HPV 相关宫颈内膜腺癌 (HPVA) 的侵袭模式具有预后价值。非破坏性（A 型）HPVA 具有与原位腺癌 (AIS) 相似的良好预后。然而，这些肿瘤中很少发生卵巢扩散，这表明部分患有这些惰性病变的患者具有侵袭性。我们假设伴有卵巢转移的 AIS/A 型 HPVA 在生物学上不同于转移性破坏性侵袭性 HPVA。检索并审查来自 HPVA 和同步或异时转移患者的样本，以确认诊断并确定原发病变中的 Silva 模式。对于每个病例，正常组织、宫颈肿瘤和至少一个转移瘤均使用 447 基因组进行了全面测序。对原发灶和转移灶以及侵袭性模式类别之间的致病性单核苷酸变异和片段拷贝数改变（CNA）、肿瘤突变负荷和分子特征进行了评估和比较。我们确定了 13 名患者：四名患者患有 AIS/A 型原发肿瘤，九名患者患有 B/C 型肿瘤。所有 AIS/A 型病变仅转移至卵巢； 50% 的卵巢受累患者，无论侵入方式如何，HPVA 也累及子宫内膜和/或输卵管粘膜。在卵巢中，AIS/A 型 HPVA 显示出具有欺骗性的分化良好的腺体，通常具有腺纤维瘤样外观。相反，C 型 HPVA 在卵巢中始终表现出明显的浸润特征。测序证实了每个病例中原发性肿瘤和转移性肿瘤之间的遗传关系。在四个具有测序转移的 AIS/A 型 HPVA 肿瘤中的三个和八个 B/C 型肿瘤中的三个中发现了 PIK3CA 改变。与 A/B 型肿瘤相比，C 型肿瘤在原发肿瘤中显示出明显更高的 CNA 数量。与原发性相比，只有一个转移性 AIS/A 型 HPVA 具有新的致病性变异。相反，具有测序转移的八个 B/C 型肿瘤中的五个在转移中产生了原发灶中未见的新致病变异。所有四名 AIS/A 型患者在初次诊断后 31、47、58 和 212 个月时均存活且无疾病。相反，在 7、20、20、43 和 87 个月的随访中，9 名 B/C 型患者中有 5 名记录了与癌症相关的死亡。从形态学和基因组学角度来看，继发性卵巢受累的 AIS/A 型 HPVA 似乎与破坏性卵巢癌不同。侵袭性肿瘤。至少在这些病例的一部分中，卵巢扩散似乎是通过跨苗勒管浅表延伸发生的，这与更具侵袭性的肿瘤典型的间质和淋巴管扩散不同（模式C）。这些差异可能解释了在罕见的 AIS/A 型 HPVA 和卵巢转移患者中观察到的惰性结果。我们的数据强调了针对 A 型 HPVA 采取保守手术治疗方法的潜力。© 2023 John Wiley

The invasive pattern in HPV-associated endocervical adenocarcinoma (HPVA) has prognostic value. Non-destructive (pattern A) HPVA has excellent prognosis mirroring adenocarcinoma in-situ (AIS). However, the rare occurrence of ovarian spread in these tumours suggests aggressiveness in a subset of patients with these otherwise indolent lesions. We hypothesise that AIS/pattern A HPVA with ovarian metastases are biologically different than metastatic destructively invasive HPVA.Samples from patients with HPVA and synchronous or metachronous metastases were retrieved and reviewed to confirm diagnosis and determine the Silva pattern in the primary lesion. For each case, normal tissue, cervical tumour and at least one metastasis underwent comprehensive sequencing using a 447-gene panel. Pathogenic single-nucleotide variants and segmental copy-number alterations (CNA), tumour mutational burden and molecular signatures were evaluated and compared between primary and metastases and among invasive pattern categories. We identified 13 patients: four had AIS/pattern A primaries, while nine had pattern B/C tumours. All AIS/pattern A lesions had metastasis only to ovary; 50% of patients with ovarian involvement, regardless of invasive pattern, also had involvement of the endometrium and/or fallopian tube mucosa by HPVA. In the ovary, AIS/pattern A HPVA showed deceptive well-differentiated glands, often with adenofibroma-like appearance. Conversely, pattern C HPVAs consistently showed overt infiltrative features in the ovary. Sequencing confirmed the genetic relationship between primary and metastatic tumours in each case. PIK3CA alterations were identified in three of four AIS/pattern A HPVAs and three of eight pattern B/C tumours with sequenced metastases. Pattern C tumours showed a notably higher number of CNA in primary tumours compared to pattern A/B tumours. Only one metastatic AIS/pattern A HPVA had a novel pathogenic variant compared to the primary. Conversely, five of eight pattern B/C tumours with sequenced metastases developed novel pathogenic variants in the metastasis not seen in the primary. All four AIS/pattern A patients were alive and free of disease at 31, 47, 58 and 212 months after initial diagnosis. Conversely, cancer-related death was documented in five of nine pattern B/C patients with follow-up at 7, 20, 20, 43 and 87 months.Morphologically and genomically, AIS/pattern A HPVA with secondary ovarian involvement appears distinct from destructively invasive tumours. In at least a subset of these cases, ovarian spread appears to occur via trans-Mullerian superficial extension, different from the stromal and lymphatic vascular spread typical of more aggressive tumours (pattern C). These differences may explain the indolent outcome observed in the rare subset of patients with AIS/pattern A HPVA and ovarian metastasis. Our data underscore the potential for conservative surgical management approaches to pattern A HPVA.© 2023 John Wiley & Sons Ltd.