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ورم الخلايا البدائية العصبية هو السرطان الأكثر شيوعا خارج القحف الصلب في مرحلة الطفولة وأكثر أنواع السرطان شيوعا في مرحلة الرضاعة، مع معدل حدوث سنوي يبلغ نحو 650 حالة جديدة سنويا في الولايات المتحدة.[1] ما يقرب من 50 في المئة من حالات ورم الخلايا البدائية العصبية تصيب الأطفال الذين تقل أعمارهم عن سنتين.[2] وهو ورم الغدد الصم العصبية، والذي ينشأ من أي عنصر من العرف العصبي في الجهاز العصبي الودي أو SNS. أنه ينشأ بشكل متكرر في إحدى الغدد الكظرية، ولكن يمكن أيضا أن يتطور في الأنسجة العصبية في الرقبة والصدر والبطن، أو الحوض.

ورم الخلايا البدائية العصبية هو أحد الأورام الخبيثة البشرية القليلة المعروفة لإظهار الانحدار التلقائي من حالة غير متمايزة إلى المظهر الخليوي الحميد كليا.[3] وهو مرض يظهر التباين الشديد، ومصنف ضمن فئات خطرة ثلاثة : منخفضة، متوسطة، وشديدة الخطورة. المرض منخفض الخطورة هو الأكثر شيوعا عند الرضع ومن الشائع ان تؤدي المراقبة فقط أو الجراحة إلى نتائج جيدة في علاجه، في حين أن المرض شديد الخطورة يصعب علاجه بنجاح حتى مع العلاجات المتعددة الوسائط المتوفرة والمكثفة.[4]

أما الورم الأرومي العصبي الحسي، والمعروف أيضا باسم ورم الخلايا البدائية العصبية الشمية، فيعتقد انه ينشأ من الظهارة الشمية وتصنيفه لا يزال عرضة للجدل. ومع ذلك، لأنه ليس خباثة في الجهاز العصبي الودي، فهو عبارة عن كيان مستقل سريريا ولا ينبغي الخلط بينه وبين ورم الخلايا البدائية العصبية.[5][6]

العلامات والأعراض

الأعراض الأولى لورم الخلايا البدائية العصبية غالبا ما تكون ملتبسة مما يجعل التشخيص صعبا. الاعراض الشائعة هي الإعياء، وفقدان الشهية، والحمى، وآلام المفاصل. تعتمد الأعراض على أماكن الورم الرئيسي والنقيلة إذا كانت موجودة :[7]

غالبا ما ينتشر ورم الخلايا البدائية العصبية إلى أجزاء أخرى من الجسم قبل ظهور أي أعراض واضحة، و 50 إلى 60 ٪ من جميع حالات ورم الخلايا البدائية العصبية تظهر مع النقائل.[8]

المكان الأكثر شيوعا لنشوء ورم الخلايا البدائية العصبية (أي الورم الرئيسي) هو على الغدد الكظرية. هذا يحدث في 40 ٪ من الأورام الموضعية وفي 60 ٪ من حالات المرض واسعة الانتشار. ويمكن أيضا ان يتطور ورم الخلايا البدائية العصبية في أي مكان على امتداد سلسلة النظام العصبي الودي من الرقبة إلى الحوض. يتكرر انتشار المرض في أماكن مختلفة تشمل : الرقبة (1 ٪) اوالصدر (19 ٪) اوالبطن (30 ٪ في غير الغدة الكظرية)، أو الحوض (1 ٪). وفي حالات نادرة، لا يمكن تمييز الورم الرئيسي.[9]

من النادر ان تشمل المظاهر المميزة اعتلال النخاع العرضي (ورم النخاع الشوكي المنضغط في 5 ٪ من الحالات)، والإسهال المقاوم للعلاج (ورم إفراز الببتيد المعوي الفعال في الأوعية في 4 ٪ من الحالات)، ومتلازمة هورنر (ورم الرحم في 2.4 ٪ من الحالات)، ومتلازمة ترجرج العيون والاختلاج العضلي[10]، والترنح (يشتبه بتسبب متلازمة الأباعد الورمية في 1.3 ٪ من الحالات)، وفرط ضغط الدم (إفراز الكاتيكولامينات أو انضغاط الشريان الكلوي في1.3 ٪ من الحالات).[11]

الأسباب

مسببات ورم الخلايا البدائية العصبية ليست مفهومة جيدا. مع ذلك تم ترشيح الاصابة ببعض الحالات بالعائلات، وجرى ربطها بعلم المورثات. وتتسبب طفرة خط الخلايا العروسية النادرة جدا في مورثة سرطان الغدد الليمفاوية المؤنزمة المتحولة (ALK) بورم الخلايا البدائية العصبية العائلية.[12]

تم العثور على مورثة LMO1 لتكون مساهمة في زيادة مخاطر تطوير الشكل الهجومي من السرطان.[13]

وقد تم ربط ورم الخلايا البدائية العصبية بمشاكل في مورثة NBPF10 فيما يتعلق بنسخ عدد المتغيرات التي تتسبب في متلازمة الحذف 1q21.1 ومتلازمة الازدواجية 1q21.1.[14]

لقد تم اقتراح العديد من عوامل الخطر لتكون موضوع البحوث الجارية. وبسبب خصائص الظهور المبكر للمرض فقد ركزت العديد من الدراسات على العوامل الأبوية حول التخصيب وأثناء فترة الحمل. وقد شمل التحقيق بالعوامل مهن الابوين (أي التعرض للمواد الكيميائية في صناعات محددة)، والتدخين وشرب الخمور، واستخدام العقاقير الطبية أثناء الحمل وعوامل الولادة، غير أن النتائج لم تأت بنتائج حاسمة.[15]

وقد فحصت الدراسات الأخرى الصلات المحتملة مع الحالة الاستشرائية والتعرض للعدوى في وقت مبكر من الحياة ،[16] واستخدام الهرمونات وأدوية الخصوبة،[17] واستخدام الأمهات لصبغة الشعر.[18][19]

التشخيص

التصوير بالرنين المغناطيسي يبين المدفن النقيلي لورم الخلايا البدائية العصبية في المحجر والجمجمة في مريض عمره سنتين

عادة ما يتم تأكيد التشخيص من قبل الطبيب الشرعي الجراحي، مع الأخذ بعين الاعتبار السمات السريرية، والنتائج المجهرية، والفحوص المخبرية الأخرى.

الكيمياء الحيوية

في حوالي 90 ٪ من حالات ورم الخلايا البدائية العصبية، تتواجد مستويات مرتفعة من الكاتيكولامينات أو نواتج استقلابها في البول أو الدم. الكاتيكولامينات ونواتج استقلابها تشمل الدوبامين، وحمض هوموفانيلك (HVA)، و/ أو حمض الفانيليل مندليك (VMA).[20]

التصوير

طريقة أخرى للكشف عن ورم الخلايا البدائية العصبية هو مسح mIBG (ميتا-ايدو بينزل غونديداين)، والذي يتولى نسبة 90 إلى 95 ٪ من جميع اورام الخلايا البدائية العصبية ويسمى غالبا "mIBG - الحاد".[21] آلية mIBG هي تناول الخلايا العصبية الودية ويعتبر أداء تماثلي بافراز الناقل العصبي نورإبينفرين. عندما يكون الإشعاع المتأين مع 131 - I أو I - 123 (نظائر اليود المشعة)، هو دواء مشع جيد جدا لتشخيص المرض ورصد الاستجابة للعلاج لهذا المرض. مع عمر نصف 13 ساعة ،فان I – 123 هو النظير المفضل لحساسية التصوير والجودة. أما I - 131 فلديه عمر نصف 8 أيام وعلى جرعات أكبر يعتبر علاج فعال كإشعاع موجهة ضد الانتكاس وورم الخلايا البدائية العصبية المقاومة للعلاج.[22]

علم الأنسجة

معاينة مجهرية للورم الأرومي العصبي العقدي السدوي الغني

على الفحص المجهري، توصف الخلايا السرطانية عادة بأنها صغيرة ومستديرة وزرقاء، ويمكن مشاهدة نماذج الوريدة (نموذج هومر رايت للوريدات الزائفة). الوريدات الزائفة هومر رايت، هي خلايا الورم حول القرص العصبي، ولا ينبغي الخلط بينها وبين الوريدات الحقيقية (فليكسنر – وينتر ستينر), هذه الوريدات[23] هي خلايا الورم حول الأوعية الدموية وغالبا ما تشاهد في اورام أرومة الشبكية.[24] وهي أيضا متميزة عن الوريدات الزائفة من الورم البطاني العصبي والتي تتكون من خلايا الورم مع البروتين الدبقي الليفي الحمضي (GFAP)--العمليات الايجابية تهوي باتجاه الاوعية الدموية (وبالتالي مزيج من الاثنين معا).[25] وتستخدم مجموعة متنوعة من الصبغات الكيميائية النسيجية المناعية من قبل خبراء الأمراض لتمييز ورم الخلايا البدائية العصبية من المحاكاة النسيجية، مثل الساركومة العضلية المخططة وسرطان الغدد الليمفاوية وساركومة يوينغ وورم ويلمز. في شباط 2007، أعلنت تقنيات ألثيا تطوير القدرة على التشخيص الجزيئي للتمييز بوضوح بين أنواع مختلفة من سرطانات الطفولة، ووضعت بالتعاون مع المعهد القومي الأميركي للسرطان (NCI).[26]

ورم الخلايا البدائية العصبية هو أحد أورام الأعصاب العالية الطرفية (pNTs) التي لديها جذور مماثلة، وتكشف عن نمط واسع من التمايز تتراوح بين الورم العصبي العقدي الحميد إلى الورم الأرومي العصبي العقدي السدوي الغني مع خلايا الأعصاب العالية المختلطة أو في العقيدات, إلى ورم الخلايا البدائية العصبية الخبيث جدا. هذا التمييز في علم أمراض الأورام السابق للمعالجة هو عامل تشخيصي مهم بالإضافة إلى التقدم في السن ومؤشر تمزق النواة بالانقسام الفتيلي (MKI). هذا النظام لتصنيف علم الأمراض يصف الأورام "الملائمة" و"غير الملائمة" بواسطة اللجنة الدولية لعلم أمراض اورام الخلايا البدائية العصبية (INPC، وتسمى أيضا نظام شيمادا) الذي أنشئ في عام 1999 والمنقح في عام 2003.[27]

التدريج

"النظام الدولي لتدريج ورم الخلايا البدائية العصبية" (INSS) الذي أنشئ في عام 1986 ونقح في عام 1988 يعمل على تصنيف ورم الخلايا البدائية العصبية وفقا لوجوده التشريحي عند التشخيص:[28][29][30]

  • المرحلة 1: الأورام الموضعية تنحصر في منطقة المنشأ.
  • المرحلة 2A: ورم في جانب واحد مع استئصال إجمالي غير مكتمل ؛ التعريف المماثل والعقدة الليمفاوية المقابلة غير مصابة بالورم.
  • المرحلة 2B: ورم في جانب واحد مع استئصال إجمالي مكتمل أو غير مكتمل، مع العقدة الليمفاوية المماثلة مصابة بالورم؛و تعريف العقدة الليمفاوية المقابلة بأنها غير مصابة بالورم.
  • المرحلة 3: الأورام تتسلل عبر خط الوسط مع أو بدون اصابة العقدة الليمفاوية المحلية، أو الأورام في جانب واحد مع اصابة العقدة الليمفاوية المقابلة، أو الورم في خط الوسط اصابة تورط العقد الليمفاوية في الجانبين.
  • المرحلة 4: انتشار الأورام إلى العقد الليمفاوية البعيدة، ونخاع العظام، والعظام والكبد، أو ال أجهزة الأخرى باستثناء ما حدد في المرحلة 4S.
  • المرحلة 4S: العمر أقل من عام واحد مع الاصابة بالورم الرئيسي الموضعي على النحو المحدد في المرحلة 1 أو 2 ،و مع انتشاريتقتصر على نخاع الكبد والجلد والعظام أو (أقل من 10 في المئة من أنوية خلايا نخاع العظم هي أورام).

على الرغم من استخدام اتفاقية دولية للتدريج (INSS)، الا انه تم الاعتراف بالحاجة إلى إجماع دولي في الآراء بشأن تقييم الخطر من أجل مقارنة أفواج مماثلة في نتائج الدراسات. ابتداء من عام 2005، التقى ممثلو المجموعات الرئيسية التعاونية لعلم الأورام عند الأطفال لمراجعة بيانات المرضى ل 8800 حالة من ورم الخلايا البدائية العصبية التي تمت معالجتها في أوروبا واليابان والولايات المتحدة وكندا وأستراليا بين عامي 1990 و 2002. وقد اقترحت فرقة العمل نظام تصنيف المجموعة الدولية لمخاطر ورم الخلايا البدائية العصبية (INRG). وكشفت الدراسات بأثر رجعي بأن معدل البقاء على قيد الحياة عالية في المجموعة التي اعمارهم تتراوح من 12-18 شهرا، والمصنفة سابقا كحالة عالية الخطورة، مما دفع بقرار إعادة تصنيف الأطفال الذين اعمارهم تتراوح من 12-18 شهرا من دون تضخيم N - myc (كما يشار إليها عادة بوصفها MYCN) إلى فئة الخطر المتوسط.[31]

إن التقييم الجديد للخطر INRG سيصنف ورم الخلايا البدائية العصبية عند التشخيص استنادا إلى نظام التدريج الجديد للمجموعة الدولية لمخاطر ورم الخلايا البدائية العصبية (INRGSS) :

  • المرحلة L1: المرض الموضعي من دون صورة محددة لعوامل الخطر.
  • المرحلة L2: المرض الموضعي مع صورة محددة لعوامل الخطر.
  • المرحلة M: المرض النقيلي.
  • المرحلة MS: المرض النقيلي "خاصة" MS حيث المرحلة تعادل المرحلة 4S.

وسوف يستند تقسيم الخطر الجديد على نظام التدريج INRGSS الجديد، والعمر (ينقسم إلى قسمين في 18 شهرا)،و درجة الورم، وتضخيم N-myc،و انحراف 11Q غير المتوازن، والصيغة الصبغية حيث ينقسم الخطر إلى أربع مجموعات خطر قبل العلاج : منخفضة جدا، منخفضة، متوسطة، وشديدة الخطورة.[32][33]

الفحص

مستوى الكاتيكولامينات بالبول يمكن أن يكون مرتفعا في مرحلة ورم الخلايا البدائية العصبية ما قبل السريرية. وقد اجري الفحص للأطفال الرضع من دون أعراض في عمر ثلاثة أسابيع، وستة أشهر، وعام واحد في اليابان وكندا والنمسا وألمانيا منذ ثمانينات القرن الماضي.[34][35] بدأت اليابان بفحص الأطفال بعمر ستة أشهر من أجل ورم الخلايا البدائية العصبية عبر تحليل مستويات حمض هوموفانيلك وحمض فانيلمانديلك في عام 1984. أوقف الفحص في عام 2004 بعد الدراسات التي أجريت في كندا وألمانيا والتي لم تظهر أي انخفاض في عدد الوفيات الناجمة عن ورم الخلايا البدائية العصبية، وإنما تسببت بدلا عن ذلك بزيادة التشخيصات التي اختفت من دون علاج، وإخضاع هؤلاء الأطفال إلى جراحة وعلاج كيميائي لا لزوم لهما.[36][37][38]

العلاج

عندما تكون الافة موضعية، فانها تشفى بشكل عام. ومع ذلك، فإن احتمال البقاء لفترة أطول ضعيف بالنسبة للأطفال المصابين بمرحلة متقدمة من المرض والأكبر سنا من 18 شهرا على الرغم من العلاج الهجومي متعدد الوسائط (العلاج الكيميائي المكثف والجراحة والعلاج الإشعاعي وزرع الخلايا الجذعية، وتمايز العامل يسوتريتينوين والمسمى أيضا حمض 13 - رتينويك، وتكرار العلاج المناعي[39] مع العلاج المضاد ل GD2 الأجسام المضادة وحيدة النسيلة).

وقد تم تحديد الخصائص البيولوجية والوراثية التي عندما تضاف إلى التدريج السريري التقليدي تسمح بتقيم المريض إلى مجموعات الخطر لتخطيط كثافة العلاج.[40] تلك المعايير تشمل عمر المريض ومدى انتشار المرض، والظهور المجهري، والسمات الوراثية بما فيها الصيغة الصبغية للDNA وتضخيم الجين الورمي N - myc (N - myc ينظم الرنا الميكروية[41])، هذه الخصائص تصنف الأمراض إلى امراض منخفضة الخطر ومتوسطة وشديدة. دراسة بيولوجية اجريت مؤخرا (COG ANBL00B1) قامت بتحليل 2687 مريضا مصابا بورم الخلايا البدائية العصبية وتم تحديد نطاق تقييم الخطر كالاتي : 37 ٪ من الحالات هي منخفضة الخطر، 18 ٪ من الحالات متوسطة الخطر، و 45 ٪ من الحالات شديدة الخطر[42](وهناك بعض الأدلة التي تشير إلى ان الأنواع شديدة الخطر ومنخفضة الخطر يمكن ان تحدث عن طريق آليات مختلفة، وليست مجرد درجتين مختلفتين للتعبير عن نفس الآلية).[43]

العلاجات لفئات الخطر المختلفة هذه مختلفة جدا.

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الكاتب: حديفة  جوهري التاريخ: 2014/05/24
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