Primary Cutaneous Cribriform Tumor with Clinical and Histological Diagnostic Challenges: Case Report and Literature Review of a Rare Skin Neoplasm

Introduction

The skin is the largest organ in the human body and serves as a critical interface between the internal environment and the external world. It functions as a protective barrier against infections and plays an active role in regulating body temperature [1]. Although the skin architecture is complex, it can be roughly divided into the epidermis, dermis, and hypodermis. The dermis contains the adnexal structures, such as nails, sweat glands, and hair follicles [1].

Cutaneous adnexal tumors are a diverse group of neoplasms that arise from sweat glands, hair follicles, or sebaceous structures. While most are benign, some can resemble malignant epithelial tumors, creating diagnostic and therapeutic challenges. Those with a cribriform growth pattern are of particular concern, as this architecture is also seen in malignancies, such as adenoid cystic carcinoma (AdCC) and metastatic adenocarcinomas [2–4].

First described by Requena et al in 1998, primary cutaneous cribriform carcinoma is an extremely rare adnexal tumor of sweat gland origin. In the updated 5th edition of the WHO Classification of Skin Tumors, it was renamed cribriform tumor [5,6]. Fewer than 50 cases of cribriform tumor have been documented in the English-language literature, highlighting both its rarity and the limited collective knowledge about this entity. Although it typically behaves in an indolent manner, its close histologic resemblance to more aggressive tumors presents significant diagnostic pitfalls, with important implications for clinical care [5].

Herein, we report the case of a man who presented with a large, firm, brown subcutaneous dermal nodule, ultimately diagnosed as a cribriform tumor, an exceptionally rare sweat gland neoplasm. We outline its morphologic and immunohistochemical characteristics, review the differential diagnoses, and emphasize the importance of distinguishing it from more aggressive mimics. This case contributes to the limited body of literature and highlights the value of combining histopathology and immunohistochemistry to avoid misclassification.

Case Report

A 33-year-old man with a noncontributory medical and family history and no history of smoking presented to our clinic for the insidious onset of a 4×2.5-cm raised, large brown dermal nodule on the medial aspect of his left leg. The lesion was a raised, firm, non-itching, painless, and non-ulcerated subcutaneous nodule that evolved, according to the patient, over the course of the 5 previous months.

On presentation, he appeared well-nourished and his vital signs were within the normal limits. He denied any recent weight loss, anorexia, or night sweats. Overall, the physical examination was unremarkable, there were no inguinal lymphadenopathies, and skin inspection did not reveal other suspicious lesions over his body. The lesion appeared firm, non-tender, and well-demarcated. Laboratory test results, including a complete blood count with differential and biochemical indicators, were within the reference range.

A complete excisional biopsy of the lesion was then performed and sent to the pathology department to determine its nature (Figure 1). His postoperative course was smooth, and he was discharged home the next day. Healing was uncomplicated on clinical examination 2 weeks after surgical excision.

The tumor appeared completely excised and well-circumscribed, measuring 2 cm. It spared the overlying epidermis while involving the dermis and subcutaneous tissue. Histologic examination of the biopsy, using hematoxylin and eosin staining, revealed solid nests of epithelial cells with oval nuclei and scant eosinophilic cytoplasm (Figure 2). Additionally, there were numerous cribriform areas with small round lumina and thin thread-like intra luminal bridging strands. Mitotic figures were rare, without atypia. Furthermore, there was no evidence of perineural or lymphovascular invasion or intratumoral necrosis or hemorrhage.

A panel of immunohistochemical markers showed that the tumor cells were positive for cytokeratin (CK) 7, while negative for p63, p40, p16, GATA3, estrogen receptor, S100, PAX8, and thyroid transcription factor 1 (TTF-1). Carcinoembryonic antigen (CEA) and epithelial membrane antigen (EMA) highlighted the ductal component of the cribriform areas (Figure 2).

After the excision, the patient was referred by the surgeon to the oncology clinic. The patient underwent a positron emission tomography-computed tomography, which showed no hypermetabolic cutaneous lesions or active distant metastasis. Consequently, the lesion was diagnosed as a primary cutaneous cribriform carcinoma (cribriform tumor). No recurrences or distal metastases were observed 1 year after the surgical removal.

Based on the previously mentioned microscopic and IHC characteristics, the diagnosis of cribriform tumor was established. As discussed in the following sections, this tumor is exceptionally rare.

Discussion

Requena et al first described primary cutaneous cribriform carcinoma, now known as cribriform tumor, in 1998 [6]. Microscopically, these tumors display a sieve-like appearance due to the diffuse cribriform pattern they display. They are rare, indolently growing sweat gland neoplasm of possibly apocrine origin, with low-grade malignant potential [5,7]. Although a limited number of cases has been reported in the literature, this tumor appears to occur more commonly in females, with a sex ratio of 2.7: 1, and tends to originate from distal extremities in middle-aged individuals [2,8]. Although they are thought to originate from apocrine glands, these tumors behave differently from other apocrine carcinomas because of their indolent growth. Additionally, to date, metastatic disease and recurrence have not been reported [2,5,9]. However, given the limited number of cases available, this conclusion should be interpreted with caution. These tumors present a diagnostic dilemma for both the histopathologist and clinician. In fact, patient medical history, physical examination, laboratory workup, imaging, morphological assessment, and IHC are necessary to establish the diagnosis of this neoplasm [9]. Generally speaking, clinical information is particularly important in any histopathological evaluation, and the histopathologist needs to have access to the clinician’s point of view for a more accurate result [10].

Histologically, cribriform tumors are primarily confined to the dermis, although some cases show infiltration into subcutaneous fat. These non-encapsulated tumors have well-defined borders and display varying proportions of solid nests, glandular-like structures, and cribriform patterns. The glandular and cribriform formations originate from solid nests, where small round spaces develop into glandular structures, eventually forming cribriform patterns with thin bridging. Tumor cells are uniform, with round to oval nuclei, deep chromatin, mild pleomorphism, inconspicuous nucleoli, and scant eosinophilic cytoplasm. Mitotic figures are rare, with no atypical mitoses or necrosis. Some cases exhibit apocrine secretion, while eosinophilic luminal secretions can be PAS-negative or Alcian blue/PAS-positive. Focal necrosis occurs occasionally, but there is no neural or vascular invasion. Lymphocytic infiltration is commonly observed [9,11]. ICH shows positivity for epithelial and glandular markers CK and CK7 in all cases. Most tumors express EMA and CEA, indicating ductal differentiation, while CK20 and GCDFP-15 are negative. Myoepithelial markers SMA and calponin are also negative, with S-100 expression observed in 7 out of 37 cases [5].

One of the most important differential diagnoses is AdCC, which also demonstrates a cribriform architecture. However, unlike primary cribriform tumors of sweat gland origin, AdCC is composed of a dual population of epithelial and myoepithelial cells and frequently exhibits perineural invasion, a feature that is uncommon in primary cribriform tumors. At the molecular level, AdCC is typically linked to a t(6;9)(q22–23;p23–24) translocation that produces the MYB–NFIB fusion gene. This alteration drives tumorigenesis through MYB upregulation and can be identified using fluorescence in situ hybridization or reverse transcriptase polymerase chain reaction. MYB protein expression, assessed by IHC, may also serve as a useful surrogate marker.

In this case, molecular testing for MYB rearrangement was not performed. However, the absence of myoepithelial differentiation on histology, the lack of perineural invasion, and an immunoprofile not consistent with AdCC supported the diagnosis of a primary cutaneous cribriform adnexal tumor. This underscores that although molecular studies can be helpful in difficult cases, thorough histopathologic and immunohistochemical evaluation often provides a reliable basis for distinction [3,4,12].

Another important differential diagnosis is cribriform apocrine carcinoma, which can histologically resemble primary cribriform tumors. However, apocrine carcinoma frequently exhibits decapitation secretion and is strongly positive for androgen receptor, aiding in its distinction. Additionally, metastatic carcinomas from visceral organs, including the prostate, breast, lung, and salivary glands, can present with a cribriform pattern, further complicating the diagnostic process. Given the possibility of metastasis, it is crucial to correlate histopathological findings with clinical and imaging data, as well as to use a broad IHC panel to determine the site of origin. Markers such as PSA for prostatic carcinoma, GCDFP-15 for breast carcinoma, TTF-1 for lung adenocarcinoma, and MYB for salivary gland tumors are essential in this differentiation [13–15].

Cribriform tumors generally lack aggressive features, such as vascular or neural invasion, lymph node metastasis, or distant spread. However, due to their complex histology, diagnosis requires a thorough approach, including clinical history, imaging, morphology, IHC, and molecular testing when needed. While no standard treatment exists, wide local excision with clear margins is the preferred option. Given the risk of local recurrence, long-term follow-up is recommended to monitor for progression [16,17].

Although cribriform tumors generally do not exhibit aggressive features, their complex histology requires a multidisciplinary diagnostic approach. Clinical history and examination help establish lesion chronicity, favored sites, and growth behavior, with cribriform tumor usually presenting as a slow-growing, firm, asymptomatic dermal nodule [1]. Radiologic imaging (ultrasound, computed tomography, magnetic resonance imaging) is valuable when deeper extension or an extracutaneous primary is suspected, especially to rule out metastasis [6]. Nevertheless, histopathology remains the diagnostic cornerstone, highlighting the cribriform pattern, luminal differentiation, and absence of aggressive features, such as perineural invasion. IHC adds key discriminatory value: cribriform tumor typically expresses CK7 and EMA but lacks myoepithelial markers (p63, SMA, S100), distinguishing it from AdCC [1,5]. Molecular testing, when available, provides further support: MYB–NFIB fusion or MYB rearrangements strongly indicate AdCC, while their absence favors cribriform tumor [2].

Most reported series show a female predominance and onset in mid-adulthood. In the largest cohort (n=26), 19 patients were women, with a median age of approximately 48 years, and lesions most commonly arose on the upper and lower limbs [2]. Our patient, a 33-year-old man with a lesion on the left leg, was therefore younger than the median and male (less typical), although his tumor site was consistent with the extremity predilection. Reported pathologic sizes are usually small (approximately 4–12 mm), although some single cases, including that of another 33-year-old man with a knee lesion, measuring approximately 2 cm, confirms that larger nodules can occur despite the tumor’s indolent behavior [18,19].

Despite demographic outliers (male sex, younger age), the histomorphology and IHC profile in our case matched the canonical pattern and showed no myoepithelial differentiation, supporting cribriform tumor over AdCC. This reinforces that clinicopathologic correlation (age/sex/site, histology, IHC, and reserving MYB testing for equivocal cases) can establish the diagnosis without routine molecular testing.

For cribriform-patterned dermal nodules on the extremities, especially in younger patients, cribriform tumor should remain in the differential to prevent misdiagnosis as AdCC or metastatic adenocarcinoma, which would prompt more aggressive staging and treatment. Management in nearly all reported cases, including ours, has been simple or wide local excision, with no reported need for adjuvant therapy, owing to the tumor’s indolent behavior [3,5,6]. Some authors have described Mohs micrographic surgery for certain anatomic sites, such as the face and digits, to ensure margin control while conserving tissue [7,11]. Importantly, current evidence shows no documented recurrence, metastasis, or disease-related mortality after complete excision, reinforcing that surgical clearance alone is sufficient. Still, because of the limited number of reported cases, most authors recommend wide excision with negative margins and long-term follow-up to monitor for progression [2,16,17].

A summary of published cribriform tumor cases, including clinical characteristics, management, and outcomes, is provided in Table 1. This comparison highlights the rarity of the disease, its consistently indolent course, and the central importance of surgical clearance.

Conclusions

In this article we reported the case of cribriform tumor, an exceptionally rare skin adnexal neoplasm. Histopathologic and IHC examination in the light of patient clinical history is needed to establish to diagnosis, and surgical excision is the definite treatment.