
sheath tumor                   Malignant peripheral nerve
                                 sheath tumor
Ovarian cancer (epithelial,    Colorectal cancer,
sex cord-stromal tumor)          hamartoma, adenoma
                               Gastric cancer, hamartoma,
                               Breast cancer
                               Ovarian cancer (epithelial,
                                 sex cord-stromal tumor)
                               Testicular cancer (sex
                                 cord-stromal tumor)
                               Pancreatic cancer
                               Cervical cancer (adenoma
Adrenocortical carcinoma       Breast cancer
                               Adrenocortical carcinoma

Strongly Associated Tumors       Mode of Inheritance

Vestibular schwannoma          Autosomal dominant

Rhabdoid tumor (renal,         Autosomal dominant

Retinoblastoma                 Autosomal dominant

Medulloblastoma with           Autosomal dominant
  extensive nodularity

Medulloblastoma                Autosomal dominant
Subependymal giant cell        Autosomal dominant

Subependymal giant cell        Autosomal dominant

Hemangioblastoma (central      Autosomal dominant
  nervous system, retina)

Cylindroma                     Autosomal dominant

Medullary thyroid cancer       Autosomal dominant

Neuroendocrine tumor           Autosomal dominant

Pleuropulmonary blastoma       Autosomal dominant

Pheochromocytoma               Autosomal dominant
Paraganglioma                  Autosomal dominant,
Pheochromocytoma                 possible parent-of-
                                 origin effect
Paraganglioma                  Autosomal dominant,
Pheochromocytoma                 parent-of-origin
Paraganglioma                  Autosomal dominant

Paraganglioma                  Autosomal dominant

Paraganglioma                  Autosomal dominant,
Pheochromocytoma                 parent-of-origin
Renal cell cancer, type II     Autosomal dominant
Leiomyosarcoma (uterus)
Leiomyomata (cutaneous,
Renal cell cancer, type I      Autosomal dominant
  papillary carcinoma
Renal oncocytoma               Autosomal dominant
Adrenal cortical hyperplasia   Autosomal dominant
  (primary pigmented nodular
  adrenocortical disease)

Sebaceous adenoma,             Autosomal dominant
carcinoma, epithelioma

Colorectal cancer, hamartoma   Autosomal dominant

Colorectal cancer, hamartoma   Autosomal dominant

Malignant peripheral nerve     Autosomal dominant
sheath tumor

Ovarian cancer (epithelial,    Autosomal dominant
sex cord-stromal tumor)

Adrenocortical carcinoma       Autosomal dominant
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Author:Sheffield, Brandon S.; Hirsch-Reinshagen, Veronica; Schrader, Kasmintan A.
Publication:Archives of Pathology & Laboratory Medicine
Date:Sep 1, 2016
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