CYSLTR2-mutant Cutaneous Melanocytic Neoplasms Frequently Simulate "Pigmented Epithelioid Melanocytoma," Expanding the Morphologic Spectrum of Blue Tumors: A Clinicopathologic Study of 7 Cases.

Recurrent activating Gαq mutations in the spectrum of blue nevi have been well studied. However, the clinicopathologic characteristics of the recently described CYSLTR2-mutant and PLCB4-mutant blue nevi remain limited, owing to their rarity. Herein, we present 7 CYSLTR2-mutant melanocytic neoplasms, including 1 cellular blue nevus, 4 atypical cellular blue nevi, and 2 blue nevus-like melanomas. They occurred on the scalp, breast, flank, forearm, thigh, leg, and ankle of 3 male patients and 4 female patients, with a median age of 43 (25 to 81) years at diagnosis. Five exhibited an exophytic growth, and 6 were heavily pigmented. A fascicular arrangement of medium to large spindle melanocytes was seen in 6 cases, but epithelioid cytology was present in only 2 cases, one of them being focal. A junctional component was present in 3 cases. Immunoreactivity for HMB45 was diffusely present, except in 1 cellular blue nevus. BAP1 nuclear immunoexpression was lost in 1 melanoma case. A canonical CYSLTR2 L129Q hotspot mutation was present in all cases. Altogether, these histopathologic findings suggest that CYSLTR2-mutant melanocytic blue neoplasms frequently exhibit a heavily pigmented exophytic tumor with a silhouette resembling "pigmented epithelioid melanocytoma" rather than usual cellular blue nevus. Moreover, most of these tumors were not clinically recognized as blue nevi and not located in the classic topography of cellular blue nevus aside from the scalp. However, a fascicular arrangement of medium to large-sized spindled melanocytes, as well as a lack of epithelioid or nevoid melanocytes, could be potential diagnostic clues to morphologically distinguish CYSLTR2-mutant tumors from "pigmented epithelioid melanocytoma."

Sinonasal small round blue cell tumors: An approach to diagnosis.

The differential diagnosis for small round cell tumors in the sinonasal tract is diverse and as the body of literature documenting not only uncommon presentations but also availability of ancillary studies grows, so does the need for a reminder to take a conservative and thorough approach before rendering a diagnosis. Small tissue samples are particularly problematic, with limitations that include volume of tumor cells available for studies, lack of architectural context and a non-specific gross description. Incorporation of patient history and presentation, radiologic findings, clinical impression and concurrent studies often guide the course of studies performed by the pathologist. If these are non-specific, the pathologist may need to perform ancillary studies, including a broad panel of immunohistochemical stains and molecular studies. If tissue is limited, a precise classification may not be achievable. Although the expectation to render a definitive diagnosis is high, the pathologist should never feel compelled to go further with a diagnosis than the tissue itself supports.

Atypia and differential diagnosis in cellular blue nevi: clinicopathological study of 21 cases.

OBJECTIVE: Cellular blue nevus differs from the classic blue nevus with characteristics such as large size, cellularity, intense pigmentation, and growing pattern with subcutaneous infiltration. It is a dermal melanocytic tumor that can be confused with melanoma due to the atypia it may contain. MATERIAL AND METHOD: Hematoxylin-eosin and MIB-1 stained slides of 21 cases diagnosed between 2000-2014 were re-evaluated. In order to attract attention to this rare lesion, 21 cases are presented with the clinical and above-mentioned histopathological findings. RESULTS: Thirteen (61.9%) cases were females and eight (38.1%) were male. The mean age was 25.4 (2-73). The most frequent localization was the sacral and gluteal region (11 cases). The mean diameter was 14.4 mm (4-60 mm). From the parameters defined to assess the atypia, ulceration was identified in four cases. Prominent cellularity and subcutaneous infiltration were seen in three and 16 cases, respectively. Mitosis was seen in six tumors. Immunohistochemically, MIB-1 was present in two cases as 3% and 2% respectively, while in others it was 1% or less. Although there is no precise definition for the "atypical cellular blue nevus", five patients were assessed as atypical cellular blue nevus (a case with infiltrative development of six cm tumor diameter, two cases with two mitosis and a MIB-1 index 3% and 2%, a case with one mitosis and confluent development and a case with one mitosis in addition to focal necrosis areas). No lymph node and/or distant metastasis was observed during follow-up. CONCLUSION: We think it is more important to rule out the possibility of conventional melanoma in cellular blue nevus with exaggerated morphological findings alongside low proliferative activity rather than to determine the atypia.

Congenital combined melanocytic nevus of the scalp with associated alopecia areata.

We report a case of a 20-year-old Chinese man with an alopecic congenital combined compound and blue melanocytic nevus of the scalp, associated with alopecia areata. The diagnosis of a combined melanocytic nevus was confirmed by histopathological examination and immunohistochemical stains, with exclusion of neurocristic hamartoma, which can have a similar clinical and histopathological appearance but different prognosis. In addition, we explore the association of this large melanocytic lesion with alopecia areata.

Recurrent blue nevus of the corneoscleral limbus.

PURPOSE: To describe an unusual corneoscleral blue nevus. METHODS: Review of clinical and histopathological characteristics and previous relevant literature supplemented with immunohistochemical studies. RESULTS: A 13-year-old Pakistani girl presented with a 5 x 2-mm, superotemporal, nonmovable, recurrent, black, limbal nodule. The lesion had been incompletely removed two and a half years earlier. Nonfascicular, variably pigmented, banal, spindle melanocytes with bland nuclei were discovered histopathologically in the conjunctival substantia propria and superficial sclera in the original and recurrent specimens. HMB-45+ and MART-1+ immunostainings established that all the variably pigmented spindle cells were melanocytes. Dispersed plump melanophages displayed clumped melanin granules and were shown to have small nuclei after decolorization. The Ki-67 proliferation index was very low (0.05%), supporting a benign diagnosis. No residual pigmentation after excision and cryotherapy was observed in follow-up examinations during a year and a half. CONCLUSIONS: Careful histopathological and immunohistochemical evaluation of recurrent, incompletely excised, blue nevi can determine if they remain benign. Adjunctive cryotherapy was performed to prevent further recurrence, based on results from published data.

Blue rubber bleb nevus syndrome: novel lymphangiomatosis-like growth pattern within the uterus and immunohistochemical analysis.

Blue Rubber Bleb Nevus Syndrome is a rare, primarily sporadic condition characterized by vascular lesions principally involving the skin and gastrointestinal tract. Although considered a venous malformation, telangiectatic capillaries, arteriovenous malformations, and lymphangiomas have been reported, but a lymphangiomatosis-like growth pattern has not been described. This case of Blue Rubber Bleb Nevus Syndrome demonstrated a labyrinth of variably sized vascular spaces lined by an attenuated layer of bland endothelial cells, dissecting uterine tissues and sequestering remaining myometrium. Immunohistochemical profile of lesional endothelial cells from the myometrium included strong, diffuse CD31; variable CD34; strong, patchy D2-40; weak, patchy factor VIII-related antigen; focal linear subendothelial collagen type IV; Ki-67 in 1% of cells; and no GLUT-1 or WT1 expression. This report expands the morphological spectrum of vascular lesions in Blue Rubber Bleb Nevus Syndrome to include a lymphangiomatosis-like growth pattern and the immunohistochemistry suggests dual vascular and lymphatic differentiation, supporting the current belief that these lesions are malformations.

[Reactivity of five different antibodies with benign and malignant melanocytic lesions]. / A különbözo antitestek reaktivitása benignus és malignus melanocitás daganatokban.

At the histological examination of an increasing number of melanocytic tumors there is a need to use various immunohistochemical methods. Currently, we are supplied by several antibodies working well on formalin-fixed, paraffin-embedded samples. We have tested five antibodies (S-100, HMB-45, Melan-A, MITF, PNL-2) on 34 benign and 34 malignant melanocytic tumors. We examined the specificity and sensitivity in the junctional and dermal component separately, with special consideration to features disturbing the evaluation (regression, halo-like inflammation, etc.). We have concluded that the histological diagnosis of melanocytic tumors is based on the detailed examination of traditional HE slides and the immunohistochemical methods only confirm or weaken our opinion.

Blue rubber bleb nevus syndrome: immunohistochemical study.

Blue rubber bleb nevus is a rare entity consisting of distinctive angiomas in the skin and gastrointestinal tract, leading to occult or profound gastrointestinal bleeding and chronic anemia. The efficacy has been documented of systemic treatment with corticoids, interferon, vincristine, and, more recently, subcutaneous octreotide in the presence of active lesion proliferation or disseminated intravascular coagulation. A case of blue rubber bleb nevus syndrome with oral hemangiomas in a 24-year-old woman is reported. The surgical specimens were subjected to immunohistochemical study, which showed all of the hemangiomas to be in an inactive phase.

Blue nevus of the endometrium.

A 36-year-old woman with a long history of amenorrhea underwent endometrial curettage. An aggregate of short spindle cells containing a finely granular, dark brown pigment with the histochemical characteristics of melanin was detected in the endometrial stroma. This finding is considered analogous to the occurrence of similar cells in the endocervical stroma and is most appropriately designated a "blue nevus" of the endometrium. The occurrence of nonneoplastic, melanin-laden cells in the endometrial stroma is an extremely rare phenomenon, which has been reported only once previously.

CD34-positive cellular blue nevi.

BACKGROUND: Although cellular blue nevi (CBN) are well known and characterized, the histopathologic and clinical spectrum of these tumors continues to evolve. We report four CBN with a distinctive histologic and immunohistochemical pattern. METHODS: The histologic features and immunohistochemical staining for S-100 protein, HMB-45, Bcl-2 and CD34 of four CBN with distinctive features were evaluated using routine methods and compared to common CBN. RESULTS: All four of these distinctive CBN where known to be congenital, and all showed aggregates of plump spindled cells with round to oval nuclei in aggregates and more slender spindled cells with thin wavy nuclei. The slender, spindled cells showed an infiltrative pattern laterally into the dermis and deep into the subcutaneous fat. All four tumors showed diffuse expression of an immunohistochemical stain for CD34, as well as for S-100 protein, Bcl-2, and HMB-45. CONCLUSION: Positive immunohistochemical staining with the progenitor marker CD34 defines a subset of CBN. These tumors appear to fit within the spectrum of neurocristic cutaneous hamartomas and may arise from more primitive neurocristically derived cells. Further follow-up of these tumors will be necessary to determine whether this subset of CBN defines a subset with a characteristic biologic behavior.

[Blue nevus of the uterine cervix: description of a case and review of the literature]. / Il nevo blu della cervice uterina: descrizione di un caso e revisione della letteratura.

Blue nevus is a pigmented lesion of dermal melanocytes; the extracutaneous locations are uncommon. We report a case of a blue nevus of the uterine cervix in a 53 years old woman, with histochemical and immunohistochemical investigations.

The carcinoembryonic antigen (CEA) family (CD66) expressed in melanocytic naevi is not expressed in blue naevuscell naevi in dendritic type.

BACKGROUND: Although sporadic reports have regarded the expression of the carcinoembryonic antigen (CEA) family in melanoma, there has been no information about the expression in precursor lesions of melanoma such as melanocytic naevi and blue naevi. METHODS: The expression was immunohistochemically studied in frozen biopsy specimens of 45 acquired and 16 congenital melanocytic naevi and 20 blue naevi, using a panel of monoclonal and polyclonal antibodies that recognize different epitopes of CEA and related molecules. RESULTS: Members of the CEA glycoprotein family were strongly expressed in all of the subtypes of melanocytic naevus. A reduced expression of the CEA glycoproteins with increased dermal depth or acquisition of a spindled morphology of naevus cells was apparent. The expression was not seen in the present blue naevi and normal epidermal melanocytes. CONCLUSIONS: Although the significance of the expression was not clarified, this report has clearly demonstrated that the CEA family is strongly expressed in melanocytic naevi and immunoreactivity is divergent between melanocytic naevi and blue naevi and between dermal naevus cell types, suggesting that the expression may be altered with architectural changes in the melanocyte-lineage cells.

Epithelioid blue nevus: a rare variant of blue nevus not always associated with the Carney complex.

Epithelioid blue nevus is a rare variant of blue nevus that has been recently described in patients with Carney complex. Some of the patients with Carney complex have multiple epithelioid blue nevi and a familial history of similar lesions is often recorded. Epithelioid blue nevus consists of an intradermal melanocytic nevus composed of polygonal epithelioid cells laden with melanin. Neoplastic cells show no maturation at the base of the lesion and, in contrast with the usual stromal changes in blue nevi, epithelioid blue nevus exhibits no fibrosis of the dermis. We have studied three cases of epithelioid blue nevus in three patients with no evidence of Carney complex. The lesions were solitary and there was no family history of similar lesions. Therefore, epithelioid blue nevus is a distinctive variant of blue nevus that may also appear as a sporadic lesion and is not always associated with Carney complex.

Concurrent Ki-67 and p53 immunolabeling in cutaneous melanocytic neoplasms: an adjunct for recognition of the vertical growth phase in malignant melanomas?

Ki-67 labeling of paraffin sections has been correlated with the number of cells in non-G(o) phases of the replicative cell cycle, and this immunohistochemical technique has been applied to the evaluation of a variety of human neoplasms. Similarly, immunolabeling for p53 protein has been used to detect mutations in the corresponding gene, as a reflection of possible cellular transformation in the same context. Both of these techniques were applied to 253 melanocytic tumors of the skin to assess their possible utility in the diagnosis and subcategorization of such lesions. They included 76 banal (common) nevi (CN), 39 Spitz nevi (SN), 62 superficial spreading malignant melanomas in radial growth (SSMMs), 32 nodular malignant melanomas (NMMs), 21 lentigo maligna melanomas in radial growth (LMMs), and 23 melanomas arising in association with preexisting compound nevi (MCN). One hundred cells were counted randomly in each tumor, and dark, exclusively nuclear reactivity was scored as positive labeling; results were recorded as percentages. Negligible Ki-67 and p53 labeling was seen in CN and SN, at a level that was similar to that obtained in cases of LMM and MCN. The largest proportion of Ki-67-positive and p53-positive cells was observed in NMMs, followed by SSMMs. Radial growth-phase SSMMs and LMMs demonstrated immunoprofiles that were similar to those of melanocytic nevi, and MCN did so as well. The prototypical malignant melanocytic tumor representing the vertical growth phase-nodular melanoma--demonstrated a statistically significant difference from all other lesions in this study with respect to Ki-67 index (P = .008, chi2) and p53 reactivity (P < .000001, chi2). Subsequent concurrent use of a Ki-67 threshold index of 10% and a p53 index of 5% correctly indicated the presence of vertical growth in 75% of NMMs, whereas only 8% of radial growth phase melanomas of other types were colabeled at the same levels of reactivity for the two markers (P < .00001, chi2). Thus, although the distinction between benign and malignant melanocytic tumors could and should not be based on immunohistology for Ki-67 and p53, these results suggest that the latter determinants may, in fact, be used as an adjunct to morphology in the recognition of the vertical growth phase in cutaneous malignant melanomas.

Epithelioid blue nevus: neoplasm Sui generis or variation on a theme?

The epithelioid blue nevus has recently been associated with the Carney complex, which is characterized by myxomas, spotty skin pigmentation, endocrine overactivity, and schwannomas. Using the general criteria proposed by Carney and Ferreiro, similar lesions were identified in 33 patients with no evidence of the Carney complex. Those lesions presented on the face, trunk and extremities of 15 males and 18 females. The mean age was 35 years, much older than those in the Carney complex (mean 16.3 years). Clinical diagnoses included malignant blue nevus, atypical nevus, melanoma, congenital nevus, and dermatofibroma. The lesions were symmetric, predominantly dermal melanocytic proliferations arranged as short fascicles, small nests, and single cells. Large polygonal and epithelioid melanocytes with moderate pleomorphism, and occasional nuclear pseudoinclusions were admixed with heavily pigmented dendritic and spindled melanocytes and melanophages. Rare mitotic figures were seen in some cases. The neoplasms showed a morphologic spectrum that encompassed a group of combined blue nevi with epithelioid melanocytes and other Spitz's nevus characteristics. These epithelioid combined nevi (ECN) fell into three phenotypes with morphologies that most closely paralleled those pictured by Carney and Ferreiro in the Carney complex: the classic or Carney complex pattern (ECN-CC), those that showed overlap with deep penetrating nevus (ECN-DPN), and those that have many dermal Spitz's nevus features, [BLue + SpITZ's nevus; (ECN-BLITZ)I. In six cases, there was such an admixture of features that it was difficult to ascribe them to one of the groups. Nine lesions had associated banal congenital nevus. Follow-up that averaged over 2.5 years (31 months) (range 6-162 months) showed no evidence of malignancy or recurrent disease after excision. Epithelioid combined nevus is a type of combined nevus with blue nevus and Spitz's nevus features, which may or may not be associated with the Carney complex. It shows morphologic overlap with the epithelioid blue nevus described by Carney (ECN-CC), deep penetrating nevus (ECN-DPN), and blue nevus with intradermal Spitz's (desmoplastic) nevus (ECN-BLITZ). Epithelioid combined nevus is thought to be a fitting nosologic designation for all of these lesions.

Hypopigmented common blue nevus.

Blue nevus is a benign pigmented lesion of dermal melanocytes with a number of histologic and clinical variants, of which the major types are the common blue nevus, cellular blue nevus and combined nevus. This study describes 9 cases of hypopigmented blue nevus (HBN), a variant of common blue nevus in which there is minimal identifiable melanin pigment. We also discuss the usefulness of the immunoperoxidase stain HMB-45 in relation to the diagnosis of HBN and the lesions with which it may be histologically confused, namely common intradermal nevus, dermatofibroma, neurofibroma, dermal scar and desmoplastic malignant melanoma. The HMB-45 stain was found to be uniformly positive in all 9 cases of HBN, in contrast to the other dermal lesions which have been reported as either negative or showing only focal positivity. The physical distribution and age range of the patients in this study was similar to the age and sites for common BN, supporting the relationship between the 2 lesions. The occurrence of HBN in predominantly young adults indicates that this lesion is not a phenomenon due to ageing or degenerative change, and should be regarded as a variant of common blue nevus.