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The Carney triad (CT) is gastrointestinal stromal tumor (GIST), paraganglioma, and pulmonary chondroma. The GISTs of CT show different clinical, molecular, and morphologic features to usual adult GISTs but are similar to the majority of pediatric GISTs. We postulated that these GISTs would show negative staining for succinate dehydrogenase B (SDHB). We performed SDHB immunohistochemistry on GISTs arising in 5 individuals with CT, 1 child, 7 individuals with GIST in young adulthood including 2 with germline KIT mutations, 3 individuals with neurofibromatosis 1, one 63-year-old female with multifocal gastric epithelioid GIST with lymph node metastases, and 104 consecutive unselected individuals with apparently sporadic GIST. The GISTs and paragangliomas arising in CT, the pediatric GIST, and the multifocal gastric GIST from the 63-year-old showed negative SDHB staining. GISTs from the 7 young adults and 3 with neurofibromatosis were SDHB positive. Of the unselected GISTs, 101 (97%) were positive. One of the negative GISTs arose in a 48-year-old female with previous recurrent multifocal gastric GISTs and the other 2 arose in females also in their 40s with gastric GISTs with epithelioid morphology. We conclude that negative staining for SDHB is characteristic of the GISTs of CT and the subgroup of pediatric GISTs which it resembles. Furthermore, when negative staining occurs in apparently sporadic GISTs in adults, the GISTs show morphologic and clinical features similar to pediatric and CT type GISTs. GISTs may therefore be divided into type 1 (SDHB positive) and type 2 (SDHB negative) subtypes.

Parathyroid carcinoma is notoriously difficult to diagnose with confidence in borderline cases. Commonly there is a long lag time between diagnosis and clinical evidence of malignant behavior even in histopathologically straightforward lesions. There is therefore a need for a novel adjunctive marker to assist in the diagnosis of carcinoma. Parafibromin is the protein encoded by the putative tumor suppressor gene HRPT2. Mutations predicted to inactivate parafibromin were first detected in the germline of patients with hyperparathyroidism-jaw tumor (HPT-JT) syndrome. Subsequently, somatic mutations have been identified in the majority of sporadic carcinomas. We performed immunohistochemistry for parafibromin on 115 parathyroid tissues comprising 4 HPT-JT-related tumors (3 adenomas and 1 carcinoma), 11 sporadic parathyroid carcinomas, 79 sporadic adenomas, 3 multiple endocrine neoplasia 2A-related adenomas, 2 sporadic primary hyperplasias, 2 multiple endocrine neoplasia (MEN)-1-related hyperplasias, 6 secondary hyperplasias, 4 tertiary hyperplasias, and 4 normal parathyroid glands. There was complete absence of nuclear staining in 3 of 4 (75%) HPT-JT-related tumors and 8 of 11 (73%) sporadic parathyroid carcinomas and focal weak staining in 1 of 4 HPT-JT tumors and 2 of 11 sporadic parathyroid carcinomas. Only 1 parathyroid carcinoma exhibited diffuse strong nuclear expression of parafibromin. In contrast, 98 of 100 non-HPT-JT-related benign parathyroids showed diffuse strong nuclear positivity and 2 of 100 showed weak positive staining. We conclude that, in the correct clinical and pathologic context, complete absence of nuclear staining for parafibromin is diagnostic of parathyroid carcinoma or an HPT-JT-related tumor.

The tumour suppressor p53 is mutated in cancer, including over 96% of high-grade serous ovarian cancer (HGSOC). Mutations cause loss of wild-type p53 function due to either gain of abnormal function of mutant p53 (mutp53), or absent to low mutp53. Massively parallel sequencing (MPS) enables increased accuracy of detection of somatic variants in heterogeneous tumours. We used MPS and immunohistochemistry (IHC) to characterise HGSOCs for TP53 mutation and p53 expression. TP53 mutation was identified in 94% (68/72) of HGSOCs, 62% of which were missense. Missense mutations demonstrated high p53 by IHC, as did 35% (9/26) of non-missense mutations. Low p53 was seen by IHC in 62% of HGSOC associated with non-missense mutations. Most wild-type TP53 tumours (75%, 6/8) displayed intermediate p53 levels. The overall sensitivity of detecting a TP53 mutation based on classification as ‘Low’, ‘Intermediate’ or ‘High’ for p53 IHC was 99%, with a specificity of 75%. We suggest p53 IHC can be used as a surrogate marker of TP53 mutation in HGSOC; however, this will result in misclassification of a proportion of TP53 wild-type and mutant tumours. Therapeutic targeting of mutp53 will require knowledge of both TP53 mutations and mutp53 expression.

Germline succinate dehydrogenase B (SDHB) mutation causes pheochromocytoma/paraganglioma syndrome type 4 (PGL4). PGL4 is characterized by pheochromocytoma and paraganglioma, type 2 (SDHB negative) gastrointestinal stromal tumors and renal tumors, which are usually classified as carcinoma. We report 4 kindreds with 5 PGL4-associated renal tumors. Four of the tumors occurred before the age of 30 years, 4 were in the left kidney, 3 were in female patients, and 4 demonstrated consistent but previously unrecognized morphology. The tumors were composed of cuboidal cells with bubbly eosinophilic cytoplasm and indistinct cell borders. Many of the cells displayed distinctive cytoplasmic inclusions, which were vacuolated or contained eosinophilic fluid-like material. The cells were arranged in solid nests or in tubules surrounding central spaces. The tumors were well circumscribed or lobulated and frequently showed cystic change. Benign tubules or glomeruli were often entrapped at the edges of the tumors. The fifth tumor lacked these features but displayed sarcomatoid dedifferentiation. Immunohistochemistry for SDHB was completely negative in all 4 available tumors. Death from metastatic disease occurred in the patient with dedifferentiated tumor 1 year after diagnosis, whereas the other 4 tumors were cured by local excision alone (mean follow-up, 11 y; range, 2 to 30 y). We conclude that morphology supported by negative immunohistochemistry for SDHB can be used to identify kindreds with germline SDHB mutations (PGL4 syndrome) presenting with this unique type of renal tumor. These renal tumors appear to have a good prognosis after complete excision unless there is sarcomatoid dedifferentiation.

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Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome secondary to germline fumarate hydratase (FH) mutation presents with cutaneous and uterine leiomyomas, and a distinctive aggressive renal carcinoma. Identification of HLRCC patients presenting first with uterine leiomyomas may allow early intervention for renal carcinoma. We reviewed the morphology and immunohistochemical (IHC) findings in patients with uterine leiomyomas and confirmed or presumed HLRCC. IHC was also performed on a tissue microarray of unselected uterine leiomyomas and leiomyosarcomas. FH-deficient leiomyomas underwent Sanger and massively parallel sequencing on formalin-fixed paraffin-embedded tissue. All 5 patients with HLRCC had at least 1 FH-deficient leiomyoma: defined as completely negative FH staining with positive internal controls. One percent (12/1152) of unselected uterine leiomyomas but 0 of 88 leiomyosarcomas were FH deficient. FH-deficient leiomyoma patients were younger (42.7 vs. 48.8 y, P=0.024) and commonly demonstrated a distinctive hemangiopericytomatous vasculature. Other features reported to be associated with FH-deficient leiomyomas (hypercellularity, nuclear atypia, inclusion-like nucleoli, stromal edema) were inconstantly present. Somatic FH mutations were identified in 6 of 10 informative unselected FH-deficient leiomyomas. None of these mutations were found in the germline. We conclude that, while the great majority of patients with HLRCC will have FH-deficient leiomyomas, 1% of all uterine leiomyomas are FH deficient usually due to somatic inactivation. Although IHC screening for FH may have a role in confirming patients at high risk for hereditary disease before genetic testing, prospective identification of FH-deficient leiomyomas is of limited clinical benefit in screening unselected patients because of the relatively high incidence of somatic mutations.

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