DICER1-pleuropulmonary blastoma familial tumor predisposition syndrome: a unique constellation of neoplastic conditions

Abstract

Germline mutations in DICER1 are associated with increased risk for a wide variety of neoplastic conditions, including pleuropulmonary blastoma (PPB), cystic nephroma, nasal chondromesenchymal hamartoma, ovarian Sertoli-Leydig cell tumors, botryoid embryonal rhabdomyosarcoma of the uterine cervix, ciliary body medulloepithelioma, pineoblastoma, pituitary blastoma and nodular thyroid hyperplasia or thyroid carcinoma. These tumors may be seen in isolation or in constellation with other characteristic tumor types in individuals or family members. Here we describe the medical history of a child with a heterozygous, loss of function germline DICER1 mutation and multiple tumors associated with the syndrome.. Although germline mutations in DICER1 are rare, tumors of these types will be seen by practicing pathologists and should prompt consideration of an underlying DICER1 mutation.

Keywords: DICER1; Sertoli-Leydig; nasal chondromesenchymal hamartoma; pleuropulmonary blastoma; thyroid carcinoma.

Figures

Figure 1. Solid area of Type II PPB, age 5

High power view shows hypercellular areas of primitive cells with hyperchromatic nuclei adjacent to less cellular, looser rhabdomyosarcomatous areas. (H&E; original magnification × x400)

Figure 2. Well differentiated thyroid carcinoma, age 8

A) Medium power view of dominant thyroid nodule showing tightly packed neoplastic follicles with a thin capsule. Other nodules showed similar morphology but were not encapsulated. B) Higher power view shows crowded nuclei with optical clearing and brisk mitotic activity. Rare abortive papillae and nuclear pseudoinclusions were seen. (H&E; original magnification x200 A, x400 B).

Figure 3. Round ligament cysts, age 13

A and B) Multilocular cysts from the peritoneal surface of the round ligament show septa with variable thicknesses and collagenous stroma. The septa are lined by flattened or cuboidal mesothelial cells. The cystic architecture is reminiscent of Type I PPB (H&E; original magnification x200 A, B).

Figure 4. Nasal chondromesenchymal hamartoma, age 13

A) Low power view of one of the polyps arising from the sinus mucosa. Multiple cysts lined by respiratory epithelium are present. B and C) Low power views of multiple irregular cartilaginous nodules in the subepithelial tissue. D) High power view shows a subepithelial nodule of cartilage surrounded by a thin layer of spindle cells. (H&E; original magnification x100 A, x200 B,C, x400 D).

Figure 5. Sertoli-Leydig cell tumor of the ovary, age 13

A) The majority of the tumor was composed of bland intestinal-type glandular epithelium with a variably cellular background stroma. B) Sertoli-cell areas and areas with primitive cells were seen focally. (H&E; original magnification x200 A, x400 B).

Figure 6. Results of germline and tumor-specific DICER1 sequencing

The loss of function germline mutation at the canonical splice site at the boundary of the eighth exon-intron was found in peripheral blood leukocyte DNA and in each of the tumor samples. Black arrows point to the positions of DICER1 germline and somatic mutations in 4 different types of tumor by Sanger sequencing (a) germline mutation c.1376+1G>A at boundary of the 8th exon-intron (b) somatic mutation c.5428G>T(exon25) in PPB (c) somatic mutation c.5438 A>T(exon25) in thyroid carcinoma (d) somatic mutation c.5439G>T(exon25) in NCMH (e) somatic mutation c.5439G>T(exon 25) in ovary SLCT

Figure 7. Classic sarcomatous patterns in solid PPB

A) Embryonal rhabdomyosarcomatous pattern is often a predominant pattern in solid PPB. This medium power photomicrograph shows a range of myogenic differentiation with bottom center showing poorly differentiated cells, upper right showing variably-shaped nuclei in a myxoid background and the left half of the photomicrograph showing differentiating rhabdomyoblasts with tails of eosinophilic cytoplasm and some visible striations. B) The blastemal pattern in PPB is characterized by relatively cohesive primitive cells with hyperchromatic nuclei and minimal cytoplasm. PPB blastema is often positive for desmin and associates with embryonal rhabdomyosarcomatous patterns. C) Cartilaginous differentiation in PPB can take the form of hypercellular but differentiated cartilage (left) or less well developed cartilaginous nodules arising from spindle cell mesenchyme resembling fetal cartilage (right). D) Spindle cell sarcomatous patterns may also be present. E) Anaplasia, similar to that seen in Wilms tumor, is a common feature of solid PPB. F) TP53 mutations and/or allelic loss are common in solid PPB. (H&E A-E, Anti-p53 immunostain F; original magnification x200 A,B,D, x100 C, x400 E,F).

Figure 8. Early Type I and non-progressive PPBs

A) Early Type I PPB in a one month-old infant shows cystic expansion of airspaces. The septa are lined by flattened or cuboidal alveolar type 1 and 2 cells. The septa contain evenly dispersed bland uncommitted cells and small capillaries in a pale matrix. B) Higher power view of same tumor. C) Low power view of this lesion from a nine month-old infant shows the typical multilocular cystic architecture with intersecting septa. The septa are collagenous and hypocellular. D) This Type I PPB shows a field with three septa showing different patterns: coagulative necrosis (upper third), paucicellular collagenous matrix (middle third), and subepithelial primitive cell proliferation (bottom third). E) Higher power views of coagulative necrosis. F) Dystrophic calcification and hemosiderin following coagulative necrosis. G and H) Paucicellular, collagenous septa with evidence of past necrosis and hemorrhage. I and J) Subepithelial mesenchyme showing differentiation toward cartilage and fibroblasts respectively (H&E; original magnification x200 A,D,G,H; x400 B,E,F,I,J; x100 C).

Figure 8. Early Type I and non-progressive PPBs

A) Early Type I PPB in a one month-old infant shows cystic expansion of airspaces. The septa are lined by flattened or cuboidal alveolar type 1 and 2 cells. The septa contain evenly dispersed bland uncommitted cells and small capillaries in a pale matrix. B) Higher power view of same tumor. C) Low power view of this lesion from a nine month-old infant shows the typical multilocular cystic architecture with intersecting septa. The septa are collagenous and hypocellular. D) This Type I PPB shows a field with three septa showing different patterns: coagulative necrosis (upper third), paucicellular collagenous matrix (middle third), and subepithelial primitive cell proliferation (bottom third). E) Higher power views of coagulative necrosis. F) Dystrophic calcification and hemosiderin following coagulative necrosis. G and H) Paucicellular, collagenous septa with evidence of past necrosis and hemorrhage. I and J) Subepithelial mesenchyme showing differentiation toward cartilage and fibroblasts respectively (H&E; original magnification x200 A,D,G,H; x400 B,E,F,I,J; x100 C).

Figure 9. Type I PPBs with primitive cell components

A) Subepithelial layer of primitive cells with hyperchromatic nuclei and inconspicuous cytoplasm. Mitotic activity is present. B) A thicker layer of primitive mesenchymal cells beneath an alveolar lining (cambium layer). Compare the worrisome cytologic features of these cells and cellular density with those in Fig. 8B, 8I and 8J. Eosinophils are common in Type I PPBs that present with pneumothorax. C) Well developed cambium layer beneath the bronchial epithelium. Note the overt skeletal muscle differentiation in deep stroma. D) A different pattern of cambium layer with a less cellular, myxoid stroma. (H&E; original magnification x400 A,B; x100 C x200D).

Figure 10. Cystic nephroma

A) Lower power view showing cystic expansion of an apparent tubule. Septa in this example are collagenous with scattered inflammatory cells. B) High power view of a cyst wall from a different patient shows a lining of plump epithelial cells. The subepithelial zone is myxoid and contains bland mesenchymal cells and scattered inflammatory cells. (H&E; original magnification x100 A, x400 B).

Figure 11. ERMS of the uterine cervix in a child with DICER1 mutation

A) Medium power view of a cervical polyp from a 14 year-old female who presented with tissue passed from the vagina. The polyp is lined by mucinous endocervical cells. The subepithelial zone (cambium layer) is more densely cellular than the deep stroma. B) A high power view shows primitive cells with hyperchromatic, irregular nuclei and mitotic activity. Desmin and myogenin stained approximately 30-40% of these cells. (H&E; original magnification x200 A, x400 B).

Figure 12. Pineoblastoma in a 30 month old girl with DICER1 mutation

A biopsy of a pineal region tumor from a two year-old female showed a primitive malignant neoplasm composed of cells with hyperchromatic nuclei and no overt differentiation by H&E stains. Synaptophysin and chromogranin were positive indicating a neurogenic phenotype. A large complex cyst in the left lung was noted on the scout radiograph of the MRI scan. Subsequent genetic testing showed a germline DICER1 mutation. (H&E, original magnification × 400).