PMC7411486_01
PMC7411486_02
Nonendocrine features present in our patient. (a) Marfanoid habitus with long arms and long legs with respect to the trunk and skeletal abnormalities. (b) Bilateral mucosal neuromas of the mouth as indicated by the 2 arrows. (c) CT cross section of the abdomen showing the megacolon. (d) MRI sagittal section of the pelvic plexiform neurofibroma.
CRIE2020-4147097.001.jpg
PMC7411486_02_CRIE2020-4147097.001.jpg
fig1
Upon presentation, she had an evident marfanoid habitus (Figure 1(a)), and bilateral mucosal neuromas of the mouth (Figure 1(b)) that were completely overlooked until that moment. The total body computed tomography (CT) scan excluded the presence of distant metastases and clearly revealed the presence of a megacolon (Figure 1(c)). Examination of the pelvic mass by MRI confirmed the presence of a large pelvic lesion (Figure 1(d)) that was substantially stable with respect to the previous radiological exam. The histological results described a multifocal, bilateral MTC (Figure 2, panels A and A1) associated with C cell hyperplasia. The largest microfocus of the tumor invaded the perithyroid soft tissue (Figure 2, panels B and B1), and extensive neoplastic lymphangiosis and vascular embolization (Figure 2, panel C) were present. In the perithyroid soft tissue, numerous neoplastic vascular emboli and tumoral deposits infiltrating an adjacent ganglioneuromatosis lesion were found (Figure 2, panels B and B1). Histopathologic revision of the pelvic lesion, which had been partially removed at 2 years of age in another center, revealed plexiform neurofibroma associated with ganglioneuromatosis involving the bladder wall (Figure 2, panels F1, F2, and F3). The plexiform neurofibroma component consisted of multiple nodules, often delimited by residual perineural sheaths (Figure 2, panel F1), formed by a proliferation of uniform bland spindle cells with scant cytoplasm and wavy nuclei, and set within fibrillary collagenous matrix with myxoid areas (Figure 2, panel F2).
Histology of MTC and other lesions. Panels A and A1: MTC hematoxylin/eosin staining, magnification 2X and 10X, respectively. Panels A2 and A3: positive anticalcitonin immunostaining (10X) and negative antithyroglobulin immunostaining (10X) confirming the diagnosis of MTC. Panels B and B1: MTC infiltrating the perithyroid gangliar tissue, as indicated by the arrows (panel B, 2X, panel B1, 4X). Panel C: MTC vascular invasion with a neoplastic embolus (4X). Panel D: central compartment lymph node metastasis (2X). Panel E: hematoxylin/eosin staining of ganglioneuromatosis in the mucosal neuromas of the mouth excised during surgery (2X). Panel F1: low-power view of the pelvic plexiform neurofibroma. Panel F2: at higher power, the neurofibroma component consists of a uniform population of bland spindle cells with wavy elongated nuclei set in a fibrillary matrix. Panel F3: the ganglioneuromatosis elements, which consist of large ganglion-like neurons.
CRIE2020-4147097.002.jpg
PMC7411486_02_CRIE2020-4147097.002.jpg
fig2
The histological results described a multifocal, bilateral MTC (Figure 2, panels A and A1) associated with C cell hyperplasia. A strong positive immunoreactivity to anticalcitonin (Figure 2, panel A2) and negative immunoreactivity to antithyroglobulin (Figure 2, panel A3) antibodies of the MTC tissue were shown. The largest microfocus of the tumor invaded the perithyroid soft tissue (Figure 2, panels B and B1), and extensive neoplastic lymphangiosis and vascular embolization (Figure 2, panel C) were present. In the perithyroid soft tissue, numerous neoplastic vascular emboli and tumoral deposits infiltrating an adjacent ganglioneuromatosis lesion were found (Figure 2, panels B and B1). Multiple central compartment (5/10) and left laterocervical (5/32) lymph nodes that were removed were confirmed to be metastases from MTC (Figure 2, panel D). The histology report of the mucosal neuromas of the mouth described the presence of diffuse ganglioneuromatosis (Figure 2, panel E). Histopathologic revision of the pelvic lesion, which had been partially removed at 2 years of age in another center, revealed plexiform neurofibroma associated with ganglioneuromatosis involving the bladder wall (Figure 2, panels F1, F2, and F3). The plexiform neurofibroma component consisted of multiple nodules, often delimited by residual perineural sheaths (Figure 2, panel F1), formed by a proliferation of uniform bland spindle cells with scant cytoplasm and wavy nuclei, and set within fibrillary collagenous matrix with myxoid areas (Figure 2, panel F2). The ganglioneuromatosis component consisted mainly of large ganglion cells with a basophilic cytoplasm, vesicular nucleus, and prominent nucleolus (Figure 2, panel F3).
The RET germline deletion in exon 11 of our patient. (a) Sanger sequence analysis of the constitutive DNA showing the heterozygous germline deletion of 6 nucleotides (C GAG CT) that determined an "in frame" deletion of the RET gene at the level of codons 631-633 in exon 11. (b) The deletion involved the third nucleotide (i.e., C nucleotide) of codon 631, the entire codon 632, and the first two nucleotides of codon 633 (i.e., C and T nucleotides). With this deletion, codon 631 returned in frame with the third nucleotide of codon 633 (G nucleotide), changing codon 631 from aspartate (Asp) to glutamic acid (Glu).
CRIE2020-4147097.003.jpg
PMC7411486_02_CRIE2020-4147097.003.jpg
fig3
A strong positive immunoreactivity to anticalcitonin (Figure 2, panel A2) and negative immunoreactivity to antithyroglobulin (Figure 2, panel A3) antibodies of the MTC tissue were shown. Histopathologic revision of the pelvic lesion, which had been partially removed at 2 years of age in another center, revealed plexiform neurofibroma associated with ganglioneuromatosis involving the bladder wall (Figure 2, panels F1, F2, and F3). The ganglioneuromatosis component consisted mainly of large ganglion cells with a basophilic cytoplasm, vesicular nucleus, and prominent nucleolus (Figure 2, panel F3).