Paolo Amico

Aberrant expression of TfR1/CD71 in thyroid carcinomas identifies a novel potential diagnostic marker and therapeutic target.

BACKGROUND Type I receptor for transferrin (TfR1/CD71) is overexpressed in several malignant tumors, but no studies are available on thyroid carcinomas. Our previous comparative analyses of the relative distribution of transferrin in benign versus papillary thyroid carcinoma (PTC) tissues highlighted a marked malignancy-associated abundance of the molecule. The aim of the present study was to evaluate whether TfR1/CD71 is also differentially expressed in benign versus malignant thyroid tissues. METHODS Tissue samples, including benign lesions and follicular-derived carcinomas, from 241 patients and a total of 35 benign and malignant fresh specimens were assayed for TfR1/CD71 expression by reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemistry. RESULTS We found that transcription of TfR1/CD71 gene is constitutive in thyroid epithelia, but the mRNA is differently translated in benign and malignant tissues. Western blot revealed higher levels of TfR1/CD71 protein in malignant versus benign tissues. Immunohistochemically, most carcinomas exhibited overexpression of the receptor, predominantly in the cytoplasm of neoplastic cells. The highest expression level was detected in primary and metastatic papillary carcinomas and anaplastic carcinomas, with positive results ranging from 86% to 100% of the cases. In contrast, most benign tissues were negative, with only a minority of cases showing focal and weak immunoreactivity. CONCLUSIONS Our findings suggest that altered expression of TfR1/CD71 may be used as a marker helpful in distinguishing PTC from papillary hyperplasia and follicular variant PTC from benign follicular-patterned lesions. Additionally, the present observations support the rationale for the use of radiolabeled transferrin/transferrin analogs and/or anti-TfR1/CD71 antibodies for diagnostic and/or radiotherapeutic purposes in TfR1/CD71-expressing thyroid tumors.

Myxoid myofibroblastoma of the breast with atypical cells: a potential diagnostic pitfall.

Sir, Myofibroblastoma of the breast is an unusual benign mesenchymal tumour that belongs to the family of the socalled benign spindle cell tumours of the mammary stroma [5, 6]. In its classic type, it is typically composed of bland-looking spindle cells exhibiting a variable fibro– myofibroblastic differentiation [5, 6]. In recent years, the morphological spectrum of this tumour has been broadened by the recognition of several variants, including epithelioid, lipomatous, fibromatosis-like, fibrous/collagenized, myxoid ones [4–6]. Recently, we have encountered two cases of mammary myofibroblastoma with atypical cells embedded within a prominent myxoid stroma. To the best of our knowledge, this unusual morphological variant has not hitherto been reported. Two male patients (63 and 56 years) presented with two nodular breast masses, measuring 3 and 3.5 cm in greatest dimension, respectively, which were surgically excised. Histologically, both surgical samples were represented by unencapsulated mesenchymal tumours with pushing borders, composed of spindle to epithelioid cells, embedded in an abundant myxoid stroma containing isolated thick eosinophilic collagen bands (Figs. 1a and 2a). Myxoid matrix stained positively with Alcian blue at pH 2.5 and negative for periodic acid-Schiff. One tumour was hypocellular (Fig. 1a), while the other one showed alternating hypocellular and moderately cellular areas (Fig. 2a). Neoplastic cells had pale to deeply eosinophilic cytoplasm and round to oval nuclei containing one or two visible nucleoli. In both cases, a significant number of neoplastic cells (50– 60%) exhibited a moderate to severe degree of nuclear pleomorphism (Figs. 1a,b and 2a,b). Some cells were bior multinucleated (Fig. 2b). A minor mature fatty component was scattered throughout both tumours. Mitoses were absent in the hypocellular tumour, while one mitosis per ten high power fields was observed in the other neoplasm. Necrosis was absent. No epithelial component was identified within both tumours. Immunohistochemically, the cells of both cases had a similar profile: diffuse and strong immunoreactivity to vimentin, α-smooth muscle actin and desmin (Fig. 1c), and a variable staining to CD34, bcl-2 protein, CD99, estrogen (ER), progesterone (PR), and androgen (AR) receptors. No immunoreactivity was obtained for pancytokeratin, epithelial membrane antigen, h-caldesmon, calponin, S-100 protein, and human melanoma black-45 (HMB-45). This immunophenotype was consistent with a fibro-myofibroblastic nature of the neoplastic cells. We believe that the tumours herein presented fit within the spectrum of breast myofibroblastoma [5, 6], representing an uncommon morphological variant, for which the descriptive term “myxoid myofibroblastoma with atypical cells” is proposed. The following morphological and immunohistochemical features, typically seen in myofibroblastoma [5, 6], support our opinion: (1) Tumours were “pure mesenchymal lesions” lacking any epithelial component; (2) Tumours had pushing borders; (3) The myxoid extracellular matrix contained thick eosinophilic collagen bands; (4) Neoplastic cells resulted to have a fibroVirchows Arch (2007) 450:483–485 DOI 10.1007/s00428-007-0373-z

Giant intramuscular lipoma of the tongue: a case report and literature review

We herein report a rare case of giant intramuscular lipoma of the tongue. A 75-year-old Italian male presented at our department with a large tumor at the tip of the tongue that had been present for over 30 years. Clinical examination revealed a yellowish lesion, measuring 10 cm in maximum diameter, protruding from lingual surface. Histological examination showed an unencapsulated lipomatous tumor composed of mature adipocytes, uniform in size and shape, diffusely infiltrating striated muscle fibers of the tongue. The patient is well with no local recurrence after a 15-month follow-up period.

Multinucleated floret-like giant cells in sporadic and NF1-associated neurofibromas: a clinicopathologic study of 94 cases

Multinucleated floret-like giant cells (MNFGCs), similar to those commonly observed in pleomorphic lipoma and giant cell fibroblastoma, have been occasionally reported in gynecomastia and neurofibromas from patients affected by neurofibromatosis type 1 (NF1). Accordingly, it has been suggested that their detection, especially in an otherwise typical neurofibroma, could be a morphological clue to diagnosis of NF1. The aim of the present study was the identification of MNFGCs in a large series (94 cases) of sporadic and NF1-associated neurofibromas, to assess if their presence may indeed be a morphological marker of NF1. Numerous MNFGCs, namely, those that were easily apparent at low magnification (×50 and ×100), were identified only in 5.3% of cases. In 18.1% of cases, a low number of these cells could be observed but only after a careful search, especially at higher magnification (×200 and ×400). Immunohistochemically, all MNFGCs were stained with vimentin and CD34, but not with S-100 protein. Interestingly, there was no statistically significant correlation between MNFGCs (presence or absence) and NF1 (p = 0.73), gender (p = 0.59), age (p = 0.43), and site of tumor (cutaneous vs deep-seated soft tissue; p = 0.27). Our clinicopathologic findings suggest that MNFGCs in an otherwise typical neurofibroma are not a reliable marker of NF1, likely representing a morphological reactive change of the indigenous dermal or endoneurial fibroblasts or dendritic cells in response to unknown microenvironmental stimuli.

Spindle cell/pleomorphic lipoma of the oral cavity.

We herein report a rare case of a lipomatous tumor of the buccal mucosa, showing intermediate morphological features between spindle cell and pleomorphic lipomas, for which the term spindle cell/pleomorphic lipoma is proposed. The presence of multinucleated floretlike cells may pose differential diagnostic problems, especially with spindle cell variant of well-differentiated liposarcoma. Morphological features helpful in the distinction between these tumors are emphasized. Although androgen receptors have been documented in most spindle cell lipomas, suggesting a potential pathogenetic role of sex steroid hormones, no immunoreactivity for androgen, estrogen, and progesterone receptors was obtained in our case. These findings would suggest a different pathogenetic pathway in spindle cell/pleomorphic lipoma of the oral cavity.

Solitary fibrous tumor of the oral cavity with a predominant leiomyomatous-like pattern: A potential diagnostic pitfall

The diagnosis of solitary fibrous tumor (SFT) is usually straightforward if the typical morphologic features, including a wide variety of growth patterns, are identified. We report the clinical, radiologic, and pathologic findings of a rare case of intraoral SFT which exhibited a predominant leiomyomatous-like appearance, closely reminiscent of a leiomyoma, at both incisional and excisional biopsy. Histologically, the tumor was composed predominantly of intersecting fascicles of eosinophilic spindle-shaped cells, variably set in a fibrous stroma. A focal hemangiopericytoma-like growth pattern with alternating hypercellular and hypocellular areas, as well as the deposition of dense keloid-type collagen, raising the suspicion of SFT, could be identified only after a careful examination of the whole tumor. Immunohistochemistry was helpful in confirming the diagnosis of SFT, revealing a diffuse staining of neoplastic cells for vimentin, CD34, bcl-2 protein, and, focally, CD99. Myogenic markers (alpha-smooth muscle actin, desmin, h-caldesmon) were not expressed. The pathologist should be aware of this variant of intraoral leiomyomatous-like SFT to avoid a misdiagnosis of leiomyoma. The distinction of SFT from leiomyoma in the oral cavity is important to assure both correct treatment and prognostic information.

Warthin tumor-like papillary thyroid carcinoma with a minor dedifferentiated component: report of a case with clinicopathologic considerations.

Warthin tumor-like papillary thyroid carcinoma is an uncommon variant of papillary thyroid carcinoma. We report a rare case of Warthin tumor-like variant of papillary thyroid carcinoma with a dedifferentiated component consisting of a solid tumor area composed of neoplastic cells with a spindle to tall cell morphology associated with marked nuclear pleomorphism, atypical mitoses, and foci of necrosis. Although our patient presented with a locally aggressive disease (T3 N1b Mo), she is disease-free without radioiodine therapy after a 23-month follow-up period. We emphasize that Warthin tumor-like papillary thyroid carcinoma, like other morphological variants of papillary carcinoma, may occasionally undergo dedifferentiation. As this component may be only focally detectable, we suggest an extensive sampling of all large-sized (>3 cm) papillary thyroid carcinoma. Recognition of any dedifferentiated component in a Warthin tumor-like papillary thyroid carcinoma should be reported, including its percentage, because it may reflect a more aggressive clinical course.

Chromophobe renal cell carcinoma with extensive rhabdomyosarcomatous component

Sir, Sarcomatoid changes may occur in all subtypes of renal cell carcinoma [1], especially in chromophobe cell carcinoma [3, 6], and are invariably associated with a poorer prognosis. It is likely that the sarcomatoid component arises from a metaplastic transformation of carcinomatous cells that may acquire a spindle cell morphology with a growth pattern, usually resembling that observed in malignant fibrous histiocytomatous, fibrosarcoma or unclassified high-grade spindle cell sarcoma [1, 2]. Although a focal rhabdomyosarcomatous differentiation has been rarely reported [2], we are not aware of any published renal cell carcinoma composed predominantly of a rhabdomyosarcomatous component. We report a rare case of chromophobe renal cell carcinoma with a dominating rhabdomyosarcomatous component accounting for 70% of the entire tumour. A 61year-old man presented with abdominal and left flank pain. Ultrasonography and computerized tomography examination revealed a tumour mass in the left kidney. Radical nephrectomy with abdominal lymph node dissection was performed. Grossly, a tumour mass measuring 16 cm in its greatest dimension and whitish in colour was located in the upper pole of the kidney. Histologically, tumour was mainly composed of spindleand large roundshaped cells with deep eosinophilic cytoplasm, frequently containing cross-striations consistent with rhabdomyoblasts (Fig. 1a). This rhabdomyosarcomatous component represented about 70% of the entire tumour. Immunohistochemical analyses, which revealed a strong and diffuse immunoreactivity for vimentin, desmin, myogenin (MyF4) and sarcomeric actin in these cells, confirmed their skeletal muscle differentiation (Fig. 1b). Focally, rhabdomyoblasts were closely intermingling with residual nests of chromophobe renal cell carcinoma (Fig. 1c), which were better highlighted by pancytokeratin immunostaining (Fig. 1d). Carcinomatous cells were also reactive to cytokeratin 7 and EMA. The remaining tumour was composed of pure chromophobe cell carcinoma (10%) and high-grade spindle cell sarcoma NOS. (20%). The latter component was immunoreactive for vimentin and, focally, for pancytokeratins. Diffuse areas of necrosis and numerous mitotic figures were observed throughout the tumour. Perirenal and renal sinus adipose tissue was infiltrated by tumour, and iliar lymph nodes were metastatic (pTNM, T3 N1 Mx). Differential diagnosis mainly revolved around primary renal rhabdomyosarcoma. Even if the possibility of the existence of this entity in adults cannot be completely excluded [4, 5], we suspect that at least some of the reported cases may represent renal cell carcinoma undergoing extensive rhabdomyosarcomatous differentiation. Accordingly, we recommend that an extensive tumour sampling be performed to rule out the existence of small carcinomatous areas in an otherwise typical rhabdomyosarcoma. However, we admit that a precise distinction between a G. Magro (*) . P. Amico . L. Puzzo Dipartimento G.F. Ingrassia, Anatomia Patologica, Universita di Catania, Via S. Sofia 87, 95123 Catania, Italy e-mail: g.magro@unict.it Tel.: +39-95-3782024 Fax: +39-95-3782023

Tumour deposits classification in colorectal cancer: is TNM5 better than TNM7?†

We read with great interest the Invited Commentary ‘Evidence-based medicine: the time has come to set standards for staging’ [1] and the Invited Response ‘Evidence-based medicine: the time has come to set standards for staging. Is a radical overhaul really needed?’ [2]. We would like to comment on some controversial issues concerning the classification of tumour deposits (TDs) in colorectal cancer and the utilization of the fifth rather than the seventh edition of the tumour, nodes, metastasis (TNM) classification. Regarding the dimensional criterion used in TNM5 about TD classification, we do not agree with the statement by Quirke et al that ‘advantages were reproducibility and correlating with imaging’ [1]. Size, in fact, is not informative on the histogenesis of TDs. A TD ≤3 mm may be a totally metastatic lymph node; on the contrary, a TD >3 mm may represent vascular invasion with extravascular tumour growth. Therefore we believe that size may not represent a valid criterion to label TD as lymph node metastasis. Goldstein et alshowed that palpable pericolonic TDs, which according to TNM5 should be classified as metastatic lymph nodes, represented perineural, perivascular or intravascular tumour growth and there was no evidence of lymph node metastasis upon step sectioning [3]. In addition, a recent study showed that even small TDs (<2 mm), which should be included in the T-stage according to TNM5, contributed to poor prognosis [4]. Therefore it is crucial not to apply a dimensional or morphological criterion (size and/or shape) to prove which TDs are true metastatic lymph nodes, but to establish whether TDs have a behaviour similar to or more aggressive than that of lymph node metastases. Regarding the statement by Quirke et al [1] about differential diagnosis between TDs and tumour budding (TB), although there is no general consensus about TB definition and quantification, we doubt that pathologists could misdiagnose them as TDs [5]. In a recent study, TB was defined as a single or a group of <5 detached tumour cells at the invasive tumour front [6]. On the contrary, TDs are defined in TNM7 as “discrete foci of tumour found in the pericolic or perirectal fat or in adjacent mesentery (mesocolic fat) away from the leading edge of the tumour, showing no evidence of residual lymph node tissue but within the lymph drainage area of primary carcinoma . . .” [7,8]. In our opinion, the difference between the two types of lesions is evident. We agree with Quirke et al that TD definition after radio-chemotherapy was not addressed in TMN7 [1]. However, this issue was not resolved even in TNM5. Regarding TNM7, it is unclear why TDs should be classified as N1c in otherwise node-negative cases of T1–T2 colorectal cancer, similarly with TNM staging of skin melanoma [2,7]. There is no clinical or biological evidence indicating why satellite nodules found in melanoma and TDs found in colorectal cancer should be considered similar lesions. It is also unclear why the interpretation of TDs in T3–T4 colorectal cancer is left to the individual pathologist, reverting to TNM4 staging, although recent data show that all patients with TDs have a prognosis similar to or even worse than that of patients with nodal metastases [3,4,9]. Ueno et al, using the Akaike Information Criteria, showed that the best prognostic model predictive of survival outcome is obtained by including extravascular TDs in the N-stage and intravascular TDs in the T-staging [9]. If these data were to be confirmed, then all TDs should be included in the N-stage, regardless of T-stage, size and shape, except for TDs defined as ‘vascular type’ or intravascular TDs, which, in our opinion, would be better classified as extramural vascular (lymphatic or venous) invasion [10]. Despite this critical analysis of TNM7, we believe that the use of this edition is mandatory because there is no evidence that TNM5 is better than TNM7. In addition, N-stage should not be based on the personal decision of a pathologist to adhere to TNM5 or TNM7 because the use of two different classifications creates poor reproducibility and stage migration. In daily practice, we believe that TDs should be included in the pathology report, specifying their total number, size (the largest diameter if there are multiple lesions), and association, or not, with large vessels and/or nerves, in order to create more homogeneous groups of patients for enrolment in clinical trials [5,11]. This is crucial to better define the actual prevalence and clinical implication of TDs.